Patent Application
20230381425
The present invention relates generally to systems for treating a patient, in particular to systems that deliver a material that provides a therapeutic benefit to the patient.
The prevalence of metabolic and pancreatic diseases is growing worldwide. Specifically, Type 2 diabetes accounts for significant morbidity and mortality of the population, with and an estimated 50 million people expected to be living with Type 2 diabetes in the United States by 2035. However, approximately 50% of the people diagnosed with Type 2 diabetes in the United States have inadequately controlled disease despite the availability of numerous diagnostic and therapeutic treatments. There is a need for improved systems, methods, and devices for diagnosing and treating metabolic disease. There is an additional need for improved treatments of various diseases and disorders, such as treatment of diabetes.
According to an aspect of the present inventive concepts, a method of treating a medical condition of a patient, comprises selecting a patient for treatment, selecting a depositing device comprising a depositing element, and performing at least one injection comprising advancing the depositing element to a location proximate an at least one deposit site in the patient and delivering treatment agent into the at least one deposit site via the depositing element. The method treats the medical condition of the patient.
In some embodiments, the medical condition comprises a metabolic disease and/or a pancreatic disease.
In some embodiments, the medical condition comprises a medical condition selected from the group consisting of: Type 1 diabetes; Type 2 diabetes; insulin resistance; a metabolic condition; and combinations thereof.
In some embodiments, the medical condition comprises a medical condition selected from the group consisting of: cystic fibrosis; chronic hyperinsulinemia; chronic pancreatitis; pancreatic cancer; and combinations thereof.
In some embodiments, the method is configured to minimize distribution of the treatment agent to non-target tissue. The non-target tissue can comprise non-target organs of the patient.
In some embodiments, the advancing the depositing element comprises advancing the depositing device into the patient through a working channel of an endoscopic ultrasound device.
In some embodiments, the at least one deposit site comprises one, two, or more locations of the pancreas and/or a blood vessel in fluid communication with the pancreas. The one, two, or more locations can be selected from the group consisting of: intraparenchymal space; anterior pararenal space; intraductal space; intraarterial space of an artery that feeds at least a portion of the pancreas; and combinations thereof. The advancing the depositing element can comprise advancing a distal end of the depositing device through the patient's mouth and through a wall of the patient's gastrointestinal tract to a location proximate the pancreas. The depositing device can be advanced through the working channel of an endoscope that has been advanced through the patient's mouth. The performing of the at least one injection can comprise delivering the treatment agent to: at least 20% of the volume of tissue of the pancreas; at least 10% or at least 20% of the islet cells of the pancreas; at least 10% or at least 20% of the alpha cells of the pancreas; and/or at least 10% or at least 20% of the beta cells of the pancreas. The method can be configured to minimize risk of the patient getting pancreatitis. The patient risk can be minimized to less than 5%, 3%, or 1%. The method can be configured to limit the impact of the treatment agent on a non-target organ to a level that is less than the level of the impact of the treatment agent on the pancreas. The at least one deposit site can comprise a non-cancerous portion of the pancreas. The at least one deposit site can comprise normal parenchymal tissue.
In some embodiments, the treatment agent comprises a gene therapy material. The gene therapy material can comprise adeno-associated virus-based gene therapy material.
In some embodiments, the treatment agent is delivered at a flow rate of no more than 5 mL/min. The treatment agent can be delivered at a flow rate of no more than 3 mL/min or 1 mL/min.
In some embodiments, the total volume of treatment agent delivered comprises a volume of at least 1 mL, a volume of no more than 25 mL, or both. Performing the at least one injection can comprise performing two or more injections in which the depositing element is advanced two or more times.
In some embodiments, the depositing element comprises one or more needles and/or at least one needle with multiple fenestrations, and each needle comprises a distal segment, and the distal segment comprises a maximum size of 25 gauge. The distal segment can comprise a maximum size of 27 gauge. The distal segment can comprise a length of at least 2 cm long.
In some embodiments, the performing of the at least one injection comprises performing a single injection only. The at least one injection can further comprise performing a second delivery of the treatment agent to at least on deposit site.
In some embodiments, the performing of the at least one injection comprises performing multiple injections at different deposit sites. A first injection can be performed at a first deposit site, and at least a second injection can be performed at a second deposit site different than the first deposit site. The performing of the at least one injection can comprise performing no more than seven injections. The performing of the at least one injection can comprise performing no more than five injections, or no more than three injections.
In some embodiments, the method further comprises performing a flush procedure during which a flush material is delivered into the depositing element. The depositing element can comprise a lumen defining a lumen volume, and the volume of the flush material delivered into the depositing element can comprise a volume at or below the lumen volume. The flush material can comprise a material selected from the group consisting of: mineral oil; lipiodol; and combinations thereof.
In some embodiments, the method further comprises delivering a tissue-disseminating agent to the at least one deposit site prior to and/or during the performing of the at least one injection of the treatment agent to the at least one deposit site. The tissue-disseminating agent can be delivered separately from the delivery of the treatment agent. The tissue-disseminating agent can be delivered simultaneously with the delivery of the treatment agent. The tissue-disseminating agent can be co-formulated with the treatment agent.
According to another aspect of the present inventive concepts, a system for treating a medical condition of a patient, comprises a treatment agent and a depositing device comprising a depositing element. The depositing element is configured to perform at least one injection comprising: advancing the depositing element to a location proximate at least one deposit site in the patient; and delivering the treatment agent into the at least one deposit site via the depositing element. The system is configured to treat the medical condition of the patient.
In some embodiments, the medical condition comprises a condition selected from the group consisting of: a metabolic condition; pancreatic disease; Type 1 diabetes; Type 2 diabetes; insulin resistance; cystic fibrosis; chronic hyperinsulinemia; chronic pancreatitis; pancreatic cancer; and combinations thereof.
In some embodiments, the system further comprises a console operably attachable to the depositing device, and the console is configured to control one or more parameters of the at least one injection performed by the depositing device.
In some embodiments, the system further comprises an access device for advancing the depositing device into the patient. The access device can comprise an ultrasound-guided endoscope.
In some embodiments, the system further comprises a syringe, and the syringe is removably attachable to the depositing device, and the syringe comprises the treatment agent prior to the treatment agent being delivered by the depositing element to the at least one deposit site. The system can further comprise a syringe drive configured to cause the treatment agent to exit the syringe and be delivered by the depositing element into the at least one deposit sites, and the syringe driver can be configured to cause the treatment agent to be delivered to the at least one deposit site at a flow rate of no more than 5 mL/min. The syringe drive can be configured to cause the treatment agent to be delivered to the at least one deposit site at a flow rate of no more than 3 mL/min, or no more than 1 mL/min. The system can further comprise a conduit that fluidly attaches the syringe to the depositing device. The conduit can comprise a length of no more than 10 cm. The depositing device, the syringe, and/or the conduit can comprise a sealed fluid pathway configured to prevent the treatment agent from exiting the fluid pathway when one of the depositing device, syringe, and/or conduit is detached from another of the depositing device, syringe, and/or conduit. The system can further comprise a second syringe and a flush material, and the second syringe can be configured to deliver the flush material to the depositing element.
In some embodiments, the depositing element comprises at least one needle comprising a luminal wall surrounding a lumen that extends through the needle. The luminal wall can comprise a material selected from the group consisting of: stainless steel; nickel-titanium alloy; titanium; cobalt chromium; fused silica; polyethylene; polypropylene; polyether ether ketone (PEEK); polytetrafluoroethylene (PTFE); a fluoropolymer; a sol-gel nanocomposite; a material comprising a hydrophobic coating and/or a hydrophilic coating; and combinations thereof. The at least one needle can comprise a distal segment with a diameter of no more than 25 gauge. The distal segment can comprise a length of at least 2 cm. The distal segment can comprise a diameter of no more than 27 gauge.
In some embodiments, the treatment agent comprises a gene therapy material. The gene therapy material can comprise an adeno-associated virus-based gene therapy material.
According to another aspect of the present inventive concepts, a method comprising advancing a depositing device comprising at least one depositing element to at least one pancreatic deposit site in a patient having a metabolic disease and/or a pancreatic disease, and delivering a treatment agent through the at least one depositing element into the at least one pancreatic deposit site. The at least one depositing element can comprise at least one needle positioned on a distal portion of the depositing device. The distal end of the depositing device can be delivered into the patient through the mouth, and advanced through a wall of the gastrointestinal tract to a location proximate the pancreas. The depositing device can be delivered through a working channel of a gastrointestinal endoscope that has been delivered through the mouth of the patient. The depositing device can be delivered alongside a gastrointestinal endoscope that has been delivered through the mouth of the patient.
In some embodiments, the metabolic disease is selected from the group consisting of: Type 1 diabetes; Type 2 diabetes; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); obesity; and combinations thereof.
In some embodiments, the pancreatic disease is selected from the group consisting of: pancreatitis; pancreatic cancer; hyperinsulinism; and combinations thereof.
In some embodiments, the at least one pancreatic deposit site is selected from the group consisting of: intraparenchymal space; anterior pararenal space; intraductal space; intraarterial space of an artery that feeds at least a portion of the pancreas; and combinations thereof.
In some embodiments, the delivering of a treatment agent comprises at least a first delivery in which a minimum volume of the treatment agent is delivered into the pancreatic parenchyma, and the minimum volume of treatment agent comprises a volume sufficient to cause at least a portion of the volume of the treatment agent to exit into the anterior pararenal space, spread, and re-enter the pancreas. The method can further comprise at least a second delivery of the treatment agent to at least one additional deposit site proximate the tail of the pancreas.
In some embodiments, the delivering of a treatment agent comprises at least a first delivery in which a minimum volume of treatment agent is delivered into the pancreatic parenchyma, and the minimum volume of the treatment agent comprises a volume of at least 2 ml, at least 3 ml, and/or at least 5 ml.
In some embodiments, the depositing device is advanced to the at least one pancreatic deposit site under image guidance. The image guidance can comprise: endoscopic ultrasound guidance; computerized tomography (CT) guidance; and/or magnetic Resonance Imaging (MRI) guidance.
In some embodiments, the at least one pancreatic deposit site comprises locations within 10 cm, 7.5 cm, 5 cm, and/or 3 cm of a portion of the pancreas, and the portion of the pancreas comprises the tail, the neck, the body, the head, and/or the uncinate process.
In some embodiments, the treatment agent and/or the at least one depositing element is configured to be visualized by an imaging device, and the method further comprises visualizing the treatment agent and/or the at least one depositing element with the imaging device to confirm proper delivery of the treatment agent.
In some embodiments, the method further comprises delivering an imaging agent through the at least one depositing element and visualizing the delivery of the imaging agent with an imaging device to confirm subsequently proper delivery of the treatment agent.
In some embodiments, the method further comprises pre-loading the depositing device with the treatment agent. The treatment agent can be loaded into the depositing device from the distal end of the depositing device.
In some embodiments, the delivering of a treatment agent is performed at a pressure of at least 3 mmHg.
In some embodiments, the delivering of a treatment agent is performed at a pressure of no more than 25 mmHg.
In some embodiments, the delivering of a treatment agent is performed at a flow rate of at least 1 ml/min.
In some embodiments, the delivering of a treatment agent is performed at a flow rate of no more than 5 ml/min.
In some embodiments, the at least one depositing element comprises multiple fenestrations along its length.
In some embodiments, the method further comprises confirming the at least one depositing element is in a proper location prior to delivering the treatment agent.
In some embodiments, the method further comprises the delivery of a permeability-enhancing agent prior to the delivery of the treatment agent and/or simultaneously with the delivery of the treatment agent. The delivery of the permeability-enhancing agent can be performed locally and/or intravenously. The permeability-enhancing agent can comprise an agent selected from the group consisting of: hyaluronidase; collagenase; losartan; and combinations thereof.
In some embodiments, the treatment agent comprises a coformulation of the treatment agent and the permeability-enhancing agent.
In some embodiments, the treatment agent is a gene therapy agent. The gene therapy agent can comprise a non-viral vector comprising a polynucleotide comprising a gene of interest. The non-viral vector can be selected from the group consisting of: plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, and minicircles. The gene therapy agent can comprise a viral vector comprising a polynucleotide comprising a gene of interest. The viral vector can be selected from the group consisting of retrovirus vectors, adenovirus vectors, Herpes simplex virus (HSV) vectors, and adeno-associated virus (AAV) vectors. The viral vector can be an AAV vector. The AAV vector can comprise an AAV vector genome comprising the polynucleotide comprising a gene of interest. The AAV vector can further comprise an AAV capsid protein. The AAV capsid protein can be selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, Rh10, Rh74, AAV-2i8, AAV-DJ, AAV-LK03, AAV-KP1, AAV-KP2, and AAV-KP3 capsid proteins and variants thereof.
In some embodiments, the method further comprises heating tissue proximate the at least one pancreatic deposit site to a temperature above 39° C. prior to, during, and/or after the delivery of the treatment agent.
In some embodiments, the method further comprises delivering a dissemination-blocking material that is configured to prevent undesired dissemination of the treatment agent to non-target locations. The dissemination-blocking material can comprise a viscous substance and/or a polymer.
In some embodiments, the method further comprises positioning a blocking element in the patient, and the blocking element is configured to prevent undesired dissemination of the treatment agent to non-target locations.
In some embodiments, the method further comprises removing at least a portion of the treatment agent from a deposit site location after the delivery of the treatment agent begins.
In some embodiments, the method further comprises removing all of the treatment agent.
According to another aspect of the present inventive concepts, a method comprising endoscopically delivering a gene therapy agent to an intraparenchymal space of the pancreas of a patient having a metabolic disease and/or a pancreatic disease. The delivering can comprise advancing a depositing device comprising at least one depositing element through the mouth and through a wall of the gastrointestinal tract to the intraparenchymal space of the pancreas. The depositing device can be delivered through a working channel of a gastrointestinal endoscope that has been delivered through the mouth of the patient. The depositing device can be delivered alongside a gastrointestinal endoscope that has been delivered through the mouth of the patient.
In some embodiments, the gene therapy agent comprises an adeno-associated virus (AAV) vector. The AAV vector can comprise (a) an AAV capsid protein and (b) an AAV vector genome comprising a polynucleotide comprising a gene of interest. The AAV capsid protein can be selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, Rh10, Rh74, AAV-2i8, AAV-DJ, AAV-LK03, AAV-KP1, AAV-KP2, and AAV-KP3 capsid proteins and variants thereof.
In some embodiments, the patient has Type 2 diabetes.
In some embodiments, the gene of interest encodes a glucoregulatory hormone (i.e., a hormone involved in the modulation of circulating blood glucose levels). The glucoregulatory hormone can be selected from glucagon, GLP-1, oxyntomodulin, glicentin, glicentin-related polypeptide (GRPP), major proglucagon fragment, intervening peptide 1 (IP-1), intervening peptide 2 (IP-2), GLP-2, glucose-dependent insulinotropic peptide (GIP), peptide tyrosine (PYY), Cholecystokinin (CCK), somatostatin, oxyntomodulin, Ghrelin, amylin, glucagon, leptin, follistatin, insulin-like growth factor 1 (IGF1), vasoactive intestinal peptide (VIP), and growth hormone 1 (GH1), and peptides, variants and fusions thereof.
According to another aspect of the present inventive concepts, a method of treating a patient with a metabolic disease and/or a pancreatic disease comprises: selecting a patient with a metabolic disease and/or a pancreatic disease; selecting one or more pancreatic deposit sites; advancing a depositing device comprising a at least one depositing element to the selected one or more pancreatic deposit sites; and delivering a treatment agent through the at least one depositing element into the selected one or more pancreatic deposit sites. The method is configured to achieve a therapeutic benefit for the patient.
In some embodiments, the at least one depositing element comprises one, two, or more needles positioned on a distal portion of the depositing device.
In some embodiments, the distal end of the depositing device is delivered into the patient through the mouth, and advanced through a wall of the gastrointestinal tract to a location proximate the pancreas. The depositing device can be delivered through a working channel of a gastrointestinal endoscope that has been delivered through the mouth of the patient. The depositing device can be delivered alongside a gastrointestinal endoscope that has been delivered through the mouth of the patient.
In some embodiments, the method treats a metabolic disease of the patient selected from the group consisting of: Type 2 diabetes; NAFLD; NASH; obesity; and combinations thereof.
In some embodiments, the method treats a pancreatic disease of the patient selected from the group consisting of: pancreatitis; pancreatic cancer; hyperinsulinism; and combinations thereof.
In some embodiments, the selected one or more pancreatic deposit sites comprise one or more sites selected from the group consisting of: intra-parenchymal space; anterior pararenal space; intraductal space; intra-arterial space of an artery that feeds at least a portion of the pancreas; and combinations thereof.
In some embodiments, the delivering of the treatment agent comprises at least a first delivery in which a minimum volume of the treatment agent is delivered into the pancreatic parenchyma, and the minimum volume of treatment agent comprises a volume sufficient to cause at least a portion of the volume of the treatment agent to exit into the anterior pararenal space, spread, and re-enter the pancreas. The method can further comprise at least a second delivery of the treatment agent to one or more additional deposit sites proximate the tail of the pancreas.
In some embodiments, the delivering of the treatment agent comprises at least a first delivery in which a minimum volume of treatment agent is delivered into the pancreatic parenchyma, and the minimum volume of the treatment agent comprises a volume of at least 2 mL, at least 3 mL, and/or at least 5 mL.
In some embodiments, the depositing device is advanced to the selected one or more pancreatic deposit sites under image guidance. The image guidance can comprise: ultrasound guidance (e.g. endoscopic ultrasound guidance); CT guidance; and/or MRI guidance.
In some embodiments, the therapeutic benefit is achieved for a time period of at least 6 months.
In some embodiments, the selected one or more pancreatic deposit sites comprise locations within 10 cm, 7.5 cm, 5 cm, and/or 3 cm of a portion of the pancreas, and the portion of the pancreas comprises the tail, the neck, the body, the head, and/or the uncinate process.
In some embodiments, the treatment agent and/or the at least one depositing element is configured to be visualized by an imaging device, and the method further comprises visualizing the treatment agent and/or the at least one depositing element with the imaging device to confirm proper delivery of the treatment agent.
In some embodiments, the method further comprises delivering an imaging agent through the at least one depositing element and visualizing the delivery of the imaging agent with an imaging device to confirm subsequently proper delivery of the treatment agent.
In some embodiments, the method further comprises pre-loading the depositing device with the treatment agent. The treatment agent can be loaded into the depositing device from the distal end of the depositing device.
In some embodiments, the delivering of the treatment agent is performed at a pressure of at least 3 mmHg.
In some embodiments, the delivering of the treatment agent is performed at a pressure of no more than 25 mmHg.
In some embodiments, the delivering of the treatment agent is performed at a flow rate of at least 1 mL/min.
In some embodiments, the delivering of the treatment agent is performed at a flow rate of no more than 5 mL/min.
In some embodiments, the at least one depositing element comprises multiple fenestrations along its length.
In some embodiments, the method further comprises confirming the at least one depositing element is in a proper location prior to delivering the treatment agent.
In some embodiments, the method further comprises the delivery of a permeability-enhancing agent prior to the delivery of the treatment agent and/or simultaneously with the delivery of the treatment agent. The delivery of the permeability-enhancing agent can be performed locally and/or intravenously. The permeability-enhancing agent can comprise an agent selected from the group consisting of: hyaluronidase; collagenase; losartan; and combinations thereof. The treatment agent can comprise a coformulation of the treatment agent and the permeability-enhancing agent.
In some embodiments, the method further comprises heating tissue proximate the selected one or more pancreatic deposit sites to a temperature above 39° C. prior to, during, and/or after the delivery of the treatment agent.
In some embodiments, the method further comprises delivering a dissemination-blocking material that is configured to prevent undesired dissemination of the treatment agent to non-target locations. The dissemination-blocking material can comprise a viscous substance and/or a polymer.
In some embodiments, the method further comprises positioning a blocking element in the patient, and the blocking element is configured to prevent undesired dissemination of the treatment agent to non-target locations.
In some embodiments, the method further comprises removing at least a portion of the treatment agent from a deposit site location after the delivery of the treatment agent begins.
The technology described herein, along with the attributes and attendant advantages thereof, will best be appreciated and understood in view of the following detailed description taken in conjunction with the accompanying drawings in which representative embodiments are described by way of example.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The content of all publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety for all purposes.
Reference will now be made in detail to the present embodiments of the technology, examples of which are illustrated in the accompanying drawings. Similar reference numbers may be used to refer to similar components. However, the description is not intended to limit the present disclosure to particular embodiments, and it should be construed as including various modifications, equivalents, and/or alternatives of the embodiments described herein.
It will be understood that the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
It will be further understood that, although the terms first, second, third etc. may be used herein to describe various limitations, elements, components, regions, layers and/or sections, these limitations, elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one limitation, element, component, region, layer or section from another limitation, element, component, region, layer or section. Thus, a first limitation, element, component, region, layer or section discussed below could be termed a second limitation, element, component, region, layer or section without departing from the teachings of the present application.
It will be further understood that when an element is referred to as being “on”, “attached”, “connected” or “coupled” to another element, it can be directly on or above, or connected or coupled to, the other element, or one or more intervening elements can be present. In contrast, when an element is referred to as being “directly on”, “directly attached”, “directly connected” or “directly coupled” to another element, there are no intervening elements present. Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g. “between” versus “directly between,” “adjacent” versus “directly adjacent,” etc.).
It will be further understood that when a first element is referred to as being “in”, “on” and/or “within” a second element, the first element can be positioned: within an internal space of the second element, within a portion of the second element (e.g. within a wall of the second element); positioned on an external and/or internal surface of the second element; and combinations of one, two, or more of these.
As used herein, the term “proximate” shall include locations relatively close to, on, in and/or within a referenced component, anatomical location, or other location. As used herein, the term “proximate”, when used to describe proximity of a first component or location to a second component or location, is to be taken to include one or more locations near to the second component or location, as well as locations in, on and/or within the second component or location. For example, a component positioned proximate an anatomical site (e.g. a target tissue location), shall include components positioned near to the anatomical site, as well as components positioned in, on and/or within the anatomical site.
Spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper” and the like may be used to describe an element and/or feature's relationship to another element(s) and/or feature(s) as, for example, illustrated in the figures. It will be further understood that the spatially relative terms are intended to encompass different orientations of the device in use and/or operation in addition to the orientation depicted in the figures. For example, if the device in a figure is turned over, elements described as “below” and/or “beneath” other elements or features would then be oriented “above” the other elements or features. The device can be otherwise oriented (e.g. rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.
The terms “reduce”, “reducing”, “reduction” and the like, where used herein, are to include a reduction in a quantity, including a reduction to zero. Reducing the likelihood of an occurrence shall include prevention of the occurrence. Correspondingly, the terms “prevent”, “preventing”, and “prevention” shall include the acts of “reduce”, “reducing”, and “reduction”, respectively.
The term “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and/or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.
In this specification, unless explicitly stated otherwise, “and” can mean “or,” and “or” can mean “and.” For example, if a feature is described as having A, B, or C, the feature can have A, B, and C, or any combination of A, B, and C. Similarly, if a feature is described as having A, B, and C, the feature can have only one or two of A, B, or C.
The expression “configured (or set) to” used in the present disclosure may be used interchangeably with, for example, the expressions “suitable for”, “having the capacity to”, “designed to”, “adapted to”, “made to” and “capable of” according to a situation. The expression “configured (or set) to” does not mean only “specifically designed to” in hardware. Alternatively, in some situations, the expression “a device configured to” may mean that the device “can” operate together with another device or component.
As used herein, the term “threshold” refers to a maximum level, a minimum level, and/or range of values correlating to a desired or undesired state. In some embodiments, a system parameter is maintained above a minimum threshold, below a maximum threshold. within a threshold range of values and/or outside a threshold range of values, to cause a desired effect (e.g. efficacious therapy) and/or to prevent or at least reduce the effects of (hereinafter “prevent” or “reduce”) an undesired event (e.g. a device and/or clinical adverse event). In some embodiments, a system parameter is maintained above a first threshold (e.g. above a first temperature threshold to cause a desired therapeutic effect to tissue) and below a second threshold (e.g. below a second temperature threshold to prevent undesired tissue damage). In some embodiments, a threshold value is determined to include a safety margin, such as to account for patient variability, system variability, tolerances, and the like. As used herein, “exceeding a threshold” relates to a parameter going above a maximum threshold, below a minimum threshold, within a range of threshold values and/or outside of a range of threshold values.
As described herein, “room pressure” shall mean pressure of the environment surrounding the systems and devices of the present inventive concepts. “Positive pressure” includes pressure above room pressure or simply a pressure that is greater than another pressure, such as a positive differential pressure across a fluid pathway component such as a valve. “Negative pressure” includes pressure below room pressure or a pressure that is less than another pressure, such as a negative differential pressure across a fluid component pathway such as a valve. Negative pressure can include a vacuum but does not imply a pressure below a vacuum. As used herein, the term “vacuum” can be used to refer to a full or partial vacuum, or any negative pressure as described hereabove.
The term “diameter” where used herein to describe a non-circular geometry is to be taken as the diameter of a hypothetical circle approximating the geometry being described. For example, when describing a cross section, such as the cross section of a component, the term “diameter” shall be taken to represent the diameter of a hypothetical circle with the same cross sectional area as the cross section of the component being described.
The terms “major axis” and “minor axis” of a component where used herein are the length and diameter, respectively, of the smallest volume hypothetical cylinder which can completely surround the component.
As used herein, the term “functional element” is to be taken to include one or more elements constructed and arranged to perform a function. A functional element can comprise a sensor and/or a transducer. In some embodiments, a functional element is configured to deliver energy and/or otherwise treat tissue (e.g. a functional element configured as a treatment element). Alternatively or additionally, a functional element (e.g. a functional element comprising a sensor) can be configured to record one or more parameters, such as a patient physiologic parameter; a patient anatomical parameter (e.g. a tissue geometry parameter); a patient environment parameter; and/or a system parameter. In some embodiments, a sensor or other functional element is configured to perform a diagnostic function. In some embodiments, a functional element comprises one or more elements constructed and arranged to perform a function selected from the group consisting of: deliver energy; extract energy (e.g. to cool a component); deliver a pharmaceutical drug or other agent; manipulate a system component or patient tissue; record or otherwise sense a parameter such as a patient physiologic parameter or a patient anatomical parameter; and combinations of one or more of these. A functional element can comprise a fluid, such as an ablative fluid (as described hereabove) comprising a liquid or gas configured to ablate or otherwise treat tissue. A functional element can comprise a reservoir, such as an expandable balloon configured to receive an ablative fluid. A “functional assembly” can comprise an assembly constructed and arranged to perform a function, such as is described hereabove. In some embodiments, a functional assembly is configured to deliver energy and/or otherwise treat tissue (e.g. a functional assembly configured as a treatment assembly). Alternatively or additionally, a functional assembly can be configured to record one or more parameters, such as a patient physiologic parameter; a patient anatomical parameter; a patient environment parameter; and/or a system parameter. A functional assembly can comprise an expandable assembly. A functional assembly can comprise one or more functional elements.
The term “transducer” where used herein is to be taken to include any component or combination of components that receives energy or any input, and produces an output. For example, a transducer can include an electrode that receives electrical energy, and distributes the electrical energy to tissue (e.g. based on the size of the electrode). In some configurations, a transducer converts an electrical signal into any output, such as light (e.g. a transducer comprising a light emitting diode or light bulb), sound (e.g. a transducer comprising a piezo crystal configured to deliver ultrasound energy), pressure, thermal energy such as heat energy and/or cryogenic energy, chemical energy; mechanical energy (e.g. a transducer comprising a motor or a solenoid), magnetic energy, and/or a different electrical signal (e.g. a Bluetooth or other wireless communication element). Alternatively or additionally, a transducer can convert a physical quantity (e.g. variations in a physical quantity) into an electrical signal. A transducer can include any component that delivers energy and/or an agent to tissue, such as a transducer configured to deliver one or more of: electrical energy to tissue (e.g. a transducer comprising one or more electrodes); light energy to tissue (e.g. a transducer comprising a laser, light emitting diode and/or optical component such as a lens or prism); mechanical energy to tissue (e.g. a transducer comprising a tissue manipulating element); sound energy to tissue (e.g. a transducer comprising a piezo crystal); chemical energy; electromagnetic energy; magnetic energy; and combinations of one, two, or more of these.
As used herein, the term “fluid” can refer to a liquid, gas, gel, and/or any flowable material, such as a material which can be propelled through a lumen and/or opening.
