The present disclosure relates generally to in vivo biological tissue perfusion and, more specifically, to systems and methods that employ a portable, patient-wearable, in vivo, normothermic perfusion system to preserve biological tissue implanted within a defect at an external surface of the patient's body until the body naturally vascularizes the biological tissue.
Free tissue transfer is a well-established technique allowing for the reconstruction of wounds (or defects) following trauma, tissue extirpation, and congenital malformations by transferring tissues with an established vascular supply to the wound site. The conventional free tissue transfer technique involves creating a defect surgically, either following the removal of a tumor or after a wound is cleaned. An incision is made in an area of a patient or a donor from where a transplant tissue flap will be taken. The top layers of the flap are dissected and freed from the surrounding tissue, such that only the underlying vasculature remains connected to the patient or donor. At least one vein and one artery (constituting the vascular pedicle) that supply blood to the flap are dissected. Before the pedicle is divided, the defect is prepared by identifying a recipient artery and vein at the defect location. After the vascular pedicle has been dissected and the recipient artery and vein in the defect have been identified, the vascular pedicle is divided and the flap is completely separated and removed from the patient or donor. When separated and removed, the flap is called a “free flap.” The free flap is brought to the defect area, and the vein and artery from the flap (vascular pedicle) are connected to the recipient vein and artery in the defect by suturing, etc. The process of establishing an anastomosis (i.e., a connection) between the respective vasculature in the flap and the defect can be performed only by highly skilled microsurgeons. The process is both time- and labor intensive and requires the use of expensive equipment, such as an operating microscope called a loupe, given the delicate nature and small size (0.3-3 mm) of the vessels involved. After an anastomosis has been established between respective veins and arteries in the defect and the free flap, the perimeter of the free flap is sutured to the defect and the blood vessels are monitored to ensure that an adequate blood flow between the defect and the free flap is maintained. The area from which the free flap was harvested in the patient or the donor is then closed, often with a Split Thickness Skin graft (STSG).
The most critical step of the conventional free tissue transfer technique is establishing an anastomosis between the vessels of free flap pedicle and the vessels of the defect. The failure rate of free-flap transplants transplanted by existing free tissue transfer procedures, commonly attributed to blood clots, lies around 3-5%. Clotting is ascribed to several factors including procedure technique, poor quality vessels (i.e., radiated or atherosclerotic vessels), poor flow in the vessels, long operative times, hypercoagulative states, etc. If the free flap fails, then the patient is at risk for additional complications, such as infection, delayed wound healing, need for second (or subsequent) surgical procedures, or even amputation in the case of traumatic limb defects with exposed bone. Current research has focused on improving anastomosis procedures and re-repairing vessels after the removal of a clot. In the case of clot removal, new recipient vessels are often used. If that is not possible, the failure rate increases. Rates of successful flap salvage after a clot have been described to be only between 30 to 60%.
Accordingly, it would be desirable to facilitate free-flap transplantation in a manner that avoids the need for time-consuming, highly skilled microsurgery to establish anastomoses, and then the necessary monitoring and follow-up to ensure continued patency of the anastomoses.
Disclosed herein is a normothermic machine perfusion (NMP) system that can be utilized in vivo to promote neovascularization of transplanted free flaps within a tissue defect. As will be further described, NMP can maintain the physiologic metabolism of a free flap during neovascularlization, avoiding the deleterious effects of hypoxia (low oxygen levels in the tissues), hypothermia (cooling), and nutrient deprivation that occur with transplant rejection. NMP also can sustain and/or preserve implanted biological tissue within a defect at an external surface of a patient's body without surgical anastomosis between respective artery(ies) and vein(s) in the tissue and the defect, for example at least for four weeks (one month) or until the body naturally vascularizes (neovascularizes) the implanted tissue.
Because NMP preserves and sustains the free flap until the body can neovascularize the free flap, preparation of and anastomosis to defect-(recipient)-site vessels are not required for a successful flap implantation. Moreover, operating times may be substantially reduced with NMP because surgical procedures are not required to establish anastomoses between the free flap and defect vasculature.
NMP may also be used for reconstruction of defects in sick patients who would not or would be less likely to endure long operative procedures, patients with hypercoagulability, as well as patients with scarred and irradiated fields or other risk factors for flap failure. NMP may also be used to salvage flaps that have failed using the conventional techniques. Finally, the use of NMP would circumvent the use of vein grafts necessary to bridge adequate vessels if these are not available in close proximity to the defect, and would present less risk of morbidity to patients. Accordingly, the disclosed normothermic machine perfusion system includes a portable, patient-wearable perfusion system that can perfuse an implanted biological tissue graft (e.g., a free flap) to preserve the implanted biological tissue graft without surgically establishing anastomoses between respective vasculature in the graft and the defect. Methods of using such a system also are disclosed.
A portable, patient wearable, perfusion system can extend the life of a biological tissue graft implanted within a defect at an external surface of a patient's body, ensuring that the implanted biological tissue graft is preserved until the body neovascularizes the reattached graft.
