WO2012166554A2 - Extracellular matrix material conduits and methods of making and using same - Google Patents
Extracellular matrix material conduits and methods of making and using same Download PDFInfo
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- WO2012166554A2 WO2012166554A2 PCT/US2012/039450 US2012039450W WO2012166554A2 WO 2012166554 A2 WO2012166554 A2 WO 2012166554A2 US 2012039450 W US2012039450 W US 2012039450W WO 2012166554 A2 WO2012166554 A2 WO 2012166554A2
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- WIPO (PCT)
- Prior art keywords
- ecm material
- material conduit
- valve
- tissue
- heart
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
- A61F2/2415—Manufacturing methods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3633—Extracellular matrix [ECM]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
- A61M39/22—Valves or arrangement of valves
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0094—Gaseous substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
Definitions
- the invention relates to extracellular matrix (ECM) material conduits and methods of using such ECM material conduits to regenerate atrioventricular (AV) valves within a heart of a subject.
- ECM extracellular matrix
- Commonly used replacement heart valves can be classified in the following three groups: mechanical valves; allograft tissue valves; and xenograft tissue valves.
- Mechanical heart valves including, for example and without limitation, caged- ball valves, bi-leaflet valves, and tilting disk valves are typically attached to a sewing ring so that the valve prosthesis can be sutured to the patient's native tissue to hold the mechanical valve in place postoperatively.
- mechanical heart valves have advantageous long- term durability, these mechanical valves also have a propensity to cause the formation of blood clots in a patient. If such blood clots form on the mechanical valve, they may preclude the valve from opening or closing correctly or, more importantly, may disengage from the valve and embolize to the brain, causing an embolic stroke.
- Allograft tissue valves are harvested from human sources, such as human cadavers. Unlike mechanical heart valves, allograft tissue valves typically do not promote blood clot formation and, therefore, avoid the need for prescribing an anticoagulant medication for the patient. However, allograft tissue valves are not available in sufficient numbers to satisfy the needs of all patients who need new heart valves. Furthermore, there have been significant complications when allograft tissue valves have been used to replace atrioventricular (AV) valves within a subject. Moreover, allograft tissue valves can be more difficult to implant than mechanical valves or xenograft valves. Because of these difficulties in implantation, the operative risk associated with allograft tissue valves is often greater than the operative risks associated with mechanical valves and xenograft valves.
- AV atrioventricular
- Xenograft tissue valves are formed from non-human tissue sources, such as cows or pigs. Most known xenograft tissue valves are constructed by sewing and/or constructing valve leaflets from a non-human tissue source and then securing the leaflets within a patient's heart using a stent and/or a sewing ring. These xenograft tissue valves are less likely to cause blood clot formation than comparable mechanical valves, and therefore, patients that receive xenograft tissue valves are not always required to take anticoagulant medications. However, xenograft tissue valves are prone to calcification and lack the long- term durability of mechanical valves and, consequently, require frequent replacement as compared to mechanical valves.
- xenograft tissue valves typically undergo to reduce antigenicity of the animal tissue. Without these chemical treatments, xenograft tissue valves can trigger an immune response in a patient, which can lead to rejection of the tissue valve by the patient.
- Another factor that may contribute to the lack of durability of the xenograft tissue valves is the presence of a stent and/or sewing ring, which can prevent the xenograft tissue valve from accurately approximating the anatomy of a normal heart valve.
- tissue prosthesis that can be easily implanted to regenerate an anatomically accurate AV valve within the heart of a subject.
- tissue prosthesis that can be implanted to regenerate an AV valve within the heart of a subject.
- Extracellular matrix (ECM) material conduits are disclosed.
- a disclosed ECM material conduit defines a lumen and has an inlet portion and an outlet portion.
- the inlet portion of the ECM material conduit includes an inlet of the lumen.
- the outlet portion of the ECM material conduit includes an outlet of the lumen.
- the inlet portion and the outlet portion of the ECM material conduit can each have an outer circumference.
- the ECM material conduit is sterile and acellular.
- atrioventricular (AV) valve to replace a defective AV valve within a heart of a subject are also disclosed.
- the methods include removing the defective AV valve from the heart of the subject.
- the methods also include implanting an ECM material conduit within the heart of the subject to regenerate a functional AV valve.
- Figure 1 is a cut-away view of a human heart.
- Figure 2 is a perspective view of an ECM material conduit as it is attached to an annulus of an atrioventricular valve and to two papillary muscles, as described herein.
- FIG. 3 is a bottom perspective view of the ECM material conduit shown in
- FIG. 3 The ECM material conduit depicted in Figure 3 is attached to a first papillary muscle at a first attachment point and to a second papillary muscle at a second attachment point.
- Figure 4 is an image of a native tri-cuspid valve following removal from the heart of a subject.
- Figure 4 includes markings corresponding to particular measurements that were performed on various native porcine and human tri-cuspid valves.
- Figure 5 is an image of an ECM material conduit following implantation of the
- FIG. 5 displays the ECM material conduit in a closed position within an in vitro model of the right heart.
- Figure 6 depicts Doppler echocardiography images taken postoperatively for an exemplary ECM material conduit functioning as a tri-cuspid valve within an animal.
- Figure 6(a) depicts the ECM material conduit one month following the operation with the valve in a closed position.
- Figure 6(b) depicts the ECM material conduit immediately post-operatively with the valve in an open position.
- Figure 6(c) depicts the ECM material conduit
- Figure 7 displays images of a regenerated tri-cuspid valve at various time points following implantation of an exemplary ECM material conduit as described herein.
- Figure 7(a) shows regeneration at 3 months.
- Figure 7(b) shows regeneration at 5 months.
- Figure 7(c) shows regeneration at 8 months.
- Figure 7(d) shows regeneration at 12 months.
- Figure 8 displays an image of a regenerated tri-cuspid valve at three months following implantation of an exemplary ECM material conduit as described herein.
- Figures 9-10 depict the results of an experiment in which DNA content was measured for small intestinal submucosa (SIS) compositions following various sterilization methods, including the sterilization methods described herein.
- Figure 9 shows the DNA content of each SIS composition following sterilization.
- Figure 10 shows the percentage of DNA that was removed from each SIS composition following sterilization, as compared to raw, unprocessed SIS.
- SIS small intestinal submucosa
- Figures 11-12 depict the results of an experiment in which native growth factor content was measured for SIS compositions following various sterilization methods, including the sterilization methods described herein.
- Figure 11 shows the bFGF content of each SIS composition (normalized by dry weight of samples) following sterilization.
- Figure 12 shows the active TGF- ⁇ content of each SIS composition (normalized by dry weight of samples) following sterilization.
- Figure 13 depicts the results of an experiment in which bFGF was incorporated into SIS compositions during rapid depressurization, as described herein.
- Figure 13 shows the bFGF content for each SIS composition (normalized by dry weight of samples) following rapid depressurization.
- Figure 14 depicts the results of an experiment in which the tensile strength of two-ply SIS compositions was measured following various sterilization methods, including the sterilization methods described herein. Figure 14 shows the tensile strength measured for each SIS composition following sterilization.
- Figure 15 depicts the results of an experiment in which native growth factor content was measured for SIS compositions following various sterilization and/or decellularization methods, including the sterilization and decellularization methods described herein. Figure 15 shows the bFGF enzyme-linked immunosorbent assay (ELISA) results for each SIS composition (normalized by dry weight of samples) following sterilization and/or decellularization.
- ELISA enzyme-linked immunosorbent assay
- Figure 16 shows the DNA content in SIS after it is processed in various ways.
- the baseline measurement is raw.
- the tissue was then exposed to supercritical C0 2 followed by rapid depressurization (RDP) to facilitate enhanced removal of DNA and cellular debris.
- RDP rapid depressurization
- PAA peracetic acid
- the comparison is to processed SIS either unsterilized or sterilized with ethylene oxide (ETO).
- Figure 17 shows the Percent removal of DNA from SIS after it is processed in various ways.
- the baseline measurement is raw.
- the tissue was then exposed to supercritical C0 2 followed by rapid depressurization (RDP) to facilitate enhanced removal of DNA and cellular debris.
- RDP rapid depressurization
- PAA peracetic acid
- the comparison is to processed SIS either unsterilized or sterilized with ethylene oxide (ETO).
