Classifications

• • 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
  • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
  • A61F2/06—Blood vessels
• • 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
  • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
  • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
  • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
  • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
• • 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
  • A61L27/3695—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 function or physical properties of the final product, where no specific conditions are defined to achieve this
• • 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
  • 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
  • A61L27/58—Materials at least partially resorbable by the body
• • 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
  • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
  • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
  • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes
  • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
  • A61F2002/9155—Adjacent bands being connected to each other
  • A61F2002/91575—Adjacent bands being connected to each other connected peak to trough
• • 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 products formed from proprietary regenerative tissue, products made from the tissue, an implant comprising this tissue, and methods of treating conditions and/or disorders using such tissue.
• Regenerative Medicine is the process of creating functional tissues to repair, replace, or restore tissue or organ structure and function lost due to age, disease, damage, or congenital defects.
• This field of medicine uses new methods and products including tissue engineering or constructed tissue (CT).
• CT tissue engineering or constructed tissue
• Coronary artery bypass grafts remain the mainstay of revascularization for multivessel coronary artery disease (CAD) (2).
• the most widely used conduits are autologous internal thoracic arteries, radial arteries and saphenous veins, which provide excellent mechanical stability and natural anti- thrombogenicity (2).
• Patients currently undergoing coronary revascularization surgery present with an increasing age and risk profile (2).
• the quality of saphenous vein grafts may be impaired if they are available at all (2, 3). Therefore, there continues to be a need for alternative bypass conduits for the coronary revascularization surgery (4-6). Further, even in patients with suitable veins, the procedure to harvest, ensuring all branches are tied and lumen diameter matches to native coronary, is associated with additional complications.
• Humacyte Inc has pioneered one of these approaches of tissue engineering a vascular graft by seeding vascular cells on a synthetic biodegradable polymer, subsequently culturing it in a bioreactor to produce final acellular ECM tube (8).
• Humacyte has implanted their vascular conduits in patients needing vascular grafts for dialysis, for femoral artery and for trauma injuries (9-11 , 13, 14).
• 6 mm internal diameter conduits of 35-42 cm length were followed up to 24 months.
• Primary and secondary patency was 58% and 74% respectively. Further, immunological panel testing showed no change in panel reactive antibodies after implant.
• Vascular graft failures are commonly associated with thrombosis, intimal hyperplasia, atherosclerosis, and/or infection. Implanted grafts of the present invention show no signs of any of these failure signs. [0010] Notwithstanding the usefulness of the above-described methods, a need still exists for increasing patency; making an implant less thrombotic in structure and/or function; minimizing calcification; and increasing the useful life of the implant.
• One embodiment of the invention is the preparation and use of constructed tissue (CT) to make implants, their use as implants, and their use in mediating treatment or therapy.
• the implant is a coronary artery bypass graft (CABG), a peripheral vascular graft, or a saphenous vein conduit.
• CABG coronary artery bypass graft
• peripheral vascular graft a peripheral vascular graft
• saphenous vein conduit a saphenous vein conduit
• the implant includes an external support structure (ESS).
• ESS external support structure
• the present invention utilizes a novel tissue engineering approach that uses human fibroblasts seeded in a biological polymer followed by bioreactor culture leading to a final acellular ECM vascular conduit that is completely biological with mechanical properties comparable to the internal mammary artery (7, 15).
• the tissue may be characterized in part by beneficial collagen alignment; anisotropy; anisotropy in vivo; acellular; compatible with terminal sterilization; non-chemically crosslinked; and typical moisture content about 85%.
• the tissue includes non-uniform collagen layers, typically, a high-density collagen layer, then a porous layer, then a high-density layer, then another porous layer.
• the non-uniform collagen layer comprises a high-density layer sandwiched between two or more porous layers.
• the inventors believe that these non-uniform collagen layers provide many advantages, including but not limited to providing more strength to the finished tissue, e.g., greater burst strength.