As used herein, the term “tissue modification procedure” refers to a procedure performed on tissue to modify a property of the tissue treated and/or tissue proximate the tissue treated (“treated tissue” herein). A tissue modification procedure can comprise a procedure in which a treatment agent, such as a gene therapy material or other agent is delivered to tissue. A tissue modification procedure can result in necrosis and/or removal of tissue, after which “replacement tissue” develops in the place of the removed tissue, the replacement tissue having different properties than the tissue that was removed. A tissue modification procedure can result in a reduction in surface area of the treated tissue (e.g. a reduction in the luminal surface area of an inner wall of tubular tissue), such as to modify secretions and/or absorptions of the tissue. A tissue modification procedure can include: delivery of energy to tissue (e.g. delivery of ablative heat, ablative cold, and/or ablative electromagnetic energy); mechanical removal and/or disruption of tissue; chemical ablation of tissue; and combinations of one, two, or more of these. Treated tissue or replacement tissue (“treated tissue” herein) can have modified properties including but not limited to: modification of one or more absorptive properties of the tissue; modification of one or more secretive properties of the tissue; modification of neuronal signaling of the tissue; and combinations of one, two or more of these. Effects of the tissue modification procedure can occur acutely and/or it can take place over time, such as days, weeks or months. In some embodiments, a tissue modification procedure includes injecting one or more materials into the submucosal tissue of a GI lumen, such as to expand a submucosal tissue layer, for example a full (360°) or partial circumferential expansion of an axial segment of the GI tract. These tissue expansion procedures can cause a relatively acute result (e.g. less than 30 minutes), such as to perform a subsequent mucosal ablation procedure wherein the expanded tissue acts as a safety margin of tissue during the ablation, protecting the underlying layers from damage. In some embodiments, the full or partial circumferential submucosal tissue expansion is performed to cause luminal narrowing at the axial segment, such as is described in applicant's co-pending application U.S. patent application Ser. No. 17/095,108 (Attorney Docket No. 41714-711.303; Client Docket No. MCT-024-US-CON2), entitled “Systems, Devices and Methods for the Creation of a Therapeutic Restriction in the Gastrointestinal Tract”, filed Nov. 11, 2020, the contents of which are incorporated herein by reference in its entirety. This luminal narrowing can be configured to last for a prolonged period of time, such as at least 1 day, at least 1 week, and/or at least one month. This luminal narrowing can be performed to restrict food intake of the patient, and/or for other purposes.
As used herein, the term “ablative temperature” refers to a temperature at which tissue necrosis or other desired tissue treatment occurs (e.g. a temperature sufficiently hot or sufficiently cold to cause tissue necrosis or any desired effect). As used herein, the term “ablative fluid” refers to one or more liquids, gases, gels or other fluids whose thermal properties cause tissue necrosis and/or another desired tissue treatment (e.g. one or more fluids at an ablative temperature). Alternatively or additionally, “ablative fluid” refers to one or more fluids whose chemical properties (at room temperature, body temperature or otherwise) cause tissue necrosis or another desired tissue treatment. A treatment element (e.g. a functional element) of the present inventive concepts can comprise one or more ablative fluids and/or comprise one or more elements that deliver one or more ablative fluids (e.g. deliver the fluids onto a tissue surface and/or into a volume of tissue).
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. For example, it will be appreciated that all features set out in any of the claims (whether independent or dependent) can be combined in any given way.
It is to be understood that at least some of the figures and descriptions of the invention have been simplified to focus on elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the invention. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.
Terms defined in the present disclosure are only used for describing specific embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Terms provided in singular forms are intended to include plural forms as well, unless the context clearly indicates otherwise. All of the terms used herein, including technical or scientific terms, have the same meanings as those generally understood by an ordinary person skilled in the related art, unless otherwise defined herein. Terms defined in a generally used dictionary should be interpreted as having meanings that are the same as or similar to the contextual meanings of the relevant technology and should not be interpreted as having ideal or exaggerated meanings, unless expressly so defined herein. In some cases, terms defined in the present disclosure should not be interpreted to exclude the embodiments of the present disclosure.
Obesity and Type 2 Diabetes are twin epidemics associated with a Western Diet and sedentary lifestyle, and both of which are increasing in prevalence at startling rates. A normal endocrine pancreas produces insulin in response to glucose intake, but in patients with Type 2 diabetes, the insulin production capacity of the pancreas is significantly reduced and is no longer sufficient to control blood glucose.
Type 1 Diabetes is also a disease of the pancreas, in which the patient's immune system attacks the insulin-producing beta cells within the pancreas, leading to significantly reduced insulin production capacity and insufficient control of blood glucose.
Cystic fibrosis (CF) is the most common genetic disorder and causes a significant damage in secretory epithelial cells due to mutations in the CTFR gene. CF in the pancreas can cause pancreatic exocrine insufficiency and consequent digestive dysfunction in the intestine, abdominal pain, an increased risk of acute pancreatitis, and a significant decrease in the quality of life.
Ex vivo gene therapy techniques have been tested in animal models to attempt to improve pancreatic function, for example to cause transgenic overexpression of hepatocyte growth factor in the endocrine pancreas to stimulate insulin production. The ex vivo approach requires a complicated removal of pancreatic cells, ex vivo transduction, and reimplantation. Intraperitoneal injection of gene therapy agents is known to enable gene therapy in rodent models, as the pancreas is accessible to the peritoneal cavity. However, in humans, the pancreas is not accessible to the peritoneal cavity. To date, the rate of gene therapy transduction of the pancreas with an intravenous delivery of gene therapy agents has been shown to be well below therapeutic thresholds.
According to the American Cancer Society, the five year survival rate for localized pancreatic cancer is 39%. Chemotherapy, using an intravenous infusion of gemcitabine or other agents, is an established therapy for pancreatic cancer. However, dosage is limited by systemic delivery and consequent off-target effects. Local drug delivery systems, such as gemcitabine-eluting membranes, have been implanted in the pancreas of mice as a means of providing local delivery of chemotherapeutic agents, but this requires both an implantable device and a complicated pancreatic surgery.
Pancreatitis is inflammation of the pancreas that can worsen over time and lead to permanent damage to the pancreas. Chronic pancreatitis eventually impairs a patient's ability to digest food and produce pancreatic hormones. Intra-pancreatic trypsinogen activation is believed to contribute to the pathogenesis of both acute and chronic pancreatitis. Trypsin inhibitors have demonstrated effectiveness in mouse models of pancreatitis. However, systemic trypsin inhibition is known to interfere with normal digestion, leading to malnutrition, delayed growth, and other metabolic and digestive disorders.
A total pancreatectomy with intraportal islet cell autotransplant is increasingly being offered to patients with chronic pancreatitis (CP). Intraportal delivery of pancreatic islets is an established therapy to restore some endocrine function to patients that have received a total pancreatectomy. Currently, the intraportal islet cell autotransplant procedure is performed with either a surgical approach or a transabdominal percutaneous approach. Complications of the current approaches include bleeding, thrombosis, and iatrogenic injury to anatomical structures.
Provided herein are systems and methods for implanting or otherwise depositing material (e.g. material including a treatment agent) at a deposit site of a patient (e.g. a mammalian patient), such as to provide a therapeutic benefit to the patient. The systems and methods can be configured to treat a “medical condition” of the patient, such as one, two, three or more diseases, disorders, and/or other medical conditions of a patient. The system includes a depositing device for the depositing material at a deposit site. The deposited material can comprise a treatment agent comprising a gene therapy material (e.g. a material comprising a gene therapy vector and/or a gene editing vector), and/or a material that is based on tissue harvested at a harvest site with a harvesting device of the system. Alternatively or additionally, the deposited material can comprise a treatment agent comprising an oncolytic virus, a cell therapy, antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and/or messenger RNAs. The deposited material “modifies” tissue (e.g. modifies existing tissue and/or causes new tissue to be generated), and the modified tissue is configured to treat the medical condition of the patient. The systems of the present inventive concepts can be configured to maximize efficacy of the delivery of one or more materials to a deposit site (e.g. target tissue) of a patient, while minimizing patient risk as well as preventing or at least reducing the delivery of the one or more materials to undesired (e.g. off-target) tissue locations. In some embodiments, a treatment agent, such as an agent comprising at least a gene therapy material, is delivered to the pancreas of a patient to provide a therapeutic benefit to the patient. The treatment material can be delivered to at least 20% of the volume of the pancreas (e.g. the volume of the pancreatic tissue), and the treatment material can be delivered at a relatively slow flow rate. Therapeutic benefit can be achieved with minimal risk of pancreatitis, and while avoiding any significant distribution of the treatment agent to non-target organs.
Referring now to
In some embodiments, system 10 delivers a gene therapy material (also referred to herein as a “gene therapy agent”) to tissue at or otherwise proximate target tissue that is to be modified by the gene therapy material. The gene therapy delivered by system 10 can deliver a material 60 comprising a gene therapy vector (e.g. a gene therapy vector which carries and adds a new transgene to a cell) and/or a material 60 comprising a gene editing vector (e.g. a gene editing vector which carries a gene editing sequence and modifies an existing gene in a cell). In some embodiments, system 10 delivers a material 60 comprising both a gene therapy vector and a gene editing vector. Alternatively or additionally, material 60 can comprise a treatment agent comprising an oncolytic virus, a cell therapy, antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and/or messenger RNAs. In some embodiments, a material 60 comprising a gene editing vector comprises a virus-based, a lipid nanoparticle-based, and/or a plasmid-based vector. In these embodiments (e.g. when material 60 comprises a plasmid-based vector), depositing device 600, an access device (e.g. an endoscope or other access device 50 as described herebelow) and/or another component of system 10 can comprise a functional element (e.g. functional element 699 of device 600, and/or a functional element 59 of an access device 50) that comprises an electroporation delivery element and/or sonoporation delivery element that is used prior to, during, and/or subsequent to the delivery of material 60. For example, electroporation and/or sonoporation can be delivered by these functional elements (e.g. electrodes and/or ultrasound transducers, respectively) to cause electrical and/or mechanical perturbation of the cell membrane (e.g. transient membrane permeabilization) allowing the uptake of large molecules in the vicinity of the energy delivery.
Depositing device and/or other components of system 10 can be configured to avoid passing through (e.g. and undesirably damaging) certain tissue, “non-target tissue” herein, such as certain blood vessels, ducts, organ tissue, and the like (e.g. tissue that is not be treating by system 10). Depositing device 600 can also be configured to prevent or at least reduce delivery of material 60 to an undesired location, also referred to as “non-target tissue” herein, including tissue that is on (e.g. skin) and/or within the patient, such as to avoid undesired effects that material 60 may have on the non-target tissue. In some embodiments, depositing device 600 is configured to minimize distribution of material 60 to one or more non-target tissue locations, such as one or more “non-target organ” locations, as described herein.
Material 60 can comprise a gene therapy material, such as a gene therapy vector and/or a gene editing vector. In some embodiments, material 60 comprises a gene editing vector comprising an RNA vector. In some embodiments, system 10 delivers a gene editing vector directly to the target tissue (e.g. organ tissue) to prevent or at least reduce (“prevent” or “reduce” or “minimize” herein) systemic delivery of the gene editing vector (e.g. to prevent undesired delivery of the gene editing vector to the venous system or other undesired location, such as to prevent an undesired delivery that would cause undesired transduction of off-target organs).
In some embodiments, system 10 includes a device for harvesting tissue of the patient, harvesting device 400 shown, which can be configured to harvest tissue, tissue 61 described herebelow, at a “harvest site” of the patient. The harvest site can include one, two, or more patient tissue locations such as one or more locations on the skin of the patient, and/or one or more locations within the patient's body. In some embodiments, system 10 includes a device, processing device 500 shown, that can be configured to process tissue 61. Processing device 500 comprises one or more elements for processing tissue 61, processing element 550 shown. Processing device 500 can be used to process tissue 61 after its harvest by harvesting device 400. In some embodiments, processing device 500 is configured to treat in-situ tissue prior to its harvest. In some embodiments, system 10 does not include harvesting device 400, such as when target tissue is modified by a gene therapy material (e.g. a gene therapy vector and/or a gene editing vector), and no tissue of the patient is harvested in order to provide a therapeutic benefit. In some embodiments, system 10 includes one or more treatment devices, treatment device 700 shown. Treatment device 700 is configured to treat tissue at a “treatment site” of the patient. The treatment site can include one or more locations on the skin of the patient, and/or one or more locations within the patient's body. In some embodiments, treatment device 700 treats tissue of a deposit site and/or tissue proximate a deposit site, such as when performing a tissue treatment procedure (e.g. of tissue at or otherwise proximate a deposit site, or remote from a deposit site) prior to the depositing of material 60 at a deposit site.
System 10 can include one or more consoles, console 200 shown. Console 200 can operably attach (e.g. fluidly, electrically, pneumatically, hydraulically, optically, and/or acoustically attach) to one or more of devices 400, 500, 600, and/or 700. Console 200 can comprise a microcontroller or other central processing unit, processing unit 210 shown. System 10 can comprise one or more algorithms, algorithm 215. Processing unit 210 can comprise one or more electronic elements, electronic assemblies, and/or other electronic components, such as components selected from the group consisting of: memory storage components; analog-to-digital converters; rectification circuitry; state machines; microprocessors; microcontrollers; filters and other signal conditioners; sensor interface circuitry; transducer interface circuitry; and combinations thereof. In some embodiments, processing unit 210 comprises a memory storage component, memory 211 shown, that can include instructions, such as instructions used by processing unit 210 to perform an algorithm, such as algorithm 215. In some embodiments, algorithm 215 includes a bias, such as a bias toward or away from false-positives or false-negatives. In some embodiments, algorithm 215 includes a bias configured to cause a trajectory used to advance a component of system 10 toward and/or away from an object. For example, algorithm 215 can include a bias to tend to cause a planned trajectory and/or an actual trajectory of depositing element 650 and/or a portion of depositing device 600 (e.g. the distal portion of device 600) to tend to travel away from particular tissue or other anatomical locations of a patient, such as to tend to cause the associated trajectory to tend to avoid certain tissue types and/or anatomical locations, as described herein. In some embodiments, console 200 comprises one or more user interfaces, user interface 220 shown, such as a user interface including one or more user input and/or user output components (e.g. a display such as a touchscreen display).
In some embodiments, system 10 is configured to provide a treatment as described herebelow in reference to
As used herebelow and otherwise herein, “producing a substance X” and its derivatives shall include: producing substance X; producing an analog of substance X; producing an agonist of substance X; activating production of substance X; activation of a receptor of substance X; and/or activating downstream signaling pathways that are triggered via the activation of the receptor for substance X. Producing substance X can include constitutive production of substance X or regulated production of substance X, such as nutrient-responsive production and/or secretion of substance X.
As used herebelow and otherwise herein, “reducing a substance X” and its derivatives shall include: removing or at least reducing substance X; sequestering substance X; providing agents that counteract substance X; sequestering, reducing, or eliminating the production of substance X; inhibiting or blocking a receptor of substance X; and/or reducing or inhibiting downstream signaling pathways influenced by a receptor of substance X.
As used herebelow and otherwise herein, the term “gene disruption” and its derivatives refer to a procedure which eliminates or at least reduces the production of functional gene products from one, both, or multiple alleles of the gene. Gene disruptions can be produced by specific targeting of a gene locus via DNA editing technologies such as CRISPR/Cas9, Zinc-finger nucleases, or TALENs, which have both DNA-binding activity that allow targeting of a specific DNA sequence or sequences as well as DNA-cleaving activity that introduces double-stranded DNA breaks that are then repaired predominantly by non-homologous end joining (NHEJ). NHEJ can lead to imprecise DNA repair whose mutations lead to effective gene disruption.
In some embodiments, the patient has Type 1 or Type 2 diabetes, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has double diabetes, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has gestational diabetes, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-land/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has hyperglycemia, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has pre-diabetes, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has monogenic diabetes, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has maturity onset diabetes of the young, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has impaired glucose tolerance, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has insulin resistance, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has hyperinsulinemia, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has hypoinsulinemia and/or relative beta cell insulin-production failure, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH), and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient is obese and/or has an obesity related disorder, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has polycystic ovarian syndrome (PCOS), and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has hypertriglyceridemia, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has hypercholesterolemia, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has coronary artery disease or a history of stroke and/or transient ischemic attack, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
In some embodiments, the patient has cognitive decline and/or dementia and/or Alzheimer's disease, and a treatment of the present inventive concepts can be performed to modify pancreatic tissue (e.g., pancreatic islet cells) in order to achieve one or more of the following effects: produce GLP-1 and/or insulin, such as constitutive and/or nutrient-responsive GLP-1 and/or insulin.
Material 60 can comprise one or more treatment agents, such as a treatment agent that includes cell genetic, viral and/or other material as described herein, that is mixed with a fluid, such as saline or other biocompatible fluid. In some embodiments, material 60 is mixed with a fluid comprising a volume of at least 1 μL, such as at least 5 μL, 10 μL, 15 μL and/or 20 μL. In some embodiments, material 60 is mixed with a fluid that is visualizable (e.g. includes a material that can be visualized under X-ray, MRI, and/or ultrasound visualization), as described herein.
In some embodiments, material 60 can include a chemotherapeutic agent such as gemcitabine, cisplatin, 5-fluorouracil (5-FU), Oxaliplatin, paclitaxel, capecitabine, Irinotecan, Altretamine, Cyclophosphamide, Etoposide, Ifosfamide, Liposomal doxorubicin, Melphalan Pemetrexed, Topotecan, Vinorelbine, or other chemotherapeutic agents or combinations of these.
In some embodiments, material 60 includes viral genetic material that can transduce into cells proximate to the deposit site and modifies and/or otherwise generates (“modifies” or “generates” herein) resultant tissue, such as when the deposited material 60 transduces pancreatic islet cells after deposit of material 60 into the pancreas, pancreatic duct, and/or other deposit site. Transduced islet cells are genetically modified by the viral genetic material that has been delivered.
Material 60 can be deposited at one or more deposit sites to modify and/or otherwise generate resultant tissue in one or more locations, such as when depositing material into the pancreas, pancreatic duct, and/or bile duct to transduce tissue into multiple locations within the pancreas and/or bile duct, gallbladder, and/or liver.
Depositing device 600, harvesting device 400, and/or treatment device 700 (singly or multiply, “devices 600, 400, 700”) can each be configured to be introduced into the body via a natural orifice (e.g. via the mouth or rectum), or via a skin incision (e.g. in an open surgical procedure or a minimally invasive surgical procedure). Devices 600, 400, 700 can comprise one or more catheters, endoscopes, flexible probes, laparoscopic tools, syringes, and/or other flexible and/or rigid elongate devices (“catheter” or “catheters” herein). Device 600 can comprise a long (e.g. greater than 110 cm) flexible device (e.g. flexible probe or flexible syringe, “syringe” herein) that fits through a lumen, conduit, and/or other “working channel” of an access device (e.g. access device 50 described herein), such as an endoscope working channel (e.g. a working channel of less than 4.2 mm diameter, such as less than 3.8 mm or less than 3.2 mm in diameter). Device 600 can comprise a syringe that has at least one distal chamber configured to hold material 60. In some embodiments, device 600 is configured to avoid waste of material 60, such as by leaving undelivered portions of material within device 600 (e.g. not ejecting all of material 60 from device 600), and/or to avoid requiring an additional fluid and/or an undesired volume of fluid (e.g. flush material) to clear material 60 from device 600 (e.g. from one or more lumens of device 600). In some embodiments, device 600 comprises a plunger (e.g. a syringe plunger as described herein) configured to deliver (e.g. force or otherwise deliver) material 60 from the device. The plunger can comprise a plunger selected from the group consisting of: a mechanical plunger, such as a flexible plunger; a flexible plunger with stiffening capability; a hydraulic plunger, such as a plunger positioned in a distal portion of device 600 and configured to be actuated using hydraulic fluid filling a lumen of device 600; a plunger comprising a sliding element configured to separate a distal chamber (e.g. a chamber for holding material 60) from a hydraulic chamber; and combinations of these. Device 600 can be configured to be delivered (e.g. inserted into the patient) under fluoroscopic guidance. In some embodiments, device 600 comprises one or more radiopaque markers and/or a radiopaque shaft so that it can be visualized fluoroscopically. Device 600 can include at least two lumens, for example device 600 can include one lumen for receiving a syringe or plunger and one lumen for receiving contrast material and/or a guidewire. In some embodiments, device 600 can comprise a configuration of two lumens in a shape approximating a smile (“smiley lumens”), two circular lumens, and/or two D-shaped lumens. Device 600 can comprise one or more lumens configured for: receiving a vacuum, such as a desufflation lumen; delivering a contrast material; depositing or otherwise delivering material 60; receiving a guidewire; enabling pressure monitoring within the patient (e.g. by fluidly connecting an area within the patient to a pressure monitor outside the patient); enabling steering of device 600, such as by receiving a steering cable; and combinations of these. Device 600 can be configured to be delivered over a guidewire. Device 600 can include an occluding mechanism (not shown, but such as a balloon) that is positioned around a distal portion of device 600 (e.g. around a of device 600 proximal to depositing element 650) and configured to prevent or at least reduce backflow of material 60 (e.g. prevent backflow of material 60 out of the pancreas and/or pancreatic duct). Alternatively or additionally, an occluding mechanism (or other mechanism of device 600) can be configured to apply suction to a luminal wall (e.g. a full circumferential portion of a luminal wall), such as to draw the wall and the shaft of device 600 toward each other (e.g. creating a seal around device 600). In some embodiments, device 600 includes an occluding mechanism that is configured to be hydraulically activated, for example when the occluding mechanism is configured to be inflated or otherwise expanded hydraulically. The occluding mechanism can be fluidly connected to a fluid conduit of device 600. In some embodiments, the occluding mechanism is expanded via a conduit external to device 600. Device 600 can be steerable in at least one direction. Device 600 can have a torque transfer mechanism that can be configured to change the direction of steering in response to a torsional force (e.g. a force provided by a torque cable). Device 600 can have variable stiffness along its length (e.g. comprise a shaft with a stiffer proximal portion than distal portion). In some embodiments, device 600 comprises an atraumatic distal tip. Device 600 can include a chamber (e.g. not shown, such as a chamber in a distal tip or other distal portion of device 600) that is sized and arrange to allow insertion of a container that contains material 60 (e.g. a container that is also used to transport material 60), such as to simplify the process of loading device 600 with material 60. Material 60 can be loaded into device 600 in a manner similar to loading a conventional syringe, where the plunger is first fully depressed, then the tip of device 600 is placed into a container with the material 60 so that a lumen is in contact with material 60, after which the plunger is withdrawn to draw material 60 into device 600. The distal end of device 600 can be configured to attach to one or more needles, depositing element 650 shown, such as one or more needles configured to puncture tissue. Depositing element 650 can comprise a flexible needle, and/or it can comprise a needle that includes one or more flexible portions (e.g. a flexible distal portion). Depositing element 650 can comprise one or more needles that include one or more orifices for delivering the material 60, such as one or more fenestrations along the length of one or more depositing elements 650 (e.g. along the length of one or more needles) and/or an opening on the distal end of one or more depositing elements 650. The lumen of depositing element 650 can be in fluid communication with the chamber containing material 60. The lumen of the depositing element 650 can also be in fluid communication with one or more of the other lumens of device 600, such a lumen configured to deliver an imaging agent (e.g. to depositing element 650). The proximal end of device 600 can include markings that are used to indicate the location of the plunger relative to the distal end. The distal end of device 600 can have a stop that prevents the plunger from exiting the device. The proximal end of the plunger can be configured to be depressed manually, and/or it can be configured to be controlled by a component (e.g. a motor of system 10 such as via algorithm 215) that provides linear force in at least a forward direction, such as both a forward direction and a backward direction. The proximal end of device 600 can be configured to be manually steered and/or it can be configured to be robotically steered. The proximal end of device 600 can be configured to measure the pressure of fluid in the device 600 and/or the pressure proximate a deposit site (e.g. when the deposit site comprises a duct or natural body lumen), such as via a sensor-based functional element 699. The proximal end of device 600 can be configured to control pressure of the fluid within a deposit site (e.g. within a duct, for example by controlling the syringe distal-facing element). Additionally or alternatively, device 600 can be configured to monitor the pressure within the deposit site, for example via a device lumen and/or by depositing a known volume of material 60 into the deposit site. In some embodiments, system 10 is configured to measure, monitor, control, and/or limit the pressure in which material 60 is delivered to a deposit site. For example, system 10 can be configured to measure and/or control the pressure within the tissue into which material 60 is delivered (e.g. to maintain a pressure within the tissue at a maximum of 8 mmHg, such as a maximum of no more than 5, 3, or 0 mmHg). In order to prevent this pressure maximum from being exceeded, system 10 can measure, monitor and/or control a pressure within one or more components of system 10, such as within a syringe and/or within a depositing device 600, such as within a fluid pathway of a syringe and/or a device 600, whereby that measured, monitored, and/or controlled pressure can be correlated to the pressure of material 60 within the tissue (e.g. within the deposit site). In some embodiments, a second syringe can be attached to a second fluid lumen of device 600, such as a lumen configured to deliver an imaging agent, a diluent, a viscous fluid, and/or a fluid that becomes a gel within the body. The second syringe can be controlled manually and/or automatically (via processing unit 210 and/or algorithm 215)), such as is in a manner as described for the first syringe. In these embodiments, the first syringe can be configured to control the volume of material 60 delivered to the patient, while the second syringe can be used to manage the pressure of the delivered materials. In some embodiments, delivery of material 60 can be performed at an elevated pressure, such as to improve contact of material 60 (e.g. a virus) with the intended treatment site. Alternatively or additionally, system 10 can include a pressure sensor, a flow rate monitor, and/or volume sensor that produces a signal that is used by system 10 (e.g. by an algorithm 215) to regulate the amount, rate, and/or pressure of injectate (e.g. material 60) within device 600 and/or within the pancreas, pancreatic duct, and/or other deposit site. Alternatively or additionally, system 10 can include a sensor (e.g. a sensor-based functional element 699 and/or other functional element of system 10) such as a pressure sensor or impedance sensor to determine whether device 600 is in contact with a target tissue location. A sensor-based functional element 699 of device 600 and/or another sensor of system 10 can assess the pressure of an occluding element (e.g. a balloon positioned around a distal portion of device 600) to ensure adequate occlusion of the duct has occurred. An algorithm of system 10 (e.g. algorithm 215 described herein) can be configured to ensure that the material is only delivered into the pancreas and/or pancreatic duct if the pressure of the occluding element positioned around device 600 is above a threshold value (e.g. via an analysis of one or more images processed by algorithm 215, one or more pressure sensor signals, and/or other information collected by system 10).
In some embodiments, depositing device 600 comprises one or more syringes, syringe 610 shown, each comprising one or more chambers, chamber 615. Chamber 615 can hold one or more materials, such as material 60 and/or an agent (e.g. agent 70 Described herebelow). Each depositing element 650 of device 600 can be operably attached (e.g. at least fluidly attached) to at least one chamber 615 of at least one syringe 610. Each depositing element 650 can comprise one or more lumens, lumens 655 shown, extending therethrough.
In some embodiments, system 10 includes flush 64, which can comprise one, two, or more fluids configured to displace other fluids (e.g. air and/or material 60) from a lumen 655 of depositing element 650. Flush 64 can comprise saline or other materials that are relatively innocuous. In some embodiments, lumen 655 (e.g. comprising one, two, or more lumens) of depositing element 650 is filled with flush 64 prior to insertion of depositing device 600 into a patient, such as to ensure no air is present within some or all of the lumens of lumen 655. Additionally or alternatively, flush 64 can be injected into lumen 655 of depositing element 650 to deliver any remaining injectate (e.g. material 60) from the lumen and into the patient.
In some embodiments, system 10 includes an assembly for actuating (e.g. driving in one or more directions) the plunger of a syringe, syringe drive 40. Syringe drive 40 can comprise a syringe pump or other mechanism for mechanically driving a plunger through the barrel of a syringe. In some embodiments, syringe drive 40 comprises a pressure source configured to fluidly attach to a syringe to pneumatically drive a plunger through the barrel of a syringe. Various embodiments of syringe drive 40 are described herein in reference to
In some embodiments, the deposit site comprises one or more locations of the pancreas, as described herein, for example when material 60 comprises a gene therapy material configured to transduce the pancreas. In some embodiments, material 60 comprises a material (e.g. a material delivered to the anterior pararenal space) that is configured to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas. Depositing device 600 can be configured to access the pancreas through a gastrointestinal wall, such as a wall of the stomach. In these embodiments, system 10 can be configured to perform image-guided access (e.g. endoscopic ultrasound-guided access) of the pancreas, such as to aid in the delivery of material 60. Material 60 can be delivered to the pancreas at a relatively slow flow rate, as described herein.
In some embodiments, the deposit site comprises a pancreatic duct. Depositing device 600 can be constructed and arranged to remove material from the duct prior to depositing material 60. For example, device 600 can remove pancreatic enzymes from the duct prior to depositing material 60 into the duct. In some embodiments, device 600 comprises a lumen for aspirating material from the deposit site prior to the deposit. The lumen can be operably connected to a syringe, pump, or other vacuum source (e.g. a vacuum source of console 200, when console 200 is operably attached to the proximal end of device 600). In some embodiments, the vacuum is applied in a closed loop fashion, such as to control the volume of material aspirated and/or the pressure (e.g. negative pressure) to be applied to the deposit site during the aspiration. In some embodiments, the lumen used for aspiration can also be used for irrigation, such as when the lumen is also operably attached to a source of irrigation fluid. Alternatively or additionally, device 600 can comprise a separate lumen for providing irrigation. In some embodiments, irrigation fluid is provided by a computer-controlled (e.g. controlled by algorithm 215) pumping assembly of console 200.
