External support for tissue implants

Abstract

This invention provides an external support, or frame, for a structural tissue that can be planted together.

Description

Technical Field

[0001] The present invention relates to products formed from unique regenerative tissue, products made from this tissue, implants composed of this tissue, and methods of treating medical conditions and / or disorders using this tissue.

Background Art

[0002] Since the early 1990s, there has been a relatively new field of medicine called regenerative medicine. Regenerative medicine is a process of generating functional tissue to repair, replace, or restore the structure and function of tissues or organs lost due to aging, disease, injury, or congenital defects. In this field of medicine, new methods and products including tissue engineering or construct tissue (CT) are utilized.

[0003] It is well known to use xenograft materials prepared for surgical transplantation into humans. More specifically, it is well known to use processed animal tissues as materials for human tissue grafts, replacement valves, and similar transplantation surgeries. However, the prior art has not adequately addressed issues of immunogenicity, thrombogenicity, calcification, material strength, and size.

[0004] Since the 1930s, medical researchers have attempted to develop natural and synthetic alternatives suitable for realizing small-diameter grafts useful in vascular surgery. Historically speaking, attempts to manufacture such tubular grafts from artificial materials have not been very successful. Allogeneic tissues are not always readily available, nor are they always readily available in the sizes required by surgeons. Furthermore, some of these tissues are immunogenic and thus may require processing or specific treatments to reduce immunogenicity.

[0005] Coronary artery bypass grafting (CABG) remains the cornerstone of vascular regeneration for multi-vessel coronary artery disease (CAD) (2). The most commonly used conduits are the autologous internal mammary artery, radial artery, and saphenous vein, which offer excellent mechanical stability and natural antithrombotic properties (2). Patients currently undergoing coronary artery regeneration are aging and at higher risk (2). In patients with co-existing vascular diseases, saphenous vein grafts may be of lower quality, even if available (2, 3). Therefore, there remains a need for alternative bypass conduits for coronary artery regeneration (4-6). Furthermore, even in patients with suitable veins, the harvesting technique, which ensures the ligation of all branches and the precise matching of the lumen diameter to the original coronary artery, can lead to further complications.

[0006] Several clinical studies have evaluated non-autologous grafts for coronary artery bypass grafting (CABG), but have shown limited success rates (4-6). These non-autologous materials were all derived from animals or cadavers, but all exhibited inferior regenerative and endothelial formation capabilities. A novel approach involving the tissue engineering of blood vessels from cells in the laboratory, decellularization, and the use of extracellular matrix produced by the cells as conduits has been shown to achieve regeneration and remodeling in both preclinical (7, 8) and clinical (9-13) studies in non-human primates.

[0007] Humacyte Inc. pioneered one of these approaches to tissue engineering vascular graft formation by seeding vascular cells onto a synthetic biodegradable polymer and then culturing them in a bioreactor to produce the final cell-free ECM tube (8). Humacyte has implanted its vascular conduits in patients requiring vascular grafts for dialysis, femoral artery, and trauma (9-11, 13, 14). In 20 patients with suprapembryo-popliteal artery bypass implants, conduits with an inner diameter of 6 mm and a length of 35-42 cm were followed up for up to 24 months. Primary and secondary patency rates were 58% and 74%, respectively. Furthermore, immunological panel testing showed no changes in panel-reactive antibodies after transplantation. The most common causes of primary patency loss were thrombosis and anastomotic stenosis (10). More recently, Humacyte reported results using these conduits for coronary artery bypass in non-human primate models (AHA Conference 2022). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] 2007 / 061800 [Patent Document 2] WO2007 / 092902 [Patent Document 3] 2016 / 0203262 [Patent Document 4] WO / 2004 / 018008 [Patent Document 5] WO2004 / 101012 [Patent Document 6] PCT / US21 / 62709 [Patent Document 7] PCT / US2017 / 026204 [Patent Document 8] U.S. Patent No. 10,111,740 [Patent Document 9] U.S. Patent No. 10,105,208 [Patent Document 10] U.S. Patent No. 10,893,928 [Patent Document 11] U.S. Patent No. 8,192,981 [Patent Document 12] U.S. Patent No. 8,399,243 [Patent Document 13] U.S. Patent No. 8,617,237 [Patent Document 14] U.S. Patent No. 8,636,793 [Patent Document 15] U.S. Patent No. 9,034,333 [Patent Document 16] U.S. Patent No. 9,126,199 [Patent Document 17] U.S. Patent Application No. 17 / 139,575 [Patent Document 18] U.S. Patent Application No. 16 / 500,147 [Patent Document 19] U.S. Patent Application No. 10 / 523,618 [Patent Document 20] U.S. Patent Application No. 10 / 556,959 [Patent Document 21] U.S. Patent Application No. 13 / 771,676 [Patent Document 22] 2015 / 0012083 [Patent Document 23] 2009 / 0319003 [Patent Document 24] 2011 / 0020271 [Patent Document 25] 2012 / 0230950 [Patent Document 26] 2013 / 0013083 [Patent Document 27] 2014 / 0330377 [Patent Document 28] 2014 / 035805 [Patent Document 29] 2017 / 0135805 [Patent Document 30] 2017 / 0296323

Patent Document 31

Patent Document 32

Patent Document 33

Patent Document 34

Patent Document 35

Patent Document 36

Patent Document 37

Summary of the Invention

Problems to be Solved by the Invention

[0009] Although various materials can be used, they all have drawbacks and there are no renewable ones. There is still a need for a solution that combines the advantages of natural collagen tissue with regenerative properties and the advantages of manufacturing in large scale and in a suitable form (i.e., conduits).

[0010] Vascular graft failure generally causes thrombosis, intimal hyperplasia, atherosclerosis, and / or infections. The grafts of the present invention show no signs of these failures.

[0011] Although the methods described above are useful, there is still a need to increase patency, reduce thrombogenicity in the structure and / or function of the implant, minimize calcification, and increase the service life of the implant.

Means for Solving the Problems

[0012] One embodiment of the present invention involves the preparation and use of structural tissue (CT) for the fabrication of implants, the use of these structural tissues as implants, and the use of these structural tissues in mediating treatment or therapy. In preferred embodiments of the present invention, the implant is a coronary artery bypass graft (CABG), a peripheral vascular graft, or a saphenous venous conduit.

[0013] In the most preferred embodiment of the present invention, the implant comprises an external support structure (ESS).

