Patent Application
20130197468
1. Field of the Invention
The present invention relates generally to the field of cardiac health and specifically to the field of heart monitoring and/or improving heart function and/or structure.
2. Description of the Background
Cardiovascular disease (CVD) is the leading cause of death in the western world. In the U.S. alone, patients suffer nearly 800,000 heart attacks per year and more then 2,200 Americans die of CVD each day. New therapeutic strategies for cardiac repair and monitoring are clearly needed.
Contemporary therapies include delivery of cellular and acellular biomaterials. Rejuvenative therapy by injection of cells has shown great promise, however, without delivering cells in a matrix (scaffold), cell retention, survival, and integration into the host tissue may be problematic. Further research has established that delivery of cells in a matrix can improve cellular retention and viability. While large-scale regeneration will likely require an exogenous cell source, many studies have also shown improvements with a matrix alone. There are numerous biomaterial matrices that have been investigated for cell delivery or used alone, including native, synthetic, and biomimetic materials. See Rane and Christman, “Biomaterials for the treatment of myocardial infarction: a 5-year update.” J. Am. Coll. Cardiol., 2011. 58(25):2615-29 for comprehensive survey, which is hereby incorporated by reference. The advantages of using native biomaterials are their constituents provide a microenvironment that contains physical, chemical, and mechanical cues similar to native tissue.
While both transepicardial and transendocardial deployments of matrices are feasible, epicardial delivery is highly invasive, with associated risks and high costs. Minimally invasive transendocardial delivery via catheter deployment is a more practical clinical approach. For such applications, the art generally believes that the material should be an injectable hydrogel precursor that has the proper gelation properties and kinetics to remain liquid within the catheter during delivery, while allowing the formation of a gel within the myocardial tissue following delivery. Several problematic issues arise with this approach: 1) gel injectability, i.e., assuring gelation does not prematurely occur in the catheter or that the material does not leak out of the catheter prior to injection; 2) maintaining gel localization at the delivery site, i.e., assure that the gel precursor remains in targeted injection locations and does not egress through the path formed by needle puncture: 3) gel retention for sufficient time needed for regeneration, i.e., does not degrade too quickly; and, 4) inherent gel stiffness properties, which may not be optimal for physiological circumstances.
One injectable considered for clinical use is based on blood plasma platelet gel. Cheng, et al., “Intramyocardial injection of platelet gel promotes endogenous repair and augments cardiac function in rats with myocardial infarction.” J. Am. Coll. Cardiol., 2012, 59(3): 256-64. This approach is similar in spirit to autologous platelet-rich plasma (aPRP) therapies currently used in sports medicine and wound healing applications. Those aPRP therapies are controversial because of the outcomes have been highly variable and unpredictable, due in past to patient-to-patient variability in platelet quantity and quality, bed-side preparation variability, and their relatively short residence times in vivo. Additionally, administration of aPRP-based formulations is traditionally more difficult as such products are not an off-the-shelf solution. Blood plasma platelet gels used in cardiac repair may suffer similar consequences, and, when used in these cardiac applications, the blood plasma/platelets must be pre-activated just prior to injection; therefore gelation kinetics and injection timing may slid be problematic for reliable deployment.
In addition, significant advances have been made in the development of materials and devices which are capable of improving tissue structure, healing, and function, as well as monitoring or protecting the tissue. Examples include heart monitoring devices that are able to measure cardiac motion, pressure, or wall stress. Placement of sensors in the heart has previously been limited to the right side of the organ due to concerns of increasing the risk of thrombosis, embolization, and sensor stability.
The present invention addresses the deficiencies of the prior art by providing novel methods and apparatuses by which materials may be administered to the heart, other solid organ, or tissue of a patient in need thereof. The present invention employs apparatuses that may controlably deliver biologically active materials or sensors directly to specific locations in the organ or tissue, e.g. heart or muscle. The apparatuses may be fabricated from the cellular and acellular biologically active components to promote appropriate integration into the tissue, healing of the tissue, and appropriate temporal and spatial administration of biologically active molecules. The delivery methods and apparatuses of the present invention may be employed in a wide variety of physiological and medical situations.
The present invention addresses the deficiencies of the prior art by providing novel methods and apparatuses by which materials may be administered to the heart, other solid organ, or tissue of a patient in need thereof. The present invention employs apparatuses that may controllably deliver biologically active materials or sensors directly to specific, locations in the organ or tissue, e.g. heart or muscle. The apparatuses may be fabricated from the cellular and acellular biologically active components to promote appropriate integration into the tissue, healing of the tissue, and appropriate temporal and spatial administration of biologically active molecules. The delivery methods and apparatuses of the present invention may be employed in a wide variety of physiological and medical situations, with cardiac implementations being particularly appropriate.
