Apparatus and method of a tubular tissue as a sheath for generating a therapeutic agent for a vascular graft

Abstract

Provided are a system, an apparatus, and a method for replacing a segment of a vascular structure, tissue, or organ. In some embodiments, the present disclosure further relates to a system for replacing a segment of a vascular structure, including a tubular vascular graft disposed concentrically with respect to an outer surface of a first mandrel, and a tubular support graft disposed concentrically with respect to an outer surface of a second mandrel and slidable on an outer surface of the tubular vascular graft, wherein an outer diameter of the second mandrel and an outer diameter of the tubular vascular graft are sized such that the tubular support graft can slide on the outer surface of the tubular vascular graft when the segment of the vascular structure is replaced.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 351,677, filed on July 13, 2022, and U.S. Provisional Patent Application No. 63 / 503,137, filed on May 18, 2023, the entire contents of each of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure relates to tissue - engineered vascular grafts.

Background Art

[0003] Tissue damage, dysfunction, or deficiency are diverse pathological features. Atherosclerotic arteriosclerosis, in which fatty plaques form in the blood vessel wall and the blood vessels narrow, is a known example. Accidents frequently cause damage to tendons, ligaments, and joints. Degenerative diseases such as arthritis are another cause of such tissue damage. Also, systemic diseases such as diabetes, cancer, and cirrhosis are yet another cause of organ destruction or dysfunction.

[0004] In many of the above situations, replacement of the damaged tissue or organ is the best or only option. Transplants from human donors (either living or cadaveric) have been very successful, and procedures such as liver, heart, and kidney transplants are overwhelmingly prevalent. However, the severe shortage of donors, the complexity of harvesting and delivering organs to recipients, and the potential for transmission of infectious agents are major drawbacks of this method. In some situations, such as replacement of blood vessels, a blood vessel is removed from one part of the body and transplanted to another site to bypass the site of the obstruction. However, the number of available blood vessels is limited, and the available blood vessels may not be optimal in terms of strength or other parameters.

[0005] The use of synthetic substances or tissues of animal origin serves as an alternative to the use of human tissues. For example, grafts made of synthetic polymers such as Dacron® are used for blood vessel replacement. Mechanical prostheses are widely used as an alternative to damaged heart valves. However, the use of synthetic materials has many drawbacks. The materials are immunogenic and often function as a nidus for infections or inflammation. Also, the use of animal tissues causes problems of immunogenicity and the potential to transmit diseases. Moreover, the harvested animal tissues have limited availability and flexibility of this method because their size, shape, or other properties are not stable. An epoch-making method is required for the problem of replacing damaged or dysfunctional organs and tissues.

[0006] In tissue engineering, efforts are made to develop techniques for culturing replacement tissues and organs in the laboratory. A common practice for producing replacement tissues is to utilize mammalian cells seeded on an appropriate substrate for cell culture. The cells can be obtained from the intended recipient (e.g., from a biopsy), in which case they always proliferate during culture before being seeded on the substrate. Also, the cells can be obtained from other sources (e.g., established cell lines). After seeding, cell proliferation usually continues in the laboratory and / or in the patient after transplantation of the engineered tissue. In certain cases, the replacement tissue is decellularized immediately before transplantation.

[0007] The tissue-engineered construct may be used for various applications such as a prosthetic device for repair or replacement of damaged organs or tissues. Of particular interest are vascular tissue-engineered constructs. In the United States, where arterial repair is needed, the number of tubular surgeries is 1.41 million. Small arteries with a diameter of less than 5-6 mm cannot be replaced with artificial materials because of the high incidence of thrombosis. Therefore, autologous vein or artery grafts are generally used to replace small arteries in the coronary or peripheral arteries. Vein grafts have thin walls that may be damaged when transplanted into the arterial system, and suitable veins are not available to all patients due to dissection or previous vein harvesting. The internal mammary artery, which comprises most of the arterial grafts, is useful only for the coronary circulation. Therefore, the potential use of tissue-engineered constructs for vascular applications can meet a rapid and persistent need.

[0008] A fibrin sheet with drug-producing cells can be produced by casting a drug-producing cell / fibrinogen / CaCl / thrombin mixture into a Pruronics®-treated square. In some methods, these fibrin patches with drug-producing cells can be reinforced with a biodegradable polymer mesh. Alternatively, the fibrin patch with drug-producing cells can have a collagen edge for suturing to a tendon or other connective tissue.

[0009] However, although promising, the implementation of tissue-engineered vascular grafts is difficult. Regarding tissue-engineered vascular grafts filled with cells, despite the recent progress in the prevascularization of tissue-engineered constructs, the cells in these constructs die immediately because of the limited anastomosis ability between the vascular network of the transplanted tissue and the recipient's blood structure. Therefore, the present disclosure provides a system and method for addressing the viability associated with tissue-engineered vascular grafts. SUMMARY OF THE INVENTION

[0010] The present disclosure relates to a system, apparatus, and method for replacing a segment of a vascular structure.