• the vascular conduit (6 mm diameter conduit) has been implanted in 16 patients in two trials to date for use in hemodialysis access (12).
• the first-in-human, 6-month study showed favorable patency and low complication rate establishing the initial safety and feasibility of the tissue’s use for dialysis access in patients with end-stage kidney disease.
• the mechanical durability and lack of immune response established the tissue as a potential regenerative material for clinical use in dialysis and other vascular applications.
• the tissue of the present invention is a completely biological, acellular collagenous matrix produced by allogeneic, neonatal, human dermal fibroblasts (nHDF).
• nHDF allogeneic, neonatal, human dermal fibroblasts
• the nHDF are mixed with thrombin and fibrinogen and molded into the desired shape, typically a tube or sheet.
• the molded structure is then cultured in a bioreactor where the nHDF degrades the fibrin gel and secretes collagen and other extracellular matrix (ECM).
• ECM extracellular matrix
• the resulting tissue is then decellularized, yielding an acellular human collagenous matrix.
• 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.
• One such use is for coronary artery bypass grafts (CABG).
• CABG coronary artery bypass grafts
• Some embodiments of the invention include the manufacture of a graft that is durable and has been demonstrated in both animal and human trials to withstand the rigorous mechanical requirements of the vascular system (8).
• 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.
• All of the biological materials, processed according to the present invention are appropriate for use in an in vivo environment, and include one or more of the following desirable properties for graft material suitable for implantation: a) size compatibility with surrounding vessels to which it will be anastomosed; b) sutureability, kink resistance, softness, radial and longitudinal compliance, and flexibility (a softer hand); c) non-thrombogenicity or low levels of thrombogenicity, particularly after regeneration or recellularization; d) durability; e) ease of sterilization; f) readily available, and available in diameters and lengths appropriate for surgical procedures; g) shelf life appropriate for market conditions (typically greater than three years); h) resistant to infection; i) sufficient strength to resist aneurysm formation; j) non-immunogenic; k) resistant to degradation; I) resistant to formation of neointimal hyperplasia; m) tactile, as expressed by surgeons using the tissue and/or grafts of the present invention
• living tissue refers to a tissue that exhibits the presence of active cells (originating from the implant recipient), e.g., including but not limited to producing elastin, producing ECM; and/or an un-paralleled lack of immunogenicity.
• an implant of the present invention provides several other advantages: the graft allows revascularization of the diseased heart using a tissue that exhibits little or no discernable immune response; isodiametrically uniform, which contributes to excellent laminar flow within the graft, which in turn reduces turbulence and turbulence-related thrombus formation; a graft that grows with the body, making this graft useful and beneficial for pediatric patients; the graft eliminates the need for vein and artery harvesting procedures, thereby eliminating the need for a second surgery; provides a small diameter, consistently uniform sized graft; and provides an excellent graft with high patency rates and mechanical characteristics.
• Figure 1 shows an implant of the present invention comprising a tissue tube supported by an external support structure.
• Figure 2 shows a close-up view of a portion of an external support structure encasing a tissue biomaterial.
• Figure 3 shows a flat non-expanded representation of a support structure of the present invention.
• Figure 4 shows an expanded and finished cell within the support structure shown in Figure 3.
• Figure 5 shows an end portion of an external support structure.
• Figure 6 shows a close-up view of a preferred ESS (A) as compared to a close-up view of a less preferred and less flexible ESS (B).
• Figure 7 shows the exemplary placement of a CABG implant in relation to the structures of an anatomical heart model.
• Figure 8 is a chart showing the primary and secondary patency of a tissue of the present invention.
• the present invention is a coronary artery bypass graft (CABG) formed from constructed tissue (CT) produced according to the present invention.
• CABG coronary artery bypass graft
• CT constructed tissue
• the graft includes an external support to prevent the graft from kinking.
• the external support prevents/reduces kinking, prevents/reduces abrasion or wear on the outside portion of the graft, prevents or controls any tissue expansion or dilation, and maintains lumen uniformity.