The apparatus may be fabricated from plasma-containing materials or other biopolymers such that the apparatus will be resorbed into the tissue following insertion. In some embodiments, the biologically active cellular or acellular component is incorporated into the material from which the apparatus is fabricated and that material serves as the source of the biologically active component. The apparatus may be in form of nails, rings, loops, screws, barbs, or any shape that is appropriate for the particular application confronting the medical practitioner. In some embodiments, the apparatus may include a hollow chamber inside. The apparatus may be implanted directly into a target organ or tissue through the vasculature. The hollow chamber within the apparatus may contain the biologically active materials that are to be delivered to the patient, instead of or in addition to the biologically active materials contained in the apparatus body. In certain contexts, it may be desirable for the apparatuses to include two components—a harder tip having physical properties conducive to insertion into more resilient or hard tissues (e.g., heart wall, bone), while preserving a different set of properties for the body of the apparatus that may achieve the desired pharmacokinetic release properties appropriate for the medical context confronting the medical practitioner.
For the present invention to be clearly understood and readily practiced, the present invention will be described in conjunction with the following figures, wherein like reference characters designate the same or similar elements, which figures are incorporated into and constitute a part of the specification, wherein:
It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating for purposes of clarity, other elements that may be well known. The detailed description will be provided hereinhelow with reference to the attached drawing.
The present invention provides methods and apparatuses for the improved treatment of solid internal organs, including the heart. The present invention further provides methods and apparatuses for the improved treatment of tissues into which the devices of the present invention may be secured. The present invention is useful tor the precise placement of sensors in the organ or tissue tor extended monitoring. The present invention is also useful in the delivery of native and exogenous biologically active materials to the solid organ or tissue both reliably and precisely. The apparatus may be fabricated from or a biologically active material. The body of the apparatus may also be fabricated from cell-based formulations or contain as a major or minor component a biologically active material, as described below. In those circumstances, the apparatus itself is the both delivery vehicle and source of biologically active material.
While the description below emphasizes the implementation of embodiments for the heart, the present invention may be employed in the monitoring or treatment of any solid organ, (e.g., heart) or tissue (e.g., muscle, brain). Additionally, the term “patients” as used herein is meant to encompass not only humans, hut any animal where the monitoring or treatment of a solid organ or tissue is desired.
The present invention encompasses devices that may be implanted into a solid organ or tissue tor the targeted delivery of biologically active components to that target organ or tissue or the targeted placement of a physiologic sensor into that location. The devices of the present invention may deliver cellular or acellular biologically active components through the device or alternatively, the body of the device may be fabricated from a biologic material itself. Those acellular biologically active components may generally referred to as a “drug” and include, for example, a wide variety of synthetic and natural components, including small molecules, peptides and proteins (including antibodies and extracellular matrix proteins), and nucleotides. In some embodiments, the apparatuses of the present invention may include one or more internal chambers in which the biologically active component is housed during placement of the apparatus. As the body of the apparatus degrades, the cellular or acellular material in the chamber(s) may escape and be delivered to the patient at the location in the body where the device has been implanted. Thus, the hollow chambers may act as reservoirs tor biologically active materials to be delivered to the patient. Additionally, the devices may include a composition that facilitates the integration of the device into the wall of the organ or tissue and reduces rejection of the device by the body.
The apparatuses of the present invention may be secured into the wall of a target organ or into any tissue. In specific implementations, the devices of the present invention may be implanted into heart tissue via either endocardial or epicardial methods. For other placement of the devices of the present invention into non-cardiac locations, the devices of the present invention may similarly be deployed either transvascularly or directly into the organ or tissue. In some embodiments, the devices of the present invention may be employed via a catheter, as discussed further below.
The devices of the present invention may be fabricated from a variety of materials. The material may be biodegradable material. In some embodiments, the devices of the present invention may be fabricated from both metal and a biodegradable substance. The metal may provide structural stability to the target organ or tissue, such as in implementations when the devices of the present invention are placed into bone. Similarly, the physical properties of the material (e.g., stiffness and porosity) may be manipulated to match the appropriate circumstance confronting the medical practitioner.
In certain embodiments, the apparatuses of the present invention are fabricated from a biodegradable material that is slowly resorbed into the body over time. The material from which the devices are fabricated may he designed to attenuate any unwanted reaction of the patient's body (e.g., inflammation) as to permit better integration of a device (e.g., pressure sensor) or biologic (e.g., cells) into the target organ or tissue.