[0014] The present invention utilizes a novel tissue engineering approach that yields a fully biological, cell-free ECM vascular conduit with mechanical properties corresponding to the internal mammary artery as the final product by using human fibroblasts seeded in a biological polymer and subsequently cultured in a bioreactor (7, 15). This tissue may be characterized in part by beneficial collagen alignment, anisotropy, in vivo anisotropy, cell-free nature, compatibility with terminal sterilization, non-chemical crosslinking, and a typical water content of about 85%. In preferred embodiments of the present invention, the tissue comprises heterogeneous collagen layers, typically comprising a high-density collagen layer followed by a porous layer, then another high-density layer, and then another porous layer. In some embodiments, the heterogeneous collagen layer comprises a high-density layer sandwiched between two or more porous layers. The inventors believe that these heterogeneous collagen layers provide numerous advantages to the finished tissue, including, but not limited to, giving it higher strength, such as higher burst strength. This vascular conduit (6 mm diameter conduit) has been implanted in 16 patients in two trials for hemodialysis access applications (12). In the initial 6-month human trial, good patency and low complication rates were observed, establishing the initial safety and feasibility of using the tissue for dialysis access in patients with end-stage renal disease. Due to its mechanical durability and lack of immune response, this tissue has been established as a potential regenerative material for clinical use in dialysis and other vascular applications.

[0015] One advantage of the present invention lies in the starting material itself.

[0016] The tissue of the present invention is a fully biological cell-free collagen matrix produced by allogeneic neonatal human dermal fibroblasts (nHDFs). The nHDFs are mixed with thrombin and fibrinogen and molded into a desired shape, typically such as a tube or sheet. The molded structure is then cultured in a bioreactor, where the nHDFs degrade the fibrin gel and secrete collagen and other extracellular matrix (ECM). The resulting tissue is then decellularized to obtain a cell-free human collagen matrix.

[0017] The products, uses, and processes of the present invention are suitable for the treatment of diseases and conditions that benefit from regenerative engineering tissue, particularly diseases and conditions relating to tubular tissue structures. One such use is for coronary artery bypass grafting (CABG).

[0018] Some embodiments of the present invention include the fabrication of grafts that are durable and have been demonstrated to withstand the stringent mechanical requirements of the vascular system in both animal and human studies (8).

[0019] The biological materials according to the present invention are processed to modify (e.g., reduce or remove) their size and shape, thickness, collagen content, and other features and properties that become apparent from the description of the present invention. The methods, uses, and products of the present invention are intended for implantation in mammals, preferably humans. Any biological materials processed according to the present invention are suitable for use in the in vivo environment and possess the following desirable properties for graft materials suitable for implantation: a) size compatibility with the surrounding blood vessels to be anastomosed, b) sutureability, kink resistance, flexibility, compliance in the radial and longitudinal directions, and flexibility (more flexible fit), c) non-thrombotic or low-level thrombotic properties, especially after regeneration or recellularization, d) durability, e) ease of sterilization, f) availability and availability in diameters and lengths suitable for surgical use, g) shelf life suitable for market conditions (generally more than 3 years), h) infection resistance, i) sufficient strength to resist aneurysm formation. j) non-immunogenic, k) resistance to degradation, l) resistance to neointimal hyperplasia, m) tactile properties as described by surgeons using the tissue and / or graft of the present invention, particularly tactile properties suitable for microsurgery, n) antibacterial properties, o) non-infectious, p) antimicrobial properties, q) the implant of the present invention does not become infected or is resistant to infection under conditions in which the implant would become infected (e.g., host / receptor cells other than the implant become infected), r) calcification properties are reduced or eliminated, s) improved or biologically appropriate or desirable reabsorption, t) becomes or migrates to living tissue, and u) is endothelializable in some embodiments. In this specification, living tissue refers to tissue that shows the presence of active cells (derived from the implant recipient), including, but not limited to, elastin production, ECM production, and / or lack of unparalleled immunogenicity.

[0020] Furthermore, surgeons recognize the superior quality of the tissue of the present invention in terms of tactile response, particularly when compared to typical vascular systems (usually autologous, such as venous grafts during coronary artery bypass procedures).

[0021] The implant of the present invention offers several other advantages. Specifically, this graft enables vascular regeneration of the affected heart using tissue that shows little to no discernible immune response. Furthermore, it is isodiametrically uniform, which contributes to excellent laminar flow within the graft, and further reduces turbulence and turbulence-related thrombus formation. Moreover, because it is a graft that grows with the body, it is a useful and beneficial graft for pediatric patients. Furthermore, this graft eliminates the need for venous and arterial harvesting procedures, thus eliminating the need for secondary surgery. In addition, it provides a small-diameter, consistently uniformly sized graft, resulting in a superior graft with high patency and mechanical properties.

[0022] While specific advantages have been listed above, various embodiments may include some, all, or none of the listed advantages.

[0023] Other technical advantages will become readily apparent to those skilled in the art by examining the following figures and descriptions.

[0024] While exemplary embodiments are shown in the drawings and described below, it should be understood from the outset that the principles of this disclosure can be implemented using any number of techniques, whether known or not at present. This disclosure is not limited in any way to the exemplary implementations and techniques shown in the drawings and described below.

[0025] The device will become apparent to those skilled in the art through the description of the diagrams that meet the following enablement requirements. [Brief explanation of the drawing]

[0026] [Figure 1] The present invention shows an implant comprising a tissue tube supported by an external support structure. [Figure 2] This is a magnified view of a portion of the external support structure surrounding the tissue biomaterial. [Figure 3] This figure shows the support structure of the present invention in a flat, non-expanded state. [Figure 4] This figure shows the expanded and completed cell within the support structure shown in Figure 3. [Figure 5] This diagram shows the end portion of the external support structure. [Figure 6] This is a magnified view comparing the preferred ESS(A) with the less desirable ESS(B) in terms of preference and flexibility. [Figure 7] This figure shows an exemplary placement of CABG implants relative to the structure of an anatomical cardiac model. [Figure 8] This graph shows the primary and secondary patency of the tissue of the present invention. [Modes for carrying out the invention]

[0027] The present invention relates to a coronary artery bypass graft (CABG) formed from a structural tissue (CT) prepared according to the present invention. In a preferred embodiment of the present invention, the graft is provided with an external support to prevent kinking of the graft. In the most preferred embodiment, the external support prevents / reduces kinking, prevents / reduces wear or abrasion of the outer portion of the graft, prevents or controls tissue expansion or swelling, and maintains lumen uniformity.

[0028] The grafts of the present invention can be used as vascular conduits at any location in the body of mammals, including humans, where they may be beneficial. Exemplary uses include, but are not limited to, saphenous vein (superficial or deep) conduits, including, but not limited to, above, around, or below the knee, for restoring blood flow to the heart, preferably by bypassing an occluded or damaged portion of a coronary artery during a CABG procedure.