• the graft of the present invention may be used as a vascular conduit anywhere it might be beneficial in vivo in a mammal, including a human.
• exemplary uses include but are not limited to CABG surgery, preferably for bypassing a blocked or damaged portion of any coronary artery, for restoring blood flow to the heart; a peripheral vascular graft; or a saphenous (superficial or deep) vein conduit, including but limited to above the knee, around the knee, or below the knee.
• the tissue is used as a bypass to a second or third target (non-LAD coronary artery) in patients needing coronary artery bypass grafting (CABG).
• the implant is a tubular bypass conduit that creates a new path for blood to flow around a blocked or partially blocked artery in the heart, improving blood flow to the heart muscle.
• the graft or conduit also includes an external support.
• suitable stents that in accordance with the present invention, have been used as external supports, include but are not limited to a Gore Tigris, Terumo Misago, Gore ViaBahn, Boston Scientific InnovaTM, Abbott Supera, Biotronik Pulsar-18; Medtronic Everflex, and Cook Zilver.
• the external support is a support as shown in Figures 1-7.
• a support of the present invention may be used with any tissue or conduit intended to establish a fluid flow path between one part of the body and another part, e.g., from a coronary artery to a lung artery, between one coronary artery and another, etc.
• a tissue, conduit, or tube of the present invention may be implanted in a first step, and in a second step, the support may be added around the implant.
• the external support has one or more of the following characteristics: is laser cut; radially flexible, biocompatible, sterile, radially strong, radially stiff, radially stiff to promote or support crush resistance; fatigue resistance, non-corrosive, precise diameter, non-toxic, precise thickness, electropolished, axially flexible, medical grade material; diameter sufficient to prevent conduit kinking; provides sufficient support to prevent conduit kinking under anatomical (in vivo) conditions (e.g., cyclic axial motion); sufficiently rigid to prevent kinking in the typically curved conditions (curvature of the heart or other anatomy, and under pulsatile flexion of an artery); sufficiently flexible to curve in the typically curved conditions of the target anatomy (e.g., curvature of the heart or other anatomy, and under pulsatile flexion of an artery); supports vascular compliance; diameter sufficiently larger than conduit to allow conduit dilation (e.g., typical of pulsatile blood flow in coronary arteries); to prevent,
• the tubular frame can be a ring-like elliptical, or cylindrical configuration or shape made from a durable, biocompatible structural material such as Nitinol or similar alloy, wherein the tubular frame is formed by manufacturing the structural material as a braided wire frame, a laser-cut frame, or a wire loop.
• the frame or support is sized in length and diameter to enclose a tissue material. In length, the support may be any length, again sized to the tissue material. In some embodiments, the support is the length of the tissue material. In other embodiments, one or both ends of the support is shorter than the tissue material. In the most preferred embodiments, the support is compressible so that one or both ends of the tissue material can be exposed.
• the support may be up to about 300 mm in length, preferably between about 80 mm and about 120 mm.
• a typical inner diameter is up to about 24 mm in diameter; preferably greater than about 4.0 mm, and in a typical range from about 4 mm to about 30 mm.
• a typical outer diameter is up to about 30 mm in diameter; preferably greater than about 4.0 mm, and in a typical range from about 4 mm to about 30 mm.
• the tubular frame can have a side-profile of a ring shape, cylinder shape, but may also have a side profile of a convex cylinder (walls bulging out), a ring or cylinder having a flared top, flared bottom, or both.
• the tubular frame used in a CABG implant may have a complex shape determined by the anatomical structures where the implant is being inserted.
• the circumference of the ESS may be substantially circular, slightly larger in diameter than the underlying tissue tube, incorporating sufficient flexibility to enlarge and shrink according to the variability in all normal and diseased vasculature.
• a CABG implant with ESS may start in a roughly tubular configuration, and be heat-shaped to diameter and length to provide adequate support for the conduit, with the annular tubular section having a uniform cross-section for most or all of its length; and having atraumatic edges along the posterior and anterior annular transition segments where it is intended that the tissue is not supported (e.g., bare conduit transition at one or both of the anterior or posterior ends of the tissue).