In an aspect, the present disclosure includes a portable, patient-wearable perfusion system that includes a patch configured to cover at least a portion of a biological tissue graft implanted within a defect in a patient, a human-portable perfusion assembly configured to be worn or carried on the patient's body, an arterial cannula, and a venous cannula. The patch includes a first sensor adapted to detect a first parameter relating to a physiologic state of the biological tissue graft. The perfusion assembly includes at least one reservoir for a perfusate, a pump, and a controller operatively coupled to the sensor and configured to operate the pump to control said physiologic state of the tissue graft based on data regarding the first parameter received from the sensor. The arterial cannula is configured to cannulate a major artery of the biological tissue graft to facilitate delivery of perfusate to the graft from the perfusion assembly. The venous cannula is configured to cannulate a major vein of the biological tissue graft to facilitate return of spent perfusate from the graft back to the perfusion assembly. The arterial cannula and the venous cannula are configured to yield a closed fluid circuit for the perfusate to circulate through the biological tissue graft.
In another aspect, the present disclosure includes a method for preserving an implanted biological tissue graft. The method includes connecting an external perfusion assembly located outside of a patient's body to a major artery and a major vein of a biological tissue graft via respective arterial and venous cannulas, thereby establishing a closed fluid circuit for a flow of perfusate between the tissue graft and the perfusion assembly, and perfusing the implanted biological tissue graft in vivo via perfusate circulating through the closed fluid circuit.
The foregoing and other features of the present disclosure will become apparent to those skilled in the art to which the present disclosure relates upon reading the description with reference to the accompanying drawings, in which:
In the context of the present disclosure, the singular forms “a,” “an” and “the” can also include the plural forms, unless the context clearly indicates otherwise.
The terms “comprises” and/or “comprising,” as used herein, can specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups.
As used herein, the term “and/or” can include any and all combinations of one or more of the associated listed items.
Additionally, although the terms “first,” “second,” etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. Thus, a “first” element discussed below could also be termed a “second” element without departing from the teachings of the present disclosure. The sequence of operations (or acts/steps) is not limited to the order presented in the claims or figures unless specifically indicated otherwise.
As used herein, the term “implanted biological tissue graft” refers to any body part, or vascular allograft or autograft originating from a donor or a patient or grown in a laboratory setting that has been implanted, such as by suturing, stapling, etc., within a defect formed (e.g., due to trauma, disease, etc.) at an external surface of the body of the patient.
As used herein, the term “detached” can refer to the state of something that was once attached no longer being attached. For example, skin tissue can be detached from a patient or a donor due to trauma or as part of a surgical procedure.
As used herein, the term “implanted” can refer to the state of something that was once detached now being attached. For example, detached skin tissue may be implanted within a defect in a patient that was formed by trauma or as part of a surgical procedure by suturing the free flap around the perimeter of the defect. As used herein, the term “implanted” does not necessarily include establishing an anastomosis between the artery(ies) and/or vein(s) of any biological tissue, extremity, allograft or autograft to any respective artery(ies) and/or vein(s) of the defect.
As used herein, the term “ex-vivo” (when used to refer to a body part) refers to the body part being outside or separated from the patient or donor, as opposed to being inside or implanted in the patient or donor under normal living conditions. In contrast, as used herein the term “in-vivo” (when used to refer to a body part) refers to the body part being inside or implanted within the patient or donor under normal living conditions. The ex-vivo or in-vivo body part can include, but is not limited to, organs such as the heart, kidney, liver, lungs, pancreas, intestines, or skin.
As used herein the terms “free flap,” “free autologous tissue transfer,” and “microvascular free tissue transfer” refer to a piece of tissue that is disconnected from its original blood supply and is moved a distance to be implanted at a recipient site (i.e., a defect). The free flap can originate with a patient, a donor, or a culture in a laboratory setting.
As used herein, the term “patient” refers to any warm-blooded organism (e.g., a human being, a primate, a cat, a dog, a rabbit, a mouse, etc.) receiving treatment for a medical condition that requires a transplant or replant of a detached biological tissue. For example, a patient may require a skin transplant or replant due to an injury or a disease. A patient can be in any location, a hospital, a doctor office, a field hospital, etc.
As used herein, the term “donor” refers to any warm-blooded organism, living or dead, that undergoes a surgical procedure to detach a biological tissue that will be transplanted to a patient. The patient may be the same or different from the donor.
As used herein, the term “normothermic” refers to an environmental temperature that does not cause increased or decreased activity of cells of a body. For a human body the peak normothermic temperature range is between approximately 36 degrees Celsius and 38 degrees Celsius.
As used herein, the term “perfusate” refers to a fluid comprising nutrients, substrates, metabolites, electrolytes, and/or an oxygen carrier that is perfused through implanted biological tissue graft to preserve the function and viability of the implanted biological tissue graft.
As used herein, the term “substrate” refers to one or more materials that are added to a perfusate to help nourish the cells in implanted biological tissue.