[0029] In a preferred embodiment of the present invention, this tissue is used as a bypass to a second or third target (non-LAD coronary artery) in patients requiring coronary artery bypass grafting (CABG). The implant is a tubular bypass conduit that improves blood flow to the myocardium by forming a new pathway for blood to flow around an occluded or partially occluded artery of the heart.

[0030] In some embodiments of the present invention, the graft or conduit further comprises an external support. Examples of suitable stents used as external supports in accordance with the present invention include, but are not limited to, Gore Tigris, Terumo Misago, Gore ViaBahn, Boston Scientific Innova®, Abbott Supera, Biotronik Pulsar-18, Medtronic Everflex, and Cook Zilver.

[0031] In the most preferred embodiment of the present invention, the external support is a support as shown in Figures 1 to 7.

[0032] The support of the present invention can be used with any tissue or conduit intended to establish a fluid flow path between one part of the body and another, for example, from a coronary artery to a pulmonary artery, or between coronary arteries.

[0033] According to some embodiments of the present invention, in a first step, the tissue, conduit, or tube of the present invention may be implanted, and in a second step, the support may be added around the implant.

[0034] In the most preferred embodiment of the present invention, the external support has the following characteristics: the external support is laser-cut, the external support is radially flexible, the external support is biocompatible, the external support is sterile, the external support has high radial strength, the external support is radially rigid, the external support has radial rigidity that promotes or supports crush resistance, the external support is fatigue resistant, the external support is non-corrosive, the external support has a precise diameter, the external support is non-toxic, the external support has a precise thickness, the external support is electropolished, the external support is axially flexible, the external support is made of medical-grade material, the external support has a diameter sufficient to prevent kinking of the conduit, the external support provides sufficient support to prevent kinking of the conduit under anatomical (in vivo) conditions (e.g., in periodic axial motion), the external support has sufficient rigidity to prevent kinking under typical bending conditions (under bending conditions of the heart or other anatomical structures, and under pulsatile bending of arteries), and the external support is the target anatomy The external support has sufficient flexibility to bend under typical bending conditions of the target structure (e.g., under bending conditions of the heart or other anatomical structures, and under pulsatile flexure of arteries), supports vascular compliance, has a diameter larger than the conduit sufficient to allow conduit expansion (typical in pulsatile coronary blood flow), prevents, mitigates, or controls harmful expansion such as aneurysms, has a size and diameter that does not fit snugly to the conduit, has a size and diameter that allows the ESS to slide on the conduit, is manually slidable on the conduit, has sufficient axial flexibility to prevent the bend from being pushed toward the end of the implant (e.g., ESS / CAB junction), has sufficient flexibility to expand in accordance with pulsatile expansion and contraction, maintains integrity through the movement of the beating heart, and has sufficient axial compressibility to expose one or both ends of the conduit to facilitate the formation of an anastomosis.The external support has one or more of the following characteristics: the external support has non-traumatic edges and structures sufficient to prevent puncture or abrasion of the conduit; the external support has non-traumatic edges and structures sufficient to prevent puncture or abrasion of anatomical structures (e.g., the heart); the external support is sterilizable and / or durable; the external support is MRI compatible; the external support has a support structure, design and configuration that does not impair the integrity of the tissue or tube it supports; the external support has a support structure, design and configuration that does not damage or abrade the outer surface of the tissue or tube it supports; the external support has a support structure, design and configuration that does not damage or abrade the anatomical structure or organ that is in contact with the implant; the external support has a support portion that fits onto the tissue or tissue tube; the external support has a support structure that fits onto the tissue or tissue tube so tightly that the frame i.e., the support does not move substantially axially under the periodic beating of the heart; the external support is crush-resistant; the external support is durable; the external support maintains a uniform lumen diameter; and the external support prevents excessive expansion. ,

[0035] Tubular frame structure The tubular frame can be a ring-shaped, elliptical, or cylindrical structure or shape made from a durable, biocompatible structural material such as nitinol or a similar alloy, and is formed by manufacturing the structural material as a braided wire frame, laser-cut frame, or wire loop. This frame, or support, is sized in length and diameter to surround the tissue material. With respect to length, the support may be of any length and is also sized to match the tissue material. In some embodiments, the support is the same length as the tissue material. In other embodiments, one or both ends of the support are shorter than the tissue material. In the most preferred embodiment, the support is compressible and compressible so that one or both ends of the tissue material can be exposed.

[0036] In some embodiments of the present invention, the support may have a maximum length of about 300 mm, and preferably a length between about 80 mm and about 120 mm.

[0037] In some exemplary embodiments, the typical inner diameter is up to about 24 mm, preferably greater than about 4.0 mm, and typically in the range of about 4 mm to about 30 mm. In some exemplary embodiments, the typical outer diameter is up to about 30 mm, preferably greater than about 4.0 mm, and typically in the range of about 4 mm to about 30 mm. As previously stated, the tubular frame may have a ring-shaped, cylindrical side profile, but may also have a ring or cylindrical side profile having a convex cylinder (with a bulging wall), a flared upper, a flared lower, or both.

[0038] In one preferred embodiment, the tubular frame used in a CABG implant may have a complex shape determined by the anatomical structure into which the implant will be inserted. For example, in a CABG implant, the outer circumference of the ESS may be substantially circular, and its diameter may be slightly larger than that of the underlying tissue tube, providing sufficient flexibility to expand and contract in response to any fluctuations in the normal and diseased vascular system. Thus, a CABG implant with an ESS may begin in a substantially tubular configuration and be heat-formed to a diameter and length that provides sufficient support to the conduit, and the annular tubular section may have a uniform cross-section for most or all of its length and may have non-traumatic edges along posterior and anterior annular transition segments (e.g., exposed conduit transitions located at one or both of the anterior or posterior ends of the tissue) that are intended not to support the tissue.

[0039] In an alternative embodiment, the ESS may be configured in a clamshell configuration. In this configuration, instead of sliding the ESS over the blood vessel (as described above), the tissue is placed within a longitudinally open support, and then the support can cover, constrict, or close the tissue.

[0040] The scaffold, support, or frame of the present invention is flexible and maneuverable, allowing the frame, or support, to be bent around or wrap around tissue tubes or tissue conduits without damaging or breaking the tissue. Furthermore, the wrap of the present invention may be flexible enough to slide over, surround, or cover tissue material.

[0041] As described above, the wrap, or tissue product, of the present invention is a tube or conduit, or has a tubular shape. One preferred embodiment is a continuous tubular body. Other preferred embodiments are shown in the drawings. Typically, these shapes have or enclose a lumen along the longitudinal length of the structure. This lumen can be open or closed at one or both ends.

[0042] Purpose of tubular frame The tubular frame has an axial central lumen, and a structural material such as a tube can be placed within the inner diameter of this frame.

