Classifications

• • 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
  • 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
  • A61F2/2418—Scaffolds therefor, e.g. support stents
• • 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
  • A61L27/14—Macromolecular materials
  • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
  • A61L27/225—Fibrin; Fibrinogen
• • 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
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • 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

Definitions

• a surgical transcatheter valve is also described in Syedain, et al., Sci Trans Med 2021 .
• the surgical implant requires a bottom edge/skirt for sewing the valve into the native anatomy.
• Leaflets made from the tissue tube can only be closed using a sutured stitch line. This design also leaves a free edge at bottom to be sewn into the native artery. Both stitch lines are in high stress areas, stitch lines that have been shown to degrade fail.
• U.S. Patent 11 ,517,428 discloses a TPV valve that uses traditional suture lines to attach the leaflets and the traditional configuration of a skirt separate from the leaflets.
• Another embodiment of the invention is the method of making an implantable valve.
• CT constructed tissue
• the products, uses, and processes of the present invention are suitable for treating diseases and conditions that would benefit from regenerative engineered tissues, especially those involving tubular tissue constructs.
• the biological materials according to the present invention are processed to modify (e.g., reduce or eliminate) size and shape, thinness, collagen content, and other characteristics and properties that will become clear from the description of the invention.
• the methods, uses, and products of the present invention are intended for implant in a mammal, preferably a human.
• Figure 3 shows a side view of the prior art method of stitching a leaflet to a frame.
• Figure 4 shows a bottom view of a typical stitch pattern for a pericardium tissue valve (4A), the tissue valve of Syedain et al cited above (4C), and the lack of stitches in a valve of the present invention (4B).
• the valves include but are not limited to surgical valves; transcatheter valves; valves with stents, supports, and/or frames; frameless valves; valve assemblies with or without a skirt; arterial valves; and venous valves.
• one or more CT tubes are configured to form both a leaflet and a portion of the skirt.
• Each tube corresponds to a single leaflet and a portion of the skirt.
• Multiple tubes may be used together to form the complete skirt.
• Multiple tubes may be combined into a tube assembly, thereby forming a multi-leaflet valve.
• Other portions of tubes are folded to form the skirt. See for example, Figs. 1 and 2C.
• Another embodiment of the invention is a transcatheter valve wherein a single piece of constructed tissue is used to form both the leaflet (or valve assembly) and the skirt. In preferred embodiments of the invention, three tubes of constructed tissue are used, each tube having a portion used to form a leaflet and a portion used to form a portion of a skirt.
• Another embodiment of the invention is a transcatheter valve formed from constructed tissue wherein a portion of the tissue is crimped inside a frame. In Examples 3 and 6, this is the first time that the tissue of the present invention has been crimped inside a frame and tested for long term mechanical and longevity properties.
• Another embodiment of the invention is a transcatheter valve formed from constructed tissue and having the durability and mechanical properties sufficient for its intended purpose, e.g., a transcatheter pulmonary heart valve or a venous valve.
• the valve can be a so-called self-expanding valve wherein the frame is made of a self-expanding material such as Nitinol.
• a selfexpanding valve can be collapsed to a smaller profile and held in the collapsed state with a restraining device such as a sheath covering the valve. When the valve is positioned at or near the target site, the restraining device is removed to allow the valve to self-expand to its expanded, functional size of open cells in the frame.
• the tissue of the present invention is folded to form a portion of the skirt. Folding the tissue makes the leaflet U-shaped (Fig 4B) leaflet rather than classic C-shape (Fig. 4A).
• the leaflet(s) and skirt are contiguous.
• the leaflet and skirt are made from a single piece of tissue.
• the skirt is first folded and stitched to the frame.
• the leaflet belly is not sewn or stitched, and the valve assembly (multiple leaflets) does not need stitches encompassing the entire commissures and belly of each leaflet.
• the skirt of a prosthetic valve serves several functions.
• the skirt functions to seal and prevent (or decrease) perivalvular leakage, to anchor the leaflet structure to the frame, and to protect the leaflets against damage caused by contact with the frame during crimping and during working cycles of the valve.
• an embodiment of the invention includes but is not limited to a tissue of the present invention that recellularizes without first degrading the tissue near and around the implant site.
• An embodiment of the invention includes other implants that may be covered or wrapped in whole or in part with a tissue of the present invention.
• the CT prevents or reduces an immune response or infection from the underlying implant.
• Embodiments of the invention include but are not limited to the form of tissue delivery. Examples include endovascular delivery and surgical implant.
• the tissue of the present invention may be any size or shape.
• the present invention is an implant, prosthesis, or covering formed from constructed (CT) regenerative, and/or engineered tissue.