• the ESS may be configured in a clamshell configuration. In this configuration, instead of sliding the ESS onto the vessel (as above), in this embodiment, a tissue is placed within a longitudinally open support, which can then be wrapped, clamped, or closed over the tissue.
• a scaffold, support, or frame of the present invention is flexible and capable of manipulation so that the frame or support can be bent or wrapped around a tissue tube or conduit, without breaking or damaging the tissue.
• a wrap of the present invention may also be flexible enough to slide over, enclose, or cover a tissue material.
• a wrap or tissue product of the present invention is a tube or conduit, or tubular is shape.
• a preferred embodiment is a continuous tubular shape.
• Other preferred embodiments are shown in the Figures.
• these shapes include or enclose a lumen through the longitudinal length of the construct. The lumen can be open or closed at one or both ends.
• the frame is made from superelastic metal wire, such as Nitinol (TM) wire or other similarly functioning material or alloy.
• the material may be used for the frame or support. It is contemplated as within the scope of the invention to use other shape memory alloys such as Cu - Zn - Al — Ni alloys, Cu - A1 Ni alloys, as well as polymer composites including composites containing carbon nanotubes, carbon fibers, metal fibers, glass fibers, and polymer fibers.
• the frame may be constructed as a braided wire frame or as a laser cut wire frame. Such materials are available from any number of commercial manufacturers, such as Pulse Systems.
• Laser cut wire frames are preferably made from Nickel - Titanium (Nitinol (TM)), but also without limitation made from stainless steel, cobalt chromium, titanium, and other functionally equivalent metals and alloys, or Pulse Systems braided frame that is shape - set by heat treating on a fixture or mandrel.
• TM Nickel - Titanium
• TM cobalt chromium, titanium, and other functionally equivalent metals and alloys
• Pulse Systems braided frame that is shape - set by heat treating on a fixture or mandrel.
• the frame is compressible to the extent that one strut can nest into an adjacent strut without contacting or binding the adjacent strut. Compare, for example, Figure 6A and 6B.
• compressibility and nesting may be accomplished by using a wide variety of strut angles and shapes, all of which is within the expertise of one skilled in the art.
• the supports have strut angles from about 15° to about 25°.
• the exemplary configuration shown in Figures 2-4 have a strut angle of about 20°
• the support may be synthetic, made from a plastic and/or fabric material, or the tissue could be printed.
• the support should still be compressible and flexible, in accordance with the teachings of this invention.
• One possible construction of the wire frame envisions the laser cutting of a thin, isodiametric Nitinol tube. The laser cuts form regular cutouts in the thin Nitinol tube.
• the tube is placed on a mold of the desired shape, heated to the Martensitic temperature and quenched.
• the treatment of the wire frame in this manner will form a device that has shape memory properties and will readily revert to the memory shape at the calibrated temperature.
• the frames are support structures that comprise a number of struts or wire portions arranged relative to each other to provide a desired compressibility and strength.
• the stents or stent frames of the present disclosure are generally tubular support structures having an internal area in which tubular tissue material may be positioned.
• Some embodiments of the stent frames can be a series of wires or wire segments arranged such that they are capable of self-transitioning from the compressed or collapsed arrangement to the normal, radially expanded arrangement.
• a number of individual wires comprising the stent frame support structure can be formed of a metal or other material. These wires are arranged in such a way that the stent frame support structure allows for folding or compressing or crimping to the compressed arrangement in which the internal diameter is smaller than the internal diameter when in the normal, expanded arrangement.
• a stent frame support structure enclosing a tissue tube can be mounted onto a delivery device.
• the stent frame support structures are configured so that they can be changed to their normal, expanded arrangement when desired, such as by the relative movement of one or more outer sheaths relative to the length of the stent frame.