An aspect of the present disclosure can include a portable, patient-wearable system 10 as shown in
The portable and patient wearable perfusion system 10 includes a patch 12 having a sensor 15 that is sized and dimensioned to cover at least a portion of the external surface of the implanted biological tissue graft 14. The system also includes a perfusion assembly 16 adapted to maintain the normothermic environment for the implanted biological tissue graft 14 by pumping a perfusate through the graft. A normothermic environment mimics at least one of the physiologic temperature, pressure, and humidity of the implanted biological tissue graft 14 to decrease the onset of cellular damage and to elongate tissue survival time. An arterial tube 18a can be adapted to connect the perfusion assembly 16 to a major artery of the implanted biological tissue graft 14 via an arterial cannula. A venous tube 18b can be adapted to connect the perfusion assembly 16 to a major vein of the implanted biological tissue graft 14 via a venous cannula, optionally after passing the used perfusate through a negative pressure venous return system 67.
Exemplary arterial 400 and venous 500 cannulas are illustrated in
The insertion ends 401, 501 and/or ports 402, 502 may contain one or more attachment features 403, 503 on the surface thereof to detachably secure or connect the cannulas to the interior lumen of the respective vessel or tube or inlet by friction or press-fit. For example, the attachment features 403 may include one or more of lipped edges, screw threads, indentations, protrusions, or grooves. In an embodiment of an arterial cannula shown in
The cannulas 400, 500 may be formed in various sizes and lengths to accommodate the particular application, such as the size of the vessel(s) to be cannulated. The cannulas 400, 500 may be made from various medical-grade materials, including stainless steel, titanium, or plastics, such as polytethylene or polypropylene.
In the embodiments illustrated in
In the illustrated embodiments, the cannulas 400, 500 are arranged respectively on a pair of feet 404, 504 configured to be co-planar with the surface of the biological tissue graft or the patient's skin. The feet 404, 504 are further configured to rest against the surface of the biological tissue graft and to stabilize the cannula in relation thereto. The shape and dimensions of the feet 404, 504 are not limited and may be selected or configured to promote stabilization based on the region of the patient's body where the defect is located. The feet may be secured to the biological tissue graft or the patient's skin surrounding the defect with, for example, surgical tape or sutures. In the embodiments shown in
Returning to
The arterial and venous tubes 18a, 18b are indicated in
The patch 12 may have any dimensions suitable to cover at least a portion of an external surface of the implanted biological tissue graft 14. The patch, for example, may be about 30 cm by about 15 cm, about 25 cm by about 10 cm, or about 20 cm by about 8 cm. In a one embodiment, the patch 12 may be configured to cover the entire implanted biological tissue graft 14. In another embodiment, the patch 12 can be configured to cover a specific type of biological tissue graft 14, for example a free flap implanted within a defect formed in a patient's chest after a mastectomy. Alternatively, the patch can be configured as a universal covering for any type of implanted biological tissue graft 14.
The patch 12 may be made of any suitable materials conventionally known in the art. For example, the patch 12 may be composed of a non-woven material, such as rayon or polyester, a woven material, a plastic or vinyl film, a silicone, a foam, an alginate, a gel, a hydrogel, or a combination thereof. In one embodiment, the patch 12 has a suitable medical-grade adhesive disposed on the bottom (skin-facing) perimeter surface to adhere the patch to the implanted biological tissue graft 14. Alternatively, the patch 12 does not include an adhesive and may be secured to the external surface of the implanted biological tissue graft 14 or another portion of the patient's body by applying a suitable medical-grade tape about the perimeter of the top surface of the patch 12.
At least one sensor 15 is included in the patch 12. When the patch 12 is applied, the sensor 15 directly contacts an external surface of the implanted biological tissue graft 14. In one embodiment, the at least one sensor 15 can be integrally formed or incorporated within the patch 12, such that the patch 12 and the at least one sensor 15 can form a single unit. In another embodiment, the at least one sensor 15 is provided separately from the patch 12 but is attached thereto (e.g., by an adhesive). In this embodiment, the at least one sensor 15 may be applied onto the bottom (skin-facing) surface of the patch 12, and then the patch 12 and sensor 15 may be applied to the implanted biological tissue graft 14, such that the sensor 15 and the bottom surface of the patch 12 contact at least a portion of the external surface of the graft.
The at least one sensor 15 can be at least one of: a tissue oximeter, a tissue temperature sensor, and a tissue optical color sensor. These or other sensors are adapted to measure characteristics of the implanted biological tissue graft 14, which then can be analyzed by a controller 24 of the perfusion assembly 16 to provide feedback control in order to adjust perfusion, control the delivery of composition of perfusate, or even to determine when it is safe to cease perfusion using perfusate. For example, a tissue oximeter can be adapted to measure oxygen saturation in one or more regions of the implanted biological tissue graft 14. In this example, when the implanted biological tissue graft 14 is a flap of skin tissue (for instance), the tissue oximeter can be a near infrared sensor on the surface of the skin tissue that is held in-place by the patch to detect tissue oxygenation at different depths within the flap of skin tissue. As will be discussed in further detail below, a degree of neovascularization of the implanted biological tissue graft 14 may be determined by stopping the flow of perfusate to the graft and measuring tissue oxygenation via one or more tissue oximetry sensors. A value of at least 70%, at least 80%, at least 90% or at least 99% tissue oxygen saturation suggests that the graft is being sufficiently oxygenated. Sufficient oxygenation indicates that the implanted biological tissue graft 14 is being neovascularized under existing conditions. A value of less than 40% tissue oxygen saturation indicates that the implanted biological tissue graft 14 is insufficiently oxygenated and that neovascularization is likely not occurring.