- FIG 18 shows the variable active Transforming Growth Factor (TGF-beta) content in SIS after it is processed in various ways.
- the baseline measurement is raw, or unprocessed SIS followed by processing with only Triton X-100 (TX-100) detergent.
- TX-100 Triton X-100
- the tissue was then exposed to supercritical C0 2 followed by rapid depressurization (RDP) to facilitate enhanced removal of DNA and cellular debris. After the RDP, the tissue was placed in supercritical C0 2 with peracetic acid (PAA) for sterilization.
- PAA peracetic acid
- the comparison is to processed SIS either unsterilized or sterilized with ethylene oxide (ETO).
- ETO ethylene oxide
- FIG. 19 shows the variable basic Fibroblast Growth Factor (bFGF) content in
- the baseline measurement is raw, or unprocessed SIS followed by processing with only Triton X-100 (TX-100) detergent.
- TX-100 Triton X-100
- RDP rapid depressurization
- PAA peracetic acid
- the comparison is to processed SIS either unsterilized or sterilized with ethylene oxide (ETO).
- Figure 20 shows the addition of basic Fibroblast Growth Factor (bFGF) content to SIS using rapid depressurization.
- the baseline measurement is raw, or unprocessed SIS.
- the comparison is to processed SIS either unsterilized or sterilized with ethylene oxide (ETO).
- an and “the” include plural referents unless the context clearly dictates otherwise.
- reference to an "attachment point” can include two or more such attachment points unless the context indicates otherwise.
- Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
- a "subject” is an individual and includes, but is not limited to, a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent), a fish, a bird, a reptile or an amphibian.
- a mammal e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent
- the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included.
- a “patient” is a subject afflicted with a disease or disorder.
- patient includes human and veterinary subjects.
- the term "subject can be used interchangeably with the term "patient.”
- the term “circumference” refers to the perimeter of, or the length measurement of the boundary defined by, a closed planar figure.
- a “circumference” can correspond to the perimeter of a closed planar circle.
- a “circumference” can correspond to the perimeter of any closed planar figure, such as, for example and without limitation, an oval, square, rectangular, trapezoidal, or nonsymmetrical closed planar figure.
- an outer “circumference” of a conduit corresponds to the perimeter of the closed planar figure defined by an outer surface of the conduit at a particular location along the longitudinal axis of the conduit.
- frusto-conical refers to the shape of a conical frustum, which corresponds to the shape of a cone that has had its tip truncated by a plane parallel to its base.
- a “frusto-conical” conduit has a substantially circular cross-section that varies in diameter along its longitudinal axis.
- the "frusto-conical” conduits disclosed herein have inlet portions and outlet portions that each have outer circumferences.
- the outer circumference of the outlet portion of a disclosed “frusto-conical” conduit can be greater than the outer circumference of the inlet portion of the "frusto-conical” conduit.
- the outer circumference of the outlet portion of a disclosed “frusto-conical” conduit can be less than the outer circumference of the inlet portion of the "frusto-conical” conduit.
- the outer circumference of the outlet portion of a disclosed “frusto-conical” conduit can be substantially equal to the outer circumference of the inlet portion of the "frusto-conical” conduit.
- the term “acellular” is meant to describe extracellular matrix compositions that are at least 80 % decellularized such that the extracellular matrix composition is at least 80 % without cells and/or cellular remnants.
- the term “acellular” can refer to extracellular matrix compositions that are at least 90 % decellularized such that the extracellular matrix composition is at least 90 % without cells and/or cellular remnants.
- the term “acellular” can refer to extracellular matrix compositions that are at least 95 % decellularized such that the extracellular matrix composition is at least 95 % without cells and/or cellular remnants.
- the term “acellular” can refer to extracellular matrix compositions that are at least 96 % decellularized such that the extracellular matrix composition is at least 96 % without cells and/or cellular remnants.
- the term “acellular” can refer to
- extracellular matrix compositions that are at least 97 % decellularized such that the extracellular matrix composition is at least 97 % without cells and/or cellular remnants.
- the term “acellular” can refer to extracellular matrix compositions that are at least 98 % decellularized such that the extracellular matrix composition is at least 98 % without cells and/or cellular remnants.
- the term “acellular” can refer to extracellular matrix compositions that are at least 99 % decellularized such that the extracellular matrix composition is at least 99 % without cells and/or cellular remnants.
- acellular can refer to extracellular matrix compositions that are decellularized at levels of 80 %, 81 %, 82 %, 83 %, 84 %, 85 %, 86 %, 87 %, 88 %, 89 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 100 %, and any percentages falling between these values.
- additive refers to materials that can be selectively incorporated into the disclosed ECM materials to impart predetermined properties to the sterilized, acellular ECM compositions disclosed herein.
- additives can include, for example and without limitation, growth factors, cytokines, proteoglycans, glycosaminoglycans (GAGs), proteins, peptides, nucleic acids, small molecules, cells and pharmaceutical agents, such as statin drugs, corticosterioids, anti-arrhythmic drugs, nonsteroidal anti-inflammatory drugs, other anti-inflammatory compounds, nanoparticles, and metallic compounds.
- the term "contemporaneously” refers to the simultaneous and/or overlapping occurrence of events, as well as the sequential occurrence of events within thirty minutes before or after one another. Thus, if a first event occurs, then a second event can be said to have occurred contemporaneously with the first event if it occurred
- a first method step is performed, then a second method step performed five minutes after the first method step can be said to be performed "contemporaneously" with the first method step.
- the second method step was performed ten minutes before performance of a third method step, then the second method step can be said to be performed "contemporaneously” with the third method step.
- the term "supercritical" refers to a fluid state of a material when it is held at or above its critical temperature and critical pressure. When a material is held at or above its critical temperature and critical pressure, then it typically adopts functional properties of both a gas and a liquid and is said to function as a supercritical fluid.
- a material when carbon dioxide is held at or above its critical temperature (31.1°C) and its critical pressure (1,071 psi), it behaves as a supercritical carbon dioxide fluid and can, for example, exhibit the expansion properties of a gas while having the density of a liquid.
- an exemplary ECM material conduit 10 can define a lumen 12 and have an inlet portion 14 and an outlet portion 18.
- the inlet portion 14 of the ECM material conduit 10 can comprise an inlet 16 of the lumen 12.
- outlet portion 18 of the ECM material conduit 10 can comprise an outlet 20 of the lumen 12.
- the inlet portion 14 and the outlet portion 18 of an ECM material conduit 10 can each have an outer circumference.
- the outer circumference of the outlet portion 18 of the ECM material conduit 10 can be substantially equal to the outer circumference of the inlet portion 14 of the ECM material conduit.
- the ECM material conduit 10 can be substantially cylindrical.
- the outer circumference of the outlet portion 18 of the ECM material conduit 10 can be greater than the outer circumference of the inlet portion 14 of the ECM material conduit.
- the ECM material conduit 10 can be substantially frusto-conical.
- the outer circumference of the outlet portion 18 of the ECM material conduit 10 can be less than the outer circumference of the inlet portion 14 of the ECM material conduit.
- the ECM material conduit 10 can be substantially frusto-conical.
- the ECM material conduit can have a longitudinal axis 24 and a longitudinal length ranging from about 10 mm to about 50 mm.
- the outer circumferences of the inlet portion 14 and the outlet portion 18 of the ECM material conduit 10 can each range from about 25 mm to about 190 mm.
- the lumen 12 of the ECM material conduit can have a diameter ranging from about 8 mm to about 60 mm.
- the ECM material conduit 10 can have a wall 22 having a thickness. In this aspect, it is contemplated that the thickness of the wall 22 of the ECM material conduit 10 can range from about 0.05 mm to about 3.00 mm.
- the outlet portion 18 of the ECM material conduit 10 can comprise one or more extension portions that protrude outwardly from the ECM material conduit 10. It is contemplated that the extension portions can be configured to provide an attachment configuration for the papillary muscles that more closely mimics native functionality. It is further contemplated that the extension portions can be configured to promote fusion between the native papillary muscles attached to the ECM material conduit 10 and the regenerated AV valve formed following implantation of the ECM material conduit as described herein.
- a disclosed ECM material conduit can comprise any known ECM component or material, including, for example and without limitation, mucosal layers and components, submucosal layers and components, muscularis layers and components, and/or basement membrane layers and components.