• the wires of these stent frame support structures in embodiments of the present disclosure can be formed from a shape memory material such as a nickel titanium alloy (e.g., NitinolTM). With this material, the support structure is selfexpandable from the compressed arrangement to the normal, expanded arrangement, such as by the application of heat, energy, and the like, or by the removal of external forces (e.g., compressive forces).
• This stent frame support structure can also be compressed and re-expanded multiple times without damaging the structure of the stent frame.
• the stent frame support structure of such an embodiment may be laser-cut from a single piece of material or may be assembled from a number of different components.
• a delivery device that can be used includes a catheter with a retractable sheath that covers the stent frame until it is to be deployed, at which point the sheath can be refracted to allow the stent frame to self-expand.
• the present invention is a product and process for use in any in vivo treatment in which endothelization and/or recellularization provides a beneficial result for the patient/recipient.
• recellularization refers to the repopulation or growth of cells and structures near the implant site aiming to reconstitute and recreate the natural tissue-specific function.
• recellularization includes the tissue growing, including somatic growth, with the patient.
• healing refers to the ability of living organisms to replace damaged or lost tissue with new cells, heal damaged tissue, restoring their structure and function, that is, becoming living tissue.
• Healing includes repopulation leading to restoration of tissue and/or body functions, including but not limited to restoration of cells, other biological molecules, and biological structures, including acellular ECM scaffolds.
• Healing is the process of renewal, regrowth, or restoration of a tissue, organ, or organism after damage, injury, or disease.
• remodeling refers to the process by which the body adapts to and integrates an implanted medical device. This process involves the interaction between the implant and the surrounding tissues, which can lead to changes in the structure and composition of the tissue, and in healing. [0065] As used herein, recellularization and remodeling are considered to be within the definition of regeneration and healing.
• the tissue of the present invention when implanted, does not mechanically weaken during the healing process.
• One of the benefits of a tissue of the present invention is that it does not need a scaffold or the like. This feature is in contrast to products that have a synthetic or biological portion that is specifically degradable, e.g., a scaffold. This feature is also distinct from the tissue as it is being manufactured. During formation, the ECM-producing cells degrade fibrin until a collagenous tissue is formed. The cell-containing tissue contains no, very little, or not detectable amounts of fibrin.
• An embodiment of the invention includes but is not limited to a tissue of the present invention that recellularizes without first degrading.
• An embodiment of the invention includes a product or implant formed from the tissue of the present invention, wherein the tissue includes an external support structure.
• Embodiments of the invention include but are not limited to the form of tissue delivery. Examples include endovascular delivery and surgical implant.
• a tube or tubular material of the present invention may be positioned to replace, surround, contain, or enclose a body structure. Examples include but are not limited to one or more coronary arteries.
• the graft or implant of the present invention may be used in a method of treating a patient having a wide variety of conditions, diseases, or injuries, the common theme of which is that the treatment involves a tissue implant.
• diseases and conditions include but are not limited to arrythmia, wound infections, kidney/renal failure, thrombosis/embolization, aneurysm, patient infection, and patient immune response.
• the tissue may include structures or agents (e.g., active agents) within the surface of the CT tissue.
• the tissue of the present invention may be any size or shape.
• the tissue is the form of a wrap, conduit, sheet, cover, envelope, or tube.
• the tissue or tube may be enclosed or covered by an external support structure (ESS).
• ESS external support structure
• the ESS substantially covers the tissue from one end to the other.
• the ESS is longitudinally flexible or compliant enough to expose one or both ends of the tube, thereby allowing access to one or both tube ends for surgical procedures.
• the ESS is of a size and dimension wherein one or both tube ends are exposed or not covered by the ESS.
• the present invention is a graft, 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.
• 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 may occur, 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 the decellularized.
• the tissue of the present invention is cultured from completely biological raw materials and allogeneic dermal cells. For example, see the patents and patent applications listed below.
• the hydrogel - the starting ingredients in a suspension - allows the tissue to grow in a volumetric 3-D process also known as casting.