The tissue temperature sensor can be adapted to measure the surface temperature in one or more regions of the implanted biological tissue graft 14. For example, the tissue temperature sensor can be a thermistor, a semi-conductor sensor, or an infrared temperature sensor. In embodiments, temperature values in a range of between about 33° C. and about 38° C. indicate normothermia suggesting that the implanted biological tissue graft 14 is being neovascularized under existing conditions. A temperature value lower than 33° C. will indicate that the biological tissue graft 14 is insufficiently vascularized and that neovascularization is not likely occurring.
The tissue optical color sensor can be adapted to detect one or more colors of the implanted biological tissue graft 14. For example, the optical color sensor can emit light from a transmitter onto the implanted biological tissue graft 14, and then detect the light reflected back from the graft with a receiver in order to determine the color(s) of the graft. Detected color may be correlated to a degree of neovascularization of the implanted biological tissue graft 14, gain after temporarily discontinuing perfusate flow so that graft temperature is affected based on the degree of vascularized blood flow, and not the degree of perfusate flow. In one embodiment, the detection of warmer colors (i.e., reds, pinks and oranges) by the color sensor indicates that the biological tissue graft 14 is adequately oxygenated and likely neovascularizing under existing conditions, while the detection of cooler colors (i.e., greens, blues or purples) indicate that the biological tissue graft is inadequately oxygenated and likely not undergoing neovascularization.
In one embodiment, the patch 12 may include one or more sensor arrays. Each sensor array includes a plurality of the same type of sensor 15 (e.g., a tissue oximeter, a tissue temperature sensor, a tissue optical color sensor) and is adapted to detect respective values of the same parameter from a multitude of corresponding locations in the implanted biological tissue graft 14. The data regarding the parameter generated by each sensor 15 in the array is received by a controller 24, which is configured to process the respective values regarding that parameter in order to control the physiologic state of the implanted biological tissue graft 14 based thereon. In one example, the patch 12 includes an array of temperature sensors adapted to detect respective temperature values across the external surface of the implanted tissue graft 14.
When two arrays of different sensors are used, the controller 24 is configured to process the respective values of the second parameter detected by the second array of sensors together with those of the first parameter. In one embodiment shown in
As used herein, the term “perfusion assembly” refers to a mechanical system for perfusing a perfusate through biological tissue that has been implanted within a defect (e.g. at an external surface) of a patient's body. Referring to
The perfusate that can be perfused through the system 10 and the implanted biological tissue graft 14 can be any suitable perfusate. For example, the perfusate can include a colloid solution with physiologic concentrations of albumin, glucose, electrolytes, and an oxygen carrier (e.g., washed red blood cells). In another example, the perfusate is specifically formulated for the preservation of vascular composite allografts.
The perfusion assembly 16 can also include at least one detection device 20. The at least one detection device 20 can measure a parameter during perfusion of the implanted biological tissue 14. Unlike the at least one sensor 15, which is included in the patch 12, the at least one detection device 20 is instead included within, or attached to, the perfusion assembly 16 or to features of the system 10 physically outside of the perfusion assembly 16 but operatively connected thereto, other than patch 12 (i.e., the arterial tube 18a and/or the venous tube 18b as shown in
The at least one detection device 20 can be at least one of: a tissue oximeter, a temperature sensor, a pressure sensor, a pH sensor, an ion-selective electrode, a flow-sensing module, and a sensor adapted to measure at least one of metabolite concentrations and/or blood gas concentrations in the perfusate. When the at least one detection device 20 is a temperature sensor, the temperature sensor can be adapted to measure the temperature of the perfusate at a location anywhere in the system 10. For example, the temperature sensor can be a thermistor, a semi-conductor sensor, or an infrared temperature sensor. In a preferred embodiment, the temperature of the perfusate will be in the range of between about 33° C. and about 38° C.
A pressure sensor can be adapted to measure the pressure of the perfusate when the perfusate is at a location anywhere in the system 10. For example, a pressure sensor placed on the arterial tube 18a can be configured to measure the in-line arterial pressure. In a preferred embodiment, the in-line arterial pressure should measure between about 30 mmHg to about 90 mmHg, about 35 mmHg to about 85 mmHG, or about 40 mmgHg to about 80 mmHg.
A pH sensor can be adapted to continuously, or at times specified by a user of the system 10 (e.g., a medical caregiver or patient), measure the pH of the perfusate in at least one of the perfusion assembly 16, the arterial tube 18a, and the venous tube 18b. In a preferred embodiment, the pH of the perfusate is within a range of about pH 7 to about pH 8, about pH 7.15 to about pH 7.75, or about pH 7.30 to about pH 7.50.