[0043] Frame structure Preferably, the frame is made from a superelastic metal wire, such as Nitinol® wire or other similarly functioning material or alloy. These materials can be used for the frame, or support. It is also conceivable within the scope of the invention to use other shape memory alloys, such as Cu-Zn-Al-Ni alloy and Cu-Al-Ni alloy, as well as polymer composite materials, including composite materials containing carbon nanotubes, carbon fibers, metal fibers, glass fibers, and polymer fibers. The frame may be constructed as a braided wire frame or a laser-cut wire frame. Such materials are available from numerous commercial manufacturers, such as Pulse Systems. Laser-cut wire frames are preferably made from nickel-titanium (Nitinol®), but may, and are not limited to, stainless steel, cobalt-chromium, titanium, other functionally uniform metals and alloys, or Pulse Systems braided frames shaped by heat treatment on a fixture or mandrel.

[0044] One important aspect of frame design is that the frame must be compressible and able to return to its original (incompressible) shape when released. This requirement may limit the possible material choices to metals and plastics with shape memory properties. With regard to metals, nitinol has proven particularly useful because it can be processed to be austenitic, martensitic, or superelastic. Martensitic and superelastic alloys can be processed to achieve the required compressive properties. The inventors have found that a support that is axially compressible in the range of about 0% to about 40% of its length is suitable for carrying out the present invention. In preferred embodiments of the present invention, any amount of axial compression can be selected, as long as the structural lumen is maintained to be relatively uniform. More preferably, the support is a support that is compressible between about 10% and about 30% of its length.

[0045] According to one embodiment of the present invention, a support that is less compressible or not compressible at all, such as being compressible between about 0% and about 5%, may be further configured such that the structural material extends beyond the ends (or both ends) of the support.

[0046] In the most preferred embodiment, the frame is compressible to such an extent that one strut can be nested within an adjacent strut without contacting or coupling with the adjacent strut. For example, compare Figures 6A and 6B.

[0047] According to various embodiments of the present invention, compressibility and nesting properties can be achieved by utilizing various strut angles and strut shapes, both of which are within the scope of the expertise of those skilled in the art. In the illustrative designs shown in the figures, the support has a strut angle of approximately 15° to approximately 25°. The illustrative configurations shown in Figures 2 to 4 have a strut angle of approximately 20°.

[0048] Alternatively, the support may be made of a synthetic material, or it may be made of a plastic material and / or a fibrous material, or the structure may be printed. In these embodiments, the support should still be compressible and flexible in accordance with the teachings of the present invention.

[0049] Laser cutting One possible configuration for the wireframe is to laser-cut thin, uniformly diameter nitinol tubes. This laser cutting creates regular notches in the thin nitinol tubes.

[0050] Next, the tube is placed on a mold of the desired shape, heated to martensite temperature, and then rapidly cooled. This wireframe processing forms a device that has shape memory properties and easily returns to its memorized shape at calibration temperature.

[0051] These frames are support structures comprising multiple struts or wire sections arranged to give desired compressibility and strength. Broadly speaking, the stent or stent frame of the present disclosure is a substantially tubular support structure having an internal region in which a tubular tissue material can be positioned.

[0052] Some embodiments of a stent frame can be a series of wires or wire segments arranged to enable self-transition from a compression or convergence configuration to a normal radial expansion configuration.

[0053] In some structures, the individual wires constituting the stent frame support structure may be formed from metal or other materials. These wires are arranged so that the stent frame support structure can be folded, compressed, or crimped into a compression configuration having an inner diameter smaller than that of the normal expanded configuration. In the compression configuration, such a stent frame support structure surrounding a tissue tube may be mounted on a delivery device. These stent frame support structures are configured to be converted to a normal expanded configuration as desired, for example, by the relative movement of one or more outer sheaths with respect to the length of the stent frame.

[0054] The wires of these stent frame support structures in embodiments of this disclosure can be formed from a shape memory material, such as a nickel-titanium alloy (e.g., Nitinol®). Using this material, the support structure becomes self-expandable from a compressed configuration to a normal expanded configuration by, for example, the application of heat and energy, or the removal of an external force (e.g., compressive force). This stent frame support structure can also be compressed and re-expanded multiple times without damaging the structure of the stent frame. Furthermore, the stent frame support structure of such embodiments may be laser-cut from a single piece of material or assembled from multiple different components. For these types of stent frame structures, an example of a usable delivery device is a catheter having a retractable sheath. This sheath covers the stent frame until it is deployed, at which point the sheath flexes to allow the stent frame to self-expand.

[0055] The present invention provides products and processes for use in any in vivo therapy that delivers beneficial outcomes to patients / transplant recipients through endothelialization and / or recellularization.

[0056] In this specification, recellularization refers to the regrowth or growth of cells and structures near the transplant site, with the aim of reconstructing and reforming the original tissue-specific functions. In some embodiments of the present invention, recellularization includes tissue growth, including the growth of the patient's body.

[0057] In this specification, healing refers to the ability of a living organism to replace damaged or lost tissue with new cells, to heal damaged tissue, and to restore its structure and function, i.e., to become living tissue. Healing includes, but is not limited to, the restoration of living structures, including cells, other biomolecules, and cell-free ECM scaffolds, which leads to the restoration of tissue and / or bodily function. Healing is the process of regeneration, regrowth, or recovery of tissue, organ, or living organism after injury, injury, or disease.

[0058] In this specification, remodeling refers to the process by which the body adapts to and integrates with an implanted medical device. This process involves interaction between the implant and surrounding tissues, which may result in changes in the structure and composition of the tissues as well as in healing.

[0059] In this specification, recellularization and remodeling are considered to fall within the definitions of regeneration and healing.

[0060] In its most preferred embodiment, the tissue of the present invention, when implanted, does not become mechanically fragile during the healing process. One of the advantages of the tissue of the present invention is that it does not require scaffolds or the like. This feature is in contrast to products that have specifically degradable synthetic or biological parts, such as scaffolds. Furthermore, this feature is also different from tissues during the manufacturing process. During the formation phase, ECM-producing cells degrade fibrin until collagen tissue is formed. Cell-containing tissues contain no fibrin, only trace amounts, or amounts that are undetectable.

[0061] One embodiment of the present invention includes, but is not limited to, the recellularization of the tissue without prior degradation.

[0062] One embodiment of the present invention includes a product or implant formed from the tissue of the present invention, the tissue comprising an external support structure.

[0063] Embodiments of the present invention include, but are not limited to, forms of tissue delivery. Examples include intravascular delivery and surgical implants.

[0064] The tube or tubular material of the present invention can be positioned to replace, surround, accommodate, or enclose a body structure. Examples include, but are not limited to, one or more coronary arteries.