• constructed or engineered refers to the fact that the inventors and others may produce or construct the tissue, e.g., the tissue is not a product of nature.
• the tissue mediates regeneration without causing degradation of tissue and other biological material in the area of the implant site.
• the invention includes methods of making the tissue and methods of making the graft or prosthesis.
• the tissue may be formed by combining ECM-producing cells in the presence of fibrinogen and thrombin under conditions that permit the formation of regenerative tissue.
• An exemplary process is shown in Figure 1 .
• the process involves forming a cell-seeded suspension comprising ECM producing cells, fibrinogen, and thrombin.
• the suspension is then cast over a form and allowed to incubate.
• an ECM/fibrin/collagen tissue begins to form.
• compaction and fiber alignment occurs, leading to remodeling of the ECM/collagen/fibrin tissue as it forms.
• the tissue is then cultured until it matures, e.g., is substantial enough to be used for its intended purpose.
• the resulting cell-containing tissue is then decellularized.
• the tissue of the present invention is cultured from completely biological raw materials and allogeneic dermal cells.
• the hydrogel - ingredients in a suspension - allows the tissue to grow in a volumetric 3-D process also known as casting.
• most if not all typical tissue engineering methods use a synthetic and/or immunogenic scaffold or the like to grow the tissue in a 2-D manner (cell suspension seeded on the surface).
• the growth eventually produces a 3-D construct, but the growth in scaffold-based constructs is different that the volumetric 3-D casting growth in tissues of the present invention.
• the scaffold degrades, leaving some type of tissue or cellular matrix.
• a preferred embodiment of the invention is any structure or shape formed from the tissue of the present invention, including but not limited to a tubular graft.
• the bioengineered tissue may be made according to U.S. Patent 10,111 ,740; U.S. Patent 10,105,208; U.S. Patent 10,893,928; and U.S. Patent 11 ,589,982, all Tranquillo, et al., each incorporated in its entirety be reference. Any process or method for producing engineered tissue involving ECM- producing cells in a hydrogel is included within the scope of the present invention.
• the CT of the present invention may be characterized by lack of evidence of patient infection (in vivo); lack of evidence of patient immune response (in vivo); lack of evidence of toxicity; lack of evidence of implanted tissue degradation; lack of evidence of residual cellular debris (e.g., particle shedding from the tissue, in contrast to polymer degradation and erosion); modified (e.g., reduce or eliminate) inflammation, calcification characteristics, resorbability, suture retention, size and shape, thinness (e.g. dilatation or aneurysm formation), collagen content, and other characteristics and properties that will become clear from the description of the invention.
• the constructed tissue of the present invention includes collagen types I, III, and VI; tenascin; and fibronectin.
• the methods, uses, and products of the present invention are intended for implant in a mammal, preferably but not limited to a human.
• a product and/or method of the present invention typically includes combining fibrinogen or fibrinogen-like material, thrombin, and matrix-producing cells to produce a fibrin gel with a homogeneous cell suspension.
• the cell infused fibrin gel undergoes casting, used herein to refer to encapsulating cells in a fibrin gel, and culturing to form the collagenous tissue or grafts. Casting may occur with or without a form or mold.
• the tissue or graft may be allowed to contract (e.g., longitudinally or radially), preferably in a controlled manner.
• the process permits customized or optimized fiber alignment during the contraction phase. Customized or optimized alignment includes, but is not limited to radial alignment, longitudinal alignment, both radial and longitudinal alignment, and a pre-determined ratio of radial and longitudinal alignment
• the CT of the present invention is distinct from certain other kinds of regenerative or engineered tissue in the use of completely biological raw materials and allogeneic dermal cells; and in the use of crosslinked fibrinogen that is later degraded during the culturing process.
• the CT of the present invention can be contracted or allowed to contract, for example, in the longitudinal direction and/or in the radial direction, among others.
• the fibers in the tissue may align or become aligned, believed to be partially due to fibrin having no or little resistance to contraction that occurs naturally as part of the collagen/ECM formation process.
• the inventors also believe that radial and/or longitudinal contraction occurs in part naturally as an inherent function of tissue forming as described herein.
• the contraction may be scalable or intentionally controlled to enhance, promote, or achieve one or more tissue characteristics, e.g., fiber alignment, or tensile strength, or suturability.
• the CT of the present invention does not include any synthetic materials, as is typical in other processes that use PLA or PGA or the like.
• One or more methods of the present invention may also include molding or forming the cell-seeded fibrin gel into a pre-determined shape; manipulating, mechanically and/or manually, the growing tissue in the presence of culture medium to produce CT; manipulating the growing tissue during the culturing phase of the tissue; manipulating the tissue during the maturation phase of the tissue; manipulating the tissue during the culturing/maturation phase of the tissue production process; manually moving the growing tissue to evenly distribute the stress relief from the contracting ends; decellularizing the CT; and automated or semi-automated versions of any of the method steps.