In some embodiments, the deposit site comprises the anterior pararenal space, for example when material 60 comprises a gene therapy material configured to transduce the pancreas. In some embodiments, material 60 comprises a material (e.g. a material delivered to the anterior pararenal space) that is configured to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas. Depositing device 600 can be configured to access the anterior pararenal space via the duodenum or via the stomach of the patient. In these embodiments, system 10 can be configured to perform image-guided access (e.g. endoscopic ultrasound-guided access) of the anterior pararenal space, such as to aid in the delivery of material 60.
In some embodiments, a method of depositing material 60 into the anterior pararenal space includes positioning the patient in an orientation selected to control the flow of material 60 (e.g. after being deposited by depositing device 600) to a desired location via gravity. For example, when the patient is positioned in a prone position, material 60 that is injected into the anterior pararenal space may “pool” proximate the pancreas (which is positioned downward in the anterior pararenal space when in the prone position). Additionally or alternatively, other patient positions can be selected, for example, left lateral, right lateral, and/or supine.
In some embodiments, depositing device 600 is configured to recirculate material 60 within the anterior pararenal space. For example, device 600 can be configured to access the anterior pararenal space via two access locations, and to inject material 60 via the first location and to aspirate material 60 via the second location. System 10 can optionally be configured to recycle the aspirated material 60 and to reinject via the first location to recirculate the material 60 within the space. In some embodiments, the recirculation of material 60 is performed at a rate selected to allow transduction of material 60 while still providing a consistent flow of material 60 throughout the space.
In some embodiments, the deposit site comprises multiple sites in the anterior pararenal space, such as when one or more deposit sites are located in the peri-pancreatic space. In some embodiments, the pen-pancreatic space can be accessed by depositing device 600 using a transgastric approach, for example to access deposit sites proximate the pancreatic body and/or the pancreatic tail. Additionally or alternatively, the peri-pancreatic space can be accessed by device 600 using a trans-duodenal approach, for example to access deposit sites proximate the pancreatic head.
As used herein, “injection” shall describe an advancement of a depositing element 650 of depositing device 600 into and/or otherwise proximate a deposit site, after which material 60 in delivered into the deposit site. In some embodiments, system 10 is configured to perform an initial injection (e.g. via a depositing element 650 of depositing device 600) proximate a deposit site. This initial injection can be analyzed, such as visually by an operator of system 10 and/or in a calculated manner (e.g. algorithmically) by algorithm 215, such as by analyzing image data captured by a one or more imaging devices, imaging device shown, to confirm proper placement of device 600 (e.g. the distal portion of device 600 relative to the desired deposit site. In some embodiments, an initial injection via device 600 (e.g. of a flush material, such as a radiopaque, ultrasonically reflective, fluid including a dye, and/or other visualizable material) is configured to generate a bleb of tissue which can be visualized by imaging device 90. If this initial injection is determined to be in the proper location, material 60 can be subsequently injected into the deposit site (e.g. without repositioning device 600 between the initial injection and the subsequent injection).
In some embodiments, system 10 is configured to perform an initial aspiration (e.g. via device 600) proximate a potential deposit site. This initial aspiration can be analyzed, such as visually by an operator of system 10 and/or in an automated arrangement by system (e.g. via algorithm 215), such as to confirm that the placement of device 600 is not in a blood vessel or other undesired location. If the initial injection is determined to be not in a blood vessel or other undesired location, material 60 can be subsequently injected into the deposit site (e.g. without repositioning device 600 between the initial injection and the subsequent injection).
Devices 600, 400, 700 can each comprise a catheter configuration, such as a catheter that includes an elongate flexible shaft. The shaft can comprise an insertable length, such as a length of at least 100 cm, 130 cm, or 150 cm, respectively. In some embodiments, harvesting device 400 comprises a longer length than depositing device 600, such as when harvesting device 400 accesses the ileum (e.g. via the mouth) and depositing device 600 accesses the duodenum and/or jejunum (e.g. via the mouth). In some embodiments, harvesting device 400 comprises a shorter length than depositing device 600, such as when harvesting device 400 accesses the colon (e.g. via the rectum) and depositing device 600 accesses the duodenum and/or jejunum (e.g. via the mouth). In some embodiments, harvesting device 400 comprises a shorter length than depositing device 600, such as when harvesting device 400 accesses the duodenum (e.g. via the mouth) and depositing device 600 accesses the jejunum (e.g. via the mouth).
Devices 600, 400, 700 can be configured to be introduced into the patient: through an endoscope or other access device 50 (e.g. through a working channel of an endoscope); alongside an endoscope or other access device 50 (e.g. through a scope-attached sheath and/or over a guidewire); through a laparoscopic port or port of another access device 50; and/or via another body access device 50 described herein.
Depositing device 600 can comprise one, two, or more devices configured to deposit material 60 at a deposit site of a patient. Depositing device 600 can comprise one or more elements for depositing material 60, depositing element 650 shown (e.g. one, two, three, or more needles, as described herein). Depositing device 600 can include two or more devices that are similar and/or dissimilar (e.g. when a first depositing device 600 and a second depositing device 600 comprise dissimilar lengths, and/or dissimilar depositing elements 650). The material deposited by depositing device 600, material 60 shown in
Material 60 can be deposited at one, two, or more deposit sites of a patient. Deposit sites can include, but are not limited to: pancreatic duct, hepatic duct, common bile duct, cystic duct, pancreas (e.g. head, body, tail, uncinate process), anterior pararenal space, anterior/posterior and superior/inferior pancreaticoduodenal arteries, inferior pancreatic artery, dorsal pancreatic artery, the great pancreatic artery, caudal pancreatic artery, common hepatic artery, splenic artery or other arteries feeding the pancreas.
In some embodiments, depositing element 650 comprises at least two depositing elements 650a,b, such as at least three depositing elements 650a,b,c. The multiple depositing elements 650 can be configured to deposit material 60 simultaneously and/or sequentially. Depositing element 650 can comprise one, two, three, or more needles through which material 60 can be deposited at one, two, or more deposit sites. Alternatively or additionally, depositing element 650 can comprise one, two, three, or more fluid jets through which material 60 is deposited at one or more deposit sites. In some embodiments, depositing element 650 comprises one or more material 60 depositing elements 650 positioned on an expandable element, such as an inflatable balloon, a flexible basket or cage, a series of radially deployable arms, and/or an unfurlable sheet. In some embodiments, depositing device 600 is configured to lift tissue (e.g. expansion of submucosal and/or other tissue via injection into the tissue of a fluid such as a balanced salt solution such as normal saline), prior to the depositing of material 60.
In some embodiments, depositing device 600 is configured to maintain material 60 at the deposit location (e.g. prevent the migration of material 60 from the deposit site). For example, agent 70 can comprise a gel configured to be delivered by depositing device 600 on top of the delivered material 60. In some embodiments, system 10 comprises a functional element 99 comprising a sleeve configured to be placed over the material 60 (e.g. a sleeve placed in a lumen whose wall has received material 60).
In some embodiments, material 60 includes a carrier element, carrier element 63 described herein, such as an adhesive, clip, stent, tubular structure, and/or other element configured to “carry” material 60, and depositing device 600 deploys carrier element 63 (e.g. at a deposit site) to deposit material 60.
In some embodiments, depositing device 600 is configured to deposit material 60 along one or more deposit sites that collectively comprise a cumulative length of at least 25 mm. In some embodiments, material 60 is deposited at one or more deposit sites that comprise a surface with a cumulative surface area (e.g. surface area of the inner wall of one or more segments of the GI tract) of at least 50 cm2, at least 100 cm2, or at least 250 cm2 (e.g. material 60 is deposited into one or more “patches” that cover 1% to 100% of that surface area).
In some embodiments, depositing device 600 is of similar construction and arrangement to a depositing device described in applicant's co-pending application U.S. patent application Ser. No. 16/742,645 (Attorney Docket No. 41714-715.301; Client Docket No. MCT-025-US), entitled “Intestinal Catheter Device and System”, filed Jan. 14, 2020, the contents of which is incorporated herein by reference in its entirety for all purposes.
In some embodiments, depositing device 600 and/or one or more depositing elements 650 can be advanced and/or retracted manually, such as by an endoscopist, nurse, or other clinician operator. Alternatively or additionally, device 600 and/or one or more depositing elements 650 can be configured to be advanced and/or retracted via a motorized controller (e.g. a controller connected to the proximal end of device 600 which can be activated by an operator). The force required to advance and/or retract device 600 and/or depositing element 650 can be monitored by system 10 (e.g. by one or more force sensor-based functional elements of device 600 or other system 10 component) during the advancement and/or retraction of depositing element 650. In some embodiments, the movement of an element 650 is stopped if the force exceeds (e.g. is above) a threshold (e.g. indicating that too much resistance has been met or that the device has malfunctioned). Additionally or alternatively, the movement can be stopped if the force is below a threshold (e.g. indicating that depositing element 650 may have entered a space such as the anterior pararenal space, a pancreatic duct, or a pancreatic vessel, and/or that the device has malfunctioned). In some embodiments, a distal portion of device 600 and/or other component of system 10 is configured to be steered (e.g. robotically steered) through a lumen of a body conduit and/or through tissue. Steering of device 600 can be performed via output of algorithm 215 (e.g. where algorithm 215 provides advancement, retraction, and/or steering instructions to a user and/or where algorithm 215 provides advancement, retraction, and/or steering control signals to a robotic mechanism of system 10). In some embodiments, algorithm 215 is configured to provide such instructions and/or control signals that cause device 600 to avoid passing through certain non-target tissue and/or other tissue to be avoided, such as ducts, arteries, and/or veins (e.g. when algorithm 215 causes device 600 to avoid these non-target tissue locations by a safety margin distance (also referred to as “safety margin” herein), such as a safety margin distance of at least 1 mm, 2 mm, or 4 mm). In some embodiments, the level (e.g. the distance) of the safety margin distance is entered into system by an operator.
In some embodiments, system 10 is configured to monitor the pressure and/or the flow rate of material 60 during a depositing step (e.g. by monitoring the change in syringe volume over time). In some embodiments, system 10 is configured to control the delivery of material 60 during a depositing step to achieve and/or maintain: a pressure of at least 3 mmHg; a pressure of no more than 25 mmHg; a flow rate of at least 0.1 mL/min, such as at least 0.3 mL/min, 0.5 mL/min, or 1 mL/min; and/or a flow rate of no more than 5 mL/min, such as no more than 2.5 mL/min or 1 mL/min. In some embodiments, depositing device 600 comprises multiple depositing elements 650 (e.g. multiple needles 6530 shown in
As described herein, depositing device 600 can be introduced into the patient via the patient's mouth. In some embodiments, depositing device 600 and an access device, access device 50 shown (e.g. a gastrointestinal endoscope comprising one or more working channels) are each introduced through the patient's mouth. In these embodiments, depositing device 600 can be introduced through a working channel of access device 50, and/or alongside access device 50.
In some embodiments, the distal end of depositing device 600 is advanced through a wall of the gastrointestinal (GI) tract and into a location proximate the pancreas, for example such that one or more depositing elements 650 are positioned for subsequent delivery of material 60 to one or more deposit sites proximate the pancreas. In these embodiments, depositing device 600 can be inserted into the patient via the mouth, either within or alongside an access device 50, as described herein.
In some embodiments, depositing device 600 comprises a needle-tipped catheter (e.g. a catheter comprising a depositing element 650 comprising a needle extending and/or extendable from the distal end of the catheter). For example, depositing element 650 can comprise a needle configured to extend from the distal end of depositing device 600. Depositing device 600 can be configured to be inserted into the patient via an image-guided device (e.g. an endoscopic ultrasound device), for example when imaging device 90 and/or access device 50 comprise an image-guided device, such as an endoscopic ultrasound device. The access device 50 can comprise a working channel (e.g. a lumen) extending therethrough, and it can be constructed and arranged to slidingly receive device 600. In some embodiments, system 10 is configured to perform endoscopic ultrasound-guided fine needle injection (EUS-FNI), such as injection of material 60 into the pancreas or other body location via an access device 50 comprising an endoscopic ultrasound device. In some embodiments, depositing element 650 comprises a needle comprising a gauge of 25, 26, 27, or greater (e.g. since gauge magnitude is inverse to diameter magnitude, a diameter of no more than that of a 25 gauge needle), such as a maximum diameter for the distal-most segment of the needle (e.g. a distal-most segment comprising a length of at least 2 cm). In some embodiments, depositing element 650 comprises a needle including one or more holes along the length of the needle (e.g. as well as at the distal end of the needle). In some embodiments, material 60 is deposited through these holes (e.g. as well as out the distal end of element 650), such that material 60 is more thoroughly diffused into the deposit site via depositing element 650.
In some embodiments, depositing device 600 comprises a reservoir configured to hold material 60 prior to injection of material 60 into the depositing site (e.g. one, two, or more deposit sites). In some embodiments, system 10 comprises a pumping mechanism configured to pump material 60 from the reservoir through depositing element 650 into the deposit site. In some embodiments, depositing device 600 comprises a syringe (e.g. as described herein) configured to hold material 60 prior to injection. In some embodiments, the syringe comprises one or more travel-limiting elements, “TLEs” herein, which are configured to limit the travel of the plunger of the syringe, such as to control the amount of material 60 delivered when the plunger is depressed (e.g. depressed until stopped by the TLE). In some embodiments, the TLEs are removable (e.g. sequentially between injections), such that multiple injections can be performed (e.g. injections at different deposit sites), and the amount of material 60 deposited during each injection is controlled by the TLEs. In some embodiments, the TLEs are configured such that each injection delivers similar amounts of material 60. Alternatively or additionally, the TLEs can be configured such that the injection volumes are different for one or more deliveries of material 60, for example when a first injection comprises a larger dose than subsequent injections. In some embodiments, the reservoir of depositing device 600 can be separate from a pneumatic or mechanical plunger system (e.g. a syringe-based system), such as to reduce dead space.
In some embodiments, depositing device 600 is configured to inject material 60 into one or more deposit sites of the pancreas and/or the anterior pararenal space via the stomach, for example when device 600 and/or an access device 50 through which device 600 is inserted comprises an endoscopic ultrasound device and/or other image-guided device, and depositing element 650 comprises a needle configured to advance through and extend from a distal portion (e.g. the distal end) of device 600. Material 60 can be delivered to one or more deposit sites of the pancreas and/or the anterior pararenal space by positioning the distal end of access device 50 and/or depositing device 600 against the stomach wall nearest to the deposit sites and advancing depositing element 650 into the deposit site. In some embodiments, depositing element 650 comprises a mechanical stop positioned to limit the advancement of the element 650 from device 600 (e.g. to limit the penetration depth of the depositing element 650). In some embodiments, the penetration depth allowed by the mechanical stop is based on the estimated thickness of the stomach wall proximate the deposit site (e.g. based on image data or a priori clinical data). In some embodiments, the penetration depth is adjustable by adjusting the location of the mechanical stop. In some embodiments, the injection angle (e.g. the angle depositing element 650 exits device 600) can be adjusted, for example: a direct injection (e.g. along the axis of device 600), a lateral injection approximately perpendicular to the axis of device 600, and/or at some angle therebetween.
In some embodiments, system 10 comprises treatment device 700. Treatment device 700 can comprise one, two, or more devices configured to ablate, remove, modify, expand, and/or otherwise treat tissue at a treatment site of a patient (e.g. a deposit site or other anatomical location of a patient). Treatment device 700 comprises one or more elements for treating tissue of the patient, treatment element 750 shown. Treatment device 700 can include two or more devices that are similar and/or dissimilar (e.g. when a first treatment device 700 and a second treatment device 700 comprise dissimilar lengths and/or dissimilar treatment elements 750). In some embodiments, treatment device 700 comprises a first treatment device 700a that causes tissue to necrose (e.g. via delivery of thermal energy, such as heat energy and/or cryogenic energy; electrical energy; and/or a chemical agent to tissue), and a second treatment device 700b that provides an abrasive force to the necrosed tissue. The second treatment device 700b can be used in the same clinical procedure as first treatment device 700a is used, or in a subsequent clinical procedure (e.g. a second clinical procedure 1, 2, or more days after the first clinical procedure). In these embodiments, tissue can be removed proximate (e.g. at and/or near) one or more deposit sites at which material 60 is to be deposited (e.g. deposited using depositing device 600).
The tissue treated by treatment device 700 can include mucosal tissue; submucosal tissue; tissue comprising at least one stem cell; tissue comprising at least one stem cell of the mucosa; tissue comprising at least one mucosal crypt containing a stem cell; and/or mucosal tissue comprising at least one stem-cell containing crypt. Tissue treated by treatment device 700 can include tissue of one or more anatomical locations selected from the group consisting of: the gastrointestinal tract; the mouth; the esophagus; the stomach; the duodenum; the jejunum; the ileum; the colon; an organ; the brain; the lungs; the liver; the bladder; the kidneys; the heart; the intestines; the skin; the peritoneal cavity; and combinations of one, two, or more of these. Tissue treated by treatment device 700 can comprise tissue that activates and/or deactivates hormonal signals and/or signaling pathways. In some embodiments, tissue treated by treatment device 700 does not include tissue of (e.g. treatment device 700 avoids adversely effecting tissue from): the lower esophageal sphincter; the pylorus; the ampulla of Vater; the ileocecal valve; and combinations of one, two, or more of these.
Treatment element 750 can comprise one, two, three, or more treatment elements configured to ablate, remove, resurface, denature, and/or otherwise effect tissue, such as mucosal tissue. Treatment element 750 can deliver an ablative fluid to treat the tissue (e.g. an ablative fluid applied directly to the tissue or delivered to a balloon placed in contact with tissue). Treatment element 750 can deliver energy to tissue, such as electrical energy; magnetic energy; chemical energy; sound energy; and/or light energy. In some embodiments, treatment element 750 comprises multiple treatment elements arranged in a circumferential pattern and/or a single element that treats a circumferential segment of tubular tissue (e.g. delivers energy and/or an agent to the full circumferential wall of a segment of intestine). The depositing of material 60 can occur before and/or after the use of treatment element 750, such as by injecting material 60 into the submucosa and subsequently performing a treatment with treatment element 750, and/or by performing a treatment with element 750 and then depositing material 60. Treating and depositing steps can be performed in the same procedure or in different procedures. These steps can be performed within minutes of one another, within 3 days, and/or within 5 days.
In some embodiments, treatment device 700 is of similar construction and arrangement to a device described in applicant's co-pending application U.S. patent application Ser. No. 16/742,645 (Attorney Docket No. 41714-715.301; Client Docket No. MCT-025-US), entitled “Intestinal Catheter Device and System”, filed Jan. 14, 2020, the contents of which is incorporated herein by reference in its entirety for all purposes.
As described hereabove, system 10 can further comprise one, two, or more devices configured to provide access within the patient, access device 50. Access device 50 can comprise an endoscope (e.g. an endoscopic ultrasound device), an endoscope-attached sheath, a laparoscopic port, a vascular introducer, and/or another patient access device. Access device 50 can further comprise one or more guidewires, for example one or more guidewires over which devices 600, 400, and/or 700 are introduced into the patient (e.g. and subsequently withdrawn from the patient), such as by using standard “over the wire” clinical techniques. Access device 50 can comprise a camera, such as camera and a display, such as when access device 50 comprises an endoscope including a camera. Access device 50 can comprise other imaging assemblies, such as an ultrasound imaging assembly (e.g. when access device 50 comprises an ultrasonically guided endoscope).
In some embodiments, depositing device 600 comprises access device 50, such as when access device 50 comprises an endoscope (e.g. an ultrasound-guided endoscope as described herein). For example, access device 50 can be integral to device 600, or vice versa, such as when the two components function as a single assembly (e.g. a single assembly advanced through the mouth of the patient into the stomach or small intestine).
Access device 50 can comprise one or more functional elements, functional element 99 shown. In some embodiments, functional element 99 comprise one, two, or more electrodes, and/or one, two or more ultrasound transducers, such as to deliver electrical energy (e.g. radiofrequency energy and/or electroporation energy) and/or ultrasound energy (e.g. ultrasound energy and/or sonoporation energy), respectively. In some embodiments, functional element 99 is configured to deliver electrical and/or sound energy to increase the update of material 60 through cellular walls of tissue (e.g. pancreatic tissue) into which material 60 is to be delivered. Functional element 99 can comprise one or more pressure sensors, such as one or more pressure sensors that produce a signal that is used by system 10 (e.g. via algorithm 215) to measure, monitor, and/or control the pressure in which material 60 is delivered by depositing device 600 into the patient (e.g. to limit the pressure, or any pressure increases, at the deposit site, as described herein). In some embodiments, functional element 99 comprises a source of vacuum, such as a source of vacuum configured to change (e.g. decrease) the pressure within one or more system 10 components, and/or within the patient (e.g. decrease the pressure at a deposit site of the patient and/or at a location proximate a deposit site). In some embodiments, functional element 99 comprises a fluid processing assembly configured to modify the state of material 60, such as a fluid processing assembly selected from the group consisting of: heater; chiller; centrifuge; agitator; fluid separator; and combinations of these.
System 10 can further comprise one or more devices configured to provide visualization of the patient to an operator, imaging device 90. In some embodiments, depositing device 600, access device 50, and/or another component of system 10 comprises imaging device 90 (e.g. imaging device 90 is integral to that component). Imaging device 90 can comprise an imaging device selected from the group consisting of: a camera such as an endoscopic camera; an MRI imager; a CAT scan imager; a fluoroscopic imager; an X-ray imager; an ultrasound imager such as an endoscopic or catheter-based ultrasound imager; and combinations of these. In some embodiments, material 60 comprises a radiopaque material and/or an ultrasonically reflective material, for example a material configured to be imaged by imaging device 90 when imaging device 90 comprises an X-ray or fluoroscopic imager, or an ultrasound imager, respectively. For example, material 60 can comprise a gene therapy material (e.g. a solution) including a chemical additive configured to be visible via an imaging device 90 (e.g. via X-ray imaging and/or ultrasound imaging modalities). Alternatively or additionally, material 60 can comprise a dye or other visualizable material, such as to be visualized via a camera. In some embodiments, the visualizable additive can be added to material 60 during the manufacturing of material 60 (e.g. at the time of packaging of material 60), and/or in a clinical setting (e.g. by a clinician, nurse, and/or other operator of system 10), prior to material 60 being deposited into the patient.
In some embodiments, imaging device 90 comprises an endoscopic ultrasound device configured to provide an endoscopic ultrasound (EUS) image (e.g. when access device 50 and/or depositing device 600 comprises imaging device 90). Alternatively or additionally, imaging device 90 comprises an ultrasound device and/or other imaging device configured to be positioned external to the patient's body during use (e.g. during imaging). In some embodiments, collected images (e.g. endoscopic ultrasound images) are analyzed (e.g. by algorithm 215 of system 10) and annotated to show one or more vessels or other anatomical features of interest (e.g. related to the advancement of depositing device 600 and/or other component of system 10 advanced through internal locations of the patient), such as features selected from the group consisting of: arteries, veins, the splenic vein; one or more ducts, such as the pancreatic duct; and combinations of these. Ultrasound images collected by system 10 (e.g. EUS images) can comprise multiple image types, such as standard ultrasound images and/or doppler ultrasound images. In some embodiments, collected ultrasound images (e.g. EUS images) comprise video. Analysis and annotation can be performed by system 10 in real-time (or near real-time, such as within 1 second of the image being captured, “real-time” herein). In some embodiments, system 10 enables an operator of system 10 to annotate one or more images, such as by using a pointing device (e.g. a computer mouse and/or a touch screen stylus) to identify and/or outline one or more anatomical features on a screen (e.g. a display of user interface 200 of console 200 or other display of system 10). Alternatively or additionally, an image analysis algorithm of system 10 (e.g. algorithm 215 described herein), such as a machine learning algorithm or other AI algorithm, automatically identifies and highlights these features on a screen. In some embodiments, system 10 enables the operator to correct or adjust the classification of any regions identified by the algorithm. In some embodiments, system 10 and/or the operator identifies target areas to be treated in one or more collected images (e.g. an EUS image), such as images including one, two, or more target areas to be treated, prior to performing the treatment. System 10 can be configured to document a treatment plan, such as a plan identifying particular regions to be treated. System 10 can be configured to document treatment plans for individual portions of a target area, such as the pancreas, such as for identifying one, two, or more deposits sites within the head, body, tail, and/or uncinate process of the pancreas. In some embodiments, system 10 (e.g. automatically by algorithm 215) and/or the operator (e.g. manually) can identify in the image (e.g. an EUS image) non-target areas to be avoided (e.g. avoided for delivery of material 60 and/or avoided as a pathway of introduction of depositing device 600). In some embodiments, an image analysis is performed (e.g. automatically by algorithm 215 of system 10 and/or manually by an operator) to recognize and track depositing element 650 or another portion of device 600 as it is advanced towards and/or into the tissue. In some embodiments, the operator is warned if depositing device 600 (e.g. depositing element 650) is advanced near and/or toward and/or into a non-target region, and/or beyond a target region. In some embodiments, the operator is warned if the projected path of depositing element 650 is not aimed at a target region. In some embodiments, system 10 is configured to automatically advance depositing element 650 to the target region, for example under motorized control of advancement. In some embodiments, system 10 is configured to prevent advancement (e.g. prevent automatic advancement) of depositing element 650 to a non-target region.
In some embodiments, imaging device 90 comprises a computed tomography (CT) device that is configured to provide a computed tomography (CT) image. In some embodiments, one or more CT images, and/or other images collected by system 10, are analyzed (e.g. by algorithm 215 of system 10) and annotated, such as to show one or more vessels or other anatomical features of interest, such as features selected from the group consisting of: arteries, veins, the splenic vein; one or more ducts, such as the pancreatic duct; and combinations of these. In some embodiments, collected CT or other images can comprise a series of images such as a video. Analysis and annotation can be performed in real-time (or near real-time, such as within 1 second of the image being captured). In some embodiments, system 10 enables an operator of system 10 to annotate one or more images (e.g. manually or in a semi-automated arrangement), such as by using a pointing device (e.g. a computer mouse and/or a touch screen stylus), such as to identify and/or outline one or more anatomical features on a display (e.g. a display of system 10). Alternatively or additionally, an image analysis algorithm of system 10 (e.g. algorithm 215 described herein), such as a machine learning algorithm or other AI algorithm, can automatically identify and note (e.g. highlight) these features on a display. In some embodiments, system 10 enables the operator to correct or adjust any regions identified by the algorithm (e.g. automatically identified by algorithm 215). In some embodiments, system 10 and/or the operator identifies target areas to be treated (e.g. identifies one or more deposit sites for depositing of material 60 by depositing device 600) in an image (e.g. a CT image), such as when one, two, or more target areas to be treated (e.g. one, two, or more deposit site) are identified (e.g. an noted in one or more images) prior to performing the treatment (e.g. depositing material 60). System 10 can be configured to document a treatment plan, such as a plan identifying one or more regions to be treated (e.g. identifying one or more deposit sites in which material 60 can be deposited by depositing device 600). System 10 can be configured to document (e.g. and store) treatment plans for particular deposit sites, such as for deposit sites comprising individual portions of the pancreas, such as for the head, body, tail, and/or uncinate process of the pancreas. In some embodiments, system 10 and/or the operator can identify in one or more images (e.g. CT images) one or more non-target areas in which treatment is to be avoided (e.g. material 60 is not to be deposited and/or depositing device 600 is not to travel through). In some embodiments, an image (e.g. a CT image) is captured after depositing element 650 and/or other portion of device 600 is advanced towards and/or into the tissue of the particular deposit site, such as to confirm that depositing element 650 and/or other portion of device 600 is in the right location. In some embodiments, an image analysis is performed to recognize and/or track depositing element 650 and/or other portion of deice 600 as it is advanced towards and/or into the tissue. In some embodiments, system 10 is configured to alert the operator if depositing element 650 is advanced near and/or toward a non-target region and/or to a location beyond a target region. In some embodiments, system 10 is configured to alert the operator if the projected depositing element 650 path is not aimed at (e.g. not sufficiently directed toward) a target region. In some embodiments, system 10 is configured to automatically advance depositing element 650 to the target region, for example under motorized control of advancement. In some embodiments, system 10 is configured to prevent advancement (e.g. prevent automatic advancement) of depositing element 650 to a non-target region.