An ion-selective electrode can be adapted to measure electrolyte concentrations (e.g., Na+, K+, Ca++, etc.) in the perfusate in the perfusion assembly 16, the arterial tube 18a and/or the venous tube 18b. In an embodiment, the concentration of Na+ is between 125 mmol/L to about 170 mmol/L, about 130 mmol/L to about 165 mmol/L, or about 135 mmol/L to about 160 mmol/L. In another embodiment, the concentration of K+ in the perfusate is between about 1 mmoL/L to about 30 mmol/L, about 1.5 mmol/L to about 25 mmol/L, or about 2 mmol/L to 20 mmol/L. In another embodiment, the concentration of Ca++ in the perfusate is between about 0.25 mmol/L to about 10 mmol/L, about 0.5 mmol/L to about 7.5 mmol/L, or about 1 mmol/L to about 5 mmol/L.
A flow sensing module can be adapted to continuously, or at times specified by a user of the system 10, measure the inflow and outflow of perfusate non-invasively. The flow sensing module may be an ultrasound sensor configured to detect real-time flow rate.
A sensor adapted to measure metabolite concentrations and/or blood gas concentrations in the perfusate can be positioned in at least one of the perfusion assembly 16, the arterial tube 18a, and the venous tube 18b. The measured metabolite concentrations can include, but are not limited to, glucose concentrations and lactate concentrations. Not wishing to be bound by theory, glucose concentrations can be used to assess the metabolic function of the implanted biological tissue graft 14 by determining the amount of glucose used by the implanted biological tissue graft 14 to generate energy. Lactate is a marker of anaerobic activity and, not wishing to be bound by theory, lactate concentrations can be used to determine the occurrence of injuries. In an embodiment, the glucose concentration is between about 10 g/dL to about 300 g/dL, about 20 g/dL to about 250 g/dL, or about 30 g/dL to about 200 g/dL. In another embodiment, the lactate concentration is between about 0.5 mmol/L to about 45 mmol/L, about 1 mmol/L to about 30 mmol/L, or about 2 mmol/L to about 15 mmol/L.
The measured blood gas concentrations can include, but are not limited to, oxygen and carbon dioxide concentrations. For example, the oxygen concentration (pO2) is between about 50 mmHg to about 900 mmHg, about 75 mmHg to about 850 mmHg, or about 100 mmHg to about 800 mmHg. In another example, the carbon dioxide concentration (pCO2) is between about 10 mmHg to about 200 mmHg, about 15 mmHg to about 150 mmHg, or about 20 mmHg to about 100 mmHg. Other metabolite and blood gas concentrations that indicate the health of an implanted biological tissue graft 14 can also be measured. More than one type of each detection device 20 can be positioned in the system 10 when the at least one detection device 20 is more than one.
The at least one parameter control device can maintain or adjust a parameter to fall within a predetermined threshold. A parameter control device can be at least one of: a pump, an oxygenator, a heating element, and a source of gas mixture. In the embodiment illustrated in
A heating element 41 is another example of a parameter control device that can be used to regulate perfusate temperature, e.g. as it flows through the oxygenator 48 in the embodiment of
A source of a gas mixture 50 can be connected to the oxygenator 48 and adapted to provide a quantity of the gas mixture to the perfusate and to maintain a desired pH level of the perfusate. The gas mixture can be a combination of at least oxygen and carbon dioxide (e.g., in some instances, oxygen is much more prevalent than carbon dioxide in a hyperoxygenated environment; for example, O2 can be more than 50%, more than 75%, more than 85%, and more than 95%; one non-limiting example is 97.5% O2 and 2.5% CO2).
As shown in
In some instances, one or more of the couplings can be via a wired connection. For example, as illustrated in
The non-transitory memory 26 of the controller 24 can store machine executable instructions (algorithms), which are executable by the processor 28. In some instances, the non-transitory memory 26 can be combined in a single hardware element (e.g., a microprocessor), but in other instances, the non-transitory memory and the processor can include at least partially distinct hardware elements. The controller 24 can be configured to receive data regarding the parameters measured by the at least one sensor 15 and, optionally, the detection devices 20, and may be configured to compare the data to predetermined thresholds or threshold ranges for that parameter. The controller 24 may also be adapted to direct the parameter control devices to control the physiological state of the tissue graft, such as by maintaining or adjusting a property of the perfusate (i.e., a concentration of an additive in the perfusate supplied from a separate additive reservoir of the external perfusion assembly), or the rate of perfusion. Based on the parameter(s) received from the at least one sensor 15 and/or the at least one detection device 20, the controller may also send an alert to be displayed on a display device 64.
In the example shown in
The first, second and third perfusate reservoirs 30, 32, 34 may have any dimension to accommodate a volume of perfusate suitable for use with a portable and patient-wearable system. In a preferred embodiment, the first, second and third perfusate reservoirs 30, 32, 34 may contain up to 1 L of perfusate or fluid. The first, second and third perfusate reservoirs 30, 32, 34 may be removable and replaceable. In a preferred embodiment, at least one of the first, second and third perfusate reservoirs 30, 32, 34 can be replaced daily.