- a disclosed ECM material conduit can comprise an ECM material obtained from any mammalian tissue source, including, for example and without limitation, stomach tissue (e.g., stomach submucosa (SS)), small intestinal tissue (e.g., small intestinal submucosa (SIS)), large intestinal tissue, bladder tissue (e.g., urinary bladder submucosa (UBS)), liver tissue (e.g., liver basement membrane (LBM)), heart tissue (e.g., pericardium), lung tissue, kidney tissue, pancreatic tissue, prostate tissue, mesothelial tissue, fetal tissue, a placenta, a ureter, veins, arteries, heart valves with or without their attached vessels, tissue surrounding the roots of developing teeth, and tissue surrounding growing bone.
- stomach tissue e.g., stomach submucosa (SS)
- small intestinal tissue e.g., small intestinal submucosa (SIS)
- large intestinal tissue e.g., large intestinal submu
- a disclosed ECM material conduit can comprise an ECM material obtained from ECM components or materials of one or more mammals including, for example and without limitation, humans, cows, pigs, dogs, sheep, cats, horses, rodents, and the like.
- a disclosed ECM material conduit can comprise ECM components or materials from two or more of the same mammalian species, such as, for example and without limitation, two or more cows, two or more pigs, two or more dogs, or two or more sheep.
- a disclosed ECM material conduit can comprise ECM components or materials from two or more different mammalian species, such as, for example and without limitation, a pig and a cow, a pig and a dog, a pig and a sheep, or a cow and a sheep. It is still further contemplated that a disclosed ECM material conduit can comprise ECM components or materials obtained from a first tissue source, such as, for example and without limitation, SIS, from a first mammal, as well as ECM components or materials obtained from a second tissue source, such as, for example and without limitation, SS, from a second mammal.
- a first tissue source such as, for example and without limitation, SIS
- a second tissue source such as, for example and without limitation, SS
- a disclosed ECM material conduit 10 can be formed from a substantially flat sheet of ECM material.
- the ECM material conduit 10 can be formed by securing a first edge of the sheet of ECM material to a second, opposed edge of the sheet of ECM material such that a lumen 12 of the ECM material conduit is defined. It is contemplated that the first edge of the sheet of ECM material can be secured to the second edge of the sheet of ECM material using any conventional surgical attachment means, including, for example and without limitation, non-absorbable sutures, absorbable sutures, surgical pastes, surgical glues, staples, and the like.
- the nonabsorbable sutures when nonabsorbable sutures are used to secure the first edge of the sheet of ECM material to the second, opposed edge of the sheet of ECM material, it is contemplated that the nonabsorbable sutures can be positioned on an outer surface of the ECM material conduit, thereby reducing the portion of the sutures positioned within the lumen of the ECM material conduit.
- the second edge of the sheet of ECM material can be secured in overlapping relation with the first edge of the sheet of ECM material.
- the portion of the ECM material conduit 10 at which the first and second edges of the sheet overlap can be everted relative to the lumen of the ECM material conduit.
- the second edge of the sheet of ECM material can be secured in substantial alignment with the first edge of the sheet of ECM material.
- a disclosed ECM material conduit 10 can comprise at least a portion of an intact, lumenal ECM material, such as, for example and without limitation, a lumenal portion of a native SIS layer.
- the intact ECM material defines a lumen.
- a disclosed ECM material conduit 10 can be formed by growing cells, such as, for example and without limitation, fibroblasts, on an outer surface of a cylindrical mandrel using known in vitro methods. In these aspects, it is contemplated that the growth of cells on the outer surface of the mandrel can lead to production of one or more ECM materials. It is further contemplated that the ECM material conduit 10 can be decellularized using known methods or as disclosed herein.
- a disclosed ECM material conduit 10 can be lyophilized using known methods.
- the ECM material conduit can be hydrated using known methods.
- the lyophilized ECM material conduit can be hydrated in sterile water, saline solution, or a balanced salt solution for a period ranging from about 5 minutes to about 30 minutes.
- a disclosed ECM material conduit 10 can be a multi-layer construction of two or more layers of ECM material.
- a multi-layer ECM material conduit 10 can be formed from a lumenal portion of an intact ECM.
- the term "lumenal" refers to a portion of a material that defines a lumen.
- the intact lumenal ECM can have a first end and a second end and can define a lumen.
- the first end of the intact ECM can be inverted into the lumen until it reaches the second end, thereby creating a multi-layer ECM material conduit.
- the first end of the intact SIS can be everted over itself until it reaches the second end, thereby creating a multi-layer ECM material conduit.
- the multi-layer ECM material conduit can be lyophilized using known techniques, thereby creating a multi-laminate ECM material conduit.
- the multi-layer ECM material conduit can be positioned over a mandrel during lyophilization.
- a cryoballoon can be positioned within the lumen of the multi-layer ECM material conduit and then inflated to press together the layers of the multi-layer ECM material conduit. It is further contemplated that any conventional lamination method can be used to laminate the layers of a multi-layer ECM material conduit together, thereby forming a multi-laminate ECM material conduit.
- a disclosed ECM material conduit 10 can comprise a sterile, acellular ECM composition.
- a sterile, acellular ECM composition can be formed by contemporaneously sterilizing and decellularizing an isolated ECM material. More particularly, as disclosed in the following methods, desired sterilization and decellularization of the isolated ECM material can occur contemporaneously such that the native properties of the tissue composition are maintained and the ECM material is rendered sterile and acellular.
- the ECM material conduit 10 can have a multi-layer structure proximate the inlet and/or outlet portion of the ECM material conduit.
- at least one end of the ECM material conduit can be everted or inverted along a portion of the length of the ECM material conduit to thereby form a multilayer structure proximate the inlet and/or outlet portion of the ECM material conduit.
- the multi-layer structure can effectively act as a sewing ring for the ECM material conduit.
- the disclosed methods make use of rapid depressurization of an isolated ECM material to decellularize the ECM material such that it is acellular.
- This rapid depressurization of the ECM material occurs at depressurization rates that are significantly higher than the depressurization rates applied in previously known methods.
- the rapid depressurization of the ECM material also can be used to incorporate desired sterilants and additives into the ECM material.
- the ECM material of a disclosed ECM valve conduit can be sterilized using a known sterilization system, such as, for example and without limitation, the system described in U.S. Patent No. 7,108,832, assigned to NovaSterilis, Inc., which patent is expressly incorporated herein by reference in its entirety.
- the system used to perform the disclosed methods can comprise a standard compressed storage cylinder and a standard air compressor used in operative association with a booster (e.g., a Haskel Booster AGT 7/30).
- the air compressor and booster can be replaced with a single compressor.
- the compressed storage cylinder can be configured to receive carbon dioxide
- the booster can be a carbon dioxide booster.
- the system can further comprise an inlet port, which allows one or more additives contained in a reservoir to be added to a reactor vessel through a valve and an additive line.
- reactor vessel refers to any container having an interior space that is configured to receive an ECM material and permit exposure of the ECM material to one or more sterilants and additives, as disclosed herein.
- the reactor vessel can be, without limitation, a basket, a bucket, a barrel, a box, a pouch, and other known containers.
- the reactor vessel can be a syringe that is filled with an ECM material.
- a selected primary sterilant such as, for example and without limitation, carbon dioxide
- a filter such as, for example and without limitation, a 0.5 ⁇ filter
- a pressure gauge can be provided
- depressurization of the reactor vessel can be accomplished using an outlet line and a valve in communication with the reactor vessel.
- the depressurized fluid can exit the vessel via the supply line, be filtered by a filter unit, and then be directed to a separator, where filtered fluid, such as carbon dioxide, can be exhausted via an exhaust line.
- valves can be incorporated into the various lines of the apparatus to permit fluid isolation of upstream components.
- the reactor vessel can comprise stainless steel, such as, for example and without limitation, 316 gauge stainless steel.
- the reactor vessel can have a total internal volume sufficient to accommodate the materials being sterilized, either on a laboratory or commercial scale.
- the reactor vessel can have a length of about 8 inches, an inner diameter of about 2.5 inches, and an internal volume of about 600 mL.
- the reactor vessel can comprise a vibrator, a temperature control unit, and a mechanical stirring system comprising an impeller and a magnetic driver.
- the reactor vessel can contain a basket comprising 316 gauge stainless steel.
- the basket can be configured to hold materials to be sterilized while also protecting the impeller and directing the primary sterilant in a predetermined manner.