• the process from initial ingredients to a complete tissue represents a remodeling continuum.
• 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.
• 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.
• any prosthesis may be formed in whole or in part using regenerative tissue (RT) or engineered tissue.
• RT refers to tissue formed or processed as disclosed in the following: 2007/061800; WO 2007/092902; 2016/0203262; WO/2004/018008; WO 2004/101012; PCT/US21/62709 (filed 09 December 2021 ); PCT/US2017/026204 (filed 5 April 2017); U.S. Patent 10,111 ,740; U.S. Patent 10,105,208; U.S. Patent 10,893,928; U.S. Patent 8,192,981 ; U.S. Patent 8,399,243; U.S.
• 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, resorption, absorption, 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 CT of the present invention is distinct from certain other kinds of constructed 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, PGA, or the like.
• the CT of the present invention may be characterized by one or more of the following: non-oriented fibers; oriented fibers; thickness up to about 2 mm, preferably between about 100 pm and about 800 pm; diameters greater than about 1 mm; diameters from about 1 mm to about 40 mm, preferably from about 2 mm to about 25 mm, most preferably from about 3 mm to about 16 mm; lengths greater than about 1 cm; lengths from about 1 cm to about 100 cm, preferably 10 cm to 30 cm, and most preferably about 12 cm to about 22 cm; non-immunogenic or minimally immunogenic; a tissue, sheet or shape that is anisotropic; a tissue, sheet, or shaped structure produced by a process that includes scaled contraction (as described above); a sheet or shape that is suitable for cutting into shapes, e.g., by scalpel, die, or laser; suppleness; suturability; no or little calcification during life of implant; crosslink density, or variations of crosslink density through the material thickness
• the diameter and diameter range may be determined by the type of graft or implant being used.
• the diameter may be any diameter, and typically less than about 6 mm (but it can also be greater).
• a CABG graft preferably has a diameter from about 3 mm to about 6 mm.
• the length and length range may be determined by the type of graft or implant being used. The length may be any length.
• a CABG graft preferably has a length from about 15 cm to about 25 cm, which is then sized as needed during the implant procedure, typically from about 8 cm to about 15 cm.
• either or both of the diameter and the length can be tapered.
• the thickness and thickness range may be determined by the type of graft or implant being used.
• a CABG graft preferably has a thickness from about 0.3 mm to about 0.8 mm; an AV access graft may have a thickness from about 0.3 mm to about 1 .0 mm.
• the external support structure is sized to fit around an external surface of the graft.
• tissue or a product of the present invention may be used to treat or repair other types of tissues including but not limited to tubular non-vascular applications, muscle, tendon, organs (e.g., kidneys and liver) skin, trachea, ureter, vasculature, bladder, fascia, and uterus.
• organs e.g., kidneys and liver
• Figure 1 shows an implant 10 comprising a tissue material 11 covered by an external support structure 12.
• This figure shows the implant configured (e.g., curved) as might be beneficial when placed near human anatomical structures in vivo (not shown).
• This view illustrates exposing the anterior end (13) and the posterior end (14) of the tissue. The uncovered or exposed ends may be used as anastomosis sites to attach to a portion of the tissue or implant to the vascular system.
• Figure 2 shows a close-up view of a portion of the ESS.
• Figure 3 shows a construction drawing (flat pattern view) of an unexpanded ESS of the present invention.
• Figure 4 shows one expanded cell of the ESS shown in Figure 3.
• Figure 5 shows an end 50 of an exemplary ESS 51 .
• cell 52 in comparing cell 52 to cell 53, cell 52’s struts are more widely spaced, allowing variation in flexibility.
• the inventors have found that longer struts tended to make the frame less flexible (e.g., end segment 52), that repeating segment 53 tended to make the frame more flexible.
• the flexibility or bending ability in the frame occurs at the connection points between the struts and the connectors, so the more connection points per length of frame, the more places for the frame to bend, all of which leads to greater flexibility.