[0011] In some embodiments, the present disclosure further relates to a system for replacing a segment of a vascular structure, including a tubular vascular graft disposed concentrically with respect to an outer surface of a first mandrel, and a tubular support graft disposed concentrically with respect to an outer surface of a second mandrel and slidable on an outer surface of the tubular vascular graft, wherein an outer diameter of the second mandrel and an outer diameter of the tubular vascular graft are sized such that the tubular support graft can slide on the outer surface of the tubular vascular graft when the segment of the vascular structure is replaced.

[0012] In some embodiments, the present disclosure further relates to an apparatus, including a tubular support graft including a three-dimensional hydrogel matrix and a cellular support structure, wherein the tubular support graft is configured to be positioned concentrically around a tubular vascular graft.

[0013] In some embodiments, the present disclosure further relates to a method for replacing a segment of a vascular structure, including providing a tubular support graft disposed concentrically with respect to an outer surface of a support mandrel, contacting at least a planar end of the support mandrel with at least a planar end of a vascular graft mandrel, and sliding the tubular support graft on an outer surface of a tubular vascular graft disposed concentrically with respect to an outer surface of the vascular graft mandrel.

[0014] In some embodiments, the present disclosure further relates to a method of forming a tubular support graft, comprising disposing a support mandrel within a tubular mold, fluidly sealing a first end of the support mandrel and a first end of the tubular mold with a first end cap, injecting a mixture of a hydrogel and a cellular support structure into a volume formed between a surface of the support mandrel and a surface of the tubular mold, fluidly sealing a second end of the support mandrel and a second end of the tubular mold with a second end cap, and removing the second end cap and a tubular sleeve after the mixture has cured to form the tubular support graft.

[0015] In some embodiments, the present disclosure further relates to a method of forming a tubular support graft, comprising injecting a mixture of a hydrogel and a cellular support structure into a culture dish, wrapping the cured mixture around a support mandrel after the mixture has cured, and securing an open end of the wrapped cured mixture to form the tubular support graft.

[0016] In some embodiments, the present disclosure further relates to a method of forming a tubular support graft, comprising rotating a support mandrel at a predetermined rate, depositing droplets of a mixture of a hydrogel and a cellular support structure onto a surface of the rotating support mandrel via a three-dimensional printer, and removing the cured mixture from the rotating support mandrel after curing to form the tubular support graft.

[0017] In some embodiments, the present disclosure further relates to an apparatus comprising a tubular support graft comprising a three-dimensional hydrogel matrix and a cellular support structure, the tubular support graft configured to be positioned concentrically around a vascular segment harvested from a patient's vascular structure.

[0018] In some embodiments, the present disclosure further relates to a method of expanding a segment of a patient's vascular structure, comprising obtaining a segment of the patient's vascular structure, sliding the obtained segment of the patient's vascular structure on a vascular graft mandrel such that the obtained segment is concentrically disposed with respect to an outer surface of the vascular graft mandrel, providing a tubular support graft concentrically disposed with respect to an outer surface of a support mandrel, contacting at least a planar end of the support mandrel with at least a planar end of the vascular graft mandrel, and sliding the tubular support graft on an outer surface of the obtained segment to expand the obtained segment.

[0019] In some embodiments, the present disclosure further relates to a method of expanding a segment of a patient's vascular structure, comprising obtaining a vascular allograft, sliding the vascular allograft on a vascular graft mandrel such that the vascular allograft is concentrically disposed with respect to an outer surface of the vascular graft mandrel, providing a tubular support graft concentrically disposed with respect to an outer surface of a support mandrel, contacting at least a planar end of the support mandrel with at least a planar end of the vascular graft mandrel, and sliding the tubular support graft on an outer surface of the vascular allograft to expand the vascular allograft. BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

Figure 1

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Figure 5

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Figure 7

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Figure 8A

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Figure 8C

Figure 8D

Mode for Carrying Out the Invention

[0028] Definitions Here, the term "one" or "a" refers to one or more of its entities, i.e., it can refer to multiple references. Thus, the terms "one", "a", "one or more", and "at least one" are used interchangeably herein. Additionally, the reference to an "element" by the indefinite article "one" or "a" does not exclude the possibility of the existence of two or more elements, unless it is clear from the context that the element is only one.

[0029] Throughout this specification, the term "about" is used to indicate that a value includes the inherent variations of error for the device or method used to determine this value, or the variations that exist between samples of the measurement object. Also, unless otherwise expressly stated or apparent from the context, the term "substantially" means within 10% of the reported numerical value (except when such a number exceeds 100% or is less than 0% of the possible values). When used with a range or series of values, the term "about" applies to each value listed at the endpoints of the range or in the series, unless otherwise specified. As used herein, the terms "about" and "substantially" are used equivalently.

[0030] As used herein, an "engineered construct" refers to a three-dimensional structure generated mainly by growing in vitro using living mammalian tissue or cells. The construct may contain one or more tissues, and each tissue may contain one or more cells. Engineered constructs are distinguished from explants of the corresponding native tissue in that the growth of the construct occurs in vitro.