- the reactor vessel can be operated at a constant pressure or under continual pressurization and depressurization (pressure cycling) conditions without material losses due to splashing or turbulence, and without contamination of pressure lines via back-diffusion. It is further contemplated that the valves within the system can permit easy isolation and removal of the reactor vessel from the other components of the system. In one aspect, the top of the reactor vessel can be removed when depressurized to allow access to the interior space of the reactor vessel.
- the system can comprise a temperature control unit that permits a user to adjustably control the temperature within the reactor vessel.
- the disclosed apparatus can be employed in a method of producing a sterilized, acellular ECM composition, such as disclosed herein.
- a method of producing a sterilized, acellular ECM composition such as disclosed herein.
- the disclosed apparatus is merely exemplary, and that any apparatus capable of performing the disclosed method steps can be employed to produce the sterilized, acellular ECM composition.
- the claimed method is in no way limited to a particular apparatus.
- CFUs colony- forming units
- the primary sterilant can be combined with one or more secondary sterilants to achieve desired sterilization.
- selected additives can be incorporated into an ECM material to impart desired characteristics to the resulting ECM composition.
- the disclosed methods can be employed to produce sterilized, acellular ECM compositions for implantation within the body of a subject.
- the disclosed methods make use of rapid depressurization of an isolated ECM material to render the ECM material acellular. This rapid
- the rapid depressurization of the ECM material occurs at depressurization rates that are significantly higher than the depressurization rates applied in previously known methods.
- the rapid depressurization of the ECM material also can be used to enhance the incorporation of desired sterilants and additives into the ECM material.
- the rapid depressurization of the ECM material can render the ECM material acellular while also improving retention of native growth factors, as compared to previously known decellularization methods.
- the rapid depressurization of the ECM material can be used to improve retention of the tensile strength of the ECM material, as compared to previously known decellularization methods.
- the disclosed methods not only do not significantly weaken the mechanical strength and bioptric properties of the ECM compositions, but also the methods are more effective in decellularizing the ECM compositions and in enhancing the incorporation of various additives into the ECM compositions.
- the disclosed sterilization and decellularization methods provide ECM compositions that are more decellularized and have a greater capacity to incorporate and then deliver more additives than ECM compositions known in the art.
- the disclosed sterilization and decellularization methods provide ECM compositions that have greater amounts and/or concentrations of retained native growth factors and that have greater tensile strength than sterilized and decellularized ECM compositions known in the art.
- the primary sterilant can be carbon dioxide at or near its supercritical pressure and temperature conditions.
- any conventional sterilant including, for example, gas, liquid, or powder sterilants that will not interfere with the native properties of the ECM material, can be used as the primary sterilant.
- the disclosed sterilization process can be practiced using carbon dioxide as a primary sterilant at pressures ranging from about 1,000 to about 3,500 psi and at temperatures ranging from about 25°C to about 60°C. More preferably, when supercritical carbon dioxide is used, it is contemplated that the sterilization process can use carbon dioxide as a primary sterilant at pressures at or above 1,071 psi and at
- the ECM material to be sterilized can be subjected to carbon dioxide at or near such pressure and temperature conditions for times ranging from about 10 minutes to about 24 hours, more preferably from about 15 minutes to about 18 hours, and most preferably, from about 20 minutes to about 12 hours.
- the carbon dioxide employed in the disclosed systems and methods can be pure or, alternatively, contain only trace amounts of other gases that do not impair the sterilization properties of the carbon dioxide.
- the term "supercritical carbon dioxide” will be used, but it will be understood that such a term is non-limiting in that carbon dioxide within the pressure and temperature ranges as noted above can be employed satisfactorily in the practice of the disclosed methods.
- the carbon dioxide can be presented to the ECM material in a gas, liquid, fluid or plasma form.
- the secondary sterilants employed in the disclosed methods can, in some aspects, include chemical sterilants, such as, for example and without limitation, peroxides and/or carboxylic acids.
- Preferred carboxylic acids include alkanecarboxylic acids and/or alkanepercarboxylic acids, each of which can optionally be substituted at the alpha carbon with one or more electron-withdrawing substituents, such as halogen, oxygen and nitrogen groups.
- Exemplary species of chemical sterilants employed in the practice of the disclosed methods include, for example and without limitation, hydrogen peroxide (H 2 0 2 ), acetic acid (AcA), peracetic acid (PAA), trifluoroacetic acid (TFA), and mixtures thereof.
- the chemical sterilants can include Sporeclenz® sterilant, which is a mixture comprising acetic acid, hydrogen peroxide, and peracetic acid.
- the secondary sterilants can be employed in a sterilization-enhancing effective amount of at least about 0.001 vol. % and greater, based on the total volume of the primary sterilant. It is further contemplated that the amount of secondary sterilant can be dependent upon the particular secondary sterilant that is employed. Thus, for example, it is contemplated that peracetic acid can be present in relatively small amounts of about 0.005 vol. % and greater, while acetic acid can be employed in amounts of about 1.0 vol. % and greater. Thus, it is contemplated that the concentration of the secondary sterilants can range from about 0.001 vol. % to about 2.0 vol. % and can typically be used as disclosed herein to achieve a sterilization-enhancing effect in combination with the disclosed primary sterilants, such as, for example and without limitation, supercritical carbon dioxide.
- the method of producing a sterilized, acellular ECM composition can comprise harvesting a selected tissue from a mammal and rinsing the selected tissue in sterile saline or other biocompatible liquid, including, for example and without limitation, Ringer's solution or a balanced biological salt solution.
- the selected tissue can be, for example and without limitation, stomach tissue (e.g., stomach submucosa (SS)), small intestinal tissue (e.g., small intestinal submucosa (SIS)), large intestinal tissue, bladder tissue (e.g., urinary bladder submucosa (UBS)), liver tissue (e.g., liver basement membrane (LBM)), heart tissue (e.g., pericardium, epicardium, endocardium, myocardium), lung tissue, kidney tissue, pancreatic tissue, prostate tissue, mesothelial tissue, fetal tissue, a placenta, a ureter, veins, arteries, heart valves with or without their attached vessels, tissue surrounding the roots of developing teeth, and tissue surrounding growing bone.
- stomach tissue e.g., stomach submucosa (SS)
- small intestinal tissue e.g., small intestinal submucosa (SIS)
- large intestinal tissue e.g., large intestinal submucosa (LIS
- the method can comprise freezing the selected tissue for a period ranging from about 12 to about 36 hours, more preferably, from about 18 to about 30 hours, and most preferably, from about 22 to about 26 hours.
- the period during which the selected tissue is frozen can be 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours. 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, and any other period of time falling between the preceding values.
- the method can comprise thawing the selected tissue in cold hypotonic tris buffer.
- the method can comprise thawing the selected tissue in cold hypotonic tris buffer on ice with 5 mM ethylenediaminetetraacetic acid (EDTA).
- EDTA ethylenediaminetetraacetic acid
- the method can comprise isolating an ECM material from the selected tissue.
- the ECM material can be any material comprising known extracellular matrix components, including, for example and without limitation, stomach tissue (e.g., stomach submucosa (SS)), small intestinal tissue (e.g., small intestinal submucosa (SIS)), large intestinal tissue, bladder tissue (e.g., urinary bladder submucosa (UBS)), liver tissue (e.g., liver basement membrane (LBM)), heart tissue (e.g., pericardium, epicardium, endocardium, myocardium), lung tissue, kidney tissue, pancreatic tissue, prostate tissue, mesothelial tissue, fetal tissue, a placenta, a ureter, veins, arteries, heart valves with or without their attached vessels, tissue surrounding the roots of developing teeth, and tissue surrounding growing bone, and the like.
- stomach tissue e.g., stomach submucosa (SS)
- small intestinal tissue e.
- the step of isolating an ECM material can comprise isolating SIS from a mammalian tissue source.
- the method can comprise: incising a wall of a small intestine along a path that is substantially parallel to the longitudinal axis of the small intestine; opening the small intestine along the path of the incision such that the small intestine lies flat on a surface;
- the ECM material can be isolated using any conventional technique, including those described in: U.S. Patent No. 4,902,508; U.S. Patent No. 5,275,826; U.S. Patent No. 5,281,422; U.S. Patent No. 5,554,389; U.S. Patent No. 6,579,538; U.S. Patent No. 6,933,326; U.S. Patent No.