In some embodiments, system 10 is configured to allow an operator to create registration data comprising data representing the location of device 600 on one or more images, such as images captured by imaging device 90. The registration data can comprise sets of data representing various locations and/or orientations of device 600 in the patient in the performance of a treatment procedure. Registration data can be collected prior to a treatment procedure, at the beginning of a treatment procedure, and/or any time throughout the treatment procedure. The registration data collected can be used to align an image (e.g. a fluoroscopic or EUS image captured just prior to a treatment procedure) with a previously defined treatment plan (e.g. a treatment plan as described herein). For example, “pre-treatment image data” comprising a set of one or more images of the patient's anatomy can be created by a first imaging device 90 (e.g. a CT imager) at a time prior to a treatment procedure (e.g. hours or days prior to a treatment procedure). A treatment plan can be created in which three to ten registration points are created in the pre-treatment image data (e.g. 3D data); the registration points representing various anatomical landmarks (e.g. branches of ducts or vessels) of the patient's anatomy. The treatment plan can also include registration points created in the pre-treatment image data that represent various locations to be treated using system 10. At the beginning of and/or during the treatment procedure, a second imaging device 90 (e.g. a fluoroscope and/or an EUS imager) can be used to create “treatment image data” representing additional images of the patient's anatomy. System 10 (via algorithm 215) can integrate the registration data of the pre-treatment image data into the treatment image data (e.g. via a registration of the two sets of image data). System 10 can be further configured to provide a display of the treatment image data to an operator of system 10, such as when the registration points are shown as an overlay on the treatment image data. The display, including the overlay, can be used by an operator to guide the treatment. In some embodiments, system 10 is configured to automatically and/or semi-automatically (“automatically” herein) guide the treatment, such as by robotic control of device 600 based on the registration data (e.g. and continuously updated images of the patient's anatomy and device 600 as provided by second imaging device 90). In some embodiments, algorithm 215 is configured to provide command signals to a robotic control portion of system 10, such as when algorithm 215 is configured to advance the distal portion of device 600 through certain tissue locations while avoiding passing through other tissue locations (e.g. avoiding ducts, arteries, and/or veins as described herein). In some embodiments, algorithm 215 is configured to avoid certain tissue locations by a safety margin distance, such as a safety margin distance of at least 1 mm, at least 2 mm, or at least 4 mm.
In some embodiments, material 60 does not include tissue 61, such as is described herebelow in reference to method 100 of
In some embodiments, material 60 comprises one or more agents, such as agent 62 described herein.
In some embodiments, agent 62 comprises a permeability-enhancing agent that is delivered prior to and/or simultaneous with the delivery of one or more other portions of material 60. Agent 62 can be separate from the other portions of material 60 (e.g. the therapeutic portion of material 60), and/or co-formulated with the other portions of material 60. In some embodiments, agent 62 comprises a permeability-enhancing agent that is delivered locally (e.g. to a location proximate the deposit location of other portions of material 60), and/or systemically (e.g. intravenously). In some embodiments, agent 62 comprises a permeability-enhancing agent selected from the group consisting of: hyaluronidase; collagenase; losartan; and combinations of these.
In some embodiments, agent 62 comprises a dissemination-blocking material (e.g. a polymer and/or a viscous material), such as a material that is configured to prevent undesired dissemination of material 60 to non-target locations. In these embodiments, the dissemination-blocking material can be delivered to one or more locations proximate a deposit site.
In some embodiments, agent 62 comprises a blocking element, such as an implant (e.g. a temporary and/or chronic implant) that is configured to prevent undesired dissemination of material 60 to non-target locations.
In some embodiments, material 60 includes one or more carrier elements 63, where each of which can be configured to aid in the depositing of material 60 and/or to maintain material 60 at the deposit site, such as when carrier element 63 comprises a temporary or chronic implant.
For example, carrier element 63 can comprise a deployment device, carrier 63a, such as a stent-like device onto which the other materials of material 60 (e.g. tissue 61 and/or a gene therapy material) is deposited, the stent-like device deployed within a lumen (e.g. the lumen of the small intestine or other body lumen) at the deposit site location. Carrier 63a can comprise a full or partial circumferential tubular structure, such as a structure seeded with tissue 61. Carrier 63a can comprise a tubular structure comprising a hydrogel.
Alternatively or additionally, carrier element 63 can comprise an adhesive, adhesive 63b, such as an adhesive gel, such as an adhesive gel used to secure material 60 to the deposit site and/or to secure multiple components of material 60 together.
Alternatively or additionally, carrier element 63 can comprise a coating or wrap, coating 63c, such as a coating or wrap configured to prevent material 60 from migrating from the deposit site (e.g. at an undesired time). In some embodiments, carrier element 63 comprises a carrier 63a, and a coating 63c configured as a protective coating or other protecting element. In some embodiments, carrier element 63 comprises a coating 63c that is applied to a deposit site in one or more procedures performed after the depositing of material 60 at the deposit site (depositing of a material 60 with or without coating 63c), as described herebelow in reference to Step 170 of
In some embodiments, carrier element 63 comprises a hemostatic gel. Carrier element 63 can be configured to promote engraftment of material 60 to target tissue. In some embodiments, carrier element 63 comprises a material including molecules configured to self-assemble into polymer chains in the presence of certain ions, for example a molecule such as RADA16. In some embodiments, carrier element 63 can comprise a concentration of RADA16 of approximately 0.5%, 1%, 1.25%, 2.5%, or 5%. Material 60 can also comprise saline, a sucrose solution, and/or a basal medium, such as DMEM (Dulbecco's Modified Eagle Medium). In some embodiments, carrier element 63 is applied topically (e.g. by depositing device 600 delivering carrier element 63 onto tissue), and/or it can be injected into a treatment site (e.g. injected by depositing device 600 with and/or after the depositing of material 60 by depositing device 600). Carrier element 63 can be delivered to the treatment site via the same lumen of device 600 in which material 60 is delivered, or via a separate lumen, for example to prevent premature polymerization of carrier element 63.
Agent 62 can comprise one or more pharmaceutical drugs, nutrients (e.g. hexoses, lipids, and/or amino acids), vitamins (e.g. water-soluble vitamins such as ascorbic acid), buffering agents, chemicals, fillers, and/or other agents that are included in material 60. In some embodiments, agent 62 comprises one or more agents selected from the group consisting of: antibiotic; adhesive agent such as a bio-adhesive agent; a trophic agent (e.g. a growth factor or other factor used to promote wound healing); a shielding agent (e.g. an agent configured to protect one or more components of material 60 after depositing); and combinations of one, two, or more of these.
In some embodiments, one or more agents 62 are included in a process for creating material 60 at a time that is proximate the time that material 60 is deposited at a deposit site (e.g. a deposit site comprising one or more deposit sites), such as a time within 8 hours of the depositing of material 60 at a deposit site.
In some embodiments, system 10 includes one or more pharmaceutical drugs or other agents, agent 70 shown, that can be delivered to the patient prior to the depositing of material 60, and/or after the depositing of material 60, such as is described herebelow in reference to
In some embodiments, agent 70 comprises one or more: antibiotics; probiotics; and/or prebiotics.
In some embodiments, agent 70 comprises one or more of: an anti-inflammatory agent, a steroid, an NSAID, and/or an immunosuppressant.
In some embodiments, agent 70 comprise a tissue-disseminating agent, such as hyaluronidase collagenase, losartan, and/or the like. The tissue-disseminating agent can be injected (e.g. via depositing device 600) prior to and/or simultaneously with material 60.
In some embodiments, system 10 comprises one or more functional elements. For example, depositing device 600 can comprise one or more functional elements, functional element 699 shown. In some embodiments, system 10 comprises treatment device 700, and described herein, and treatment device 700 can comprise one or more functional elements, functional element 799 shown. In some embodiments, system 10 comprises harvesting device 400, as described herein, and harvesting device 400 can comprise one or more functional elements, functional element 499 shown. In some embodiments, system 10 comprises processing device 500, as described herein, and processing device 500 can comprise one or more functional elements, functional element 599 shown. Functional elements 499, 599, 699, and/or 799 can comprise one, two, or more sensors, transducers, and/or other functional elements as described herein. In some embodiments, functional element 699 comprises one or more valves, such as one or more valves in the various flow pathways of depositing device 600, such as valve 2356 described in reference to
In some embodiments, system 10 includes diagnostic kit 81 shown, which can include one or more components configured to perform an analysis, such as an analysis to determine the potential safety and efficacy of the delivery of material 60 to a patient. Diagnostic kit 81 can include components (e.g. equipment and/or supplies) configured to perform one or more diagnostic tests on the patient to assess the physiologic response to proteins and/or peptides that would be produced by transgenic cells receiving material 60 in the body. For example, diagnostic kit 81 can assess the circulating levels of a hormone and/or deliver a therapeutic peptide and/or hormone to the patient and assess the circulating levels of that delivered therapeutic peptide and/or hormone and/or the physiologic effects of that therapeutic, such as to determine the patient's candidacy for the procedure.
In some embodiments, system 10 includes a diagnostic kit 81 which includes one or more components configured to perform an analysis, such as an analysis of one or more patients (e.g. analysis of tissue of a patient, e.g. a tissue donor patient), and/or an analysis of material 60. Diagnostic kit 81 can include components (e.g. equipment and/or supplies) configured to perform multiple tests during the creation of material 60 and/or the depositing of material 60 into a patient (e.g. a recipient of donor tissue and/or autologous tissue).
In some embodiments, diagnostic kit 81 comprises components used to perform a screening endoscopy, such as when diagnostic kit 81 comprises an endoscope. The endoscopy can be used to screen out patients with cancer, an infection, and/or other gastrointestinal pathology.
Diagnostic kit 81 can comprise one or more components configured to perform a “tissue test”, such as a test to determine whether desired and/or undesired conditions of the tissue are present. In some embodiments, a sample of tissue is tested to confirm the absence of: infected tissue; undesired bacteria; endotoxins and/or other toxins; cancerous tissue; mycoplasma; undesired proteins (e.g. GIP, GLP-1, and/or other incretins, such as a test including a response to a glucose-based stimulus); a virus; undesired bacteria; E. coli; an adventitious agent; and/or other undesirable tissue characteristic. For example, this testing can be used to screen for a medical condition (e.g. disease and/or disorder) selected from the group consisting of: cancer (e.g. cancer of the GI tract); infection (e.g. an infection of the GI tract); presence of Clostridium difficile bacteria (C. difficile); HIV; Hepatitis virus A, B, and/or C; syphilis; tuberculosis; and combinations of one, two, or more of these. Alternatively or additionally, a tissue test performed using diagnostic kit 81 can comprise a test of tissue to confirm desired characteristics of the tissue are present, such as to confirm tissue is from a particular donor, and/or to confirm the presence of desired material, such as a material selected from the group consisting of: desired proteins (e.g. GIP, GLP-1, and/or other incretins, such as a test including a response to a glucose-based stimulus); immune cells; stem cells; enteroendocrine cells; a genetic sequence; an mRNA expression; cell surface antigens; and combinations of these. A tissue test comprising a donor confirmation test performed using diagnostic kit 81 can comprise a test selected from the group consisting of: DNA test; mRNA assay; proteomics assay; flow cytometry assay; immunohistochemical analysis; enzyme-linked immunosorbent assay (ELISA); and combinations thereof. In some embodiments, diagnostic kit 81 comprises components configured to perform a test for mycoplasma and/or virus, and the kit 81 is used to test a culture in which material 60 is expanded.
Diagnostic kit 81 can include components configured to assess a parameter related to an expansion of tissue, components configured to assess a quantity of tissue (e.g. a quantity of cells present in a sample), and/or components configured to assess a concentration and/or ratio of one or more substances in tissue. For example, during and/or after material 60 expansion (e.g. an expansion of material 60 comprising harvested tissue), diagnostic kit 81 can be configured to assess a parameter (e.g. to confirm adequate quantity and/or confirm other desired expansion parameter) selected from the group consisting of: cell growth rate; organoid growth rate; organoid density (e.g. in growth substrate); morphometry of organoids, including a quantification of the number of buds and/or crypts in the organoids; cell culture media secretions (e.g. GIP, GLP-1, insulin and/or other marker peptide not normally secreted by this cell type); and combinations of these. Diagnostic kit 81 can include components to assess a tissue parameter selected from the group consisting of: number of crypts in a tissue sample; basement membrane matrix seeding density (e.g. derived from crypt count); presence and/or concentration of immune cells; fraction of Lgr5+ cells relative to other cell types; spatial distribution of cells (e.g. distribution of cells in an organoid such as distribution of: stem cells at the ends of crypt buds; Paneth cells immediately adjacent to Lgr5+ stem cells; and differentiated cells clustered near the central cystic area of an organoid); and combinations of these.
In some embodiments, diagnostic kit 81 is configured to perform one or more tests to determine successful modification of cells. For example, diagnostic kit 81 can comprise components configured to perform a test (e.g. of material 60 comprising harvested tissue) selected from the group consisting of: PCR-based test; reporter proteins (e.g. eGFP) test; his-tagging test (e.g. of a reporter protein and/or of an otherwise functional protein of interest); antibiotic selection test (e.g. a test for resistance to puromycin); a test for modified surface/transmembrane proteins; a test for secreted peptides and/or hormones; a test of the body's potential physiologic response to material 60 on insulin resistance, beta cell function, glucose control, weight; and combinations of these.
In some embodiments, diagnostic kit 81 is configured to perform one or more tests on byproducts produced during the creation of material 60 (e.g. material 60 comprising harvested tissue), such as to avoid losing a portion of material 60 to testing. For example, diagnostic kit 81 can include components configured to perform an FACS analysis on trypsinized waste tissue, such as to determine a ratio of K cells to L cells or ratio of GIP producing cells to GLP-1 producing cells, such as to confirm identity of the donor.
In some embodiments, diagnostic kit 81 is configured to perform a test to determine safety and/or efficacy of material 60 prior to implantation into a patient. For example, diagnostic kit 81 can comprise components configured to confirm a parameter level selected from the group consisting of: endotoxin and/or other toxin levels are below a threshold; bioburden is below a threshold; mycoplasma level below a threshold; adventitious agent below a threshold; cell viability above a threshold, such as above a threshold of 70%; percentage of Lgr5+ cells above a threshold, such as above a threshold of 1%, or 2%, or 30%; percentage of Paneth above a threshold, such as above a threshold of 1%, or 2%, or 30%; transduction copies per cell above a threshold; potency above a threshold; and combinations of these. In some embodiments, diagnostic kit 81 can include components configured to assess potency of material 60. For example, the potency assessment can include a quantified expression of incretins and/or an expression ratio of one incretin to another (e.g. expressions that can be compared to a threshold to determine adequacy of material 60). Alternatively or additionally, the assessment can comprise a quantification of the number of cells, crypts, and/or organoids present in the sample. Diagnostic kit 81 can include components configured to provide identity information (e.g. anatomical location information) of the material 60, such as by quantifying and/or detecting markers of source tissue from cells other than enteroendocrine cells. For example, presence of fatty acid binding proteins (that are produced abundantly by enterocytes in the duodenum) would indicate duodenal tissue versus distal intestinal tissue. Diagnostic kit 81 can include components configured to perform a blood test, such as a blood test of one or more patients (e.g. a donor patient and/or a recipient patient). Blood tests of a patient can be used to evaluate that patient's suitableness for the procedure (e.g. a tissue harvesting procedure and/or a material 60 implantation procedure). Blood tests that evaluate circulating levels of hormones, presence of particular antibodies, and/or some other blood borne marker can be performed, such as to assess applicability of the patient, to perform dosimetry calculations, and/or to assess projected success of the treatment.
In some embodiments, system 10 includes safety assembly 83 shown, which can include one or more components configured to assure the safety and/or efficacy of material prior to its implantation in a patient. In some embodiments, safety assembly 83 comprises one or more components configured to confirm that tissue 61 and/or material 60 is not exposed to an undesired temperature (e.g. including at a high or low temperature for an undesired amount of time), at an undesired pressure, at an undesired force, at an undesired pH level; or at another undesired physical state, such as when safety assembly 83 comprises one or more temperature, pressure, force, pH, and/or other sensors and safety assembly 83 is configured to accompany tissue 61 during its storage and/or transportation (e.g. travel from one location to another location). For example, safety assembly 83 can comprise a color strip configured to change colors when an undesired condition is met (e.g. an undesired temperature). Safety assembly 83 can comprise a tensile force indicator, such as a string or other filament that is positioned between two containers containing tissue 61 and/or material such that breakage of the filament is indicative of an undesired force having been imparted on the containers.
Safety assembly 83 can comprise one or more components configured to destroy material 60 if an adverse condition is detected (e.g. by one or more sensors of safety assembly 83), such as to absolutely prevent material 60 from being deposited in a patient. For example, safety assembly 83 can include a portion of a tissue modification kit, tissue modification kit 86 shown, the portion including genetic material that can be included (e.g. inserted into) material 60 to cause the death of a cell when undesired (e.g. unsafe) conditions are encountered, such as is described herein.
In some embodiments, system 10 includes an identification kit, ID kit 84 shown, which can include one or more components configured to identify tissue 61 and/or material prior to the depositing of material 60 into a patient. The ID provided by ID kit 84 can be configured to travel with tissue 61 and/or material 60 during its transportation between settings, and/or during processing. ID kit 84 can provide traceability information that is compatible with clinical electronic record systems (e.g. such as through the use of unique barcodes identifying the material and/or the intended patient). ID kit 84 can provide identifiers that are applied to one or more storage containers of a storage kit, storage kit 82 shown (e.g. one or more lockable storage containers). In some embodiments, ID kit 84 can include identifiers (e.g. serial numbers or other identifiers) for one or more components of system 10 used to create material 60 and/or deposit material 60 in a patient (e.g. identifiers for harvesting device 400, processing device 500, depositing device 600, and/or treatment device 700).
In some embodiments, system 10 includes a kit for assembling material 60, deposit material assembly kit 88 shown, which can include one or more pieces of equipment, materials, containers, and/or other components configured to assemble material 60.
Deposit material assembly kit 88 can include one or more preservatives (e.g. cryopreservative), one or more antibiotics (e.g. penicillin), growth enhancers, growth inhibitors, media, and/or other materials for combining with material 60 (e.g. for storage and/or transportation). Alternatively, the additive can be introduced at locations proximate the deposit site, in a separate step from delivering material 60 (e.g. prior to, during, and/or after the delivery of material 60 to the deposit site).
In some embodiments, deposit material assembly kit 88 (and/or storage kit 82), includes a container and associated storage medium for storing a portion of material 60, portion 60′, that is not to be deposited in the patient. Retention of portion 60′ can be used as a “backup”, in instances where a subsequent depositing of material 60 is desired.
System 10 can be configured to treat a metabolic disease and/or a pancreatic disease. In some embodiments, material 60 is delivered to one or more deposit sites comprising pancreatic deposit sites. Depositing device 600 can comprise one, two or more distally positioned depositing elements 650 (e.g. one or more needles) positioned on the distal end and/or at least a distal portion of device 600. The one, two or more depositing elements 650 can be configured to be visualized, and/or material 60 can be configured to be visualized (e.g. via ultrasound and/or fluoroscopy), such as a visualization performed just prior to, during, and/or after the delivery of material 60 to each deposit site. Depositing device 600 can be configured to be advanced to one or more deposit sites under image guidance (e.g. as provided by ultrasound imaging such as endoscopic ultrasound imaging, CT imaging, and/or MRI imaging). Depositing device 600 can be configured to deposit material 60 at one or more pancreatic deposit sites, as described herein, such as to achieve a therapeutic benefit for the patient (e.g. a benefit achieved that achieves an efficacy duration of at least 6 months), such as a therapeutic benefit provided in treating a patient afflicted with Type 1 diabetes, Type 2 diabetes, NAFLD, NASH, PCOS, obesity, pancreatitis, pancreatic cancer, and/or hyperinsulinism. The pancreatic deposit sites can include one, two, or more sites selected from the group consisting of: intra-parenchymal space; anterior pararenal space; intraductal space; intra-arterial space of an artery that feeds at least a portion of the pancreas; and combinations of these. The one or more pancreatic deposit sites can comprise locations within 10 cm, 7.5 cm, 5 cm, and/or 3 cm of a portion of the pancreas, such as when the portion of the pancreas comprises the tail, the neck, the body, the head, and/or the uncinate process of the pancreas.
In some embodiments, depositing device 600 is configured to deliver material 60 to one or more deposit sites comprising the pancreatic parenchyma. In these embodiments, a minimum volume of material 60 can be delivered into the intra-parenchymal space (e.g. in a single delivery or multiple deliveries to be performed). The minimum volume can be configured such as to cause at least a portion of the volume of material 60 to exit into the anterior pararenal space, spread, and re-enter the pancreas. The minimum volume of this material 60 delivery can comprise a volume of at least 2 mL, 3 mL, and/or 5 mL. In some embodiments, one or more additional deliveries of material 60 are also performed, such as deliveries to one or more additional deposit sites proximate the tail of the pancreas.
Depositing device 600 can be pre-loaded with material 60 (e.g. one or more treatment agents that are loaded into device 600 prior to device 600 being advanced into the patient). In some embodiments, material 60 is loaded into the distal end of depositing device 600. System 10 can be configured to allow an operator to confirm the proper location of the one or more depositing elements 650 prior to, during, and/or after the delivery of material 60 to a deposit site.
In some embodiments, depositing device 600 (e.g. via a functional element 699 comprising a heating element) and/or another component of system 10 is configured to heat tissue proximate the one or more deposit sites (e.g. one, two, or more pancreatic deposit sites), such as to heat the tissue to a temperature of at least 39° C. prior to, during, and/or after the delivery of material 60 to the one or more deposit sites.
In some embodiments, system 10 is configured to allow an operator to remove at least a portion of material 60 that has been deposited into the patient. For example, depositing device 600 and/or another component of system 10 can be configured to allow an operator to remove all or a portion of the amount of material 60 that has been previously delivered to the patient (e.g. using a functional element 699 and/or other functional element of system 10 that is configured to provide a vacuum).
Depositing device 600 can comprise materials that are configured to be sterilized, such that depositing device 600 can be sterilized prior to use (e.g. in a manufacturing process). In some embodiments, depositing device 600 comprises an insertable length (e.g. insertable into the patient's GI tract via the mouth) comprising a length between 135 cm and 210 cm, such as between 150 cm and 190 cm.
Depositing device 600 can comprise a handle, handle 601 shown. Handle 601 can be similar to positioning assembly 6050 described in reference to
Handle 601 can include one or more syringe adapters for attaching one or more syringes 610 to depositing device 600. The syringe adapters can be located at a proximal portion of handle 601. In some embodiments, one or more of the syringe adapters can comprise a luer lock adapter. The syringe adapters can include one or more one-way valves (e.g. a functional element 599 comprising one or more check valves and/or other valves) that prevent backward flow through the syringe adapter. The syringe adapters can provide haptic feedback to the operator, for example feedback that is provided when syringe 610 is properly connected.
In some embodiments, handle 601 comprises a locking mechanism that is configured to prevent translation of depositing element 650 relative to handle 601.
In some embodiments handle 601 is configured to operably attach to an access device 50, such as to an endoscope.
Handle 601 can comprise an advancement mechanism configured to advance depositing element 650, such as via rotation and/or translation of at least a portion of the advancement mechanism. The advancement mechanism can comprise a threaded channel, and a rotating member that is attached to depositing element 650 and configured to rotate within the channel. In some embodiments, the advancement mechanism is constructed and arranged to advance depositing element 650 an extension distance, such as a distance between 5 cm and 50 cm, such as between 10 cm and 20 cm.
Depositing device 600 can comprise an elongate filament, shaft 6010, which can comprise one or more lumens, lumen 6011 shown. One or more lumens 6011 of shaft 6010 can operably attach (e.g. at least fluidly attach) to depositing element 650. In some embodiments, device 600 (e.g. shaft 6010) comprises one, two, three, or more lumens. For example, device 600 can comprise a lumen 6011a for delivering material 60 to depositing element 650. This lumen 6011a can comprise an inner diameter of no less than 0.05 mm and/or it can comprise an inner diameter of no greater than 1 mm. Device 600 can comprise a lumen 6011b for delivering flush 64 (e.g. saline, an imaging agent such as contrast, or a polymerizing agent) to depositing element 650. This lumen 6011b can comprise an inner diameter of no less than 0.05 mm, and/or it can comprise an inner diameter of no greater than 1 mm. Depositing device 600 can comprise stylet 651, such as is described herein. Depositing device 600 can comprise a lumen 6011c for slidingly receiving stylet 651, as described herein, such as a stylet configured to stiffen device 600 and/or to prevent ingress of fluids or other materials into device 600 during advancement (e.g. advancement of depositing element 650 into tissue). In some embodiments, a lumen 6011 receives (e.g. slidingly receives) depositing element 650, for example a depositing element 650 comprising an elongate shaft and a distal needle tip. A lumen 6011 can operably attach to a vacuum source (e.g. on its proximal end), such as to provide aspiration at the distal end of depositing device 600, for example aspiration used to assess if device 600 (e.g. depositing element 650) has punctured a blood vessel. In some embodiments, device 600 uses aspiration to hold a portion of device 600 against tissue (against the stomach wall). In some embodiments, vacuum applied to a lumen 6011 prevents or at least limits tenting of tissue while depositing element 650 is inserted into tissue.
Shaft 6010 can comprise a textured outer surface configured to lower friction and/or to help prevent kinking of shaft 6010. In some embodiments, shaft 6010 comprises a cross-sectional shape including one or more projections, such as when shaft 6010 comprise a star-like shape. In some embodiments, shaft 6010 can comprise a wound coil on and/or otherwise proximate its outer surface. In some embodiments, shaft 6010 can comprise a coating, such as a coating configured to create a bumped surface. Shaft 6010 can comprise a length between 125 cm and 200 cm, such as between 140 cm and 180 cm. At least a portion of shaft 6010 can extend through at least a portion of handle 601. In some embodiments, shaft 6010 comprises a material similar to depositing element 650. In some embodiments, shaft 6010 comprises a biocompatible material such as polyether ether ketone (PEEK). In some embodiments, depositing element 650 is fixedly positioned on the distal end of shaft 6010 such that element 650 extends from the distal end of shaft 6010.
In some embodiments, shaft 6010 comprises a sheath, such as a sheath which is configured to slidingly receive depositing element 650. Shaft 6010 can comprise a lubricious or other low-friction material, for example polyoxymethylene (POM) or polytetrafluoroethylene (PTFE). In some embodiments, shaft 6010 comprises a lubricant, such as a parylene coating and/or a coating applied using vapor deposition. Shaft 6010 can comprise an outer diameter between 1.4 mm and 3.5 mm, such as between 1.8 mm and 2.2 mm. Shaft 6010 can comprise an inner diameter (i.e. the diameter of lumen 6011) between 0.25 mm and 2 mm, such as between 0.5 mm and 1 mm. Shaft 6010 can comprise a length between 130 cm and 190 cm, such as between 135 cm and 170 cm. In some embodiments, shaft 6010 is slidingly received within a lumen of an access device 50 (e.g. an endoscope). In some embodiments, handle 601 is configured to fixedly attach to the proximal portion of shaft 6010 and the proximal portion of access device 50. Handle 601 can be configured to adjust the longitudinal orientation of shaft 6010 relative to access device 50. For example, handle 601 can adjust the relative longitudinal positions (e.g. the relative position of the distal end of shaft 6010 and the distal end of access device 50) up to 8 cm. In some embodiments, handle 601 comprises a set screw that locks the relative longitudinal position of shaft 6010 and access device 50.
In some embodiments, depositing element 650 comprises a needle with a gauge between 18G and 34G, such as between 22G and 30G. Depositing element 650 can comprise a shaped distal tip (e.g. a beveled distal tip). For example, depositing element 650 can comprise an anti-coring tip shape, such as a hanging bevel, a tapered conical shape, or a side channel conical shape. Depositing element 650 can comprise a single bevel or multiple bevels. In some embodiments, the shape of the distal tip of depositing element 650 is configured to alter the path of depositing element 650 as it is inserted into tissue, for example to cause depositing element 650 to follow a curved path by causing uneven forces on depositing element 650 while interacting with the tissue. Depositing element 650 can comprise (e.g. at least the inner surface of depositing element 650 can comprise) a material selected from the group consisting of: stainless steel; nickel-titanium alloy; titanium; cobalt-chromium alloy; fused silica, polyethylene; polypropylene; polyether ether ketone (PEEK); polytetrafluoroethylene (PTFE); fluoropolymer; a sol-gel nanocomposite; a material with a hydrophobic and/or hydrophilic coating; and combinations of these. In some embodiments depositing element 650 comprises a surface that has been modified (e.g. during manufacture of depositing element 650), such as a surface modification configured to increase the visibility of depositing element 650 (e.g. via ultrasonic or X-ray imaging). For example, depositing element 650 can comprise a surface modification selected from the group consisting of: bead and/or sand blasting; laser etching; dimpling; corrugation; a coating, such as a radiopaque coating; a physical vapor deposition (PVD) coating, such as a gold PVD coating; and combinations of these. In some embodiments, depositing element 650 comprises a shape selected from the group consisting of: straight; curved; corkscrew; and combinations of these. In some embodiments, the distal diameter of depositing element 650 can be chosen to be smaller than the minimum diameter than can be visualized by an imaging device (e.g. imaging device 90), such as by endoscopic ultrasound imaging device.
As described herein, depositing device 600 can comprise an elongate tool, stylet 651. Stylet 651 can comprise a diameter that is between 0.2 mm and 0.5 mm less than the inner diameter of depositing element 650 and/or a lumen 6011. Stylet 651 can be removable from depositing device 600 (e.g. by an operator of system 10). In some embodiments, depositing device 600 and stylet 651 are configured such that the position of stylet 651 relative to device 600 can be adjusted during a clinical procedure. For example, stylet 651 can be advanced from a first position to a second position in which the tip of stylet 651 is proximate the tip of depositing element 650. In some embodiments, depositing device 600 comprises a biasing mechanism (e.g. a mechanism including a spring) configured to bias stylet 651 towards the first position when stylet 651 is advanced beyond the first position (e.g. a position where the distal end of stylet 651 is approximately 5 mm from the distal end of depositing element 650). Stylet 651 can comprise a material selected from the group consisting of: stainless steel; nickel-titanium; cobalt-chromium; and combinations of these. In some embodiments, stylet 651 comprises a gold tip.