• Figure 6 compares two different configurations of an ESS of the present invention.
• Figure 6A shows a preferred embodiment wherein one lobe 60 nests within another lobe 61 without individual struts contacting.
• Figure 6B the struts of a first lobe contact 62 the struts of a second lobe.
• Configurations such as Figure 6A are more flexible than configurations such as Figure 6B.
• FIG. 7 shows the exemplary placement of an implant 70 in relation to the various anatomical structures of a model heart.
• Implant 70 has a tubular tissue tube 71 partially covered by an ESS 72 of the present invention.
• Implant 70 also shows two ends 73 and 74 of the tissue uncovered or exposed - these are both anastomosis sites.
• Figure 8 is a Kaplan Meier plot of primary and secondary patency of a graft of the present invention.
• tissues of the present invention can be and are grown having desirable or beneficial structural properties, which eventually develop toward a native-like architecture (i.e. , the tissues of the present invention are a biomimetic material).
• the tissue of the present invention may be handled in a similar way like a native vein or artery when surgically implanted.
• Some embodiments of the invention may further include storing and/or sterilizing a medical device or tissue of the present invention. These embodiments may include preselected storage solution; preselected sterilization solution or technique; storage packaging; and/or sterilization packaging.
• the 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.
• a CABG tissue conduit is intended to be used with an outer metal support providing outer support, preventing or reducing conduit kinking; prevents or reduces tissue abrasion or wear; maintains uniform lumen diameter; and prevents or controls tissue dilation.
• the external support may also reduce or prevent abrasion to other tissues or parts of the anatomy that come into contact with the implant.
• the outer or external stent may be a standalone, commercially available product.
• a tissue of the present invention may also define or enclose a total volume from about 3 mm 3 to about 65,000 mm 3 .
• the tissue of the present invention may include one or more collagens, including but not limited to collagen types I, III, and VI; tenascin, and fibronectin.
• a tissue product of the present invention may be unsupported or may further include a support member, such as a nitinol stent or scaffold.
• the support member many be internal, external, or embedded in the tissue.
• the implant is a tissue including an external stent that provides the benefits described above.
• a tissue product of the present invention may be a tube or conduit, or tubular in shape.
• a preferred embodiment is a continuous tubular shape.
• these shapes include or enclose a lumen through the longitudinal length of the construct.
• the lumen can be open or closed at one or both ends and may be shaped at one or both ends.
• the implanted tissue, graft, or implant is capable of endothelialization, even substantial endothelialization, a feature that provides evidence of the long-term biocompatibility of the tissue and mediation in vascular repair.
• CT tissue grafts have been shown to provide anatomical and functional characteristics that mimic native structures, e.g., native vessels around the heart and saphenous veins.
• native structures e.g., native vessels around the heart and saphenous veins.
• CT tissue was evaluated for its mechanical properties and hemodynamics. All of these evaluations showed that the CT tissue of the present invention has functional compliance and “hand” to native structures.
• the CABG is a sterile, ⁇ 4-6 mm inner diameter, ⁇ 15 cm long tubular conduit composed of a naturally produced acellular human collagen matrix.
• the collagen matrix is produced by culturing human dermal fibroblast (HDF) cells in a controlled process.
• HDF human dermal fibroblast
• the product possesses structural integrity with burst strength and suture retention strengths similar to native arteries and veins (e.g., 1000-5000 mmHg burst strength).
• the present invention also is a surgical kit comprising one or more of the following: a regenerative tissue implant or graft processed or produced according to the present invention; one or more instruments for implanting the graft; a rinse tray; a rinse solution, e.g., heparin; and suture material.
• One of the embodiments of the present invention is a sterile closed package containing a biological material of the present invention and an external support structure configured to slide over the biological material.
• a separate container may hold individual or multiple samples having known size or dimensions.
• the present invention also includes tubular grafts in a variety of diameters and lengths as needed to match the anatomy.
• An implant of present invention maybe delivered in any medically acceptable manner.