Referring again to
Referring again to
The controller 24 can pump perfusate through arterial tube 18a into the implanted biological tissue graft 14 through a cannula in a major artery of the implanted biological tissue graft 14. The perfusate can then perfuse through the implanted biological tissue graft 14, optionally facilitated by pump 46, and out through a cannula in a major vein of the implanted biological tissue graft 14, into the venous tube 18b, into a negative pressure venous return system 67, back into the venous tube 18b into a perfusate collection receptacle (e.g., a perfusate reservoir). The major vein of the implanted biological tissue graft is in fluid communication with the first perfusate reservoir 30 via the venous tube(s) 18b and the negative pressure venous return system 67, where used perfusate can re-enter the first perfusate reservoir 30, thereby completing the machine perfusion circuit.
The introduction of a venous cannula into the major vein of the biological tissue graft 14 may create resistance in the form of back pressure that could oppose the flow of perfusate and result in vein collapse. Additionally, the length of the venous return tube 18b and changes in orientation of the venous tube 18b as the patient ambulates may also result in pressure differentials affecting venous return. System 10 may include a negative pressure venous return system 67 to compensate for the pressure differentials with negative pressure, improve venous return by preventing vein collapse, and ensure that the flow of used perfusate is unimpeded. The negative pressure venous return system 67 may be provided at the second end of the venous cannula or at any point along the length of the venous tube 18b between the venous cannula and the first perfusate reservoir 30.
The negative pressure venous return system 67 may regulate the flow rate of the used perfusate, the pressure in the venous return circuit, or a combination thereof. Referring to
The negative pressure venous return system 67 may be operated with or without a vacuum to control the rate at which the used perfusate is drawn through the system. When the negative pressure venous return system 67 is vacuum-operated, a pump (e.g., a roller pump or a peristaltic pump) may be included in-line downstream of outlet 75 and upstream of the first perfusate reservoir 30 to draw a vacuum against the outlet 75 of the venous return system 67, thereby motivating venous return flow from the graft 14 through the venous return system 67 at a controlled rate. Alternatively, if no vacuum is to be drawn, then the pump 46 configured to deliver perfusate to the graft via the arterial tube 18a may be sufficient regulate the flow of used perfusate through the negative venous return system 67 at a desired rate.
When vacuum is used, the pressure valve 74 will effectively regulate the degree of negative pressure that can be drawn within the chamber 70, and thus effectively against the venous return tube 18b leading from the graft 14, so that the negative pressure drawn thereon cannot exceed a threshold level of vacuum. The threshold level of vacuum at which the pressure valve 74 will crack to admit external air (or other gas) can be selected or tuned to correspond to a degree of vacuum at which the venous return tube 18b will remain reliably patent; i.e. so that it will not be collapsed by the force of vacuum. The one-way pressure valve 74 may also contain a filter (i.e., a HEPA filter) to prevent bacteria or other undesired contaminants in the external environment from entering the closed-loop fluid circuit. The one-way pressure valve 74 may be adjusted manually, such as by a twisting action, or may be adjusted automatically (electrically), in order to regulate its threshold cracking pressure (degree of vacuum). The chamber 70 may contain one or more pressure sensors in operative communication with the controller 24 that are configured to monitor the pressure in the chamber 70 and to adjust the valve 74 (in case it is electrically adjustable) to ensure that the degree of vacuum therein remains within a threshold range. When the one-way pressure valve 74 is automatically controlled, it and pressure sensors in the chamber 70 may operate in a feedback loop with the controller 24 to measure pressure in the chamber 70 and automatically adjust the one-way pressure valve 74 to maintain the threshold pressure value range in the chamber 70.
One or more inner walls 71 are disposed within the chamber 70 and are offset from a wall 72 of the negative pressure venous return system 67, such that a narrow channel 73 is formed therebetween. When more than one inner wall 71 is employed, the additional inner wall(s) may be offset from one another in chamber 70 to create a series of narrow channels 73 communicating between a sink at the base of the chamber where perfusate will pool, and the outlet 75 through which the used perfusate will leave the chamber 70 and enter the downstream venous tubing to be returned to the first perfusate reservoir 30. In this manner, capillary action helps to ensure that substantially only the liquid perfusate solution pooled at the bottom of the chamber 70 will be drawn out through the outlet 75, and not air or other gas within the headspace of that chamber, which may diminish the efficiency of the system.
Specifically, referring to
Returning to
The perfusion assembly 16 is patient-wearable and human-portable, such that the components thereof are confined within dimensions such that they may be worn and/or carried by the patient. For example, the perfusion assembly may be confined within a structure, such as a box, a capsule or other container that is human-portable to be worn and/or carried by the patient. The perfusion assembly 16 may be placed into a backpack, a messenger bag, or other carrying case to be human portable, e.g. having a shoulder strap so that it can be easily carried or worn by an ambulatory patient. For example,
Wearable portability of the system 10 in combination with longer preservation times from normothermic machine perfusion can reduce surgical transplantation time and allow an implanted biological tissue graft 14 to naturally vascularize to and with the patient's body as the patient goes about his or her everyday life without the need to remain hospitalized under continuous medical supervision. The system 10 described above permits an implanted biological tissue graft 14 to be preserved and sustained for at least four weeks (one month) or until the body neovascularizes the reattached tissue.