In some embodiments, syringe 610 comprises multiple chambers, such as two or more parallel chambers or concentric chambers. In some embodiments, syringe 610 comprises a pre-filled syringe (e.g. filled in a manufacturing process, filled in a hospital pharmacy or other non-patient setting, or otherwise filled prior to the performance of the clinical procedure in which material 60 is deposited in a patient). In some embodiments, device 600 is constructed and arranged to accept a pre-filled cartridge comprising a material to be injected (e.g. material 60 or flush 64). For example, handle 601 can include a port that operably engages a pre-filled chamber such that the pre-filled material can be injected via depositing element 650. In some embodiments, syringe 610 comprises a material selected from the group consisting of: glass; plastic; stainless steel; and combinations of these.
In some embodiments, syringe drive 40 is constructed and arranged to fill and/or empty syringe 610. Syringe drive 40 can be operated in an open-loop and/or a closed-loop arrangement, for example a closed-loop arrangement based on a desired flow rate and/or pressure (e.g. a flow rate of no more than 5 mL/min, such as no more than 3 mL/min or 1 mL/min, such as when delivering material 60 to the pancreas). In some embodiments, operation of syringe drive 40 is operator controlled, such as manually via console 200. Syringe drive 40 can provide feedback (e.g. haptic feedback and/or audible feedback), such as to confirm proper engagement with syringe 610.
System 10 can be configured to maximize efficacy of the delivery of a treatment agent, material 60, to a deposit site (e.g. target tissue) of a patient, while minimizing patient risk as well as preventing or at least reducing the delivery of material 60 to undesired (e.g. off-target) tissue locations. In some embodiments, material 60 comprises at least a gene therapy material, and material 60 is delivered to the pancreas of a patient to provide a therapeutic benefit to the patient (e.g. treat a medical condition of the patient, such as insulin resistance, Type 1 diabetes, Type 2 diabetes, and/or another medical condition as described herein). System 10 can be configured to achieve a therapeutic benefit while minimizing risk of pancreatitis, and while avoiding any significant distribution of the treatment agent to non-target organs (e.g. and thus avoiding the undesired side effects that may ensue). In these embodiments, material 60 can be delivered by depositing device 600 to a minimum volume of tissue, such as to deliver to a volume of tissue selected from the group consisting of: at least 20% of the volume of the pancreas (e.g. the volume of the pancreatic tissue); at least 10% or 20% of the islet cells of the pancreas; at least 10% or 20% of the alpha cells of the pancreas; at least 10% or 20% of the beta cells of the pancreas; at least 10% or 20% of the pancreatic exocrine cells; at least 10% or 20% of the ductal epithelial cells of the pancreas; and combinations of these. In these embodiments, material 60 can be delivered by depositing device 600 to a maximum volume of tissue, such as to deliver to a volume of tissue selected from the group consisting of: at less than 60%, such as less than 50%, of the volume of the pancreas (e.g. the volume of the pancreatic tissue); less than 60%, such as less than 50%, of the islet cells of the pancreas; less than 60%, such as less than 50%, of the alpha cells of the pancreas; less than 60%, such as less than 50%, of the beta cells of the pancreas; less than 60%, such as less than 50%, of the pancreatic exocrine cells; less than 60%, such as less than 50%, of the ductal epithelial cells of the pancreas; and combinations of these. System 10 can be configured to deliver material 60 using endoscopic ultrasound (EUS) guided injection (e.g. EUS fine needle injection), such as when access device 60 comprises an endoscopic ultrasound device, and depositing device 600 is configured to be delivered to the pancreas via a working channel of the access device 600. System 10 can be configured to deliver material at a flow rate below a maximum, such as a maximum flow rate of no more than 5 mL/min, such as no more than 3 mL/min, or 1 mL/min. Depositing element 650 of depositing device 600 can comprise one or more needles, such as one or more needles with a gauge (e.g. a diameter of a distal-most segment, such as a segment of at least 2 cm) of no larger than 25, such as no larger than 27. An operator can deliver material 60 to the pancreas via multiple injections using depositing device 600, such as a number of injections that does not exceed 7 total injections, such as no more than 5, 3, or 1 total injections. The total amount of material delivered to the pancreas can comprise a volume that does not exceed 25 mL such as a total volume of no more than 15 mL. In some embodiments, the total amount of material 60 delivered to the pancreas comprises a total volume of at least 1 mL, such as a total volume of at least 5 mL. In some embodiments, the total amount of material 60 delivered to the pancreas comprises a volume between 0.010 mL/cm3 and 0.6 mL/cm3 relative to the volume of the pancreas. System 10 can be configured to deliver material 60 to a deposit site that comprises non-cancerous tissue, such as when material 60 is delivered by depositing to a non-cancerous portion of the pancreas. System 10 can be configured to deliver material 60 to the “normal” parenchyma. System 10 can be configured to delivery material 60, such as a material 60 comprising a gene therapy material, to the pancreas or other tissue location to treatment Type 1 diabetes, Type 2 diabetes, and/or other medical condition as described herein. In some embodiments, material 60 comprises a gene therapy material that comprises an adeno-associated virus-based (AAV-based) gene therapy material, such as when material 60 is delivered to the pancreas and/or other organ of the patient. System 10 can be configured to flush (e.g. allow an operator to flush) depositing element 650 with a small volume (e.g. a volume less than the volume of the lumen of depositing element 650) of flush material, flush 64, after delivery of material 60 into tissue (e.g. into the pancreas). Flush 64 can comprise one or more fluids with a relatively high viscosity, for example, a viscosity of at least 0.015 poise, at least 0.02 poise, or at least 0.03 poise, such as mineral oil, lipiodol, and/or other material as described herein. In some embodiments, flush 64 comprises a viscosity of no more than 0.10 poise, such as no more than 0.07 poise, or no more than 0.05 poise. As described hereabove, system 10 can be configured to deliver material 60 to the pancreas while minimizing risk of pancreatitis. For example, risk of pancreatitis for a patient can comprise a risk of no more than 5%, such as no more than 3% or 1%. As described hereabove, system 10 can be configured to limit the effects that material has on non-target organs or other non-target tissue. For example, in embodiments in which material 60 is delivered to the pancreas (e.g. to treat insulin resistance and/or diabetes as described herein), system to can be configured to have an effect on other organs (e.g. the liver, kidney, heart, gonads, brain, and/or other organ) that is less than the effect achieved in the pancreas. System 10 can be configured to deliver a tissue-disseminating agent (e.g. an agent 70 comprising a tissue-disseminating agent), such as hyaluronidase collagenase, or the like. The tissue-disseminating agent can be injected (e.g. via depositing device 600) prior to and/or simultaneously with material 60. Alternatively or additionally, material 60 can be co-formulated with a tissue-disseminating and/or a dissociating agent such as hyaluronidase, collagenase, or the like, to improve the distribution of material 60 to the pancreas.
As described herein, system 10 can comprise an access device 50 comprising a endoscopic ultrasound device, and depositing device 600 can be configured to be introduced to a tissue location such as the pancreas through a working channel of the access device 50. Depositing device 600 can include and/or can be operably attachable (e.g. at least fluidly attachable) to a reservoir, such as syringe 610 or another syringe as described herein. Material 60 (e.g. a gene therapy material and/or other treatment agent) can be included in the syringe, and/or material 60 can be drawn into the syringe by an operator. A syringe driving assembly, such as syringe drive 40 or other syringe drive as described herein, can be configured to cause the syringe and depositing element 650 of depositing device 600 to deliver material 60 into tissue (e.g. the pancreas) at a relatively slow flow rate, such as a flow rate of no more than 5 mL/min, such as no more than 3 mL/min, or 1 mL/min. Controller 200 can be configured to activate the syringe drive via a flexible drive conduit (e.g. conduit 2402 described in reference to
In some embodiments, system 10 is configured to deliver a material 60 (e.g. a material 60 comprising an AAV-based and/or other gene therapy material) to tissue of the patient, such as to the pancreas. In these embodiments, system 10 can be configured to treat diabetes, such as Type 1 or Type 2 diabetes. Alternatively or additionally, material 60 can be delivered (e.g. to the pancreas), to treat one or more of multiple diseases affecting the pancreas. In some embodiments, material 60 comprises non-gene therapy agents. In some embodiments, delivery of material 60 be system 10 is configured to treat a medical condition selected from the group consisting of: diabetes such as Type 1 diabetes and/or Type 2 diabetes; cystic fibrosis; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; and combinations of these. In some embodiments, system 10 is configured to perform endoscopic ultrasound guided injection of material 60, as described herein, into the portal vein, such as to deliver material 60 to the liver.
As described herein, system 10 can be configured to treat various medical conditions of a patient. A depositing device 600 comprising at least one depositing element 650 (e.g. at least one needle, at least one fluid jet, and/or at least one other element configured to deliver material 60 and/or other materials) can be advanced to at least one deposit site (e.g. at least one site in the pancreas) to a patient, such as a patient having a metabolic disease and/or a pancreatic disease. Material 60 can be delivered through the at least one depositing element 650 into the at least one pancreatic deposit site. In some embodiments, the at least one depositing element 650 comprises at least one needle positioned on a distal portion of the depositing device 600. In some embodiments, the distal end of depositing device 600 is delivered into the patient through the mouth, and advanced through a wall of the gastrointestinal tract to a location proximate the pancreas. In some embodiments, depositing device 600 is delivered through a working channel of an access device 50 comprising a gastrointestinal endoscope that has been delivered through the mouth of the patient. Alternatively, depositing device 600 can be delivered alongside an access device 50 comprising a gastrointestinal endoscope that has been delivered through the mouth of the patient. In some embodiments, system 10 treats a metabolic disease selected from the group consisting of: Type 1 diabetes; Type 2 diabetes; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); obesity; and combinations thereof. Alternatively or additionally, system 10 can treat a pancreatic disease selected from the group consisting of: pancreatitis; pancreatic cancer; hyperinsulinism; and combinations thereof. In some embodiments, the at least one pancreatic deposit site is selected from the group consisting of: intraparenchymal space; anterior pararenal space; intraductal space; intraarterial space of an artery that feeds at least a portion of the pancreas; and combinations thereof. In some embodiments, the delivering of material 60 (e.g. a treatment agent) comprises at least a first delivery in which a minimum volume of material 60 is delivered into the pancreatic parenchyma, and wherein the minimum volume of material 60 comprises a volume sufficient to cause at least a portion of the volume of material 60 to exit into the anterior pararenal space, spread, and re-enter the pancreas. At least a second delivery of material 60 to at least one additional deposit site proximate the tail of the pancreas can be performed. In some embodiments, the delivering of material 60 comprises at least a first delivery in which a minimum volume of material 60 is delivered into the pancreatic parenchyma, and wherein the minimum volume of the treatment agent comprises a volume of at least 2 ml, at least 3 ml, and/or at least 5 ml. In some embodiments, depositing device 600 is advanced to the at least one pancreatic deposit site under image guidance. The image guidance can comprise: endoscopic ultrasound guidance; computerized tomography (CT) guidance; and/or magnetic resonance imaging (MRI) guidance. In some embodiments, the at least one pancreatic deposit site comprises locations within 10 cm, 7.5 cm, 5 cm, and/or 3 cm of a portion of the pancreas, and the portion of the pancreas can comprise the tail, the neck, the body, the head, and/or the uncinate process. In some embodiments, material 60 and/or the at least one depositing element 650 is configured to be visualized by an imaging device (e.g. imaging device 90 and/or an imaging component of access device 50). Material 60 and/or the at least one depositing element 650 can be visualized with the imaging device to confirm proper delivery of material 60. In some embodiments, an imaging agent (e.g. an agent 70, agent 62, and/or other component of system 10 comprising an imaging agent) can be delivered through the at least one depositing element 650. The delivery of the imaging agent can be visualized with an imaging device (e.g. imaging device 90 and/or an imaging component of access device 50) to confirm (e.g. confirm after the delivery of at least a portion of material 60 has occurred) that a proper delivery of material 60 has occurred. In some embodiments, material 60 is pre-loaded into depositing device 600. Material 60 can be loaded into depositing device 600 from the distal end of depositing device 600. In some embodiments, system 10 is configured to deliver material 60 at a pressure of at least 3 mmHg. In some embodiments, system 10 is configured to delivery material 60 at a pressure of no more than 25 mmHg. In some embodiments, system 10 is configured to deliver material at a flow rate of at least 1 ml/min. In some embodiments, system 10 is configured to deliver material 60 at a flow rate of no more than 5 ml/min. In some embodiments, the at least one depositing element 650 comprises multiple fenestrations along its length. In some embodiments, the location (e.g. the anatomical location) of the at least one depositing element 650 is confirmed prior to delivering material 60. In some embodiments, system 10 comprises a permeability-enhancing agent (e.g. an agent 70, an agent 62, and/or another agent of system 10 comprising a permeability-enhancing agent). The permeability-enhancing agent can be delivered prior to the delivery of material 60 and/or simultaneously with the delivery material 60. System 10 can deliver the permeability-enhancing agent locally and/or intravenously. The permeability-enhancing agent can comprise an agent selected from the group consisting of: hyaluronidase; collagenase; losartan; and combinations thereof. Material can comprise a coformulation of a treatment agent and another agent, such as a permeability-enhancing agent (e.g. material 60 can comprise a coformulation comprising a gene treatment material and an agent 62 comprising a permeability-enhancing agent and/or other agent). As described herein, material 60 can comprise a gene therapy material (also referred to as a “gene therapy agent”). The gene therapy material can comprise a non-viral vector comprising a polynucleotide comprising a gene of interest. The non-viral vector can comprise a material that is selected from the group consisting of: plasmids; bacterial artificial chromosomes; yeast artificial chromosomes; minicircles; and combinations of these. The gene therapy material can comprise a viral vector comprising a polynucleotide comprising a gene of interest. The viral vector can comprise a material that is selected from the group consisting of: retrovirus vectors; adenovirus vectors; Herpes simplex virus (HSV) vectors; adeno-associated virus (AAV) vectors; and combinations of these. In some embodiments, material 60 comprises a viral vector such as an AAV vector. The AAV vector can comprise an AAV vector genome comprising a polynucleotide comprising a gene of interest. The AAV vector can further comprise an AAV capsid protein. The AAV capsid protein can comprise a capsid protein selected from the group consisting of AAV1; AAV2; AAV3; AAV4; AAV5; AAV6; AAV7; AAV8; AAV9; AAV10; AAV11; Rh10; Rh74; AAV-2i8; AAV-DJ; AAV-LK03; AAV-KP1; AAV-KP2; AAV-KP3; and variants of any of these; and combinations of these. System 10 can be configured to heat tissue proximate the at least one pancreatic deposit site, such as heating performed to heat the tissue to a temperature above 39° C. prior to, during, and/or after the delivery of material 60. System 10 can be configured to deliver a dissemination-blocking material (e.g. an agent 62, 70, and/or other agent of system 10 comprising a dissemination-blocking material) that is configured to prevent undesired dissemination of material 60 to non-target locations. The dissemination-blocking material can comprise a viscous substance and/or a polymer. System 10 can comprise a blocking element, such as when agent 62, functional element 99, and/or another component of system 10 comprises a blocking element. The blocking element (e.g. a temporary or chronic implant) can be positioned in the patient, such that the blocking element can prevent undesired dissemination of material 60 to non-target locations. In some embodiments, at least a portion of material 60 is removed from a deposit site location after the delivery of material 60 begins. In some embodiments, all, or at least a majority (e.g. greater than 50%) of the amount of material 60 delivered into the patient is removed
As described herein, system 10 can be configured to deliver (e.g. endoscopically deliver) material 60 (e.g. a gene therapy agent, also referred to as gene therapy material) to an intraparenchymal space of the pancreas of a patient having a metabolic disease and/or a pancreatic disease. The delivering can comprise: advancing depositing device 600 comprising at least one depositing element 650 through the mouth and through a wall of the gastrointestinal tract to the intraparenchymal space of the pancreas. Depositing device 600 can be delivered through a working channel of an access device 50 (e.g. a gastrointestinal endoscope) that has been delivered through the mouth of the patient. Depositing device 600 can be delivered alongside an access device 50 (e.g. a gastrointestinal endoscope) that has been delivered through the mouth of the patient. Material 60 can comprise a gene therapy agent that comprises an adeno-associated virus (AAV) vector. The AAV vector can comprise: (a) an AAV capsid protein; and (b) an AAV vector genome comprising a polynucleotide comprising a gene of interest. The AAV capsid protein can comprise a capsid protein selected from the group consisting of: AAV1; AAV2; AAV3; AAV4; AAV5; AAV6; AAV7; AAV8; AAV9; AAV10; AAV11; Rh10; Rh74; AAV-2i8; AAV-DJ; AAV-LK03; AAV-KP1; AAV-KP2; and AAV-KP3; and variants of any of these; and combinations of these. The patient treated by system 10 can have Type 2 diabetes. The gene of interest described herein can encode a glucoregulatory hormone (i.e., a hormone involved in the modulation of circulating blood glucose levels). The glucoregulatory hormone can comprise a hormone selected from the group consisting of: glucagon; GLP-1; oxyntomodulin; glicentin; glicentin-related polypeptide (GRPP); major proglucagon fragment; intervening peptide 1 (IP-1); intervening peptide 2 (IP-2); GLP-2; glucose-dependent insulinotropic peptide (GIP); peptide tyrosine (PYY); Cholecystokinin (CCK); somatostatin; oxyntomodulin; Ghrelin; amylin; glucagon; leptin; follistatin; insulin-like growth factor 1 (IGF1); vasoactive intestinal peptide (VIP); growth hormone 1 (GH1); peptides, variants and fusions of any of these; and combinations of these.
Referring now to
In Step 110, a patient is selected, such as is described herebelow.
In Step 120, an optional step of material processing is performed to produce material 60. For example, material processing can be performed by processing device 500 to create a transgenic virus and/or other tissue modifying material, material 60, that is applied to and/or within a deposit site.
In Step 130, an optional step of performing a pre-deposit procedure, Procedure B, can be performed, such as is described herebelow.
In Step 140, material 60 is deposited at one or more deposit sites, such as is described herebelow. Material 60 can comprise one or more materials, such as those that are described in reference to
In Step 150, an optional step of performing a post-deposit procedure, Procedure C, can be performed, such as is described herebelow.
In some embodiments, Step 110, selects a patient (e.g. a mammalian patient) with an HbA1c level of at least 6.5%, at least 7.0%, at least 7.5%, or at least 8%. In some embodiments, in Step 110 of method 100, a patient is selected that is obese, has a body mass index (BMI) of at least 30, has Type 2 diabetes, and has a HbA1c level above 7.0. In some embodiments, the patient is selected to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas.
In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 1 of Type 1 diabetes, whereby stage 1 is defined as the presence of p-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 2 of Type 1 diabetes, whereby stage 2 is defined as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 3 of Type 1 diabetes, whereby stage 3 is defined as onset of symptomatic disease.
In some embodiments a patient is selected that has: cystic fibrosis; non-cystic-fibrosis; pancreatic exocrine insufficiency; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; pancreatic metastases; a partial pancreatectomy; and/or another disease of the pancreas.
In some embodiments, a patient is selected that has a BMI of at least 25, 30, 35, and/or 40.
In some embodiments, a patient is selected in Step 110 that has a pancreas with a minimum level of functionality, such as when the patient has a C-Peptide level of at least 0.2, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of at least 7 μU/mL, 9 μU/mL, or 12 μU/mL.
In some embodiments, a patient is selected in Step 110 that has a relatively non-cirrhotic liver, such as when the patient has: a Fib-4 level of no more than 4; a Fib-4 level of at least 1.3, 2.0, and/or 2.5 (e.g. when the patient has NAFLD and/or NASH); an ALT level of at least 30, 35, and/or 40; an AST level of at least 25, 30, and/or 35; and combinations of one, two, or more of these.
In some embodiments, a female patient is selected in Step 110 that has impaired ovarian function, such as a patient that has oligomenorrhea (e.g. menses with a cycle of at least 35 days) and/or amenorrhea (e.g. no menses for at least 6 months). In some embodiments, a male patient is selected in Step 110 that has impaired testosterone levels and/or impaired sexual function (such as impotence).
In some embodiments, a patient is selected in Step 110 that has insulin resistance, such as when the patient has: a triglyceride/HDL ratio of at least 1.65 and/or 2.75; a HOMA-IR level of at least 2.0, 2.5, and/or 3.0; a fasting insulin of at least 5 μU/mL, 7 μU/mL, and/or 10 μU/mL; and/or a fasting glucose of at least 100 mg/dL and/or 125 mg/dL.
In some embodiments, a patient is selected in Step 110 that has liver disease, such as fatty liver disease or other liver disease diagnosed and/or prognosed via magnetic resonance (MR) imaging and/or ultrasound imaging. For example, magnetic resonance imaging can be used to determine a proton densitometry fat fraction (PDFF), also referred to as magnetic resonance fat fraction, where the patient is selected for treatment if their intra-hepatic triglyceride (IHTG) is at least 5%. Ultrasound imaging can be used to determine a hepato-renal index of echo levels (HRI), wherein the patient is selected for treatment if the HRI difference is at least 4.0 dB and/or the HRI ratio is no more than 1.0. A fibroscan (transient elastography) can be used to assess a patient for treatment. For example, a patient can be selected for treatment if their vibration controlled transient elastography is determined to be at least 6 kPa, or at least 8 kPa (e.g. when measured at 50 Hz). Alternatively or additionally, a patient can be selected for treatment if their controlled attenuation parameter (CAP), also referred to as ultrasound attenuation rate, is at least 200 dB/m or at least 250 dB/m.
In some embodiments, a patient is selected in Step 110 that has a metabolic disease, such as a metabolic disease diagnosed and/or prognosed via metabolomics. For example, a patient can be selected for treatment if their level of 2-hydroxybutyrate is no more than 5 μg/mL.
In some embodiments, a patient is selected in Step 110 that has a hormonal defect, such as a patient with insufficient GLP-1 secretions (e.g. as determined by measuring circulating levels of these).
In some embodiments, optional Procedure B of Step 130 is performed prior to depositing of material 60. In some embodiments, optional Procedure B, comprises a mucosal tissue modification procedure (e.g. an ablation, denaturing and/or removal procedure). The mucosal tissue modification procedure can comprise a tissue modification of a full or partial circumferential portion of an axial segment of a GI lumen (e.g. a duodenal or other intestinal lumen), such as an ablation procedure of the post-ampulla duodenal mucosa of at least 4 cm where the most proximal segment of the ablation is at least 1 cm distal to the ampulla of Vater.
In some embodiments, Procedure B of Step 130 comprises a procedure performed using treatment device 700 described hereabove in reference to
In some embodiments, a first step of Procedure B includes delivery of energy and/or an agent to tissue (e.g. by a treatment device 700 to cause the tissue to necrose), and a second step includes removing the treated tissue (e.g. by the same or a different treatment device 700, in the same or a subsequent clinical procedure).
Procedure B of Step 130 can comprise a diet undertaken by the patient, such as a diet selected from the group consisting of: a high sugar diet; a low sugar diet; a high carbohydrate diet; a low carbohydrate diet; a high fiber diet; a low fiber diet; a fast carbohydrate diet; a slow carbohydrate diet; a liquid diet; and combinations of one, two, or more of these. In some embodiments, Procedure B comprises a diet configured to change the deposit site (e.g. to change the mucosal thickness and/or other tissue property at the intended deposit site).
Procedure B of Step 130 can comprise a pharmaceutical therapy undertaken by the patient, such as a pharmaceutical therapy that is undertaken for at least 2, 4, 6, and/or 8 weeks (e.g. to assess tolerability). In some embodiments, the patient undergoes a pharmaceutical therapy to assess tolerance to exogeneous GLP-1 prior to a delivery of material 60 intended to alter (e.g. permanently alter) the patient's pancreas (as described herein).
Procedure B of Step 130 can comprise an adjustment to an existing pharmaceutical therapy, such as an adjustment comprising eliminating or at least reducing an existing pharmaceutical therapy (e.g. a reduction in insulin, GLP-1, or similar pharmaceutical), such as a reduction initiated at least 1, 2, 4, 6, and/or 8 weeks prior to delivery of material 60 (e.g. a material 60 comprising a gene therapy, such as gene therapy delivered proximate the pancreas).
Procedure B of Step 130 can comprise a diagnostic procedure, such as an endoscopic or other visualization procedure that is used to assess one or more deposit sites of the patient as it relates to safety and/or efficacy of Step 140 and/or other steps of method 100.
Procedure B can be performed at a minimum time before the depositing of material performed in Step 140. Alternatively or additionally, Procedure B of Step 130 can be performed within a maximum time of the performance of Step 140. In some embodiments, Procedure B comprises a mucosal or other tissue modification procedure, and the depositing of material 60 performed in Step 140 is performed at least 1 day, or at least 2 days after Procedure B. Alternatively or additionally, Procedure B can comprise a mucosal or other tissue modification procedure that is performed no more than 7 days before the depositing of material 60 of Step 140.
In some embodiments, material 60 is deposited in Step 140 at one, two, or more deposit sites, such as by using depositing device 600 described hereabove in reference to
In some embodiments, material 60 includes a component configured to aid in the depositing of material 60 and/or to maintain material 60 at the deposit site, such as is described hereabove in reference to
In some embodiments, Procedure C of Step 150 comprises a mucosal or other tissue modification procedure, such as performed with treatment device 700 described hereabove in reference to
In some embodiments, Procedure C of Step 150 can comprise a diet undertaken by the patient, such as a diet selected from the group consisting of: a high sugar diet; a low sugar diet; a high carbohydrate diet; a low carbohydrate diet; a high fiber diet; a low fiber diet; a fast carbohydrate diet; a slow carbohydrate diet; a liquid diet; a soft-foot diet; and combinations of one, two, or more of these. In some embodiments, Procedure B of Step 130 can also comprise the patient undergoing a diet, and the diet of Procedure C can be a different diet than that of Procedure B.
In some embodiments, the elapsed time between Step 140 and Procedure C is at least a minimum duration of time (for example, at least one month, 3 months, 6 months, and/or 12 months). In some embodiments, the elapsed time between Step 140 and Procedure C is no more than a maximum duration of time (for example, no more than one month, 3 months, 6 months, and/or 12 months).
Procedure C of Step 150 can comprise delivery of one or more agents to the patient, such as agent 70 described hereabove in reference to
In some embodiments, material 60 comprises coating 63c described hereabove in reference to
In some embodiments, Procedure C comprises a diagnostic procedure, such as an endoscopic or other visualization procedure.
In some embodiments, Procedure C comprises an “augmentation procedure” configured to increase or otherwise enhance the effects on the patient of the depositing of material 60 (and/or other effects caused by the previous steps of method 100). If a desired result is obtained after depositing of material 60 at the one or more deposit sites, but a greater magnitude or duration of the effect is also desired, additional material 60 (e.g. material 60 that had been stored) can be deposited (e.g. using depositing device 600) proximate the deposit site to cause the augmentation (e.g. after the deposit site tissue is removed or at least modified, such as via an ablation or other tissue modifying procedure performed using treatment device 700). The deposit performed in Procedure C can include depositing material over the entirety of the earlier deposit site, over a partial segment of the earlier deposit site, and/or over a different area than the earlier deposit site.
In some embodiments, system 10 and the methods of the present inventive concepts are configured to treat one, two or more medical conditions of a patient, such as Type 1 diabetes, Type 2 diabetes, and/or other medical condition, such as are described hereabove in reference to
System 10 and the methods of the present inventive concepts can be configured to treat at least two medical conditions, such as Type 2 diabetes and NAFLD; Type 2 diabetes and hypertension; Type 2 diabetes and hypertriglyceridemia; Type 2 diabetes and iron overload; NALFD and iron overload; NASH and iron overload; or Type 2 diabetes and NASH.
In some embodiments, method 100 is performed to treat at least Type 1 diabetes, Type 2 diabetes and/or obesity, such as to treat both Type 2 diabetes and obesity. For example, in Step 110, a patient is selected, such as a patient with two, three, or more of the following characteristics: obesity; Type 2 diabetes; body mass index of at least 30; and/or an HbA1c of at least 7. In Step 130, a procedure is performed prior to depositing of material 60, Procedure B described herein, such as a mucosal tissue modification procedure (e.g. an ablation, denaturing and/or removal procedure). The mucosal tissue modification procedure can comprise a tissue modification of a full or partial circumferential portion of an axial segment of a GI lumen (e.g. a duodenal or other intestinal lumen), such as an ablation procedure of the post-ampulla duodenal mucosa of at least 4 cm where the most proximal segment of the ablation is at least 1 cm distal to the ampulla of Vater. In Step 140, material 60 is deposited in one or more deposit sites (e.g. deposit sites in the pancreas and/or pancreatic duct(s) of the patient) with device 600. The depositing can occur in the same clinical procedure in which Procedure B is performed, prior to the performance of Procedure B, and/or in a subsequent clinical procedure performed on a later day. In some embodiments, the depositing step and Procedure B are separated in time by at least two weeks, at least three months, and/or at least 6 months. Material 60 can be deposited in one or more locations in the pancreas, as described herein. Alternatively or additionally, material 60 can be deposited along the length of the pancreatic ducts and/or at the common pancreatic duct. Intraductal delivery can be performed to cause material 60 to travel in a retrograde direction through the ductal tree and/or otherwise travel to achieve paracellular delivery to reach pancreatic cells outside of the duct. Step 150 can be performed, comprising Procedure C. Procedure C can include one, two, or more of: restricted food intake for a minimum time period (e.g. an elemental diet for approximately 48 hours); a pureed diet for a minimum time period (e.g. at least 2 weeks); and/or intake of one or more NSAID or anti-inflammatory agent.