[0065] The grafts or implants of the present invention can be used in methods of treating patients with a variety of medical conditions, diseases, or injuries, the common theme being that the treatment involves tissue implantation. Exemplary diseases and medical conditions include, but are not limited to, arrhythmias, wound infections, renal failure, thrombosis / embolism, aneurysms, patient infections, and patient immune responses.

[0066] In another embodiment of the present invention, the tissue may contain structural elements or drugs (e.g., activators) within the surface of the CT tissue.

[0067] The structure of the present invention may be of any size or shape. In one preferred embodiment, the structure may be in the form of a wrap, conduit, sheet, cover, envelope, or tube.

[0068] According to the present invention, the tissue or tube may be surrounded or covered by an external support structure (ESS). In the most preferred embodiment, the ESS substantially covers the tissue from one end to the other. In some embodiments, the ESS has sufficient flexibility or conformity in the longitudinal direction to expose one or both ends of the tube, thereby allowing access to one or both ends of the tube for surgical procedures.

[0069] In another embodiment, the ESS has a size and dimensions such that one or both ends of the tube are exposed or not covered by the ESS.

[0070] The present invention relates to grafts, prosthetics, or coverings formed from constructed (CT) regenerated tissue and / or engineered tissue. In this specification, “constructed” or “engineered” means that the inventors and others can produce or construct the tissue, for example, that the tissue is not a natural product. In preferred embodiments of the present invention, the tissue mediates regeneration without causing the degradation of tissue and other biological material in the area of ​​the transplantation site. The present invention includes methods for producing this tissue and methods for producing grafts or prosthetics.

[0071] This tissue can be formed by mixing ECM-producing cells in the presence of fibrinogen and thrombin under conditions that enable the formation of regenerative tissue. Typically, this process involves forming a cell seeding suspension containing ECM-producing cells, fibrinogen, and thrombin. This suspension is then poured into a mold and incubated. During incubation, the ECM / fibrin / collagen tissue begins to form. As part of this process, compression and fiber alignment occur, and remodeling may occur as the ECM / collagen / fibrin tissue is formed. This tissue is then cultured until it matures, for example, until it is large enough to be used for its intended purpose. The resulting cell-containing tissue is a decellularized tissue. The tissue of the present invention is cultured from allogeneic dermal cells, which are entirely biological raw materials. See, for example, the patents and patent applications listed below.

[0072] In a preferred embodiment of the present invention, the hydrogel, which is the starting material in the suspension, allows the tissue to grow in a volumetric 3D process also known as casting. In many senses, the process from the initial material to the complete tissue corresponds to a continuum of remodeling. In contrast, most, if not all, typical tissue engineering methods grow tissue in a 2D manner (by seeding a cell suspension onto a surface) using synthetic and / or immunogenic scaffolds, etc. This growth eventually forms a 3D structure, but growth in scaffold-based structures differs from growth by volumetric 3D casting in the tissue of the present invention.

[0073] A preferred embodiment of the present invention is any structure or shape formed from the tissue of the present invention, including but not limited to tubular grafts.

[0074] According to embodiments of the present invention, any artificial organ can be formed by using regenerated tissue (RT) or engineered tissue, either whole or in part. In this specification, RT is referred to in the following documents: 2007 / 061800, WO2007 / 092902, 2016 / 0203262, WO / 2004 / 018008, WO2004 / 101012, PCT / US21 / 62709 (filed December 9, 2021), PCT / US2017 / 026204 (filed April 5, 2017), and U.S. Patent No. 10,111,740. U.S. Patent No. 10,105,208, U.S. Patent No. 10,893,928, U.S. Patent No. 8,192,981, U.S. Patent No. 8,399,243, U.S. Patent No. 8,617,237, U.S. Patent No. 8,636,793, U.S. Patent No. 9,034,333, U.S. Patent No. 9,126,199, U.S. Patent Application No. 17 / 139,575 (filed December 31, 2020, issuance fee) (Fees paid), U.S. Patent Application No. 16 / 500,147 (filed October 2, 2019, issuance fee paid), U.S. Patent Application No. 10 / 523,618, U.S. Patent Application No. 10 / 556,959, U.S. Patent Application No. 13 / 771,676, 2015 / 0012083, 2009 / 0319003, 2011 / 0020271, 2012 / 0230950, 2013 / 0013083 This refers to tissues formed or processed as disclosed in U.S. Patent Nos. 8,198,245, 9,127,242, 9,556,414, 9,657,265, and 9,650,603. All of these documents are incorporated herein by reference in their entirety.

[0075] In one embodiment of the present invention, the bioengineered tissues may all be prepared in accordance with U.S. Patents 10,111,740, 10,105,208, 10,893,928, and 11,589,982 by Tranquillo et al. These documents are all incorporated herein by reference in their entirety. Any process or method for preparing an engineered tissue with ECM-producing cells in a hydrogel is included in the scope of the present invention.

[0076] The CT of the present invention may be characterized in the following respects: namely, no signs of patient infection (in vivo), no signs of patient immune response (in vivo), no toxicity, no signs of degradation of implanted tissue, no residual cell fragments (e.g., no shedding of particles from tissue, as opposed to polymer degradation and erosion), modification of inflammation (e.g., reduction or removal), calcification properties, reabsorption, re-absorption, absorption, suture retention, size and shape, thinness (e.g., swelling or aneurysm formation), collagen content, and other features and properties that may become apparent from the description of the present invention.

[0077] The CT of the present invention differs from certain other types of constructive tissues in its use of entirely biological raw materials and allogeneic dermal cells, as well as the use of cross-linked fibrinogen that is subsequently degraded during the culture process. Furthermore, the CT of the present invention is capable of, or can tolerate, contraction in the longitudinal and / or radial directions, for example. According to some embodiments of the present invention, the fibers within the tissue can align or become aligned, which may be partly due to the fibrin having little to no resistance to contraction that occurs naturally as part of the collagen / ECM formation process. Furthermore, the inventors believe that contraction in the radial and / or longitudinal directions occurs partly naturally as an inherent function of tissue formation as described herein. In another embodiment of the present invention, contraction may be tunable or deliberately controlled to enhance, promote, or achieve one or more tissue properties, such as fiber alignment, tensile strength, or sutureability. Furthermore, the CT of the present invention does not involve any synthetic materials, as is typical in other processes using PLA or PGA, etc.