- the method can comprise incubating the isolated ECM material for 24 to 48 hours in 0.5-1% Triton X-100/0.5-1% Deoxycholic acid with 5 mM EDTA in Dulbecco's Phosphate Buffered Saline (DPBS) (Lonza Walkersville, Inc.).
- DPBS Dulbecco's Phosphate Buffered Saline
- flat or sheet-like ECM materials such as stomach submucosa (SS), small intestinal submucosa (SIS), and bladder submucosa (UBS) can be incubated in a stretched configuration.
- ECM material conduits or other lumenal ECM materials such as ureters, arteries, veins, and tubular SIS, can be perfused with the various disclosed solutions through soaking and by use of a peristaltic pump.
- the method can comprise rinsing the ECM material with DPBS.
- the step of rinsing the ECM material can comprise rinsing the ECM material up to six times, including one, two, three, four, five, or six times, with each rinse lasting for about thirty minutes.
- the step of rinsing the ECM material can comprise rinsing the ECM material three times, with each rinse lasting for about thirty minutes.
- the method can further comprise a second incubation procedure.
- the second incubation procedure can comprise incubating the ECM material in isotonic tris buffer containing 10-50 ⁇ g/mL of RNAase/0.2- 0.5 ⁇ g/mL DNAase with 5 mM EDTA. It is contemplated that the step of incubating the ECM material in isotonic tris buffer can be performed at a temperature of about 37°C, substantially corresponding to the temperature of a human body.
- the step of incubating the ECM material in isotonic tris buffer can be performed for a period ranging from about 30 minutes to about 24 hours, more preferably, from about 1 hour to about 18 hours, and most preferably, from about 2 hours to about 12 hours.
- the second incubation procedure can further comprise rinsing the ECM material with DPBS.
- the step of rinsing the ECM material can comprise rinsing the ECM material three times, with each rinse lasting for about thirty minutes.
- the method can comprise storing the ECM material at a temperature ranging from about 1°C to about 10°C, more preferably, from about 2°C to about 6°C, and, most preferably, from about 3°C to about 5°C.
- the ECM material can be stored at 4°C.
- the method can comprise introducing the ECM material into the interior space of the reactor vessel.
- one or more secondary sterilants from the reservoir can be added into the interior space of the reactor vessel along with the ECM material.
- the one or more secondary sterilants from the reservoir can be added into the interior space of the reactor vessel before, after, or contemporaneously with the ECM material.
- the temperature control unit can be selectively adjusted to produce a desired temperature within the interior space of the reactor vessel.
- the method can comprise equilibrating the pressure within the reactor vessel and the pressure within the storage cylinder.
- the pressure within the reactor vessel and the pressure within the storage cylinder can be substantially equal to atmospheric pressure.
- the method can comprise operating the magnetic driver to activate the impeller of the reactor vessel.
- the method can comprise selectively introducing the primary sterilant from the storage cylinder into the reactor vessel until a desired pressure within the reactor vessel is achieved.
- the step of selectively introducing the primary sterilant into the reactor vessel can comprise selectively activating the air compressor and the booster to increase flow of the primary sterilant into the reactor vessel.
- the air compressor and booster can be activated to subject the ECM material to supercritical pressures and temperatures, such as, for example and without limitation, the pressures and temperatures necessary to produce supercritical carbon dioxide, for a time period ranging from about 20 minutes to about 60 minutes.
- the method can comprise rapidly depressurizing the reactor vessel.
- a predetermined amount of primary sterilant such as, for example and without limitation, supercritical carbon dioxide, can be released from the reactor vessel through the depressurization line. It is contemplated that the primary sterilant can be released from the reactor vessel through opening of the valve coupled to the reactor vessel to thereby rapidly reduce the pressure within the reactor vessel.
- the term "rapid depressurization" refers to depressurization of the reactor vessel at a rate greater than or equal to 400 psi/min. For example, it is contemplated that the reactor vessel can be rapidly depressurized at a depressurization rate ranging from about 2.9 MPa/min.
- the disclosed rapid depressurization rates increase the level of decellularization achieved in the ECM material.
- the rapid depressurization of a disclosed ECM material can lead to levels of decellularization in the ECM material of greater than about 96%, including 96.1%, 96.2%, 96.3%, 96.4%, 96.5%, 96.6%, 96.7%, 96.8%, 96.9%, 97.0%, 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98.0%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.7%, 99.2%, 99.3%, 99.4%, 99.5%
- the method can further comprise the step of
- the one or more additives can be provided in either a powder or a liquid form.
- the step of incorporating the one or more additives can comprise introducing the one or more additives into the reactor vessel during the step of rapidly depressurizing the reactor vessel.
- the introduction of the one or more additives can be characterized as a conventional foaming process.
- the step of incorporating the one or more additives can comprise introducing the one or more additives into the reactor vessel after the step of rapidly depressurizing the reactor vessel.
- the one or more additives can be added to the ECM material after the rapid depressurization of the reactor vessel has caused the ECM material to swell and/or expand, thereby permitting improved penetration of the additives into the ECM material. It is further contemplated that, in an exemplary aspect, the one or more additives can be added to the ECM material within about thirty minutes after the rapid depressurization of the reactor vessel. In a further optional aspect, the step of incorporating the one or more additives can comprise introducing the one or more additives into the reactor vessel both during and after the step of rapidly
- the one or more additives can be released into the reactor vessel in both a quick manner and a slow, extended manner.
- the step of incorporating the one or more additives can comprise introducing the one or more additives into the reactor vessel before the step of rapidly depressurizing the reactor vessel.
- the disclosed additives can be incorporated into the ECM material to impart selected properties to the resulting sterilized, acellular ECM composition.
- the one or more additives can be selected to replace or supplement components of the ECM material that are lost during processing of the ECM material as described herein.
- the one or more additives can comprise growth factors, cytokines, proteoglycans, glycosaminoglycans (GAGs), proteins, peptides, nucleic acids, small molecules, drugs, or cells. It is further contemplated that the one or more additives can be selected to incorporate non-native components into the ECM material.
- the one or more additives can comprise, for example and without limitation, growth factors for recruiting stem cells, angiogenic cytokines, and antiinflammatory cytokines. It is still further contemplated that the one or more additives can be pharmaceutical agents, such as statins, corticosteroids, non-steroidal anti-inflammatory drugs, anti-inflammatory compounds, anti-arrhythmic agents, and the like.
- the one or more additives can be nanoparticles, such as, for example and without limitation, silver nanoparticles, gold nanoparticles, platinum nanoparticles, iridium nanoparticles, rhodium nanoparticles, palladium nanoparticles, copper nanoparticles, zinc nanoparticles, and other metallic nanoparticles. It is still further contemplated that the one or more additives can be metallic compounds. In one exemplary aspect, the one or more additives can be selected to pharmaceutically suppress the immune response of a subject following implantation of the resulting ECM composition into the body of a subject.
- the one or more additives can comprise one or more growth factors, including, for example and without limitation, transforming growth factor- ⁇ 1, 2, or 3 (TGF- ⁇ 1, 2, or 3), fibroblast growth factor-2 (FGF-2), also known as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), connective tissue growth factor (CTGF), hepatocyte growth factor (HGF), Insulin-like growth factor (IGF), macrophage colony stimulating factor (M-CSF), platelet derived growth factor (PDGF), epidermal growth factor (EGF), and transforming growth factor-a (TGF-a).
- TGF- ⁇ 1, 2, or 3 transforming growth factor- ⁇ 1, 2, or 3
- FGF-2 also known as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), connective tissue growth factor (CTGF), hepatocyte growth factor (HGF), Insulin-like growth factor (IGF), macro
- the one or more additives can comprise one or more cytokines, including, for example and without limitation, stem cell factor (SCF), stromal cell- derived factor- 1 (SDF-1), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), Interleukin-3, Interleukin-4, Interleukin-10, Interleukin-13, Leukemia inhibitory factor (LIF), amphiregulin, thrombospondin 1, thrombospondin 2, thrombospondin 3, thrombospondin 4, thrombospondin 5, and angiotensin converting enzyme (ACE).