Step 140 can include, after a delivery of material 60 to the deposit site (e.g. one, two, or more deposit sites), the evacuation of at least a portion of the volume of material 60 that remains within the lumen of depositing element 650 from which material 60 is delivered. The evacuation can be performed by delivery of flushing material, such as flush 64 described herein, into the lumen of the associated depositing element 650. If multiple material 60 deliveries are made (e.g. to multiple deposit sites), this evacuation procedure can be performed after the delivery at the final deposit site. The flush 64 (e.g. a sterile, viscous, biocompatible fluid) can comprise one or more materials selected from the group consisting of: mineral oil; ethiodized oil; a contrast agent; phosphate buffered saline; lipiodol; a gas, such as CO2 or atmospheric air; and combinations of these. The volume of the flush 64 introduced into the lumen of the associated depositing element 650 can comprise at least 50% of the volume of the lumen of the depositing element 650, and/or no more than 100%, 90%, 80% and/or 75% of the volume of the lumen of the depositing element 650. The volume of flush 64 introduced into the lumen of the depositing element 650 can comprise a volume of no more than 250 μL. Flush 64 can be introduced into the lumen of the depositing element 650 in a manner configured to avoid mixing of the flush 64 with the material 60 already present in the lumen of the depositing element 650. In some embodiments, flush 64 can comprise a fluid with a density different than material 60, such as to prevent and/or at least limit mixing of the two. For example, flush 64 can comprise an oil, such as sterile mineral oil, or a gas, such as CO2 or atmospheric air. In some embodiments, flush 64 comprises a density between 0.75 g/cm3 and 0.95 g/cm3 such as between 0.8 g/cm3 and 0.9 g/cm3 or a density between 1.1 g/cm3 and 4.5 g/cm3.
Each component of system 10 that is advanced into the patient during the performance of method 100 can be removed at an appropriate time after its use.
Referring now to
In Step 2010, a patient is selected. In some embodiments, the patient is selected to receive gene therapy of the pancreas. In some embodiments, the patient is selected to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas.
In some embodiments, in Step 2010 a patient is selected (e.g. a mammalian patient) with an HbA1c level of at least 6.5%, at least 7.0%, at least 7.5%, or at least 8%. In some embodiments, in Step 2010, a patient is selected that is obese, has a body mass index (BMI) of at least 30, has Type 2 diabetes, and has a HbA1c level above 7.0.
In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 1 of Type 1 diabetes, whereby stage 1 is defined as the presence of D-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 2 of Type 1 diabetes, whereby stage 2 is defined as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 3 of Type 1 diabetes, whereby stage 3 is defined as onset of symptomatic disease.
In some embodiments a patient is selected that has: cystic fibrosis; non-cystic-fibrosis; pancreatic exocrine insufficiency; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; pancreatic metastases; a partial pancreatectomy; and/or another disease of the pancreas.
In some embodiments, a patient is selected in Step 2010 that has a BMI of at least 30, 35, and/or 40.
In some embodiments, a patient is selected in Step 2010 that has a pancreas with a minimum level of functionality, such as when the patient has a C-Peptide level of at least 0.2, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of at least 7 μU/mL, 9 μU/mL, or 12 μU/mL. Alternatively or additionally, a patient is selected in Step 2010 with a C-Peptide level of less than 0.6, 0.8, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of less than 12 μU/mL, 14 μU/mL, or 16 μU/mL.
In some embodiments, a patient is selected in Step 2010 that has a relatively non-cirrhotic liver, such as when the patient has: a Fib-4 level of no more than 4; a Fib-4 level of at least 1.3, 2.0, and/or 2.5 (e.g. when the patient has NAFLD and/or NASH); an ALT level of at least 30, 35, and/or 40; an AST level of at least 25, 30, and/or 35; a creatinine clearance rate of greater than at least 40 mL/min; a serum creatinine level of no more than 1.5 mg/dL; a urine volume of at least 500 mL/day; a urine sodium level of at least 10 mEq/L; absence of portal hypertension; absence of ascites; and combinations of one, two, or more of these.
In some embodiments, a female patient is selected in Step 2010 that has impaired ovarian function, such as a patient that has oligomenorrhea (e.g. menses with a cycle of at least 35 days) and/or amenorrhea (e.g. no menses for at least 6 months). In some embodiments, a male patient is selected in Step 2010 that has impaired testosterone levels and/or impaired sexual function (such as impotence).
In some embodiments, a patient is selected in Step 2010 that has insulin resistance, such as when the patient has: a triglyceride/HDL ratio of at least 1.65 and/or 2.75; a HOMA-IR level of at least 2.0, 2.5, and/or 3.0; a fasting insulin of at least 5 μU/mL, 7 μU/mL, and/or 10 μU/mL; and/or a fasting glucose of at least 100 mg/dL and/or 125 mg/dL.
In some embodiments, a patient is selected in Step 2010 that has liver disease, such as fatty liver disease or other liver disease diagnosed and/or prognosed via magnetic resonance (MR) imaging and/or ultrasound imaging. For example, magnetic resonance imaging can be used to determine a proton densitometry fat fraction (PDFF), also referred to as magnetic resonance fat fraction, where the patient is selected for treatment if their intra-hepatic triglyceride (IHTG) is at least 5%. Ultrasound imaging can be used to determine a hepato-renal index of echo levels (HRI), wherein the patient is selected for treatment if the HRI difference is at least 4.0 dB and/or the HRI ratio is no more than 1.0. A fibroscan (transient elastography) can be used to assess a patient for treatment. For example, a patient can be selected for treatment if their vibration controlled transient elastography is determined to be at least 6 kPa, or at least 8 kPa (e.g. when measured at 50 Hz). Alternatively or additionally, a patient can be selected for treatment if their controlled attenuation parameter (CAP), also referred to as ultrasound attenuation rate, is at least 200 dB/m or at least 250 dB/m.
In some embodiments, a patient is selected in Step 2010 that has a metabolic disease, such as a metabolic disease diagnosed and/or prognosed via metabolomics. For example, a patient can be selected for treatment if their level of 2-hydroxybutyrate is no more than 5 μg/mL.
In some embodiments, a patient is selected in Step 2010 that has post-bariatric hypoglycemia. For example, a post-bariatric surgery patient can be selected: if a post-prandial blood sugar level is determined by system 10 to be below 70 mg/dL, 60 mg/dL, and/or 50 mg/dL; if the patient has known hypoglycemia unawareness; and/or if the patient has documented history of severe hypoglycemia, such as one or more hypoglycemic events requiring third party assistance.
In some embodiments, a patient is selected in Step 2010 that has a hormonal defect, such as a patient with insufficient GLP-1 secretions (e.g. as determined by measuring circulating levels of these).
In Step 2020, a duct of the biliary tree is selected as a deposit site, such as when the deposit site comprises the pancreatic duct, cystic duct, common bile duct, right hepatic duct, left hepatic duct, and/or common hepatic duct.
In Step 2030, an endoscope, such as a duodenoscope, is advanced to ampulla of Vater.
In Step 2040, an optional step of advancing a guidewire through the endoscope into the selected duct using fluoroscopic guidance can be performed.
In Step 2050, an optional step is performed of pre-loading depositing device 600 (e.g. a catheter device) with the treatment agent, material 60. In some embodiments, the distal end of depositing device 600 is pre-loaded with material 60.
In Step 2060, depositing device 60 (e.g. a catheter with a lumen extending therethrough) is advanced through the endoscope into the selected duct. If a guidewire was placed in the duct in the previous step 2050, then device 600 can be advanced over the guidewire.
In Step 2070, an optional step can be performed of injecting a visualization agent into the duct to confirm proper depositing device 600 location. The visualization agent can comprise saline, fluoroscopic contrast, CO2, and/or another agent visible via an imaging device, such as imaging device 90 described herein. If device 600 is not in the desired location, it can be re-positioned (e.g. and reconfirmed). If this confirmatory step is performed, a sub-step of aspirating the visualization agent can then optionally be performed prior to continuing.
In Step 2080, the selected duct can be occluded in a region proximal to the distal end of depositing device 600, while leaving the lumen of device 600 open, such as to prevent unwanted backflow around the outside of device 600. Optionally a visualizable occlusion element, as described herein, can be deployed and visualized by fluoroscopic imaging to ensure appropriate location and function.
In Step 2090, the treatment agent, material 60, (e.g. a gene therapy material, chemotherapy agent, saline, anti-pancreatitis agent, and/or other treatment agent as described in reference to
In some embodiments, of Step 2090, pressure within the tissue can be maintained at or below interstitial pressure (e.g. at or below 0, 3, 5, and/or 8 mmHg) such as by adding and/or withdrawing fluid through depositing device 600 (fluid such as material 60, a visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure achieved can be maintained below interstitial pressure, or the pressure control can be pulsatile such that the average pressure remains below interstitial pressure. In some embodiments, system 10 is configured to maintain the pressure of delivery of material 60 to a level of no more than 25 mmHg.
In another embodiment of Step 2090, pressure within the tissue can be maintained above interstitial pressure (e.g. above 0, 3, 5, and/or 8 mmHg) and at or below capillary pressure (e.g. at or above 15, 20, and/or 25 mmHg), such as by adding and/or withdrawing fluid through depositing device 600 (fluid such as material 60, a visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below capillary pressure, or pressure control can be pulsatile so that average pressure remains below capillary pressure. In some embodiments, system 10 is configured to maintain the pressure of the material 60 to a level of at least 3 mmHg.
In some embodiments of Step 2090, pressure can be increased by instilling material through device 600 until acinarization is visualized (e.g. as seen on fluoroscopy), then maintaining that same pressure within a tight range, such as within a pressure range of +/−3 mmHg or +/−5 mmHg.
In Step 2110, an optional step can be performed of aspirating a significant portion of material 60 from the patient (e.g. aspirating at least 30%, 50%, and/or 70% of the injected volume).
In Step 2120, an optional step of depositing one or more treatment agents (e.g. material 60) in additional ducts can be performed, for example as follows. Device 600 and guidewire (if present) can be withdrawn from the selected duct. A second duct can be identified, and device 600 can be repositioned into the second duct in the same way as was performed for the first duct. Additional treatment agent, material 60, is delivered, maintaining pressure in the same manner that was performed for the previous injection. Cumulative volume injected can be at least 5 mL or 10 mL or 20 mL or 40 mL. The total number of injections can be less than 5, 7, 10 or 12 injections. In some embodiments, the total number of injections is at least 2, 3, 4 or 5 injections. After delivery of material 60 to a deposit site, at least a portion of the material 60 that remains within the lumen of the depositing element 650 can be evacuated from the lumen (e.g. into the patient at the deposit site), such as via introduction of a flushing material into the lumen (e.g. as described hereinabove in reference to
In Step 2130, depositing device 600 and guidewire (if present) are withdrawn into the endoscope and the procedure is completed as per a standard interventional endoscopic procedure. Appropriate devices are then removed from the patient.
Referring now to
In Step 3010, a patient is selected. In some embodiments, the patient is selected to receive gene therapy of the pancreas. In some embodiments, the patient is selected to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas.
In some embodiments, in Step 3010 a patient is selected (e.g. a mammalian patient) with an HbA1c level of at least 6.5%, at least 7.0%, at least 7.5%, or at least 8%. In some embodiments, in Step 3010, a patient is selected that is obese, has a body mass index (BMI) of at least 30, has Type 2 diabetes, and has a HbA1c level above 7.0.
In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 1 of Type 1 diabetes, whereby stage 1 is defined as the presence of P-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 2 of Type 1 diabetes, whereby stage 2 is defined as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 3 of Type 1 diabetes, whereby stage 3 is defined as onset of symptomatic disease.
In some embodiments a patient is selected that has: cystic fibrosis; non-cystic-fibrosis; pancreatic exocrine insufficiency; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; pancreatic metastases; a partial pancreatectomy; and/or another disease of the pancreas.
In some embodiments, a patient is selected in Step 3010 that has a BMI of at least 30, 35, and/or 40.
In some embodiments, a patient is selected in Step 3010 that has a pancreas with a minimum level of functionality, such as when the patient has a C-Peptide level of at least 0.2, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of at least 7 μU/mL, 9 μU/mL, or 12 μU/mL. Alternatively or additionally, a patient is selected in Step 3010 with a C-Peptide level of less than 0.6, 0.8, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of less than 12 μU/mL, 14 μU/mL, or 16 μU/mL.
In some embodiments, a patient is selected in Step 3010 that has a relatively non-cirrhotic liver, such as when the patient has: a Fib-4 level of no more than 4; a Fib-4 level of at least 1.3, 2.0, and/or 2.5 (e.g. when the patient has NAFLD and/or NASH); an ALT level of at least 30, 35, and/or 40; an AST level of at least 25, 30, and/or 35; and combinations of one, two, or more of these.
In some embodiments, a female patient is selected in Step 3010 that has impaired ovarian function, such as a patient that has oligomenorrhea (e.g. menses with a cycle of at least 35 days) and/or amenorrhea (e.g. no menses for at least 6 months). In some embodiments, a male patient is selected in Step 3010 that has impaired testosterone levels and/or impaired sexual function (such as impotence).
In some embodiments, a patient is selected in Step 3010 that has insulin resistance, such as when the patient has: a triglyceride/HDL ratio of at least 1.65 and/or 2.75; a HOMA-IR level of at least 2.0, 2.5, and/or 3.0; a fasting insulin of at least 5 μU/mL, 7 μU/mL, and/or 10 μU/mL; and/or a fasting glucose of at least 100 mg/dL and/or 125 mg/dL.
In some embodiments, a patient is selected in Step 3010 that has liver disease, such as fatty liver disease or other liver disease diagnosed and/or prognosed via magnetic resonance (MR) imaging and/or ultrasound imaging. For example, magnetic resonance imaging can be used to determine a proton densitometry fat fraction (PDFF), also referred to as magnetic resonance fat fraction, where the patient is selected for treatment if their intra-hepatic triglyceride (IHTG) is at least 5%. Ultrasound imaging can be used to determine a hepato-renal index of echo levels (HRI), wherein the patient is selected for treatment if the HRI difference is at least 4.0 dB and/or the HRI ratio is no more than 1.0. A fibroscan (transient elastography) can be used to assess a patient for treatment. For example, a patient can be selected for treatment if their vibration controlled transient elastography is determined to be at least 6 kPa, or at least 8 kPa (e.g. when measured at 50 Hz). Alternatively or additionally, a patient can be selected for treatment if their controlled attenuation parameter (CAP), also referred to as ultrasound attenuation rate, is at least 200 dB/m or at least 250 dB/m.
In some embodiments, a patient is selected in Step 3010 that has a metabolic disease, such as a metabolic disease diagnosed and/or prognosed via metabolomics. For example, a patient can be selected for treatment if their level of 2-hydroxybutyrate is no more than 5 μg/mL.
In some embodiments, a patient is selected in Step 3010 that has post-bariatric hypoglycemia. For example, a post-bariatric surgery patient can be selected: if a post-prandial blood sugar level is determined by system 10 to be below 70 mg/dL, 60 mg/dL, and/or 50 mg/dL; if the patient has known hypoglycemia unawareness; and/or if the patient has documented history of severe hypoglycemia, such as one or more hypoglycemic events requiring third party assistance.
In some embodiments, a patient is selected in Step 3010 that has a hormonal defect, such as a patient with insufficient GLP-1 secretions (e.g. as determined by measuring circulating levels of these).
In Step 3020, one, two, or more locations within the pancreas is selected as a deposit site, such as one, two, or more locations within the head, body, tail, and/or uncinate process of the pancreas, and that location can be visualized by imaging such as endoscopic ultrasound (EUS), ultrasound, MRI, fluoroscopy, and/or computed tomography. Alternatively or additionally, a deposit site can be selected from the group consisting of: anterior, posterior, superior, and/or inferior pancreaticoduodenal arteries; inferior pancreatic artery; dorsal pancreatic artery; the great pancreatic artery; caudal pancreatic artery; common hepatic artery; splenic artery; other arteries feeding the pancreas; and combinations of these. The deposit site can be selected by visualizing the pancreas (e.g. with an EUS-based imaging device 90 and/or other imaging device of system 10), and selecting a deposit site that avoids ducts, arteries, and/or veins (e.g. avoids all of these). In some embodiments, an imaging device 90 is configured to perform doppler ultrasound imaging, such as doppler imaging that is used to identify locations of arteries and/or veins.
In Step 3030, an optional step is performed of pre-loading depositing element 650 of depositing device 600 with material 60. In some embodiments, the distal end of depositing element 650 is pre-loaded with material 60. In some embodiments, the dead space (e.g. internal volume) within depositing element 650 is sufficiently small such that pre-loading of depositing element 650 with material 60 is not performed prior to placing depositing element 650 in the pancreas.
In Step 3040, depositing element 650 is advanced into the selected pancreatic location under image guidance, without crossing a duct, artery or vein. This image-guided depositing device 650 placement can comprise one or more of: EUS-guided needle placement, CT-guided needle placement, and the like. If an EUS-guided placement is performed, the endoscope is first placed in the proper position in the stomach or duodenum, and depositing element 650 is advanced through the endoscope, through the wall of the stomach or duodenum, and into the pancreas to the desired treatment location.
In Step 3050, an optional step can be performed of injecting a visualization agent into the pancreas to confirm proper depositing device 600 location. The visualization agent can comprise saline, fluoroscopic contrast, CO2, and/or another agent visible via an imaging device. such as imaging device 90 described herein. If depositing element 650 is not in the desired location, it can be re-positioned. If this confirmatory step is performed, a sub-step of aspirating the visualization agent can then optionally be performed prior to continuing.
In Step 3060, material 60 (e.g. a gene therapy material such as a gene therapy vector and/or a gene editing vector, chemotherapy agent, saline, anti-pancreatitis agent, and/or other treatment agent) is injected via depositing element 650 into the pancreas, under image guidance, while maintaining pressure at or below a desired level, as described herebelow. In some embodiments, material 60 comprises a treatment agent comprising an oncolytic virus, a cell therapy, antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and/or messenger RNAs. The injected volume in this location can be at least 0.5 mL, 1 mL, or 2 mL. In some embodiments, the injected volume is sufficiently large such that some of material 60 escapes from the pancreas into the anterior pararenal space. In some embodiments, system 10 can be configured to prevent each delivery of material 60 from exceeding a maximum volume of material 60 delivery, such as a maximum volume of no more than 2.5 mL, no more than 5.0 mL, and/or no more than 10.0 mL. Material 60 can comprise a liquid, powder, and/or a biodegradable polymer designed to elute a treatment agent (e.g. a pharmaceutical) over a time period, such as at least 1 hour, 2 hours, 3 hours, 1 week, 2 weeks, 4 weeks, and/or 8 weeks. Material 60 can be configured to be visualized by imaging device 90 (e.g. mixed with ultrasound contrast and/or fluoroscopic contrast agent). In some embodiments, a tissue-disseminating agent, such as hyaluronidase collagenase, or the like, is injected (e.g. via depositing device 600) prior to and/or simultaneously with material 60. Alternatively or additionally, material 60 can be co-formulated with a tissue-disseminating and/or a dissociating agent such as hyaluronidase, collagenase, or the like, to improve the distribution of material 60 to the pancreas.
In some embodiments of Step 3060, pressure within the tissue can be maintained at or below interstitial pressure (e.g. at or below 0, 3, 5, and/or 8 mmHg), such as by adding and/or withdrawing fluid through the depositing device 600 (fluid such as material 60, a visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below interstitial pressure, or the pressure control can be pulsatile so that the average pressure remains below interstitial pressure.
In some embodiments of Step 3060, pressure within the tissue can be maintained above interstitial pressure (e.g. above 0, 3, 5, and/or 8 mmHg) and at or below capillary pressure (e.g. at or below 15, 20, or 25 mmHg), such as by adding and/or withdrawing fluid through depositing device 600 (fluid such as material 60, visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below capillary pressure, or pressure control can be pulsatile so that average pressure remains below capillary pressure. In some embodiments, Step 3060 can include controlling the flow rate of delivery, such as to control the flow rate to a rate of at least 0.1 mL/min, such as at least 0.3 mL/min, 0.5 mL/min, or 1 mL/min; and/or a flow rate of no more than 5 mL/min, such as no more than 2.5 mL/min or 1 mL/min.
In Step 3070, an optional step of withdrawing depositing element 650 from the pancreas, identifying a second pancreatic location for injection, and repeating the injection steps can be performed. The second pancreatic deposit site can be selected based on the avoidance of certain body locations and/or structures, such as to avoid ducts, arteries, and/or veins (e.g. as described hereabove in reference to the selection of the first deposit site in Step 3020). In some embodiments, multiple injections in additional locations can be performed in the same or a different manner. In some embodiments, a first injection is performed, after which depositing element 650 is partially withdrawn, then re-oriented, and then advanced to a second location in which a second injection is performed. The selected locations can be within the same portion of the pancreas (i.e. the head, body, tail, and/or uncinate process), or the locations can cover two or more portions of the pancreas. Spacing between deposit site locations for injection can be at least 0.5 cm, 1 cm, and/or 2 cm. Cumulative volume injected across all injections can be at least 5 mL, 10 mL, 20 mL, and/or 40 mL. The total number of injections can be at least 2, 5, 10, or 20 injections. In some embodiments, the total number of injections is at least 2, 3, 4 or 5 injections. In some embodiments, no more than 7 injections are performed, such as no more than 5, 3, and/or 1 injection are performed in the delivery of material 60 (e.g. to the pancreas or other tissue of the patient). In some embodiments, advancement of one or more depositing elements 650 (e.g. one or more needles) is along a trajectory to the target site, that avoids one or more anatomical locations of the patient, such as avoidance targets selected from the group consisting of: an artery; a vein; a chamber; a nerve; a duct; and combinations of these.
In some embodiments, optional Step 3080 is performed in which at least a portion of material 60 present within the lumen of the depositing element 650 after performance of Step 3060 is evacuated from the lumen (e.g. into the patient at a deposit site) via introduction of a flushing material into the lumen, such as is described hereinabove in reference to
After all material 60 deliveries are performed, appropriate devices are removed from the patient in Step 3090.
Referring now to
In Step 4010, a patient is selected. In some embodiments, the patient is selected to receive gene therapy of the pancreas. In some embodiments, the patient is selected to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas.
In some embodiments, in Step 4010 a patient is selected (e.g. a mammalian patient) with an HbA1c level of at least 6.5%, at least 7.0%, at least 7.5%, or at least 8%. In some embodiments, in Step 4010, a patient is selected that is obese, has a body mass index (BMI) of at least 30, has Type 2 diabetes, and has a HbA1c level above 7.0.
In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 1 of Type 1 diabetes, whereby stage 1 is defined as the presence of D-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 2 of Type 1 diabetes, whereby stage 2 is defined as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 3 of Type 1 diabetes, whereby stage 3 is defined as onset of symptomatic disease.
In some embodiments a patient is selected that has: cystic fibrosis; non-cystic-fibrosis; pancreatic exocrine insufficiency; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; pancreatic metastases; a partial pancreatectomy; and/or another disease of the pancreas.
In some embodiments, a patient is selected in Step 4010 that has a BMI of at least 30, 35, and/or 40.
In some embodiments, a patient is selected in Step 4010 that has a pancreas with a minimum level of functionality, such as when the patient has a C-Peptide level of at least 0.2, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of at least 7 μU/mL, 9 μU/mL, or 12 μU/mL. Alternatively or additionally, a patient is selected in Step 4010 with a C-Peptide level of less than 0.6, 0.8, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of less than 12 μU/mL, 14 μU/mL, or 16 μU/mL.
In some embodiments, a patient is selected in Step 4010 that has a relatively non-cirrhotic liver, such as when the patient has: a Fib-4 level of no more than 4; a Fib-4 level of at least 1.3, 2.0, and/or 2.5 (e.g. when the patient has NAFLD and/or NASH); an ALT level of at least 30, 35, and/or 40; an AST level of at least 25, 30, and/or 35; and combinations of one, two, or more of these.
In some embodiments, a female patient is selected in Step 4010 that has impaired ovarian function, such as a patient that has oligomenorrhea (e.g. menses with a cycle of at least 35 days) and/or amenorrhea (e.g. no menses for at least 6 months). In some embodiments, a male patient is selected in Step 4010 that has impaired testosterone levels and/or impaired sexual function (such as impotence).
In some embodiments, a patient is selected in Step 4010 that has insulin resistance, such as when the patient has: a triglyceride/HDL ratio of at least 1.65 and/or 2.75; a HOMA-IR level of at least 2.0, 2.5, and/or 3.0; a fasting insulin of at least 5 μU/mL, 7 μU/mL, and/or 10 μU/mL; and/or a fasting glucose of at least 100 mg/dL and/or 125 mg/dL.
In some embodiments, a patient is selected in Step 4010 that has liver disease, such as fatty liver disease or other liver disease diagnosed and/or prognosed via magnetic resonance (MR) imaging and/or ultrasound imaging. For example, magnetic resonance imaging can be used to determine a proton densitometry fat fraction (PDFF), also referred to as magnetic resonance fat fraction, where the patient is selected for treatment if their intra-hepatic triglyceride (IHTG) is at least 5%. Ultrasound imaging can be used to determine a hepato-renal index of echo levels (HRI), wherein the patient is selected for treatment if the HRI difference is at least 4.0 dB and/or the HRI ratio is no more than 1.0. A fibroscan (transient elastography) can be used to assess a patient for treatment. For example, a patient can be selected for treatment if their vibration controlled transient elastography is determined to be at least 6 kPa, or at least 8 kPa (e.g. when measured at 50 Hz). Alternatively or additionally, a patient can be selected for treatment if their controlled attenuation parameter (CAP), also referred to as ultrasound attenuation rate, is at least 200 dB/m or at least 250 dB/m.
In some embodiments, a patient is selected in Step 4010 that has a metabolic disease, such as a metabolic disease diagnosed and/or prognosed via metabolomics. For example, a patient can be selected for treatment if their level of 2-hydroxybutyrate is no more than 5 μg/mL.
In some embodiments, a patient is selected in Step 4010 that has post-bariatric hypoglycemia. For example, a post-bariatric surgery patient can be selected: if a post-prandial blood sugar level is determined by system 10 to be below 70 mg/dL, 60 mg/dL, and/or 50 mg/dL; if the patient has known hypoglycemia unawareness; and/or if the patient has documented history of severe hypoglycemia, such as one or more hypoglycemic events requiring third party assistance.
In some embodiments, a patient is selected in Step 4010 that has a hormonal defect, such as a patient with insufficient GLP-1 secretions (e.g. as determined by measuring circulating levels of these).
In Step 4020, a location in the anterior pararenal space (e.g. adjacent to the head, body, tail, and/or uncinate process of the pancreas) is selected as a deposit site, and that location is visualized by imaging such as endoscopic ultrasound (EUS), ultrasound, MRI, fluoroscopy, and/or computed tomography.
In Step 4030, an optional step is performed of pre-loading depositing element 650 of depositing device 600 with material 60. In some embodiments, the distal end of depositing element 650 is pre-loaded with material 60.
In Step 4040, depositing element 650 is advanced into the selected location in the anterior pararenal space under image guidance, such as to avoid injuring the pancreas. Such image-guided needle placement can comprise one or more of: ultrasound-guided needle placement (e.g. EUS-guided needle placement), CT-guided needle placement, and the like. If an EUS-guided placement is performed, the endoscope is first placed in the proper position in the stomach or duodenum, and depositing element 650 is advanced through the endoscope, through the wall of the stomach or duodenum, and into the anterior pararenal space to the desired treatment location.
In Step 4050, an optional step can be performed of injecting a visualization agent into the anterior pararenal space to confirm proper depositing device 600 location. The visualization agent can comprise saline, fluoroscopic contrast, CO2, and/or another agent visible via an imaging device, such as imaging device 90 described herein. If depositing element 650 is not in the desired location, it can be re-positioned. If this confirmatory step is performed, a sub-step of aspirating the visualization agent can then optionally be performed prior to continuing.
In Step 4060, an optional step can be performed of insufflating the anterior pararenal space, such as with CO2 or saline, to improve access to the exterior of the pancreas.