• the delivery apparatus is a catheter.
• a further embodiment includes a method of treating a patient for a valvular disease including identifying a valvular disease in a patient, and implanting an artificial heart valve into a blood vessel of the patient, wherein the leaflet structure is constructed of a constructed tissue, and the inner skirt is constructed of a constructed tissue, the same or different from the tissue used to form the leaflets.
• tissue may be stored in PBS and refrigerated until use.
• the tissue may be partially or fully dehydrated.
• the storage is in a sterile dry container.
• Other storage/sterilization processes may include one or more additives known to those with skill in the art.
• the tissue may be E-beam sterilized in PBS alone.
• the tissue exhibited greater cellularization.
• the tissues of the present invention exhibited greater cellularization (faster cellularization over time).
• the present invention is recellularized with smooth muscle actin-positive cells across the entire thickness.
• the tissue exhibited recellularization where it was not expected to be.
• Lawson shows sparse smooth muscle actin positive cells near the human surface of their tissue.
• the tissue of the present invention exhibits consistent presence of smooth muscle actin positive cells across the thickness of implanted tissue.
• the tissue when implanted in humans did not degrade prior to recellularization or body cell infiltration.
• the tissue utilized for the inner skirt and leaflet structure is regenerative tissue, such that the artificial valve will integrate into the body of the individual receiving the artificial valve.
• Suitable materials will allow the patient's body to fully integrate the material, such that the material will continue growing with the body of the patient.
• Such material will allow the valvular structure and skirt to grow in a concomitant manner as the patient's heart grows such that replacement is not required.
• Regenerative materials may include decellularized tissue from a natural source, which may require ligation of branching blood vessels. Examples of regenerative tissue and methods of constructing these materials can be found in PCT/US2021/62709, the disclosure of which is incorporated herein by reference in its entirety.
• a decellularized vessel consists essentially of the extracellular matrix (ECM) components of the vascular tree.
• ECM components can include any or all of the following: fibronectin, fibrillin, laminin, elastin, members of the collagen family (e.g., collagen I, III, and IV), glycosaminoglycans, ground substance, reticular fibers and thrombospondin, which can remain organized as defined structures such as the basal lamina.
• Successful decellularization is defined as the absence of detectable myofilaments, endothelial cells, smooth muscle cells, and nuclei in histologic sections using standard histological staining procedures.
• residual cell debris also has been removed from the decellularized organ or tissue.
• biomimetics or biomimicry refer to imitating the models, systems, and elements of nature for the purpose of solving complex human or animal problems. In the present invention, biomimetics is used for therapeutic purposes. References:
• a tissue of the present invention was implanted as a CABG graft into an ovine model, and after six months showed long-term performance and regeneration into a living blood vessel.
• a tissue of the present invention was implanted as a vascular patch into an ovine model, and after six months showed appropriate performance, lack of calcification, and no sign of infection.
• a tissue of the present invention was implanted as a pediatric vascular conduit into a lamb model, and after 18 months showed somatic growth and regeneration.
• a tissue of the present invention was implanted as a pulmonary valve conduit into a lamb model, and after one year showed somatic growth and lack of calcification.
• a tissue of the present invention was implanted as an aortic frameless valve into an adult sheep model, and after six months showed durability and normal hemodynamics.
• a tissue of the present invention was implanted as a transcatheter pulmonary valve into a juvenile sheep model, and after 18 months showed durability and normal hemodynamics, and lack of calcification.
• valve made with constructed tissue mounted inside a nitinol stent was implanted as pulmonary valve replacement in juvenile sheep model.
• the hemodynamics properties of valve function were monitored over the course of implant for eighteen months.
• no change was observed in systolic pressure drop as measured by both mean and peak pressure drop.
• the effective orifice area stayed stable between 2-3 cm 2 .
• the regurgitation monitored for the course of implanted stayed at trivial to mild.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Animal Behavior & Ethology (AREA)
• Transplantation (AREA)
• Oral & Maxillofacial Surgery (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Cardiology (AREA)
• Medicinal Chemistry (AREA)
• Dermatology (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Urology & Nephrology (AREA)
• Zoology (AREA)
• Botany (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Prostheses (AREA)

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• 2023
  • 2023-09-15 EP EP23866249.8A patent/EP4586959A4/de active Pending
  • 2023-09-15 WO PCT/US2023/032894 patent/WO2024059281A1/en not_active Ceased

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