- SCF stem cell factor
- SDF-1 stromal cell- derived factor- 1
- GM-CSF granulocyte macrophage colony-stimulating factor
- IFN-gamma interferon gamma
- Interleukin-3 Interleukin-4
- Interleukin-10 Interleukin-13
- LIF
- the one or more additives can comprise one or more proteoglycans, including, for example and without limitation, heparan sulfate proteoglycans, betaglycan, syndecan, decorin, aggrecan, biglycan, fibromodulin, keratocan, lumican, epiphycan, perlecan, agrin, testican, syndecan, glypican, serglycin, selectin, lectican, versican, neurocan, and brevican.
- proteoglycans including, for example and without limitation, heparan sulfate proteoglycans, betaglycan, syndecan, decorin, aggrecan, biglycan, fibromodulin, keratocan, lumican, epiphycan, perlecan, agrin, testican, syndecan, glypican, serglycin, selectin, lectican, versican, neurocan, and brevican.
- the one or more additives can comprise one or more glycosaminoglycans, including, for example and without limitation, heparan sulfate, hyaluronic acid, heparin, chondroitin sulfate B (dermatan sulfate), and chondroitin sulfate A.
- glycosaminoglycans including, for example and without limitation, heparan sulfate, hyaluronic acid, heparin, chondroitin sulfate B (dermatan sulfate), and chondroitin sulfate A.
- the one or more additives can comprise one or more proteins, peptides, or nucleic acids, including, for example and without limitation, collagens, elastin, vitronectin, versican, laminin, fibronectin, fibrillin- 1, fibrillin-2, plasminogen, small leucine-rich proteins, cell-surface associated protein, cell adhesion molecules (CAMs), a matrikine, a matrix metalloproteinase (MMP), a cadherin, an immunoglobin, a multiplexin, cytoplasmic domain-44 (CD-44), amyloid precursor protein, tenascin, nidogen/entactin, fibulin I, fibulin II, integrins, transmembrane molecules, and osteopontin.
- proteins, peptides, or nucleic acids including, for example and without limitation, collagens, elastin, vitronectin, versican, laminin, fibronectin, fibrillin- 1, fibrillin-2
- the one or more additives can comprise one or more pharmaceutical agents, including, for example and without limitation, statin drugs, for example, cerevastatin, atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, corticosteroids, non-steroidal anti-inflammatory drugs, anti-inflammatory compounds, anti-arrhythmic agents, antimicrobials, antibiotics, and the like.
- statin drugs for example, cerevastatin, atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin
- corticosteroids non-steroidal anti-inflammatory drugs, anti-inflammatory compounds, anti-arrhythmic agents, antimicrobials, antibiotics, and the like.
- the steps of introducing the one or more additives into the reactor vessel can comprise opening the valve to allow the one or more additives to flow from the reservoir into the inlet port.
- the one or more additives Prior to pressurization, it is contemplated that the one or more additives can be introduced directly into the reactor vessel prior to sealing and/or via the inlet port.
- the disclosed rapid depressurization and repressurization of the reactor vessel can be repeated for any desired number of cycles. It is further contemplated that the cycles of depressurization and repressurization, as well as the introduction of the primary sterilants and/or secondary sterilants and/or additives, can be automatically controlled via a controller that is configured to selectively open and/or close the various valves of the system to achieve desired pressure conditions and cycles.
- the disclosed methods can further comprise the step of agitating the contents of the reactor vessel.
- the step of agitating the contents of the reactor vessel can comprise periodically agitating the contents of the reactor vessel using a vibrator. It is further contemplated that the agitation of the reactor vessel can be intermittent, continual, or continuous. In exemplary aspects, the step of agitating the contents of the reactor vessel can occur during the step of introducing the primary sterilant into the reactor vessel.
- the agitation of the contents of the reactor vessel can enhance the mass transfer of the sterilants and/or additives by eliminating voids in the fluids within the reactor vessel to provide for more complete contact between the ECM material and the sterilants and/or additives. It is further contemplated that the step of agitating the contents of the reactor vessel can comprise selectively adjusting the intensity and duration of agitation so as to optimize sterilization times, temperatures, and pressurization/ depressurization cycles .
- the method can further comprise depressurizing the reactor vessel and deactivating the magnetic drive so as to cease movement of the stirring impeller.
- the method can comprise the step of removing the resulting sterilized, acellular ECM
- a method of regenerating an atrioventricular (AV) valve to replace a defective AV valve within a heart of a subject is disclosed.
- the defective AV valve is attached at an annulus between an atrium and a ventricle within the heart of the subject and is functionally coupled to a plurality of papillary muscles 32 within the ventricle of the heart of the subject.
- atrioventricular (AV) valve can refer to either a mitral (bi-cuspid) valve or a tri-cuspid valve within the heart of the subject.
- the defective AV valve is a mitral valve
- the defective AV valve is attached at an annulus between the left atrium and the left ventricle of the heart of the subject. It is further contemplated that, if the defective AV valve is a tri-cuspid valve, then the defective AV valve is attached at an annulus between the right atrium and the right ventricle of the heart of the subject.
- annular region 30 refers to the portion of the heart of a subject that is proximate to the native position of an annulus between an atrium and a ventricle within the heart of the subject.
- annular region 30 includes the annulus as well as the heart muscle proximate the annulus.
- the annular region 30 includes the heart muscle proximate the former position of the annulus within the heart of the subject.
- annulus of the annular region is contemplated that the annulus of the annular region
- the step of removing the defective AV valve can further comprise placing the subject on cardiopulmonary bypass. It is further contemplated that the step of removing the defective AV valve can further comprise arresting and/or fibrillating the heart of the subject and exposing the defective valve through an incision in an atrium of the heart of the subject.
- a disclosed method of regenerating an AV valve can further comprise implanting an ECM material conduit 10, such as those disclosed herein.
- the ECM material conduit 10 can define a lumen 12 and have an inlet portion 14 and an outlet portion 18, with each of the inlet portion and the outlet portion having an outer circumference. It is contemplated that the lumen 12 defined by the ECM material conduit 10 can have a center point 13 proximate the outlet portion 18 of the ECM material conduit.
- the step of implanting an ECM material conduit 10 can comprise securing the inlet portion 14 of the ECM material conduit to the annular region 30 and securing the outlet portion of the ECM material conduit to at least two of the plurality of papillary muscles 32.
- the inlet portion 14 of the ECM material conduit 10 can be secured to the annulus. It is further contemplated that, when the annulus is removed from the heart of the subject, the inlet portion 14 of the ECM material conduit 10 can be secured to heart muscle proximate the native location of the excised annulus.
- the ECM material conduit 10 can be secured to the annular region 30 and/or the papillary muscles 32 using any conventional surgical attachment means, including, for example and without limitation, non-absorbable sutures, absorbable sutures, surgical pastes, surgical glues, staples, and the like.
- the ECM material conduit 10 can be secured to the papillary muscles 32 before it is secured to the annular region.
- the length of the ECM material conduit 10 along the longitudinal axis 24 can be trimmed as necessary to eliminate any excess length while retaining adequate tissue for proper attachment of the ECM material conduit to the annular region 30.
- the ECM material conduit 10 can be secured to the annular region 30 before it is secured to the papillary muscles 32.
- the length of the ECM material conduit along the longitudinal axis 24 can be trimmed as necessary to eliminate any excess length while retaining adequate tissue for proper attachment of the ECM material conduit to the papillary muscles.
- the disclosed method can be used to regenerate a bi-cuspid AV valve within the heart of the subject.
- the step of implanting an ECM material conduit 10 can comprise securing the outlet portion 18 of the ECM material conduit to only two papillary muscles (i.e., only a first papillary muscle 32a and a second papillary muscle 32b) of the plurality of papillary muscles.
- the left ventricle only has two papillary muscles, whereas the right ventricle has three papillary muscles.
- the replacement AV valve regenerated by the ECM material conduit will be a bi-cuspid valve.
- the defective AV valve is a tri-cuspid valve
- the first papillary muscle 32a can be the anterior papillary muscle of the right ventricle and that the second papillary muscle 32b can be the posterior papillary muscle of the right ventricle.
- the first papillary muscle 32a can be the anterior papillary muscle of the right ventricle and that the second papillary muscle 32b can be the septal papillary muscle of the right ventricle.
- the first papillary muscle 32a can be the posterior papillary muscle of the right ventricle and that the second papillary muscle 32b can be the septal papillary muscle of the right ventricle.