In Step 4070, an optional step can be performed of injecting a viscous filling agent into the lesser sac, such as to prevent a subsequent injection of material 60 from migrating into the lesser sac. In some embodiments, the viscous filling agent can comprise a visualizable agent (e.g. fluoroscopic contrast agent), or it can comprise a submucosal lifting agent, such as a lifting agent which biodegrades (e.g. Eleview, Orise, or other similar agent).
In Step 4080, an optional step can be performed of instilling a tissue-disseminating and/or a dissociating agent (e.g. hyaluronidase, collagenase, or the like) into the anterior pararenal space, such to improve the permeability of the pancreas prior to the subsequent delivery of material 60.
In Step 4090, material 60 (e.g. a gene therapy, chemotherapy agent, saline, anti-pancreatitis agent, and/or other treatment agent) is injected via depositing element 650 into the anterior pararenal space, under image guidance, such as while maintaining pressure at or below a desired level, as described herebelow. In some embodiments, material 60 comprises a treatment agent comprising an oncolytic virus, a cell therapy, antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and/or messenger RNAs. The injected volume in this location can be at least 0.5 mL, 1 mL, and/or 2 mL. In some embodiments, system 10 can be configured to prevent each delivery of material 60 from exceeding a maximum volume of material 60 delivery, such as a maximum volume of no more than 2.5 mL, no more than 5.0 mL, and/or no more than 10.0 mL. Material 60 can include a liquid, powder, and/or a biodegradable polymer designed to elute a treatment agent (e.g. a pharmaceutical) over a time period, such as a time period of at least 1 hour, 2 hours, 3 hours, 1 week, 2 weeks, 4 weeks, and/or 8 weeks. Material 60 can optionally be configured to be visualized by imaging device 90 (e.g. mixed with ultrasound contrast and/or fluoroscopic contrast agent). Material 60 can optionally be co-formulated with hyaluronidase to improve the distribution of material 60 to the pancreas, or hyaluronidase can be injected at the same time as material 60. In some embodiments, a tissue-disseminating agent, such as hyaluronidase collagenase, or the like, is injected prior to and/or simultaneously with material 60. Alternatively or additionally, material 60 can be co-formulated with a tissue-disseminating and/or a dissociating agent such as hyaluronidase, collagenase, or the like.
In some embodiments of Step 4090, pressure within the tissue can be maintained at or below interstitial pressure (e.g. at or below 0, 3, 5, and/or 8 mmHg) such as by adding and/or withdrawing fluid through depositing device 600 (fluid such as material 60, visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below interstitial pressure, or the pressure control can be pulsatile, and the average pressure can be maintained to remain below interstitial pressure. The pressure can be maintained in this manner for at least 1 minute, or at least 5, 10, 20 or 30 minutes.
In some embodiments of Step 4090, pressure within the tissue can be maintained above interstitial pressure (e.g. above 0, 3, 5, or 8 mmHg) and at or below capillary pressure (e.g. at or below 15, 20, or 25 mmHg), such as by adding and/or withdrawing fluid through depositing device 600 (fluid such as material 60, visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below capillary pressure, or pressure control can be pulsatile so that average pressure remains below capillary pressure. The pressure can be maintained in this manner for at least 1 minute, or at least 5, 10, 20 or 30 minutes.
In Step 4110, an optional step of withdrawing depositing element 650 from the first location in the anterior pararenal space, identifying a second location in the anterior pararenal space for another injection, and repeating the injection steps can be performed. In some embodiments, multiple injections in additional locations can be performed in the same manner. The selected locations can be adjacent to the same portion of the pancreas (e.g. adjacent to the head, body, tail, and/or uncinate process of the pancreas), or the location(s) can be adjacent to two or more portions of the pancreas. Spacing between deposit site locations for injection can be at least 0.5 cm, 1 cm, and/or 2 cm. Cumulative volume injected across all injections can be at least 5 mL, 10 mL, 20 mL, and/or 40 mL. The total number of injections can be less than 5, 7, 10 or 12 injections. In some embodiments, the total number of injections is at least 2, 3, 4 or 5 injections.
In Step 4120, an optional step of aspirating material 60 (e.g. aspirating at least 30%, 50%, and/or 70% of injected volume of material 60) is performed, such as to remove excess fluid. Aspiration can be performed from multiple locations (e.g. deposit locations and/or locations proximate deposit locations), as fluid may have spread from the site of the injection.
In Step 4120, if the lesser sac was filled in a previous step, an optional step can be performed of aspirating some or all of the filling agent from the lesser sac.
After delivery of material 60 to a deposit site, at least a portion of the material 60 that remains within the lumen of the depositing element 650 can be evacuated from the lumen (e.g. into the patient at the deposit site), such as via introduction of a flushing material into the lumen (e.g. as described hereinabove in reference to
Each component of system 10 that is advanced into the patient during the performance of method 4000 can be removed at an appropriate time after its use.
Referring now to
In Step 5010, a patient is selected. In some embodiments, the patient is selected to receive gene therapy of the pancreas. In some embodiments, the patient is selected to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas.
In some embodiments, in Step 5010 a patient is selected (e.g. a mammalian patient) with an HbA1c level of at least 6.5%, at least 7.0%, at least 7.5%, or at least 8%. In some embodiments, in Step 5010, a patient is selected that is obese, has a body mass index (BMI) of at least 30, has Type 2 diabetes, and has a HbA1c level above 7.0.
In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 1 of Type 1 diabetes, whereby stage 1 is defined as the presence of P-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 2 of Type 1 diabetes, whereby stage 2 is defined as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 3 of Type 1 diabetes, whereby stage 3 is defined as onset of symptomatic disease.
In some embodiments a patient is selected that has: cystic fibrosis; non-cystic-fibrosis; pancreatic exocrine insufficiency; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; pancreatic metastases; a partial pancreatectomy; and/or another disease of the pancreas.
In some embodiments, a patient is selected in Step 5010 that has a BMI of at least 30, 35, and/or 40.
In some embodiments, a patient is selected in Step 5010 that has a pancreas with a minimum level of functionality, such as when the patient has a C-Peptide level of at least 0.2, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of at least 7 μU/mL, 9 μU/mL, or 12 μU/mL. Alternatively or additionally, a patient is selected in Step 5010 with a C-Peptide level of less than 0.6, 0.8, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of less than 12 μU/mL, 14 μU/mL, or 16 μU/mL.
In some embodiments, a patient is selected in Step 5010 that has a relatively non-cirrhotic liver, such as when the patient has: a Fib-4 level of no more than 4; a Fib-4 level of at least 1.3, 2.0, and/or 2.5 (e.g. when the patient has NAFLD and/or NASH); an ALT level of at least 30, 35, and/or 40; an AST level of at least 25, 30, and/or 35; and combinations of one, two, or more of these.
In some embodiments, a female patient is selected in Step 5010 that has impaired ovarian function, such as a patient that has oligomenorrhea (e.g. menses with a cycle of at least 35 days) and/or amenorrhea (e.g. no menses for at least 6 months). In some embodiments, a male patient is selected in Step 5010 that has impaired testosterone levels and/or impaired sexual function (such as impotence).
In some embodiments, a patient is selected in Step 5010 that has insulin resistance, such as when the patient has: a triglyceride/HDL ratio of at least 1.65 and/or 2.75; a HOMA-IR level of at least 2.0, 2.5, and/or 3.0; a fasting insulin of at least 5 μU/mL, 7 μU/mL, and/or 10 μU/mL; and/or a fasting glucose of at least 100 mg/dL and/or 125 mg/dL.
In some embodiments, a patient is selected in Step 5010 that has liver disease, such as fatty liver disease or other liver disease diagnosed and/or prognosed via magnetic resonance (MR) imaging and/or ultrasound imaging. For example, magnetic resonance imaging can be used to determine a proton densitometry fat fraction (PDFF), also referred to as magnetic resonance fat fraction, where the patient is selected for treatment if their intra-hepatic triglyceride (IHTG) is at least 5%. Ultrasound imaging can be used to determine a hepato-renal index of echo levels (HRI), wherein the patient is selected for treatment if the HRI difference is at least 4.0 dB and/or the HRI ratio is no more than 1.0. A fibroscan (transient elastography) can be used to assess a patient for treatment. For example, a patient can be selected for treatment if their vibration controlled transient elastography is determined to be at least 6 kPa, or at least 8 kPa (e.g. when measured at 50 Hz). Alternatively or additionally, a patient can be selected for treatment if their controlled attenuation parameter (CAP), also referred to as ultrasound attenuation rate, is at least 200 dB/m or at least 250 dB/m.
In some embodiments, a patient is selected in Step 5010 that has a metabolic disease, such as a metabolic disease diagnosed and/or prognosed via metabolomics. For example, a patient can be selected for treatment if their level of 2-hydroxybutyrate is no more than 5 μg/mL.
In some embodiments, a patient is selected in Step 5010 that has post-bariatric hypoglycemia. For example, a post-bariatric surgery patient can be selected: if a post-prandial blood sugar level is determined by system 10 to be below 70 mg/dL, 60 mg/dL, and/or 50 mg/dL; if the patient has known hypoglycemia unawareness; and/or if the patient has documented history of severe hypoglycemia, such as one or more hypoglycemic events requiring third party assistance.
In some embodiments, a patient is selected in Step 5010 that has a hormonal defect, such as a patient with insufficient GLP-1 secretions (e.g. as determined by measuring circulating levels of these).
In Step 5020, an optional step is performed of pre-loading depositing device 600 with the treatment agent, material 60. In some embodiments, the distal end of device 600 is pre-loaded with material 60.
In Step 5030, a guidewire, such as a steerable guidewire, is advanced via an arterial puncture site (e.g. a femoral artery puncture site) into one of the arteries feeding the pancreas, such as the superior pancreaticoduodenal artery, inferior pancreaticoduodenal artery, gastroduodenal artery, superior mesenteric artery, celiac artery, hepatic artery, splenic artery, common hepatic artery, and/or gastroduodenal artery (GDA).
In Step 5040, depositing device 600 is delivered over the guidewire into the artery.
In Step 5050, material 60 is injected through depositing device 600 into the artery. The agent can be injected slowly, such as a delivery over a time period of at least 30 seconds, 1 minute, 2 minutes, and/or 5 minutes. Material 60 can comprise one or more materials, such as those that are described in reference to
In Step 5060, an optional step is performed where depositing device 600 and guidewire (if present) are withdrawn into the aorta, and the guidewire is then advanced into a second artery feeding a different portion of the pancreas. Device 600 is then re-delivered over the guidewire, and additional material 60 is injected through device 600, in the same manner as the first injection.
After delivery of material 60 to a deposit site, at least a portion of the material 60 that remains within the lumen of the depositing element 650 can be evacuated from the lumen (e.g. into the patient at the deposit site), such as via introduction of a flushing material into the lumen (e.g. as described hereinabove in reference to
In Step 5070, depositing device 600 and guidewire (if present), and other associated system 10 devices, are withdrawn from the body and the puncture site is closed in the usual manner.
Referring now to
In Step 6010, a patient is selected. In some embodiments, the patient is selected to receive gene therapy of the liver. In some embodiments, the patient is selected to receive cell therapy, such as the instillation of pancreatic islets. In some embodiments, the pancreatic islets have been genetically transduced prior to instillation to improve secretory function. In some embodiments, the patient is selected to receive an intravenous infusion agent for the treatment of a liver condition, such as when the patient is selected to receive one or more anti-cancer agents, such as an immunotherapeutic agent or chemotherapeutic agent. In some embodiments, the patient is selected to receive an agent to treat acute pancreatitis, such as an anti-cytokine agent, an anti-inflammatory agent, or other agents.
In some embodiments, in Step 6010 a patient is selected (e.g. a mammalian patient) with an HbA1c level of at least 6.5%, at least 7.0%, at least 7.5%, or at least 8%. In some embodiments, in Step 6010, a patient is selected that is obese, has a body mass index (BMI) of at least 30, has Type 2 diabetes, and has a HbA1c level above 7.0. In some embodiments, a patient is selected who has had a pancreatectomy for chronic pancreatitis. In some embodiments a patient is selected who has hepatocellular carcinoma. In some embodiments, the patient is selected to treat: Type 1 or Type 2 diabetes, other forms of diabetes; NAFLD/NASH; obesity; Alzheimer's disease; acute or chronic pancreatitis; pancreatic cancer; pancreatic metastases; cystic fibrosis; exocrine pancreatic insufficiency; partial pancreatectomy; hyperinsulinemia; hyperglucagonemia; and/or another disease or disorder of the pancreas.
In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 1 of Type 1 diabetes, whereby stage 1 is defined as the presence of P-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 2 of Type 1 diabetes, whereby stage 2 is defined as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic. In some embodiments, a patient is selected that has Type 1 diabetes, such as a patient that has stage 3 of Type 1 diabetes, whereby stage 3 is defined as onset of symptomatic disease.
In some embodiments a patient is selected that has: cystic fibrosis; non-cystic-fibrosis; pancreatic exocrine insufficiency; chronic hyperinsulinemia; chronic pancreatitis; a pancreatic cancer; pancreatic metastases; a partial pancreatectomy; and/or another disease of the pancreas.
In some embodiments, a patient is selected in Step 6010 that has a BMI of at least 30, 35, and/or 40 Kg/m 2.
In some embodiments, a patient is selected in Step 6010 that has a pancreas with a minimum level of functionality, such as when the patient has a C-Peptide level of at least 0.2, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of at least 7 μU/mL, 9 μU/mL, or 12 μU/mL. Alternatively or additionally, a patient is selected in Step 6010 with a C-Peptide level of less than 0.6, 0.8, 1.0, and/or 2.0 (nM or nmol/l) and/or a fasting insulin of less than 12 μU/mL, 14 μU/mL, or 16 μU/mL.
In some embodiments, a patient is selected in Step 6010 that has a relatively non-cirrhotic liver, such as when the patient has: a Fib-4 level of no more than 4; a Fib-4 level of at least 1.3, 2.0, and/or 2.5 (e.g. when the patient has NAFLD and/or NASH); an ALT level of at least 30, 35, and/or 40; an AST level of at least 25, 30, and/or 35; a creatinine clearance rate of greater than at least 40 mL/min; a serum creatinine level of no more than 1.5 mg/dL; a urine volume of at least 500 mL/day; a urine sodium level of at least 10 mEq/L; absence of portal hypertension; absence of ascites; and combinations of one, two, or more of these.
In some embodiments, a female patient is selected in Step 6010 that has impaired ovarian function, such as a patient that has oligomenorrhea (e.g. menses with a cycle of at least 35 days) and/or amenorrhea (e.g. no menses for at least 6 months). In some embodiments, a male patient is selected in Step 6010 that has impaired testosterone levels and/or impaired sexual function (such as impotence).
In some embodiments, a patient is selected in Step 6010 that has insulin resistance, such as when the patient has: a triglyceride/HDL ratio of at least 1.65 and/or 2.75; a HOMA-IR level of at least 2.0, 2.5, and/or 3.0; a fasting insulin of at least 5 μU/mL, 7 μU/mL, and/or 10 μU/mL; and/or a fasting glucose of at least 100 mg/dL and/or 125 mg/dL.
In some embodiments, a patient is selected in Step 6010 that has liver disease, such as fatty liver disease or other liver disease diagnosed and/or prognosed via magnetic resonance (MR) imaging and/or ultrasound imaging. For example, magnetic resonance imaging can be used to determine a proton densitometry fat fraction (PDFF), also referred to as magnetic resonance fat fraction, where the patient is selected for treatment if their intra-hepatic triglyceride (IHTG) is at least 5%. Ultrasound imaging can be used to determine a hepato-renal index of echo levels (HRI), wherein the patient is selected for treatment if the HRI difference is at least 4.0 dB and/or the HRI ratio is no more than 1.0. A fibroscan (transient elastography) can be used to assess a patient for treatment. For example, a patient can be selected for treatment if their vibration controlled transient elastography is determined to be at least 6 kPa, or at least 8 kPa (e.g. when measured at 50 Hz). Alternatively or additionally, a patient can be selected for treatment if their controlled attenuation parameter (CAP), also referred to as ultrasound attenuation rate, is at least 200 dB/m or at least 250 dB/m.
In some embodiments, a patient is selected in Step 6010 that has a metabolic disease, such as a metabolic disease diagnosed and/or prognosed via metabolomics. For example, a patient can be selected for treatment if their level of 2-hydroxybutyrate is no more than 5 μg/mL.
In some embodiments, a patient is selected in Step 6010 that has post-bariatric hypoglycemia. For example, a post-bariatric surgery patient can be selected: if a post-prandial blood sugar level is determined by system 10 to be below 70 mg/dL, 60 mg/dL, and/or 50 mg/dL; if the patient has known hypoglycemia unawareness; and/or if the patient has documented history of severe hypoglycemia, such as one or more hypoglycemic events requiring third party assistance.
In some embodiments, a patient is selected in Step 6010 that has a hormonal defect, such as a patient with insufficient GLP-1, PPY, oxyntomodulin, glucagon, or insulin secretions (e.g. as determined by measuring circulating levels of these).
In Step 6020, one, two, or more locations within the hepatic portal venous system is selected as a deposit site, such as one, two, or more locations within the hepatic portal vein, splenic vein, superior mesenteric vein, inferior mesenteric vein, or the tributaries that lead to any of these veins (gastrocolic trunk, first jejuna vein, left gastric vein, posterior superior pancreatic-duodenal vein, left gastro-epiploic vein, the short gastric vein, and the posterior pancreatic veins), and that location can be visualized by imaging such as endoscopic ultrasound (EUS), ultrasound, MRI, fluoroscopy, and/or computed tomography.
In Step 6030, an optional step is performed of pre-loading a depositing element 650 of depositing device 600 with material 60. In some embodiments, depositing element 650 is pre-loaded from its distal end (e.g. when material 60 is drawn into depositing element 650 from its distal end).
In Step 6040, depositing element 650 is advanced into the selected venous system location under image guidance. This image-guided depositing element 650 placement can comprise one or more of: ultrasound-guided needle placement (e.g. EUS-guided needle placement), CT-guided needle placement, and the like. If an EUS-guided placement is performed, the endoscope is first placed in the proper position in the stomach or duodenum, and depositing element 650 is advanced through the endoscope, through the wall of the stomach or duodenum, and into the desired treatment location.
In Step 6050, an optional step can be performed of injecting a visualization agent through depositing element 650 to confirm proper depositing device 600 location. The visualization agent can comprise saline, ultrasonic contrast, fluoroscopic contrast, CO2, and/or another agent visible via an imaging device, such as imaging device 90 described herein. If depositing element 650 is not in the desired location, it can be re-positioned.
In Step 6060, material 60 (e.g. a gene therapy material such as a gene therapy vector and/or a gene editing vector, chemotherapy agent, immunotherapy agent, saline, anti-pancreatitis agent, and/or other treatment agent) is injected via depositing element 650 into the selected location in the portal venous system, under image guidance, while maintaining pressure at or below a desired level, as described herebelow. In some embodiments, material 60 comprises a treatment agent comprising an oncolytic virus, a cell therapy, antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and/or messenger RNAs. The injected volume in this location can be at least 10 mL, 15 mL, or 50 mL. In some embodiments, system 10 can be configured to prevent each delivery of material 60 from exceeding a maximum volume of material 60 delivery, such as a maximum volume of no more than 2.5 mL, no more than 5.0 mL, and/or no more than 10.0 mL. Material 60 can comprise a liquid, powder, and/or a biodegradable polymer designed to elute a treatment agent (e.g. a pharmaceutical) over a time period, such as at least 1 hour, 2 hours, 3 hours, 1 week, 2 weeks, 4 weeks, and/or 8 weeks. Material 60 can be configured to be visualized by imaging device 90 (e.g. mixed with ultrasound contrast and/or fluoroscopic contrast agent).
In some embodiments of Step 6060, pressure can be maintained at or below hepatic arterial pressure (e.g. at or below 60, 80, and/or 100 mmHg), such as by adding and/or withdrawing fluid through depositing device 600 (fluid such as material 60, a visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below interstitial pressure, or the pressure control can be pulsatile so that the average pressure remains below hepatic arterial pressure.
In some embodiments of Step 6060, pressure can be maintained above minimal venous pressure (e.g. above 5, 7 or 9 mmHg) and/or at or below a maximum portal venous pressure (e.g. at or below 10, 12 or 14 mmHg), such as by controlling the rate of fluid flow through depositing device 600 (fluid such as material 60, visualization agent, saline, and/or other diluent), or optionally by using a computer-controlled device (e.g. a pumping assembly of console 200) attached to the proximal end of device 600. In this configuration, the maximum pressure can be maintained below maximum portal venous pressure, or pressure control can be pulsatile so that average pressure remains below maximum portal venous pressure.
After delivery of material 60 to a deposit site, at least a portion of the material 60 that remains within the lumen of the depositing element 650 can be evacuated from the lumen (e.g. into the patient at the deposit site), such as via introduction of a flushing material into the lumen (e.g. as described hereinabove in reference to
Each component of system 10 that is advanced into the patient during the performance of method 6000 can be removed at an appropriate time after its use.
Referring now to
Depositing device 6001 can include depositing element 650, comprising a single lumen needle including lumen 655 that is operably attached (e.g. at least fluidly attached) to the distal ends of both lumens 6011a and 6011b. Depositing element 650 can comprise a needle with a gauge of as large as 19G, and/or as small as 25G. Depositing element 650 can comprise the same outer diameter as shaft 6010, or it can comprise a different (e.g. smaller) outer diameter than shaft 6010. Depositing element 650 and at least a distal portion of shaft 6010 can comprise an outer diameter of no greater than 2.2 mm, 2.8 mm, and/or 3.8 mm, such that at least the distal portion of depositing device 6001 can be slidingly received within a working channel of an access device 50 described herein (e.g. an endoscope). In some embodiments, depositing element 650 is fixedly attached to shaft 6010 of device 6001 (e.g. fixedly attached during a manufacturing process of device 6001). Alternatively, depositing element 650 can be removably attached and/or removably attachable (“removably attached” or “removably attachable” herein) to shaft 6010 (e.g. when depositing element 650 is attached to shaft 6010 by the operator prior to insertion into a patient). In some embodiments, depositing element 650 comprises a sealed distal end with one or more openings to lumen 655 along its length (e.g. as described in reference to
In some embodiments, the proximal portion of shaft 6010 is bifurcated into a Y-shape, with the proximal portions of lumens 6011a and 6011b each extending through a unique portion of the bifurcation, as shown.
In some embodiments, depositing device 6001 includes one or more functional elements, functional element 699 shown. Functional element 699 can be positioned on a distal portion of device 6001, such as when positioned on depositing element 650. Functional element 699 can comprise a sensor configured to detect when depositing element 650 is in contact with tissue, such as an impedance and/or a pressure sensor. In some embodiments, a functional element 699 comprising a sensor is positioned proximal to the distal tip of depositing element 650, such as between 2 mm and 10 mm from the distal tip. Functional element 699 can transmit signals to console 200 (not shown but described herein) indicating when depositing element has been inserted into a deposit site (e.g. inserted an appropriate distance into the pancreas, such as 2 mm to 10 mm into the pancreas). In some embodiments, functional element 699 comprises a sensor configured to measure the electrical properties of the tissue surrounding depositing element 650, such as the conductivity and/or the resistivity of the tissue. Functional element 699 can comprise a sensor selected from the group consisting of: a pH sensor; physiologic sensor; blood glucose sensor; blood gas sensor; blood sensor; respiration sensor; EKG sensor; EEG sensor; neuronal activity sensor; blood pressure sensor; flow sensor, such as a flow rate sensor; volume sensor; pressure sensor; force sensor; sound sensor, such as an ultrasound sensor; electromagnetic sensor, such as an electromagnetic field sensor or an electrode; gas bubble detector, such as an ultrasonic gas bubble detector; strain gauge; magnetic sensor; ultrasonic sensor; optical sensor, such as a light sensor; chemical sensor; visual sensor, such as a camera; temperature sensor, such as a thermocouple, thermistor, resistance temperature detector, or optical temperature sensor; impedance sensor, such as a tissue impedance sensor; and combinations of two or more of these. In some embodiments, functional element is configured to detect a pH, such as to identify tissue based on pH data. For example, a particular deposit site can be identified based on pH within a range indicative of that deposit site, such as a pH between 7.5 and 8 that is indicative of the fluids present within the pancreas. In some embodiments, functional element 699 is configured to detect a temperature indicative of a particular deposit site, and/or to detect a change in temperature indicative of leaving one location and entering a deposit site, for example a change in temperature indicative of leaving interstitial space and/or a first organ, and entering a second organ (e.g. the pancreas). In some embodiments, a positive signal from functional element 699 (e.g. a signal indicating depositing element 650 is properly inserted into a deposit site, such as pancreatic tissue) could be required by system 10 to allow the initiation of a depositing procedure (e.g. a “go/no go” signal required to be “go” to perform an injection). In some embodiments, functional element 699 comprises a flexible circuit board wrapped at least partially circumferentially around depositing element 650. In some embodiments, depositing element 650 comprises a recess, such as a laser etched recess within which at least a portion of functional element 699 is positioned. In some embodiments, functional element 699 comprises a pressure sensor configured to record pressure information of a fluid pathway in which material 60 passes through and/or from which material 60 is delivered.(e.g. a fluid pathway of depositing element 650).
System 10 can include one or more syringe drivers 40, such as drivers 40a and 40b shown. Drivers 40a,b can operably attach to device 6001, such as to actuate plungers 6012a and 6012b, respectively. In some embodiments, drivers 40a,b comprise computer-controlled (e.g. via console 200) motorized drivers that are configured to actuate plungers 6012a,b.
Referring now to
Device 6002 can include a flexible conduit, trocar 6550 shown, that slidingly receives catheter 6501. Trocar 6550 can be configured to be slidingly received within a working channel of an access device (e.g. access device 50, not shown), such as when received by a working channel that is less than 4.2 mm in diameter, such as less than 3.8 mm in diameter. Trocar 6550 can comprise a handle, handle 6551 shown. In some embodiments, catheter 6510 comprises a handle, handle 6512, also shown. Trocar 6550 and/or catheter 6510 can be manually advanced and/or retracted (e.g. via handles 6551 and/or 6512, respectively) relative to each other and/or relative to an access device 50 (not shown), such as an endoscope. Alternatively or additionally, system 10 can comprise one or more actuators, such as one or more actuators configured to operably attach to handle 6551, handle 6512, and or the handle of an endoscope to advance and/or retract catheter 6510, trocar 6550, and/or an access device 50.
In some embodiments, the proximal portion of catheter 6510 is bifurcated into a Y-shape, with the proximal portions of lumens 655a and 655b each extending through a unique portion of the bifurcation, as shown.
System 10 can include one or more syringes 610, such as syringes 610a and 610b shown. Syringes 610a and 610b can each operably attach to the proximal ends of lumens 655a and 655b, respectively. System 10 can include one or more syringe drivers 40, such as drivers 40a and 40b shown. Drivers 40a,b can operably attach to syringes 610a and 610b, respectively. In some embodiments, drivers 40a,b comprise computer-controlled (e.g. via console 200) motorized drivers configured to actuate plungers of syringes 610a,b. Syringe 610a can be configured to inject a first material (e.g. flush 64 shown) through a first lumen of catheter 6510 (e.g. lumen 655a shown). Syringe 610b can be configured to inject a second material (e.g. material 60 shown) through a second lumen of catheter 6510 (e.g. lumen 655b shown). Alternatively, catheter 6510 can comprise a single lumen catheter, and one or more syringes can be configured to attach (e.g. one at a time) to the proximal end of the lumen (e.g. to inject one or more material through the lumen into the patient). In some embodiments, device 6002 comprises an elongate plunger, such as a plunger configured to be positioned within a lumen of catheter 6510, which can be similar to plunger 6012b described herein in reference to
In some embodiments, depositing device 6002 includes one or more functional elements, functional element 699 shown. Functional element 699 can be positioned on a distal portion of device 6001, such as on a distal portion of trocar 6550 or catheter 6510 (as shown). Functional element 699 can comprise a sensor configured to detect when a portion of device 6002 is in contact with tissue, such as an impedance and/or a pressure sensor. In some embodiments, functional element 699 comprises a marker positioned on depositing element 650, such as a radiopaque or other marker configured to indicate a distance from the distal end of depositing element 650 and/or a distance from the most proximal opening along the length of depositing element 650 (e.g. openings 6503 described immediately herebelow). A functional element 699 comprising a marker can be positioned less than 1.5 cm, 1.0 cm, and/or 0.5 cm from the distal end and/or most proximal opening of depositing element 650. The marker can comprise a high-density material (e.g. higher density than depositing element 650), a radiopaque material, and/or a surface modification to depositing element 650, such as a surface comprising micro-dimples, micro-ridges, and/or other surface contours, or a surface modification created used bead blasting and/or sand blasting. Material such as gold or platinum can be sputtered onto depositing element 650 to form the marker.