[0078] The CT of the present invention is formed by a process including the following: non-oriented fibers, oriented fibers, a thickness up to about 2 mm, preferably between about 100 μm and about 800 μm, a diameter greater than about 1 mm, about 1 mm to about 40 mm, preferably about 2 mm to about 25 mm, most preferably about 3 mm to about 16 mm, a length greater than about 1 cm, about 1 cm to about 100 cm, preferably 10 cm to 30 cm, most preferably about 12 cm to about 22 cm, non-immunogenic or minimally immunogenic, anisotropic tissue, sheet, or shape, scale shrinkage. The tissue, sheet, or molded structure (as described above) may be characterized by one or more of the following: a sheet or shape suitable for cutting into a certain shape by a scalpel, die, or laser, adaptability, sutureability, little to no calcification throughout the life of the implant, crosslinking density i.e., variation in crosslinking density over the entire thickness of the material, collagen concentration, collagen density i.e., variation in crosslinking density over the entire thickness of the material, remodeling tendency, absorption, reabsorption, degradability, higher rigidity, and higher flexibility.

[0079] In some embodiments of the present invention, the diameter and diameter range may be determined by the type of graft or implant to be used. The diameter may be any diameter, typically less than about 6 mm (but larger diameters are also possible). For example, CABG grafts preferably have a diameter of about 3 mm to about 6 mm.

[0080] In some embodiments of the present invention, the length and length range may be determined by the type of graft or implant to be used. The length may be any length. For example, a CABG graft is preferably about 15 cm to about 25 cm in length, which is then typically resized to about 8 cm to about 15 cm as needed during the implantation procedure.

[0081] In some embodiments of the present invention, either the diameter or the length, or both, can be tapered.

[0082] In some embodiments of the present invention, the thickness and thickness range may be determined by the type of graft or implant to be used. For example, CABG grafts may preferably have a thickness of about 0.3 mm to about 0.8 mm, and AV access grafts may have a thickness of about 0.3 mm to about 1.0 mm.

[0083] According to the present invention, the external support structure is sized to fit around the outer surface of the graft.

[0084] The tissues or products of the present invention may be used to treat or repair other types of tissues, including but not limited to tubular non-vascular applications, muscles, tendons, organs (e.g., kidneys and livers), skin, trachea, ureters, vascular system, bladder, fascia, and uterus.

[0085] Referring to the drawings, Figure 1 shows an implant 10 comprising tissue material 11 covered by an external support structure 12. This figure shows an implant configured (e.g., curved) to be beneficial when placed near a human anatomical structure (not shown) in vivo. This figure shows the anterior end (13) and posterior end (14) of the tissue exposed. These uncovered, i.e., exposed ends can be used as anastomosis sites for attaching a portion of the tissue or implant to a vascular system.

[0086] Figure 2 shows a magnified view of a portion of the ESS.

[0087] Figure 3 shows a structural diagram (planar pattern) of the ESS in its non-expanded state according to the present invention. Figure 4 shows one cell of the ESS shown in Figure 3 in its expanded state.

[0088] Figure 5 shows the end 50 of an exemplary ESS 51. In this embodiment, comparing cell 52 and cell 53, the struts of cell 52 are spaced more widely apart, resulting in a change in flexibility. The inventors have found that longer struts tend to result in lower flexibility of the frame (e.g., end segment 52), while repeating segments 53 tend to result in higher flexibility of the frame. The flexibility, or bending ability, of the frame is obtained at the connection points between the struts and connectors; therefore, the more connection points there are per unit length of the frame, the more places the frame can bend, and all of these contribute to higher flexibility.

[0089] Figure 6 compares two different configurations of the ESS of the present invention. Figure 6A shows a preferred embodiment in which one lobe 60 is nested within another lobe 61 without the individual struts being in contact. In Figure 6B, the strut of the first lobe is in contact with the strut of the second lobe (62). The configuration as shown in Figure 6A has greater flexibility than the configuration as shown in Figure 6B.

[0090] Figure 7 shows exemplary placement of the implant 70 to various anatomical structures of a model heart. The implant 70 has a tubular tissue tube 71 partially covered by the ESS 72 of the present invention. Furthermore, the implant 70 shows two uncovered, i.e., exposed tissue ends 73 and 74, which together constitute the anastomosis site.

[0091] Figure 8 shows Kaplan-Meier plots of primary and secondary patency of the graft according to the present invention.

[0092] Various methods and steps By mimicking the extracellular matrix of the natural environment, the tissues of the present invention can have and grow desirable or beneficial structural properties, which ultimately develop into structures close to those of nature (i.e., the tissues of the present invention are biomimetic materials). In preferred embodiments of the present invention, when surgically implanted, the tissues of the present invention can be handled in a manner similar to that of natural veins or arteries.

[0093] Some embodiments of the present invention may further include preserving and / or sterilizing the medical device or tissue of the present invention. These embodiments may include a pre-selected preservation solution, a pre-selected sterilization solution or sterilization technique, preservation packaging, and / or sterilization packaging. In one embodiment, the tissue may be preserved in PBS and refrigerated until use. In another embodiment, the tissue may be partially or completely dehydrated. In one embodiment, the preservation is carried out in a sterile drying container. Other preservation / sterilization processes may include one or more additives known to those skilled in the art. In another embodiment, the tissue may be electron beam sterilized only in PBS.

[0094] Those skilled in the art will understand that other preservation and sterilization protocols may be used in conjunction with the organization of the present invention.

[0095] In some embodiments of the present invention, the tissue, when implanted in humans, did not degrade before recellularization or somatic cell infiltration.

[0096] In some embodiments, the CABG tissue conduit is intended to be used with an external metal support that provides external support, thereby preventing or reducing kinking of the conduit, preventing or reducing tissue wear or abrasion, maintaining a uniform lumen diameter, and preventing or controlling tissue expansion. Furthermore, this external support may reduce or prevent abrasion to other tissues or parts of the anatomical structure that come into contact with the implant. The external stent or external stent may be a commercially available standalone product.

[0097] Other Embodiments The microstructure of the present invention is approximately 3 mm 3 ~approximately 65,000 mm 3 The total volume may be defined or contained within it.

[0098] The structure of the present invention may include, but is not limited to, one or more collagens, including type I collagen, type III collagen, and type VI collagen, tenascin, and fibronectin.

[0099] The tissue product of the present invention may be unsupported or may further comprise a support member, such as a nitinol stent or scaffold. This support member may be located inside or outside the tissue, or implanted within the tissue. In a preferred embodiment of the present invention, the implant is a tissue comprising an external stent, which provides the above-mentioned advantages.

[0100] As described above, the structural product of the present invention may be a tube or conduit, or it may be tubular in shape. A preferred embodiment is a continuous tubular body. Typically, these bodies have a lumen along the longitudinal length of the structure, or enclose a lumen. This lumen may be open or closed at one or both ends, or it may be molded at one or both ends.