Another aspect of the present disclosure can include a method (
As a preliminary step, the perfusion assembly, which is external to a patient's body, is connected to a detached biological tissue graft harvested from a donor or the patient by cannulating arterial and venous tubes of the perfusion assembly to a major artery and a major vein, respectively, of the graft via respective cannula. Once the perfusion assembly has been connected to the detached biological tissue graft, the perimeter of the detached biological tissue graft is sutured to a defect at an external surface of the patient's body to form an implanted biological tissue graft. A patch including at least one sensor is applied to the external (outward-facing) surface of the implanted biological tissue graft, such that the at least one sensor is in direct contact with the external surface of the graft. A user (i.e., a patient or a medical caregiver) activates the system, for example via operational controls on the display device, to initiate the flow of perfusion through the perfusion assembly to the implanted biological tissue graft via the arterial tube. Perfusate flow to the major artery of the biological tissue graft is pressure controlled. In one embodiment, the system may be initiated by slowly increasing the flow of perfusate to the graft to reach a minimum pressure of 40 mmHg. Because vasoconstriction occurs in the graft vessels immediately after cannulation, the flow of perfusate may be initiated at a rate of 3 mL/min and maintained for between 10 minutes to 15 minutes to stabilize the pressure. Thereafter, the flow rate may be adjusted from between 2 mL/min to 30 mL/min every 10 minutes to 15 minutes until the minimum pressure is achieved and maintained. Spent perfusate is collected from the implanted biological tissue graft via the venous tube and transported to the perfusion assembly. In this manner, the arterial and venous tubes yield a closed fluid circuit between the perfusion assembly and the implanted biological tissue graft. Once perfusion has been initiated, a controller including a processor executes an algorithm stored in memory to perform the following steps.
At Step 201, the controller halts the operation of at least one pump at a first time interval for a predetermined first duration of time. The pump may be, for example, an infusion pump for controlling the amount of an additive added to a perfusate reservoir or the amount of perfusate added to or removed from a perfusate reservoir, or a pump responsible for controlling the rate at which perfusion flows from the perfusion assembly to the implanted biological tissue graft. In any event, halting the operation of any pump in the system stops the provision of perfusate to the implanted biological tissue graft. The first time interval can be programmed into the controller's memory. For example, the controller's memory may halt the pump after the expiration of 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, or so on. Alternatively, the time interval can be input by a user before perfusion has been initiated or during perfusion. For example, the controller may signal the display device to prompt the user (i.e., the patient or a medical caregiver) to input a time interval several hours after perfusion has begun. In one embodiment, a first time interval of 72 hours is used to create a period of gradient to force the body to neovascularize. The predetermined first duration of time may also be programmed into the controller's memory, or may be input by a user via the display device in the same manner as the time interval. In one embodiment, the predetermined first duration of time is 15 minutes.
At Step 202, the controller receives data regarding a first parameter measured by at least one sensor in direct contact with the external surface of the implanted biological tissue graft during the predetermined first duration. The first parameter is a physiologic parameter (e.g., temperature, pressure, oxygen saturation, etc.) and the data may include a single value (i.e., a single temperature measurement), or two or more values measured at time points within the predetermined first duration. In one embodiment, the sensor continuously measures the first parameter, and the controller only begins receiving data regarding said first parameter from the sensor once the pump has halted. In another embodiment, the controller signals the sensor to begin measuring the first parameter for the predetermined period of time once the pump has halted, to communicate the data regarding the first parameter to the controller, and to cease measuring the first parameter after the predetermined period of time. In an embodiment where the system includes a sensor array, the controller processes the respective values of the first parameter from each sensor in the array (i.e., by calculating the average, mean or median value).
At Step 203 the controller compares the data regarding the first parameter received from the sensor to a predetermined first threshold range for the at least one parameter. The predetermined first threshold range for the first parameter is programmed into memory and represents a parameter range for vascularized biological tissue. For example, if the first parameter is oxygen saturation, the predetermined first threshold range for oxygen saturation may be set at 80% oxygen saturation. In one embodiment, the controller may compare data for a single first parameter (i.e., temperature, oxygen saturation, and/or color) to a predetermined threshold range for that parameter. The data regarding the first parameter may include a single value (i.e., one temperature reading) or multiple values measured at distinct time periods or continuously during the predetermined period of time. When the data includes multiple values, the controller may, for example, calculate the average, mean or median of said values for comparison with a predetermined threshold range for the at least one parameter. In another embodiment, the controller may compare data for one or more parameters (i.e., temperature, oxygen saturation and/or color) measured by one or more sensors with predetermined threshold ranges for the respective parameters.