The devices of the present invention may be used to deliver biologically active components to a target organ or tissue in other manners as well. As noted above, the chamber or chambers of the devices of the present invention may include a single or numerous biologically active materials. Additionally, the shell of the device may be fabricated from a therapeutic biologic material. For example, its some embodiments, the shell of the device may be fabricated from a plasma-derived composition, as disclosed in U.S. Pat. No. 8,293,530, which is hereby incorporated by reference.
Plasma-based materials (PBM) may be manufactured starting with pooled, allogenic blood plasma and platelet fraction. Unlike platelet concentrators used in aPRP therapies, which concentrate the platelets and subsequently discard a significant volume of plasma, PBMs employed within the context of the present invention may utilize the entire plasma, including the platelets, which will often include growth factors and other components that are not platelet-derived. Gelling with calcium chloride to saturate the sodium citrate anticoagulate activates the platelets, and the resulting hydrogel is freeze-dried and ground into a powder. The powdered material is then mixed with glycerol as a plasticizer. The resultant mixture forms a dough-like material that is compression molded at low temperatures (approximately 50-70° C.) and high-pressures (approximately 2,000 to 10,000 psi) into highly concentrated, dense solid forms as shelf-stable PBM that retain native biological activity.
Prior to molding, additional components may be added to the dough, as needed, including porogens, cross-linking agents, other ECM powders (e.g., cardiac ECM; “CECM”), minerals, growth factors, or immunoresponse regulators such as IL-10. For example, the elution rate of drugs from PBMs, PBM mechanical properties, and degradation rates can be further modulated with the addition of the plant-based cross-linker genipin (see, e.g., U.S. Pat. No. 8,293,530) which is substantially less toxic than glutaraldyde used in the prior art to control CECM gel stiffness. Porous bioplastics may be created by adding mannitol powder to the mix; after hydration, the mannitol dissolves in vitro or in vivo. For cell delivery, cells may be seeded on porous PBMs after the molding process. To assure safety, PBMs may also virally inactivated using a combination of pasteurization and gamma radiation as an added safety precaution against the remote possibility that any of the donated and screened blood products arc contaminated with unknown pathogens. Using pooled plasma/platelets overcomes patient-to-patient plasma/platelet variability associated with autologous sourcing approaches. In addition, use of pooled PRP enables these products to be rapidly available for off-the-shelf use and lowers manufacturing costs, which translates into relatively low cost products.
This composition may be useful in treating a medical condition in the solid organ or tissue in which the device is placed and/or promote incorporation of the apparatus into the local biological environment. When fabricated from a PBM, the device of the present invention may include a coating that maintains the integrity of the device daring any medical procedures employed to insert the device into the target organ or tissue. The devices of the present invention may be fabricated in whole or in part of a PBM or other compositions that include platelets or other biologically derived materials as a minor component.
The apparatuses of the present invention may also be fabricated from bioplastics processing technology that can form native protein and peptide (i.e., proteinaceous) materials into complex three-dimensional shapes using a low-temperature, high-pressure compression molding process that maintains bio-activity of proteins. Such bioplastic materials become rubbery upon hydration, however, their microstructural, mechanical, and degradation properties can be modified by varying the relative amounts of plasticizer, porogens, or plant-based cross-linkers mixed in with the proteinaceous material prior to molding of the device. That manufacturing process also enables growth factors, immunoresponse regulators, and drugs to be directly composited with bioplastics. The bioplastic may include ECM or CECM as a major or minor component. Additionally, porous bioplastics could be seeded with cells, post-molding, to enhance cell delivery.
The materials that make up the device may be in part or in whole a therapeutic material that provides a benefit to the organ or tissue into which it is placed, e.g., plasma-based materials, formulations containing ECM or CECM. The devices of the present invention may also be fabricated from a material that is able to achieve a controlled release of a biologically active agent into the target organ or tissue. Apparatuses fabricated from PBMs are believed to be degraded by the patient's body by proteolysis. As such, control over release of a biologically active agent is achieved through cellular-mediated enzymatic digestion of the apparatus. When fabricated from biologically compatible plastics, such as, but not limited to, those PBM compositions described above, the apparatuses of the present invention may be fabricated using a compression molding approach.