Referring now to
Device 6003 can comprise drive assembly 6020, which can include plunger 6021, pneumatic fluid 6022, and a translating element, plug 6023, each as shown. Plug 6023 and plunger 6021 can be slidingly received within a lumen, lumen 6521 shown, of syringe 6520, creating a sealed chamber therebetween, chamber 6024. The chamber 6024 is filled with pneumatic fluid 6022, operably joining plunger 6021 to plug 6023. When plunger 6021 is advanced and/or retracted within syringe 6520, plug 6023 advances and/or retracts in unison due to the pneumatic force imparted via pneumatic fluid 6022. Plug 6023 can be advanced and/or retracted (e.g. via plunger 6021) to push material 60 from syringe 6520 and/or draw material 60 into syringe 6520, respectively. In some embodiments, device 6003 comprises a second syringe, not shown, but operably attached (e.g. at least fluidly attached) via a removable umbilical to chamber 6024 (e.g. when chamber 6024 comprises the sealed proximal portion of syringe 6520). The second syringe can be filled with pneumatic fluid 6022 and it can be configured to pneumatically advance and/or retract plug 6023 similar to plunger 6021 shown. In some embodiments, plunger 6021 and/or the second syringe are driven by a syringe driver, such as a syringe driver as described herein.
Referring now to
Needles 6530 can be advanced and/or retracted relative to shaft 6010. For example, needles 6530 can be advanced from shaft 6010 and inserted into patient tissue, for example into pancreatic tissue as shown in
Referring additionally to
Device 6004 can comprise drive assembly 6020, which can be similar to drive assembly 6020 described in reference to
As shown in
As shown in
Referring now to
Syringe 6101 can comprise multiple plungers, such as plungers 616a and 616b shown, that are each slidingly received within a chamber, chambers 615a and 615b respectively. In some embodiments, plungers 616a and 616b are uniquely marked (e.g. labeled) to indicate to the operator which chamber holds material 60 and which chamber holds flush 64, for example, the plungers could be different colors that indicate to the operator the contents of the chambers. During a clinical procedure, material 60 can be injected first (e.g. via depression of plunger 616a), followed by injection of flush 64 (e.g. via depression of plunger 616b). Flush 64 can force material 60 from the dead space of depositing device 600, limiting the volume of material 60 that is not fully injected into the patient. For example, syringe 6101 can be configured to inject at least 90% of material 60 into the patient by displacing material 60 from the dead space via injection of flush 64. Alternatively or additionally, flush 64 can be used to prime (e.g. fill dead space of) depositing device 600 prior to injection of material 60.
In some embodiments syringe 6101 includes one or more locking mechanism, pins 617a,b shown, that prevent the depression of plungers 616a and 616b, respectively. Pins 617a,b can be disengaged (e.g. removed) to allow plungers 616a,b, respectively, to be depressed. In some embodiments, pins 617a,b can interact with each other and/or with plungers 616a and/or 616b, such that the pins can only be disengaged in a predetermined order, for example such that pin 617b cannot be removed unless plunger 616a has been at least partially depressed. In some embodiments, syringe 6101 includes a sealing element, cap 618 shown. Cap 618 can be constructed and arranged to seal both of chambers 615a,b, preventing mixing of material 60 and flush 64 while cap 618 is in place. In some embodiments, syringe 6101 operably attaches to a syringe driver (not shown, but such as is described herein) that is configured to drive each plunger 616a,b independently.
In some embodiments, syringe 6101 includes a single output pathway, tip 619, which can be configured to attach to depositing device 600. Each chamber 615a,b can be operably attached (e.g. at least fluidly attached) to tip 619 (when cap 618 is removed, as shown). Alternatively, syringe 6101 can comprise multiple tips 619, such as a tip 619a that is operably attached (e.g. at least fluidly attached) to chamber 615a, and a tip 619b that is operably attached (e.g. at least fluidly attached) to chamber 615b. In these embodiments, syringe 6101 can be configured to operably attached (e.g. at least fluidly attach) to a depositing device 600 comprising multiple syringe inputs, such as multiple syringe inputs that merge via a Y-shaped manifold into a single lumen.
Referring now to
Referring now to
In some embodiments, lumen 6011 can comprise one or more inward protrusions, stops 6013a,b shown, that prevent depositing element 650 from advancing beyond a set distance from device 6005, this advancement limit representing the maximum depositing element 650 penetration depth, depth D1 shown. For example, stops 6013a,b can interfere with a projection (e.g. a radial projection), lip 6502, extending from depositing element 650. Stops 6013a,b, can be positioned at the distal ends of lumen 6011, and lip 6502 can be positioned approximately a distance D1 (e.g. less the thickness of stops 6013a,b and/or lip 6502) from the distal end of depositing element 650. In some embodiments, distance D1, comprises a distance of no more than 3 cm, such as no more than 2 cm, 1 cm, or 0.5 cm. In some embodiments, distance D1 is selected to allow a maximum penetration depth beyond the stomach wall (e.g. when depositing element 650 is positioned through the stomach wall into the anterior pararenal space).
Referring now to
Assembly 6050 can include a ring, stopper 6054, which can be slidingly received on the top portion of hub 6051, and stopper 6054 can be adjustable, such as to adjust the distal-most allowable position of cap 6052 (and as such depositing element 650) relative to hub 6051. Stopper 6054 can be temporarily affixed to hub 6051, such as via a fixation element, set screw 6055 shown. In some embodiments, assembly 6050 is constructed and arranged such that cap 6052 is prevented from unintentionally moving proximally (e.g. after distal advancement) along hub 6051. Assembly 6050 can include a motion resisting element, lock 6057. In some embodiments, lock 6057 comprises a set of magnets (shown) positioned on the distal end of cap 6052 and stopper 6054, such that when cap 6052 is fully advanced (distally advanced), the magnets of lock 6057 prevent cap 6052 from retracting proximally without sufficient force being applied (e.g. by the operator) to retract cap 6052 (e.g. to overcome the magnetic force). Alternatively or additionally, lock 6057 can comprise a thumb screw configured to lock cap 6052 in an advanced position. In other embodiments, lock 6052 can comprise a ratcheting mechanism, where the ratcheting mechanism can be configured to allow advancement of cap 6057, but to prevent retraction without releasing the ratchet mechanism. In some embodiments, lock 6052 comprises a spring-loaded locking mechanism, such as a locking mechanism that prevents (or at least limits) motion of cap 6052 relative to hub 6051 in either and/or both directions unless the locking mechanism is actively released (e.g. an operator overcomes the spring force to temporarily release the lock). In some embodiments, lock 6052 provides sufficient locking force to maintain the position of cap 6052 when 6050 is held in an upside-down position.
Cap 6053 can be slidingly positioned on the bottom portion of hub 6051 (as shown), and it can slidingly receive shaft 6010, which is attached to the distal end of hub 6051. The proximal end of access device 50 (e.g. an endoscope) can operably engage cap 6053, for example via a threaded engagement, such that shaft 6010 moves relative to access device 50 (e.g. within a working channel of an endoscope) as cap 6053 moves relative to hub 6051. Cap 6053 can be temporarily affixed to hub 6051, such as via a fixation element, set screw 6056 shown.
Referring specifically to
In some embodiments, depositing device 6006 includes stylet 651 shown, which can be slidingly received within depositing element 650, for example prior to insertion of depositing element 650 into tissue. After insertion into tissue, stylet 651 can be removed to allow a material (e.g. material 60) to be injected into the patient via depositing element 650. Stylet 651 can prevent or at least limit undesired material (e.g. tissue) from entering the lumen of depositing element 650, such as while element 650 is advanced through the patient (e.g. through patient tissue). Alternatively or additionally, depositing element 650 can be primed (e.g. filled with material, such as flush 64) prior to insertion of depositing element 650 into the patient. Flush 64 can be maintained within the lumen of element 650 during insertion, preventing or at least limiting undesired material from entering the lumen of depositing element 650. In some embodiments, depositing element 650 comprises a super-elastic and/or a shape memory material such as a nickel-titanium alloy or a cobalt-chromium alloy.
Referring specifically to
Referring now to
Referring now to
Referring now to
Referring now to
Referring now to
Referring now to
In some embodiments, prior to insertion into a patient, lumen 6011a is filled with a material (e.g. flush 64) and lumen 6011b slidingly receives stylet 651. After insertion, to prevent or at least limit undesired material (e.g. tissue) from being drawn into depositing element 650, additional material (e.g. flush 64 or material 60) can be injected into lumen 6011a while stylet 651 is retracted from lumen 6011b (e.g. to relieve any vacuum pressure created during the removal of stylet 651). In some embodiments, the vacuum created by the removal of stylet 651 can be used advantageously, for example by drawing a priming material (e.g. flush 64) in a proximal direction into lumen 6011b, while material 60 is injected into lumen 6011a. In these embodiments, the volume of priming material injected into the patient prior to material 60 can be minimized. In some embodiments, stylet 651 includes a distal portion configured to seal with the inner walls of lumen 6011a to increase the vacuum pressure created when stylet 651 is retracted.
Referring now to
Depositing device 600 can comprise depositing element 650. Depositing element 650 can comprise a multi-part construction, such as a two-part construction comprising a distal portion, tip 6504, and a proximal portion, shaft 6506. Shaft 6506 can comprise lumen 6507 therethrough. Tip 6504 can comprise lumen 6505 therethrough. In some embodiments, shaft 6506 comprises a silica needle shaft, such as a shaft configured as a fused silica capillary tube. In some embodiments, shaft 6506 comprises fused silica lined with PEEK tubing. Silica tubing can comprise a smooth surface (e.g. smoother than a standard stainless steel needle), to which material 60 is less likely to stick, and which would provide less fluid resistance than other materials, such as stainless steel or other metal materials. In some embodiments, tip 6504 comprises a stainless steel needle fixedly attached to the distal end of shaft 6506. In some embodiments, depositing element 650 comprises an adapter (not shown) configured to attach tip 6504 to shaft 6506.
Referring additionally to
Referring additionally to
Referring now to
Syringe adapter 2350 can include a second syringe 2351 and a third syringe 2352, which can be positioned “back-to-back” with each other as shown. A second plunger, plunger 2353 can be positioned between syringes 2351 and 2352 as shown. In some embodiments, second plunger 2353 comprises two separate elongate members that are mechanically fixed to each other (e.g. via a clip), where the fixation allows both delivery of material 60 from third syringe 2352 as well as filling of third syringe 2352. In some embodiments, the two separate elongate members are not mechanically fixed to each other, such that only delivery of material 60 from third syringe 2352 can be performed (e.g. push only). Drive 2300 can comprise hydraulic fluid 2304, positioned within a closed hydraulic system between syringe 2301, tube 2303, and syringe 2351. Plunger 2353 can be configured to actuate within syringe 2351 as fluid 2304 is manipulated within the hydraulic system by plunger 2302 (e.g. as plunger 2302 drives fluid 2304 through tube 2303 into syringe 2351, plunger 2353 is driven through syringe 2351, into syringe 2352). As plunger 2353 is driven into and/or retracted from syringe 2352, material 60 can be delivered from and/or drawn into syringe 2352, respectively (e.g. via depositing element 650 operably attached (e.g. at least fluidly attached) to syringe 2352). In some embodiments, syringes 2301, 2351, and 2352 can comprise different size syringes (e.g. different diameter syringes), such as to provide a hydraulic advantage.
In some embodiments, syringe drive 2300 and/or linear drive 2400 can comprise a load cell, and the load cell can be configured to monitor the pressure being applied to the syringe containing material 60 (syringes 2352 or 2451, respectively), such as to measure, monitor, control, and/or limit the pressure in which material 60 is delivered to a deposit site.
Referring now to
Referring additionally to
Referring now to
Depositing device 600 can be operably attached (e.g. at least fluidly attached) to depositing element 650, such as is described herein. In some embodiments, syringe adapter 2350 is removably attached to depositing device 600 such that the distal end of syringe 2352 is positioned upward (relative to the page), opposite the distal end of depositing device 600. Syringe adaptor 2350 can comprise a fluid connector, tube 2355 shown, that fluidly connects syringe 2352 to depositing element 650 (e.g. via depositing device 600). Tube 2355 can be configured to redirect flow (e.g. approximately 180°) from syringe 2352 into depositing device 600. In some embodiments, tube 2355 comprises a length of no more than 10 cm, such as no more than 8 cm. In some embodiments, tube 2355 includes a fluid control element, valve 2356 shown. Valve 2356 can allow the operator to control (e.g. prevent or allow) the flow of fluid (e.g. material 60) into depositing element 650. Valve 2356 can be used to prevent or at least limit leakage or other egress (“leakage” or “egress” herein) of fluid from depositing element 650 (e.g. after depositing element 650 is primed as described herein), and/or to prevent accidental injection of material 60 via depositing element 650 into the patient. In some embodiments, tube 2355 includes one or more connectors, two connectors 2359a,b shown, that operably attach to syringe 2352 and depositing device 600 (connectors 2359a and 2359b, respectively). In some embodiments, one or more of connectors 2359 comprise self-sealing connectors (e.g. connectors that comprise one or more valves and/or sealing elements) that prevent or at least limit flow through the connector when a mating connector is not attached (e.g. a self-sealing luer type connector that is sealed while a mating luer connector, such as that on the end of a syringe, is not connected), such as to prevent material 60 from undesirably exiting device 600.
In some embodiments, syringe adaptor 2350 comprises one or more operator controls, switch 2357 shown. Switch 2357 can be operably (e.g. electrically) connected to a syringe drive of console 200 (not shown but described herein) via a conduit including one or more wires, wire 2358 shown. Switch 2357 can be configured to allow the operator to start and/or stop injection via depositing element 650 by starting and/or stopping the operation of the syringe drive (e.g. via a control signal and/or by supplying and/or interrupting power to the drive). In some embodiments, a syringe drive of console 200 comprises an electromagnetic drive mechanism (e.g. a mechanism including a solenoid) configured to drive and/or retract a plunger into a syringe. Switch 2357 can be operably connected to activate the electromagnetic drive mechanism. Alternatively or additionally, switch 2357 can provide a signal to a controller (e.g. processing unit 210 not shown but described herein), such that the controller can activate the electromagnetic drive mechanism in response to the signal from switch 2357.
Referring now to
Syringe drive assembly 2500 can comprise a set of components configured to enable an operator of system 10 to remotely (e.g. via one or more mechanical linkages, as shown, and/or via electromechanical signals and devices) advance and/or retract plunger 2512. For example, as shown, syringe drive assembly 2500 can comprise a system of linkages and pulleys configured to advance and/or retract plunger 2512 as the operator actuates a control knob attached to the linkages (as described herebelow). Alternatively or additionally, a syringe drive assembly can comprise one or more electromechanical drive mechanisms configured to advance and/or retract plunger 2512 in response to a control signal received from the operator (e.g. received from console based on actions performed by the operator).
Syringe drive assembly 2500 can include a control assembly, control assembly 2550 shown, that can include one or more user actuatable devices, control knob 2551 shown. Control knob 2551 can rotate about a central hub, hub 2552 shown. Syringe drive assembly 2500 can include one or more linkages, cable 2502 shown. Cable 2502 can loop about hub 2552, and extend through a channel, conduit 2555, such as a flexible, fixed length conduit configured to maintain tension in cable 2502 between control assembly 2550 and console 200. In some embodiments, conduit 2555 is a portion of an umbilical assembly of system 10, such as a bundle of two or more conduits, wires, fluid tubes, and/or other elongate components that operably attach (e.g. fluidly, electrically, pneumatically, hydraulically, optically, and/or acoustically attach) console 200 to depositing device 600. In some embodiments, conduit 2555 comprises a multi-lumen extrusion (e.g. including a lumen for each cable portion 2502a,b). In some embodiments, handle 601 (not shown) of depositing device 600 comprises at least a portion of control assembly 2550 (e.g. handle 601 comprises one or more switches, levers, knobs, and/or other operator controls of control assembly 2550). Cable 2502 can be attached to hub 2552, such that as knob 2551 is rotated in a first direction, a first portion of cable 2502, cable portion 2502a, is pulled and a second portion of cable 2502, cable portion 2502b, is released. When knob 2551 is rotated in an opposite, second direction, cable portion 2502b is pulled, and cable portion 2502a is released. In some embodiments, cable portions 2502a,b comprise separate cables.
Plunger 2512 can comprise an attachment portion, control bar 2513, that attaches to the ends of cable portions 2502a,b. For example, as shown, cable portion 2502a can attach to the top (as shown on the page) of control bar 2513, such when cable portion 2502a is retracted (e.g. into conduit 2555), plunger 2512 is retraced from syringe 2511. In some embodiments, cable portion 2502b is split into multiple segments, two shown, engages a system of one or more pulleys, pulleys 2501, and attaches to the bottom of control bar 2513. In this configuration, when cable portion 2502b is retracted (e.g. into conduit 2555), plunger 2512 is pulled into syringe 2511. In some embodiments, as shown, cable portion 2502b attaches to opposite sides of control bar 2513 to prevent or at least limit twisting forces that may be applied to plunger 2512 if unbalanced forces were applied to advance plunger 2512 (e.g. if cable portion 2502b did not split and attached to one side of control bar 2513. In some embodiments, syringe 2511 comprises a standard syringe, for example a standard, commercially available syringe that can be adapted for use with system 10, where console 200 is configured to attach to syringe 2511 and control bar 2513 is configured to fixedly attach to syringe 2511. Alternatively or additionally, syringe 2511, plunger 2512, and control bar 2513 can comprise components integral to and/or specifically designed for use with syringe drive assembly 2500. In some embodiments, syringe drive assembly 2500 and/or control assembly 2550 each comprise one or more housings, covers, and/or other protective elements configured to prevent an operator from being injured during the operation of syringe drive assembly 2500 (e.g. by protecting and/or eliminating any “pinch points”). In some embodiments, syringe drive assembly can comprise a lid (e.g. a portion of a housing comprising a lit) that is removably attachable and/or held in place with twistable tabs. In the embodiments, the lid can be removed and/or opened such that the mechanisms of syringe drive assembly 2500 can be accessible to the operator.
Referring additionally to
Drive assembly 2520 includes a translating component, cart 2521, that attaches (e.g. removably attaches) to a plunger of a syringe (not shown), such that as cart 2521 advances and/or retracts (e.g. advances to the left as shown on the page), the plunger advances and/or retracts. Cart 2521 can be slidingly positioned on a linear guide, rail 2522, that is fixedly positioned relative to other fixed components of drive assembly 2520 (e.g. fixed relative to console 200). A linkage, wire 2523, can be fixedly attached to cart 2521 and loop around a fixed pulley, pulley 2525 as shown, such that when ends 2524a,b are pulled and/or released (e.g. by a control assembly as described herein), cart 2521 retracts and/or advances, respectively.
Drive assembly 2530 includes a translating component, rack 2532, including an attachment mechanism, mount 2531, that attaches (e.g. removably attaches) to a plunger of a syringe (not shown), such that as rack 2532 advances and/or retracts, the plunger advances and/or retracts. Rack 2532 can be slidingly fixed relative to other fixed components of drive assembly 2530 (e.g. slidingly fixed to console 200), such that rack 2532 is free to translate left and right as shown on the page. A linkage, belt 2523, can be looped around a fixed pulley assembly, pulley 2535. Pulley 2535 can comprise one or more circumferential projections, teeth 2536, such that when pulley 2535 rotates, teeth 2356 engage one or more mating projections of rack 2532, teeth 2537. When teeth 2536 engage teeth 2537, and pulley 2635 is rotated, rack 2532 translates left or right. When ends 2534a,b of belt 2533 are pulled and/or released, (e.g. by a control assembly as described herein), pulley 2535 rotates, and rack 2532 retracts and/or advances, respectively. In some embodiments, belt 2533 comprises a toothed belt and/or a chain that engages pulley 2535.
Referring now to
A biasing mechanism, spring 2544, can be positioned between a fixed location and control bar 2543, such as to apply a bias to control bar 2543 (e.g. biased toward a retracted position of plunger 2542, as shown). A linkage, cable 2545, can be fixedly attached to control bar 2543, and it can extend in a direction opposite the bias of spring 2544, such that a pulling force applied to cable 2545 acts against the bias of spring 2545 and causes the translation (e.g. advancement) of plunger 2542. In some embodiments, syringe drive assembly 2540 comprises a motor and bobbin, a linear drive, or other force applying assembly that applies a pulling force to cable 2545. Alternatively or additionally, a control assembly, not shown but described herein, can comprise a mechanism configured to enable the operator to apply a pulling force to cable 2545 to actuate plunger 2542. In some embodiments, spring 2544 comprises a compression spring configured to apply a pushing force on control bar 2543 to apply a bias (e.g. as shown). Alternatively, spring 2533 can comprise an extension spring configured to apply a pulling force on control bar 2543 to apply a bias. In some embodiments, spring 2543 comprises a compression spring with a fully expanded length less than the translation distance of plunger 2542, such as less than 20%, less than 10%, or less than 5% of the translation distance of plunger 2542, such that spring 2543 only applies a biasing force to control bar 2543 if plunger is advanced within 20%, 10%, or 5% (respectively) of the fully advanced position.
The above-described embodiments should be understood to serve only as illustrative examples; further embodiments are envisaged. Any feature described herein in relation to any one embodiment can be used alone, or in combination with other features described, and may also be used in combination with one or more features of any other of the embodiments, or any combination of any other of the embodiments. Furthermore, equivalents and modifications not described hereabove may also be employed without departing from the scope of the invention, which is defined in the accompanying claims.
This application is a continuation of PCT Application No PCT/US22/16200 (Attorney Docket No. 41714-725.601), filed Feb. 11, 2022, which claims the benefit of: U.S. Provisional Patent Application Ser. No. 63/148,551 (Attorney Docket No. 41714-725.101; Client Docket No. MCT-053-PR1), entitled “System for Treating a Patient”, filed Feb. 11, 2021; U.S. Provisional Patent Application Ser. No. 63/214,160 (Attorney Docket No. 41714-725.102; Client Docket No. MCT-053-PR2), entitled “System for Treating a Patient”, filed Jun. 23, 2021; and U.S. Provisional Patent Application Ser. No. 63/280,383 (Attorney Docket No. 41714-725.103; Client Docket No. MCT-053-PR3), entitled “System for Treating a Patient”, filed Nov. 17, 2021; the content of each of which is incorporated herein by reference in its entirety for all purposes. This application is related to: U.S. patent application Ser. No. 16/438,362 (Attorney Docket No. 41714-704.302; Client Docket No. MCT-002-US-CON1), entitled “Heat Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed Jun. 11, 2019; U.S. patent application Ser. No. 14/515,324 (Attorney Docket No. 41714-705.301; Client Docket No. MCT-003-US), entitled “Tissue Expansion Devices, Systems and Methods”, filed Oct. 15, 2014; U.S. patent application Ser. No. 16/711,236 (Attorney Docket No. 41714-706.302; Client Docket No. MCT-004-US-CON1), entitled “Electrical Energy Ablation Systems, Devices and Methods for the Treatment of Tissue”, filed Dec. 11, 2019; U.S. patent application Ser. No. 14/673,565 (Attorney Docket No. 41714-708.301; Client Docket No. MCT-009-US), entitled “Methods, Systems and Devices for Performing Multiple Treatments on a Patient”, filed Mar. 30, 2015; U.S. patent application Ser. No. 16/379,554 (Attorney Docket No. 41714-709.302; Client Docket No. MCT-013-US-CON1), entitled “Methods, Systems and Devices for Reducing the Luminal Surface Area of the Gastrointestinal Tract”, filed Apr. 9, 2019; U.S. patent application Ser. No. 14/917,243 (Attorney Docket No. 41714-710.301; Client Docket No. MCT-023-US), entitled “Systems, Methods and Devices for Treatment of Target Tissue”, filed Mar. 7, 2016; U.S. patent application Ser. No. 16/742,645 (Attorney Docket No. 41714-715.301; Client Docket No. MCT-025-US), entitled “Intestinal Catheter Device and System”, filed Jan. 14, 2020; U.S. patent application Ser. No. 16/798,117 (Attorney Docket No. 41714-714.303; Client Docket No. MCT-028-US-CIP1-CON2), entitled “Systems, Devices and Methods for Performing Medical Procedures in the Intestine”, filed Feb. 21, 2020; U.S. patent application Ser. No. 16/400,491 (Attorney Docket No. 41714-716.301; Client Docket No. MCT-035-US), entitled “Systems, Devices and Methods for Performing Medical Procedures in the Intestine”, filed May 1, 2019; U.S. patent application Ser. No. 16/905,274 (Attorney Docket No. 41714-717.301; Client Docket No. MCT-036-US), entitled “Material Depositing System for Treating a Patient”, filed Jun. 18, 2020; U.S. patent application Ser. No. 17/021,798 (Attorney Docket No. 41714-709.303; Client Docket No. MCT-013-US-CON2), entitled “Methods, Systems and Devices for Reducing the Luminal Surface Area of the Gastrointestinal Tract”, filed Sep. 15, 2020; International PCT Patent Application Serial Number PCT/US2020/056627 (Attorney Docket No. 41714-720.601; Client Docket No. MCT-050-PCT), entitled “Systems, Devices, and Methods for Performing Medical Procedures in the Intestine”, filed Oct. 21, 2020; U.S. patent application Ser. No. 17/095,108 (Attorney Docket No. 41714-711.303; Client Docket No. MCT-024-US-CON2), entitled “Systems, Devices and Methods for the Creation of a Therapeutic Restriction in the Gastrointestinal Tract”, filed Nov. 11, 2020; U.S. patent application Ser. No. 17/096,855 (Attorney Docket No. 41714-713.302; Client Docket No. MCT-029-US-CON1), entitled “Methods and Systems for Treating Diabetes and Related Diseases and Disorders”, filed Nov. 12, 2020; International PCT Patent Application Serial Number PCT/US2021/013072 (Attorney Docket No. 41714-721.601; Client Docket No. MCT-039-PCT), entitled “Tissue Treatment Devices, Systems, and Methods”, filed Jan. 12, 2021; International PCT Patent Application Serial Number PCT/US2021/013600 (Attorney Docket No. 41714-722.601; Client Docket No. MCT-051-PCT), entitled “Automated Tissue Treatment Devices, Systems, and Methods”, filed Jan. 15, 2021; U.S. patent application Ser. No. 17/181,969 (Attorney Docket No. 41714-713.501; Client Docket No. MCT-029-US-CIP1), entitled “Methods and Systems for Treating Diabetes and Related Diseases and Disorders”, filed Feb. 22, 2021; U.S. patent application Ser. No. 17/192,671 (Attorney Docket No. 41714-707.302; Client Docket No. MCT-005-US-CON1), entitled “Ablation Systems, Devices, and Methods for the Treatment of Tissue”, filed Mar. 4, 2021; International PCT Patent Application Serial Number PCT/US2021/022938 (Attorney Docket No. 41714-723.601; Client Docket No. MCT-041-PCT), entitled “Systems, Devices and Methods for Treating Diabetes”, filed Mar. 18, 2021; U.S. patent application Ser. No. 17/214,157 (Attorney Docket No. 41714-718.301; Client Docket No. MCT-037-US), entitled “Systems and Methods for Deposition Material in a Patient”, filed Mar. 26, 2021; U.S. patent application Ser. No. 17/222,480 (Attorney Docket No. 41714-703.303; Client Docket No. MCT-001-US-CON2), entitled “Devices and Methods for the Treatment of Tissue”, filed Apr. 5, 2021; International PCT Patent Application Serial Number PCT/US2021/038371 (Attorney Docket No. 41714-724.601; Client Docket No. MCT-034-PCT), entitled “Tissue Treatment System with Fluid Delivery Console”, filed Jun. 22, 2021; U.S. patent application Ser. No. 17/384,421 (Attorney Docket No. 41714-714.304; Client Docket No. MCT-028-US-CIP2-CON2), entitled “Systems, Devices and Methods for Performing Medical Procedures in the Intestine”, filed Jul. 23, 2021; U.S. patent application Ser. No. 17/490,947 (Attorney Docket No. 41714-719.301; Client Docket No. MCT-040-US), entitled “Systems, Devices and Methods for Treating Metabolic Medical Conditions”, filed Sep. 30, 2021; U.S. patent application Ser. No. 17/494,277 (Attorney Docket No. 41714-712.303; Client Docket No. MCT-027-US-CIP1-CON2), entitled “Injectate Delivery Devices, Systems and Methods”, filed Oct. 5, 2021; U.S. patent application Ser. No. 17/516,503 (Attorney Docket No. 41714-713.304; Client Docket No. MCT-029-US-CIP1-CON2), entitled “Methods and Systems for Treating Diabetes and Related Diseases and Disorders”, filed Nov. 1, 2021; U.S. Provisional Patent Application Ser. No. 63/292,761 (Attorney Docket No. 41714-726.101; Client Docket No. MCT-056-PR1), entitled “Methods and Systems for Treating Mucosal Hyperplasia and other Medical Conditions of a Patient”, filed Dec. 22, 2021; and U.S. patent application Ser. No. 17/568,145 (Attorney Docket No. 41714-708.302; Client Docket No. MCT-009-US-CON1), entitled “Methods, Systems and Devices for Performing Multiple Treatments on a Patient”, filed Jan. 4, 2022; the contents of each of which is incorporated herein by reference in its entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 63148551 | Feb 2021 | US | |
| 63214160 | Jun 2021 | US | |
| 63280383 | Nov 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US22/16200 | Feb 2022 | US |
| Child | 18366898 | US |