[0101] In some embodiments of the present invention, the implanted tissue, graft, or implant is capable of endothelialization, or even substantial endothelialization, which is a characteristic that results in indications of long-term biocompatibility of the tissue and mediation in vascular repair.

[0102] In various embodiments of the present invention, including but not limited to CABG, excellent hemodynamic and biomimetic functions were observed in preclinical studies.

[0103] In preferred embodiments of the present invention, CT tissue grafts have been found to exhibit anatomical and functional properties that mimic natural structures such as the biological blood vessels and saphenous veins surrounding the heart.

[0104] In preferred embodiments of the present invention, the CT tissue was evaluated with respect to its mechanical properties and hemodynamics. Both of these evaluations demonstrated that the CT tissue of the present invention possesses functional compliance and "fit" to natural structures.

[0105] In some embodiments of the present invention, CABG is a sterile tubular conduit having an inner diameter of approximately 4–6 mm and a length of approximately 15 cm, composed of a naturally produced cell-free human collagen matrix. This collagen matrix is ​​produced by culturing human dermal fibroblasts (HDF) in a controlled process. The product has structural integrity with burst strength and suture retention strength similar to that of natural arteries and veins (e.g., burst strength of 1000–5000 mmHg).

[0106] Furthermore, the present invention relates to a surgical kit comprising one or more of the following: a regenerative tissue implant or graft processed or manufactured in accordance with the present invention; one or more instruments for implanting the graft; a rinse tray; a rinse solution such as heparin; and suture material.

[0107] One embodiment of the present invention is a sterile, sealed package containing a biological material of the present invention and an external support structure configured to slide on the biological material. Typically, separate containers may hold individual or multiple samples of known size or dimensions.

[0108] Furthermore, the present invention includes tubular grafts of various diameters and lengths as required to conform to anatomical structures.

[0109] The implant of the present invention can be delivered in any medically acceptable manner. In one preferred embodiment, the tissue is delivered surgically. In another embodiment, the tissue is delivered via a catheter or tube.

[0110] Those skilled in the art will understand that the process steps described herein may be modified in various ways to achieve an organization having certain characteristics according to the present invention.

[0111] definition The following definitions are used in connection with the present invention.

[0112] As described herein, decellularized blood vessels consist essentially of extracellular matrix (ECM) components of the vascular tree. ECM components may include any or all of the following: fibronectin, fibrillin, laminin, elastin, elements of the collagen family (e.g., type I, type III, and type IV collagen), glycosaminoglycans, matrix, reticular fibers, and thrombospongin, which can maintain an organized state as well as well-defined structures such as the basement membrane. Successful decellularization is defined as the absence of detectable myofilaments, endothelial cells, smooth muscle cells, and nuclei in tissue sections using standard histological staining methods.

[0113] In this specification, biomimetics or biomimicry refers to the practice of mimicking models, systems, and elements from nature to solve complex human or animal problems. In this invention, biomimetics is used for therapeutic purposes.

[0114] (References)

[0115] (Examples) (Example 1) When the tissue of the present invention was implanted as a CABG graft in a sheep model, long-term performance and regeneration into living blood vessels were observed after one year.

[0116] When the tissue of the present invention was implanted in a sheep model as a pediatric vascular conduit, body growth and regeneration were observed after one year.

[0117] (Example 2) The flexibility or flexural compliance of the exemplary support of the present invention was compared with different designs and various commercially available stents. The preferred design of the present invention was found to have higher flexibility and flexural compliance than the commercially available Innova® stent previously evaluated using the tissue of the present invention. The flexibility of the present invention was found to have flexural compliance between Innova® and Pulsar-18, both commercially available stents that have been found to be safe and effective as permanent implants in patients. Thus, the present invention achieves flexibility to bend to conform to the anatomical structure of the CABG graft while maintaining sufficient durability to ensure safety as a permanent implant in the patient.

[0118] (Example 3)

[0119] [Table 1]

[0120] (Example 4) Tissues recovered from animals were fixed in formalin and then treated for staining. - In H&E-stained sections, small clusters of inflammatory / immune cells, including eosinophils, PMNs, lymphocytes, and macrophages, were observed in the extracutaneous region of the ducts, but these were assessed as absent to mild / diffuse in all 6-month excised grafts. In the 3-month excised graft (BAVG 7), these were assessed as prominent / localized in the extracutaneous region of the graft in some sections. - In most trichrome-stained sections, elongated cells with circumferential orientation were observed in both 3-month and 6-month excised grafts, suggesting good remodeling. As seen in the trichrome-stained sections, all of these ducts were rich in collagen. - Fibrin immunohistochemical staining revealed a thin thrombus layer on the lumen surface of grafts excised at 3 months, and this was similarly evident with trichrome staining. Fibrin staining was minimal in grafts excised at 6 months. - In Verhoeff-van Gieson stained sections, mature elastic fibers were observed within the implant near the proximal anastomosis in two of the 6-month excised grafts, but not in the other sections. - No calcification was observed in the ducts at either 3 months or 6 months using Von Kossa staining. - In both the 3-month and 6-month sections, a large number of cells occupying the ductal stroma were vimentin-positive. - In numerous sections, the majority of elongating cells in a specific region adjacent to the lumen surface showed positive staining for α-smooth muscle actin (αSMA) at both time points. The thickness of this region varied considerably when clearly distinguishable, but was typically 100–300 μm. - Scattered smootherin staining was observed in elongating cells along the base of the aforementioned region. - At 3 months, limited endothelium was observed in the distal duct region by CD31 staining, but not in the intermediate duct region. On the other hand, in sections at 6 months, complete endothelium was observed in the proximal and distal regions of two of the three patent ducts, and in the intermediate duct region of one duct, while the remaining sections showed some degree of incomplete endothelial coverage. - Consistent with ultrasound examination, histological evaluation revealed no stenosis at the distal anastomosis site, but mild to slight (generally less than 250 μm thick) intimal thickening and fibrosis were observed in the vein located at the junction with the implant.

[0121] Overall, immunological analyses did not reveal any adverse acute or chronic immune responses or sensitization to the transplanted engineering tissue.

[0122] (Example 5) In the first-generation study, four animals survived for more than six months, and angiography, macroscopic examination, and histopathological diagnosis were performed on planned excised grafts from three of these animals to evaluate CABG graft remodeling and adverse events in myocardial tissue. Animals 22S0026, 22S0032, and 22S0034 all had patent conduits, showed no abnormalities on macroscopic findings, and did not show any signs of myocardial tissue damage or embolism.