The apparatuses of the present invention may be formed into numerous shapes. The apparatuses may be in the form of nails, rings, screws, loops, barbs, or any shape that is appropriate for the particular application confronting the medical practitioner. The specific fixation approach employed may be adapted to satisfy any anatomical requirements of the tissue substrate into which the apparatuses are being delivered. In many medical applications, screws are used to implant a device at a particular location in the patient's body. While some of the description below centers on implementations of the present invention having the structure of a screw, the general concepts are equally applicable to any shape of apparatus that might be needed for the application at hand.
The present invention will provide a clinically practical approach for highly controlled, localized delivery of biologically active materials because the placement of these devices will not rely on gelation kinetics of a formulation. Instead, the apparatus will preferably ‘lock’ into place of deployment of the biologically active material at the site of implanting. The inherent bioactivity of the apparatuses of the present invention fabricated from plasma- or protein-based materials may be sufficient to aid repair or could be used to enhance the actions of other biologic components such as cells and growth factors dub these screws could deliver. Moreover, bioplastic apparatuses of the present invention have tailorable degradation and mechanical properties, and represent off-the-shelf devices, storable at room temperature, that are easily and conveniently employed by medical practitioners.
A screw-shaped embodiment 100 of the present invention is shown in
As noted above, the present invention is a generalized tool for the delivery of such cellular and acellular materials to solid organs and tissues. As such, the specific components that may be included in the internal chamber of the apparatuses of the present invention may be tailored to the specific physiological or disease state that confronts the treating physician.
In other embodiments, the device may include one or mom chambers incorporated within the body of the device 200 as shown in
In some instances, it may be desired to have a particular stiffness and porosity of screw (or other apparatus shape) that might be incompatible with insertion of that screw into the target tissue or organ. Such circumstances may arise when the target tissue or organ (e.g., bone or cardiac wall) dictates stiffer or more resilient properties tor insertion into the tissue or penetration of the organ. At the same time, those stiller physical properties may result in apparatuses have other properties (e.g., dissolution rate, drug release rate, or porosity) that are incompatible with the medical application for which the apparatuses are being employed. To address such situations, the present invention provides apparatuses that may include multiple components—for example, one having the appropriate physiological and physical properties for the medical application and a second having the physical components appropriate for penetrating the target tissue or organ.
An example of such an embodiment 300 is shown in
In some embodiments, such as shown in
An example of such an embodiment is shown in
Other physiological sensors may be employed in the context, of the present invention, including pH sensors, glucose sensors, temperature sensors, flow sensors, biochemical sensors, motion sensors, and others. Additionally, the device to be implanted into the target organ or tissue may include a mechanism for generating power for use by the sensor and transmission circuitry. The sensor may employ specialized materials and circuitry (e.g., piezoelectric circuitry) to generate power for the sensor to employ. The piezoelectric circuitry may scavenge energy from heart wall contractions or horn heart wall motion, or from blood flow inside the heart. As one embodiment, wire 428 in
As noted above, the devices of the present invention may be deployed either transvascularly or directly into the organ or tissue. In the specific circumstance of cardiac deployment, the screw apparatuses of the present invention may be inserted either transepicardially or transendocardially. An example of transendocaridal implantation is shown in
A spring clasp 520 may be used to keep the screw 516 engaged with the guide wire 512 to prevent the screw 516 from disengaging until it is secured in the myocardium 504, or, if needed, to back it out. The following insertion sequence may be employed: (1) deploy catheter 508 to desired screw delivery site; insert screw/guide-wire 512/516 into catheter 508 and advance the screw 516 until the screw/catheter 516/508 is in contact against endocardium 504—
Because the present invention may be firmly fixed in the wall of a patient's organ or into tissue, the placement may be stably maintained after implantation. This attribute is of particular benefit when treating or monitoring organs that move significantly, such as the heart.
Because the apparatuses of the present invention are a solid-phase material, they may be fixed into a wall of a solid organ or into tissue. As a result, issues that accompany liquid-phase delivery vehicles, such as migration of the injected solution and subsequent dilution of any delivered biologically active material are mitigated. Accordingly, the present invention is able to achieve reliable and precise administration of biological active agents to a target tissue. Furthermore, the present invention provides for the controlled degradation of biologically active components over time.
Nothing in the above description is meant to limit the present invention to any specific materials, geometry, or orientation of elements. Many modifications are contemplated within the scope of the present invention and will be apparent to those skilled in the art. The embodiments described herein were presented by way of example only and should not be used to limit the scope of the invention.
This application claims priority to U.S. Patent Application Ser. No. 61/590,938 filed on Jan. 26, 2012.
This invention was made with government support under grant number 2 UL1 RR024153-06 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 61590938 | Jan 2012 | US |