At Step 204, based on the comparison in Step 203, the controller adjusts at least one of: (i) a property of the perfusate, or (ii) a rate that the perfusate circulates from the perfusion assembly to the biological tissue graft. The property of the perfusate may be a concentration of an additive in the perfusate supplied from a separate additive reservoir of the external perfusion assembly, and said adjustment may include increasing, decreasing or maintaining the concentration of an additive added to the perfusate and/or the rate at which the perfusate circulates. As the patient's body naturally vascularizes the implanted biological tissue graft, the implanted biological tissue graft's dependence on the perfusate for sustenance decreases. Thus, if the data regarding the at least one parameter measured by the sensor during the predetermined first duration is within the predetermined range for that parameter, then the controller determines that the implanted biological tissue graft is being naturally vascularized by the patient's body and is less dependent (or, in some cases, no longer dependent) on perfusate for sustenance. Accordingly, the controller may adjust a property of the perfusate (i.e., the concentration of additive added to the perfusate supplied from a separate additive reservoir of the external perfusion assembly) and/or the rate at which perfusate is circulated to the implanted biological tissue graft down. Conversely, if the data for the at least one parameter obtained by the sensor after the pump has been halted is outside of the predetermined range for that parameter, then the controller determines that the implanted biological tissue graft has not yet been adequately vascularized by the body and remains dependent on perfusate for sustenance. In that instance, the controller may adjust the property of the perfusate (i.e., the concentration of additive added to the perfusate supplied from a separate additive reservoir) and/or the rate at which the perfusate is provided to the implanted biological tissue up, or maintain them at their existing settings. Taking the oxygen saturation example above, if the controller determines during the comparison step 203 that the data regarding oxygen saturation received from the sensor is greater than the first threshold range of 80%, then the controller will reduce the rate of perfusion by 3 mL/min to create a gradient for neovascularization.
At Step 205, the controller resumes operation of the at least one pump to resume circulation of perfusate to the implanted biological tissue graft for another time interval. Each subsequent time interval may be the same as the first time interval, or they may be different from the first time interval. In one embodiment, all time intervals may be 1 day, 2 days, or 3 days. In another embodiment, the first time interval may be 1 day, a second time interval may be 1 day, and a third time interval may be 3 days.
At Step 206, steps 201-205 are repeated. Each subsequent predetermined duration may be the same as the predetermined first duration, or they may be different. In one embodiment, all predetermined durations are 15 minutes. In another embodiment, the predetermined first duration of time may be 1 minute, a predetermined second duration of time may be 2 minutes, a predetermined third duration of time may be 3 minutes, and so on. Steps 201-205 are repeated until the first parameter remains within the predetermined first threshold range despite cessation perfusion of the biological tissue graft for a predetermined final duration. The predetermined final duration may be set by a user or may be programmed into the controller's memory as detailed above. When programmed into memory, the predetermined final duration may be specific to a type, size or weight of an implanted biological tissue graft.
At Step 207, when the controller determines that the data regarding the first parameter at the predetermined final duration of cessation of perfusion of the implanted biological tissue graft remains within the predetermined first threshold range, the controller sends an alert (i.e., via the display device) to the patient and/or the medical caregiver indicating that the perfusion assembly is ready to be disconnected from the implanted biological tissue graft. At this step, the controller has determined that the implanted biological tissue graft has been sufficiently vascularized by the patient's body, such that the implanted biological tissue graft no longer requires sustenance from the perfusate.
At Step 304, the controller can add, by the second infusion pump, perfusate from the second perfusate reservoir to the first perfusate reservoir when the amount of perfusate and/or concentrations of compounds (i.e., analytes) or additive(s) detected in the first perfusate reservoir are below the at least one predetermined threshold. The second perfusate reservoir can hold cooled perfusate (e.g., cooled on ice and/or with a nitrogen gas mixture) with no additional compounds added. The addition of the cooled perfusate to the first perfusate reservoir can increase the concentrations of perfusate compared to the substrates and analytes detected by the at least one detection device without having to remove perfusate from the first perfusate reservoir.
At Step 305, the controller can detect, by the at least one detection device, that a concentration of analytes in the perfusate is above a predetermined concentration threshold after the perfusate has perfused the implanted biological tissue graft. Analytes enter the perfusate from the implanted biological tissue graft and can be detrimental to effective perfusion of the implanted biological tissue graft when their concentration in the perfusate is above a predetermined level. At Step 306, the controller can remove, via the third infusion pump, at least a portion of the perfusate comprising the analytes from the first perfusate reservoir to the third perfusate reservoir (e.g., to be discarded or cleaned of analytes by a user). The controller can then add clean, cooled perfusate, via the second infusion pump, and additional substrates, via the first infusion pump to the first perfusate reservoir to maintain an amount of perfusate circulating through the system. The controller may detect, by at least one detection device, when the third reservoir is filled with perfusate and may alert the user that the third reservoir is ready to be replaced or emptied. Similarly, the controller may detect, by at least one detection device, when the second perfusate reservoir is empty, and may alert the user to replace or refill the second perfusate reservoir.
The controller may repeat steps 301-306 at predetermined time intervals, for example every 12 hours. Alternatively, the controller may continuously repeat steps 301-306.
From the above description, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications are within the skill of one in the art and are intended to be covered by the appended claims.
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 63/413,291 filed Oct. 5, 2022, whose contents are incorporated by reference.
Number | Date | Country | |
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63413291 | Oct 2022 | US |