[0123] Angiography at 180 days showed a uniform diameter transition from the CABG to the natural coronary artery. Furthermore, macroscopic examination revealed no signs of hyperplasia at the distal anastomosis. The anastomotic sutures were visible in the graft excised at 180 days. In the cross-section of the graft, remodeling tissue was observed, with a glossy lumen surface area and an area with a thin thrombus layer. Mechanical testing was performed on excised tissue from n=2 conduits. The mean lumen rupture strength was 3500±1405 mmHg, which, compared to the implant lumen rupture strength of 3109±624 mmHg, confirmed graft remodeling without weakening of tissue mechanical strength.

[0124] Histological examination of the excised grafts at the initial stage revealed a clear lack of immune response, with only slight neutrophil infiltration on day 8. 180 days after implantation, the implanted grafts were completely remodeled by stromal cells, with signs of endothelial cells observed in the proximal one-third of the conduit. Although luminal endothelium was absent along the entire length of the implant, stromal cell remodeling was observed similarly along the length of the implant. Furthermore, graft remodeling in coronary artery grafts was found to be comparable to previously reported remodeling in baboons at 6 months after transplantation as arteriovenous conduits, and in sheep as femoral artery grafts.

[0125] (Example 6) For stent 22S0051, the graft extracted on day 39 allowed for macroscopic examination of the external support, and further macroscopic examination of the macroscopic differences with first-generation implants (stent-free tissue conduits). Macroscopically, the stent showed good integration with the surrounding scar tissue. No signs of inflammatory or fibrotic reactions were observed. After exposure and extraction from the heart, only a thin layer of remodeling tissue was observed around the external stent. On the detached lumen surface, mainly fresh thrombi were observed, with one thrombus region located 2-3 cm away from the distal anastomosis. No signs of stenosis or hyperplasia were observed at any of the anastomoses. No macroscopic infarction was observed in the extracted cardiac section.

[0126] Histological examination of the intermediate conduit of 22S0051 revealed graft remodeling comparable to that of first-generation excised grafts from the same period. A small number of inflammatory cells, mainly neutrophils, were observed on the lumen surface. In the tissue surrounding the stent outside the conduit, remodeled collagen structures were observed without clear immune response.

[0127] Grafts with external stent support (second generation) offer the advantage of not showing kinking or sharp bending up to 30 days post-implantation. Furthermore, no complications were observed during the implantation procedure. Similar stent supports have been used in at least two major clinical trials to support autologous saphenous veins (30, 31). This remodeling does not show immediate adverse effects from the external support, both macroscopically and histologically. Overall, the initial data support the use of external stents in CABG to prevent adverse events.

[0128] (Example 7) In studies of tissue conduits in baboon and sheep models, all excised grafts were histologically evaluated for graft tissue remodeling. In the sheep model, at 4 and 8 weeks, the cell-free zone of the original graft was surrounded by remodeling matrix tissue on both the lumen-side and outer membrane-side surfaces of excised grafts. By 6 months, the width of this cell-free zone had decreased significantly, suggesting that the original tissue matrix had been remodeled by invading host cells. Mechanical properties of the excised tissue at 180 days surpassed those of the graft material, suggesting host tissue formation leading to more robust grafts. Since both the original matrix and the remodeling matrix are collagenous, immunohistochemical staining is not available to distinguish and quantify newly cell-produced collagen from the transplanted collagen.

[0129] In a baboon model implanted with tissue grafts, the grafts were fully cellularized by 3 months, suggesting complete remodeling of the transplanted grafts by host cells. This was confirmed by an increase in the mechanical rupture strength of the excised grafts to 136% of that of the transplanted grafts. Furthermore, at 6 months, the excised grafts showed 156% higher strength compared to the transplanted grafts, including in areas with repeated punctures using a 16G dialysis needle. ECM remodeling is a natural phenomenon and does not involve any chemical processes or products that do not occur naturally.

[0130] (Example 8) Tissue conduits with external support covering 80% of their length were implanted over a 12-month period. Angiographic evaluation over the 12-month period showed uniform conduit diameter within the externally supported section, with no kinking or dilation, and maintaining uniform diameter. Sections not covered by the external support showed signs of swelling and heterogeneity in diameter.

[0131] Without departing from the scope of this disclosure, modifications, additions, or omissions may be made to the systems, apparatus, and methods described herein. For example, the components of these systems and apparatus may be integrated or separated. Furthermore, the operation of the systems and apparatus disclosed herein may be carried out by more components, fewer components, or other components, and the methods described herein may include more steps, fewer steps, or other steps. Furthermore, the steps may be carried out in any suitable order. In this specification, “each” refers to each element of a set or each element of a subset of a set.

[0132] While the present invention has been described in detail through descriptions and examples, it should be understood that the present invention is not limited to the specific embodiments shown in the examples, and various modifications and alternative forms are possible. It should be understood that these specific embodiments are not intended to limit the present invention, but rather to encompass all modifications, equivalents, and alternatives that fall within the spirit and scope of the present invention. [Explanation of Symbols]

[0133] 10 Implants 11 Tissue materials 12 External support structure 13 Front end 14 Rear end 50 End 51 ESS 52 cells 53 cells 60 robes 61 robes 62 contact 70 Implants 71 Tubular tissue tubes 72 ESS 73 End 74 End

Claims

1. An implant suitable for use in humans and animals, comprising a conduit engineered or constructed from tissue formed using a composition comprising ECM-producing cells, thrombin, and fibrinogen, and an external support structure.

2. The aforementioned external support is Formed from superelastic metals, Laser-cut, Compressible in the longitudinal direction, Having sufficient compressibility to expose one or both ends of the tissue surrounded by the support, MRI compatible, Having sufficient rigidity to prevent kinking, Having kink resistance when the aforementioned tissue or implant bends, It possesses sufficient flexibility in the axial and longitudinal directions to curve around anatomical structures. Having wear resistance, Having a non-traumatic edge, Slidable on tissue including tissue tubes or conduits, and It can be up to approximately 300 mm in length. The implant according to claim 1, having one or more of the following characteristics.

3. The implant according to claim 1 or 2, wherein the external support comprises a strut configured to be nested within an adjacent strut.

4. The implant according to claim 1, wherein the implant is a coronary artery bypass graft, a peripheral bypass graft, a vascular bypass graft, or a pediatric bypass graft.

5. A coronary artery bypass implant comprising a constructive tissue formed from a composition containing ECM-producing cells, fibrinogen, and thrombin, and an external support.

6. The implant according to claim 1, wherein the tissue is acellular.

7. The implant according to claim 1, wherein the tissue induces cell regeneration or remodeling of the transplanted person at or near the transplant site.

8. The implant according to claim 1, wherein the tissue or the implant is biomimetic.

9. The implant according to claim 1, wherein the implant is a pediatric bypass.

10. The implant according to claim 1, wherein the tissue comprises a heterogeneous collagen layer.

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