- the step of implanting an ECM material conduit can comprise securing the outlet portion of the ECM material conduit 10 to the first papillary muscle 32a at a first attachment point 34a and to a second papillary muscle 32b at a second attachment point 34b.
- the second attachment point 34b can be spaced from the first attachment point 34a along the outer circumference of the outlet portion 18 of the ECM material conduit 10.
- the center point 13 of the lumen 12 of the ECM material conduit 10 can correspond to a vertex of an angle 40 formed between the first attachment point 34a and the second attachment point 34b.
- the angle 40 formed between the first attachment point and the second attachment point can have a desired magnitude.
- the desired magnitude of the angle 40 formed between the first attachment point 34a and the second attachment point 34b can range from about 120° to about 150°.
- the angle 40 formed between the first attachment point 34a and the second attachment point 34b can have a complementary angle 42 within the lumen 12. It is further contemplated that the complementary angle 42 within the lumen 12 can have a magnitude ranging from about 210° to about 240°.
- the 10 comprises at least one extension portion as described herein, it is contemplated that one or more of the first and second attachment points 34a, 34b can be positioned on a corresponding extension portion of the at least one extension portion.
- the at least one extension portion can comprise two extension portions, with each of the first and second attachment points 34a, 34b being positioned on a respective extension portion.
- the disclosed method can be used to regenerate a tri-cuspid AV valve within the heart of the subject.
- the step of implanting an ECM material conduit 10 can comprise securing the outlet portion 18 of the ECM material conduit to each of the three papillary muscles within the right ventricle.
- the step of implanting an ECM material conduit 10 can comprise securing the outlet portion 18 of the ECM material conduit to a first papillary muscle at a first attachment point, to a second papillary muscle at a second attachment point, and to a third papillary muscle at a third attachment point.
- first, second, and third attachment points can be spaced from one another along the outer circumference of the outlet portion of the ECM material conduit.
- first, second, and third attachment points can optionally be substantially equally spaced along the outer circumference of the outlet portion of the ECM material conduit.
- spacing of the first, second, and third attachment points can vary depending upon the native anatomy and positioning of the papillary muscles.
- the first, second, and third attachment points can be spaced such that 40% of the operative circumference of the ECM material conduit is between the septal and anterior papillary muscles, 30% of the circumference of the ECM material conduit is between the anterior and posterior papillary muscles, and 30% of the circumference of the ECM material conduit is between the posterior and septal papillary muscles.
- the outlet portion 18 of the ECM material conduit 10 comprises at least one extension portion as described herein, it is contemplated that one or more of the first, second, and third attachment points can be positioned on a corresponding extension portion of the at least one extension portion.
- the at least one extension portion can comprise three extension portions, with each of the first, second, and third attachment points being positioned on a respective extension portion.
- the atrium of the heart of the subject can be closed and the heart of the subject can be restarted.
- the ECM material conduit can become populated with cells from the subject that will gradually remodel the ECM material of the ECM material conduit into heart valve tissue that is identical or substantially identical to properly functioning native heart valve tissue. It is further contemplated that stem cells can migrate to the ECM material conduit from the points at which the ECM material conduit is attached to the papillary muscles and the annular region within the heart of the subject. It is still further contemplated that, during circulation of epithelial and endothelial progenitor cells, the surfaces of the ECM material conduit can rapidly become lined or covered with epithelial and/or endothelial progenitor cells.
- the points at which the ECM material conduit is attached to the papillary muscles and the annular region can serve as points of constraint that direct the remodeling of the ECM material into leaflet tissue or chordae tendineae that are identical or substantially identical to properly functioning native leaflet tissue and properly functioning native chordae tendineae. It is still further contemplated that, where the annulus is removed from the annular region prior to attachment of the ECM material conduit, the inlet portion of the ECM material conduit can direct the remodeling of an annulus that is identical or substantially identical to a properly functioning native annulus. Examples
- Exemplary valve dimensions were measured for both porcine and human valves as shown in Figure 4 and Table 1. These measurements supported the use of ECM material conduits having a 30 mm annular diameter and a length ranging from about 32-35 mm. These design criteria also suggested that the distal valve should be implanted so as to achieve 40% of the circumference between the septal and anterior papillary muscles, 30% between the anterior and posterior papillary muscles, and 30% between the posterior and septal papillary muscles.
- FIG. 7 shows 3, 5, 8, and 12-month explants from sheep implanted with the ECM Material Conduit.
- Echocardiography showed good hemodynamics for the valves out to 12 months. Some of these animals exhibited a mild level of backflow through the valve after closure, which was recorded by the echocardiography technician as "mild” or “mild to moderate”. Echocardiography showed complete coaptation of the leaflets with no leaflet prolapse ( Figure 6). The degree of apparent valvular insufficiency in these tubular prosthetic valves is exaggerated on echocardiography because of the residual fluid that is trapped within the cylinder when the valves are open. This "closing volume” fluid may be ejected retrograde upon valve closure, which on ECHO would appear to be regurgitant volume when there is no actual regurgitation present.
- Figure 7 shows images of the valve as seen from the right atrium in the closed position demonstrate the progressive remodeling that is occurring over time in the sheep.
- Figure 7(a) remodeling has already occurred at the valve annulus and is extending to the leaflets to regenerate apparently normal valve tissue.
- Figure 7(d) the leaflets have remodeled and appear similar to native valve tissue.
- selected tissues were harvested and rinsed in sterile saline. The selected tissues were then frozen for 24 hours. The frozen tissues were thawed in cold hypotonic tris buffer on ice with 5 mM ethylenediaminetetraacetic acid (EDTA). An extracellular matrix material was then isolated from each selected tissue, as described herein.
- EDTA ethylenediaminetetraacetic acid
- the isolated extracellular matrix materials were incubated for 24 to 48 hours in 0.5-1% Triton X-100/0.5-1% Deoxycholic acid with 5 mM EDTA in Dulbecco's Phosphate Buffered Saline (DPBS) (Lonza Walkersville, Inc.).
- DPBS Dulbecco's Phosphate Buffered Saline
- Flat extracellular matrix materials such as stomach submucosa (SS), small intestinal submucosa (SIS), and bladder submucosa (UBS) were incubated in a stretched configuration.
- Tubular extracellular matrix materials such as ureters, arteries, veins, and tubular SIS, were perfused with the solutions through soaking and by use of a peristaltic pump.
- each extracellular matrix material was rinsed three times with DPBS. Each rinsing with DPBS lasted 30 minutes. Some extracellular matrix materials were then incubated for 2 to 12 hours at 37°C in isotonic tris buffer containing 10-50 ⁇ g/mL of R Ase/0.2-0.5 ⁇ g/mL DNAse with 5 mM EDTA. Following this incubation step, the extracellular matrix materials were again rinsed three times with DPBS. Each rinsing with DPBS lasted 30 minutes. The extracellular matrix materials were stored at 4°C.
- the extracellular matrix materials were processed in supercritical carbon dioxide as disclosed herein for 20-60 minutes at temperatures at or greater than 31.1°C and pressures at or greater than 1,071 psi. After this sterilization step, the extracellular matrix materials were rapidly depressurized at a rate of 2.7 MPa/10 sec. (391.6 psi/ 10 sec.) for a minute and 19 seconds. During this time, the pressure applied to the extracellular matrix materials rapidly decreased from 9.9 MPa to 0.69 MPa.
- the extracellular matrix materials were then processed in supercritical carbon dioxide and peracetic acid (PAA) as disclosed herein for 30 minutes to 6 hours to achieve terminal sterilization.
- PAA supercritical carbon dioxide and peracetic acid
- the pressure applied to the extracellular matrix materials was increased to 9.9 MPa.
- Tyvek® E.I. du Pont de Nemours & Company
- Table 3 summarizes the sterilization and decellularization of porcine ureter, bovine pericardium, and porcine mesothelium.
- the DNA content of ECM material samples was measured as an indicator of decellularization of the respective ECM material samples using various sterilization and decellularization techniques.
- the measured DNA content was evaluated with a pico green assay in which DNA was labeled with a fluorescent label that was detected with a
- DNA content was normalized by the dry weight of the samples. DNA content was measured and evaluated for the following treatment groups: (1) Lyophilized, non-sterile SIS; (2) Ethylene Oxide (EtO)-sterilized SIS; (3) Lyophilized, non- sterile SIS that was sterilized through a 60 minute treatment with PAA and supercritical C0 2 , as disclosed herein; (4) Lyophilized, non-sterile SIS that was sterilized through a 20 minute treatment with PAA and supercritical C0 2 , as disclosed herein; and (5) Raw, unprocessed SIS.