• the tissue is surgically delivered.
• the tissue is delivered via catheter or tube.
• 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.
• 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.
• a tissue of the present invention was implanted as a CABG graft into an ovine model, and after one year showed long-term performance and regeneration into a living blood vessel.
• a tissue of the present invention was implanted as a pediatric vascular conduit into a lamb model, and after one year showed somatic growth and regeneration.
• the flexibility or bend compliance of an exemplary support of the present inventions was compared to different designs and various commercially available stents.
• the preferred design of the present invention was found to be more flexible and bend compliant than the InnovaTM commercially available stent which has been previously evaluated with the tissue of the present invention.
• the flexibility of the present invention was found to have bend compliance that falls between InnovaTM and Pulsar-18, both commercially available stents that have been proven safe and effective as permanent implant in patients. This gives the present invention the flexibility to curve with the anatomy seen of the CABG graft while remaining durable enough to be safe for permanent implant in patients.
• Tissue recovered from the animals were fixed in formalin and processed for staining.
• H&E-stained sections show small aggregates of inflammatory/immune cells including eosinophils, PMNs, lymphocytes, and macrophages within the abluminal area of the conduits, but rated as absent to minimal/diffuse in all 6- month explants.
• the 3-month explant (BAVG 7), where they were rated as marked/focal in the abluminal areas of the graft in some sections.
• Fibrin immunohistochemical staining confirmed a thin thrombus layer on the luminal surface of the 3-month explant, also evident in the trichrome staining. Minimal fibrin staining was evident in the 6-month explants.
• Verhoeff-van Gieson stained sections revealed mature elastic fibers within the implant near the proximal anastomosis in two of the 6-month explanted conduits, but not seen in other sections.
• Gen 1 study 4 animals survived past 6 months with 3 planned explants accessed for angiography, gross pathology, and histopathology to evaluate remodeling of a CABG graft and any adverse outcomes in myocardial tissue.
• the angiogram at 180 days showed uniform diameter transition from a CABG into the native coronary. Further, gross examination showed distal anastomosis without evidence of hyperplastic response. The anastomotic sutures were visible in the 180-day explants. A cross-section of the graft showed remodeled tissue with areas of glossy lumen surface and areas with thin layer of thrombus.
• a 39-day explant permitted gross examination of the external support and any gross differences from the graft Gen 1 implants (non-stent supported tissue conduit). Grossly, the stent was well fused within the scar tissue around the heart. There was no evidence of any inflammatory or fibrotic response. Once exposed and removed from the heart, there was only a thin layer of remodeled tissue around the external stent. The dissected lumen surface showed predominantly fresh clots with one area of thrombus 2-3 cm from distal anastomosis. There was no evidence of stenosis or hyperplastic response at either anastomosis. The explanted heart sections also showed no gross infraction.
• a graft (Gen 2) with external stent support provides the benefit of no kink or sharp bend seen up to 30 days post-implant. Further, there was no complication in implant procedure. Similar stent support has been used in at least two major clinical trials to support autologous saphenous vein (30, 31 ). The remodeling both grossly and histologically shows no immediate adverse effects of the external support. Overall, the initial data supports the use of an external stent with a CABG to prevent adverse events.
• the graft was fully cellularized by 3 months, suggesting complete remodeling of the implanted graft by host cells. This was confirmed by an increase in mechanical burst pressure strength of the explanted graft, which was 136% of implanted grafts. At 6 months, the explanted grafts were also stronger by 156% compared to implanted grafts, including areas with repeated puncture using a 16G dialysis needle.
• the ECM remodeling is a natural phenomenon and does not include any chemical processes and products that would not occur naturally.
• Tissue conduit with external support spanning 80% of the conduit length was implanted for a duration of 12 months.
• the angiogram assessment during the 12 months showed uniform conduit diameter within the externally supported segment with no kink, no dilation and maintained uniform diameter.
• the section not covered by the external support showed evidence of dilation and nonuniform diameter.

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