- EtO Ethylene Oxide
- Figure 9 shows the total DNA content for the respective samples, as normalized by dry weight.
- Figure 10 shows the percent of DNA that was removed from each respective sample, as compared to raw, unprocessed SIS.
- Ureters were processed with a gentle detergent (0.5% Triton X-100/0.5% Sodium Deoxycholate in 5mM EDTA in DPBS) for 24 hours and then rinsed three times in DPBS as disclosed herein. After this pretreatment, the ureters were decellularized and sterilized using rapid depressurization and treatment with PAA and supercritical C0 2 , as disclosed herein. Hematoxylin and Eosin (H&E) Stains were prepared for one sample ureter at the following stages of treatment: (A) native ureter; (B) pretreated ureter; and (C) pretreated ureter with rapid depressurization and treatment with PAA and supercritical C0 2 , as disclosed herein. These stains indicated that DNA content was significantly reduced with rapid depressurization.
- H&E Hematoxylin and Eosin
- ECM material samples were measured. Enzyme- linked immunosorbent (ELISA) assays were performed on the ECM material samples to quantify the content of bFGF and the active form of TGF- ⁇ in each respective sample.
- the following treatment groups were evaluated: (1) Lyophilized, non-sterile SIS; (2) Ethylene Oxide (EtO)-sterilized SIS; (3) Lyophilized, non-sterile SIS that was sterilized through a 60 minute treatment with PAA and supercritical C0 2 , as disclosed herein; (4) Lyophilized, non- sterile SIS that was sterilized through a 20 minute treatment with PAA and supercritical C0 2 , as disclosed herein; and (5) Raw, unprocessed SIS.
- EtO Ethylene Oxide
- supercritical C0 2 was used as a primary sterilant and as a carrier for adding bFGF into SIS sheets.
- the respective SIS sheets were placed into Tyvek® pouches along with varying amounts of bFGF.
- the pouches were exposed to supercritical C0 2 for 60 minutes at 9.6 MPa.
- the pouches were rapidly depressurized at a rate of 7.20 MPa/min.
- Samples were directly processed in 16 mL PAA in supercritical C0 2 for 20 minutes.
- the following treatment groups were evaluated: (1) No bFGF added; (2) 5 bFGF added; and (3) 15 ⁇ , bFGF added.
- Each ⁇ of bFGF contained 0.1 ⁇ g of bFGF.
- Rapid depressurization was used following gentle detergent soaks or perfusion of the ECM materials listed in Table 4 (below) at the noted concentrations and for the noted time periods.
- Tissues were harvested and rinsed in saline. The tissues were frozen for at least 24 hours. The tissues were thawed in cold hypotonic tris buffer on ice with 5 mM EDTA. The ECM of interest was isolated.
- flat tissues e.g., stomach submucosa, small intestine submucosa, and bladder submucosa
- the tissue was stretched on a tissue stretching device and incubated in solutions in a stretched configuration.
- tubular tissues e.g., ureters, arteries, veins, and tubular SIS
- the tissue was perfused with solutions using a peristaltic pump and were soaked during incubation.
- the tissues were incubated for 2 to 24 hours in 0.5% Triton X- 100/0.5% Deoxycholic acid with 5 mM EDTA in DPBS.
- the tissues were rinsed 3 times for 15-30 minutes each time in DPBS.
- the tissues were stored at 4° C.
- bFGF basic fibroblast growth factor
- SIS was used to compare an ECM composition processed with and without RDP to SIS provided by Cook Biotech, Inc. Some of the processed SIS was also sterilized using the described SCC0 2 + PAA method after decellularization. The measured growth factor content of the respective ECM compositions is shown in Figure 15. [00127] These results indicate that the rapid depressurization process was more effective than other decellularization processes at preserving the bFGF content and that the additional RDP processing to remove residual DNA and cell fragments results in only a small loss of bFGF. By comparison, the PAA sterilization process appeared to remove almost all of the remaining bFGF, even in the absence of RDP.
- the rapid depressurization process preserved more of the bFGF content in the native SIS than the Cook decellularization methods.
- the bFGF content was reduced, it is assumed that all other growth factor content was similarly reduced since the growth factors are all bound to the ECM compositions in a similar manner.
Abstract
Description
Claims
Priority Applications (8)
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AU2012262554A AU2012262554B2 (en) | 2011-05-27 | 2012-05-24 | Extracellular matrix material conduits and methods of making and using same |
EP12793466.9A EP2714068B1 (en) | 2011-05-27 | 2012-05-24 | Extracellular matrix material conduits and methods of making and using same |
BR112013030482A BR112013030482A2 (en) | 2011-05-27 | 2012-05-24 | method of regeneration of an atrioventricular valve and duct of extracellular matrix material |
CA2835859A CA2835859A1 (en) | 2011-05-27 | 2012-05-24 | Extracellular matrix material conduits and methods of making and using same |
KR1020137031538A KR20140145954A (en) | 2011-05-27 | 2012-05-24 | Extracellular matrix material conduits and methods of making and using same |
JP2014512122A JP2014519379A (en) | 2011-05-27 | 2012-05-24 | Extracellular matrix material conduit and methods for making and using the same |
SG2013083167A SG194878A1 (en) | 2011-05-27 | 2012-05-24 | Extracellular matrix material conduits and methods of making and using same |
IL229287A IL229287B (en) | 2011-05-27 | 2013-11-06 | Extracellular matrix material conduits and methods of making and using same |
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US201161490873P | 2011-05-27 | 2011-05-27 | |
US201161490693P | 2011-05-27 | 2011-05-27 | |
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US61/490,693 | 2011-05-27 | ||
US201161491723P | 2011-05-31 | 2011-05-31 | |
US61/491,723 | 2011-05-31 | ||
US201261650911P | 2012-05-23 | 2012-05-23 | |
US61/650,911 | 2012-05-23 |
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WO2012166554A8 WO2012166554A8 (en) | 2014-01-23 |
WO2012166554A3 WO2012166554A3 (en) | 2014-05-08 |
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JP (2) | JP2014519379A (en) |
KR (1) | KR20140145954A (en) |
AU (1) | AU2012262554B2 (en) |
BR (1) | BR112013030482A2 (en) |
CA (1) | CA2835859A1 (en) |
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Cited By (2)
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JP2016512989A (en) * | 2013-03-01 | 2016-05-12 | コーマトリックス カーディオバスキュラー, インコーポレイテッドCorMatrix Cardiovascular, Inc. | Two-piece artificial valve |
US11147673B2 (en) | 2018-05-22 | 2021-10-19 | Boston Scientific Scimed, Inc. | Percutaneous papillary muscle relocation |
Families Citing this family (1)
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KR20140026541A (en) | 2011-05-27 | 2014-03-05 | 코매트릭스 카디오바스컬라 인코포레이티드 | Extracellular matrix material valve conduit and methods of making thereof |
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JP2016512989A (en) * | 2013-03-01 | 2016-05-12 | コーマトリックス カーディオバスキュラー, インコーポレイテッドCorMatrix Cardiovascular, Inc. | Two-piece artificial valve |
US11147673B2 (en) | 2018-05-22 | 2021-10-19 | Boston Scientific Scimed, Inc. | Percutaneous papillary muscle relocation |
US11678988B2 (en) | 2018-05-22 | 2023-06-20 | Boston Scientific Scimed, Inc. | Percutaneous papillary muscle relocation |
Also Published As
Publication number | Publication date |
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SG194878A1 (en) | 2013-12-30 |
CA2835859A1 (en) | 2012-12-06 |
IL229287A0 (en) | 2014-01-30 |
WO2012166554A3 (en) | 2014-05-08 |
BR112013030482A2 (en) | 2016-09-27 |
JP2017060776A (en) | 2017-03-30 |
AU2012262554A8 (en) | 2014-02-27 |
AU2012262554B2 (en) | 2016-09-15 |
WO2012166554A8 (en) | 2014-01-23 |
JP2014519379A (en) | 2014-08-14 |
KR20140145954A (en) | 2014-12-24 |
AU2012262554A1 (en) | 2013-11-28 |
IL229287B (en) | 2019-05-30 |
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