[0031] As used herein, a "porous substrate" refers to a three-dimensional substrate of a biocompatible material that is suitable for the deposition or adhesion of mammalian cells and that is sufficiently porous to allow the infiltration of seeded cells and the diffusion of nutrients and waste to and from the cells deposited on the substrate, the three-dimensional substrate including cells deposited in the internal pores or internal spaces of the substrate. Thus, a porous substrate has pores or interstitial spaces dispersed in its structure and is in fluid communication with the exterior such that cells may penetrate into the interior of the substrate. The pores or interstitial spaces may be substantially spherical spaces such as pores in a sponge-like material, longitudinally extending and intersecting spaces such as the inter-fiber spaces of a fibrous mesh material, or any other arbitrary shape. As used herein, there is no distinction between the "pores" of a sponge-like material, the "interstitial spaces" of a fibrous mesh material, or any arbitrary shaped "spaces" of any other material, and the term "porous" includes materials characterized by any of these.

[0032] As used herein, the term "synthetic polymer" refers to non-natural polymers produced, for example, by ex vivo synthesis and is physically distinguishable from natural polymers. Thus, the term as used herein is used simply to distinguish synthetic polymers, such as those described herein as being effective, from natural polymers such as collagen, elastin, polysaccharides, cellulose, and chitosan. Synthetic polymers may include one or more natural subunits such as natural amino acids or sugar units in non-natural polymers (e.g., copolymers of lysine or arginine with lactic acid or glycolic acid).

[0033] As used herein, the term "proteinaceous polymer" means a polymer consisting of natural or chemically modified amino acid residues linked by peptide bonds. The proteinaceous polymers of the present invention may be natural polymers extracted from animal tissues (e.g., collagen obtained from connective tissue), recombinant-produced polymers obtained from genetically engineered organisms (e.g., bacteria engineered to produce elastin), or those produced in vitro by chemical synthesis. Thus, for example, as used herein, the term includes such natural proteinaceous polymers as collagen, elastin, fibronectin, and laminin. Also, the proteinaceous polymer may include one or more non-natural subunits, e.g., modified amino acids (e.g., acylated, sulfonated, glycosylated, or otherwise attached via a reactive amino acid side chain group to a site that enhances hydrophilicity or provides higher cell adhesiveness), or non-peptide bonds (e.g., polyesters, polypeptides copolymerized with polyanhydrides or modified polypeptides) that link two or more proteinaceous fragments.

[0034] As used herein, the term "cellular support structure" refers to any component that supports cell viability and graft viability in vitro, excluding the material and structure of the tubular support graft itself. In embodiments, the cellular support structure refers to cells, cytoplasm, and / or proteins. The cellular support structure may include, as described below, drugs, drug-releasing particles, other cell types, organoids, therapeutic agents, growth factors, enzymes, peptides, nucleic acids, and molecules, among others.

[0035] As used herein, the term "organoid" refers to a miniaturized, self-organized three-dimensional tissue culture derived from cells, particularly stem cells. Such cultures can largely reproduce the complexity of organs or can represent selective modes of generating only certain types of cells. Organoids can range in size from less than the width of a human hair to about 5 millimeters, depending on experimental constraints. Organoids can also be derived from one or several cells from tissues, adult stem cells, pluripotent stem cells, hematopoietic stem cells, embryonic stem cells, or induced pluripotent stem cells, and because they have the ability to self-replicate and differentiate, they can self-organize in three-dimensional culture.

[0036] The present disclosure describes systems, devices, and methods for replacing vascular segments or organ segments within a host vascular structure. The system includes, for example, a tubular support graft disposed concentrically with respect to the outer surface of a tubular vascular graft. In embodiments, the tubular vascular graft may be native tissue harvested from a patient's vascular structure or an allograft. The native tissue or allograft may be cellularized or decellularized. In embodiments, the tubular vascular graft may be an engineered vascular graft or may be cellularized or acellular. The engineered vascular graft may, in this specification, be alternatively referred to as a tissue-engineered construct. In embodiments, the tubular support graft may carry an organ piece, tissue piece, cell, etc. that secretes a therapeutic agent or may carry the therapeutic agent itself. When the tubular support graft carries a component (e.g., an organ piece, tissue piece, cell) that generates a therapeutic agent or the therapeutic agent itself, the tubular support graft may, in this specification, be referred to as a doped tubular support graft.

[0037] In embodiments where the tissue-engineered construct is filled with cells such as, for example, endothelial cells and smooth muscle cells at the time of transplantation, the doped tubular support graft improves the survival and functionality of the cells in the tissue-engineered construct.

[0038] In embodiments where the tissue-engineered construct is acellular at the time of implantation, the doped tubular support graft can prevent thrombosis and stenosis and can greatly promote (1) cell infiltration into the tissue-engineered construct and (2) the survival rate of the implanted tissue-engineered construct.

[0039] In an embodiment, the tubular support graft includes a cellular support structure.

[0040] In an embodiment, the tubular support graft includes fibrin gel (formed of fibrinogen and thrombin), collagen, agarose, silk, chitosan, alginate, gelatin methacryloyl, and elastin, etc., or any combination thereof.

[0041] In an embodiment, the tubular support graft includes, as structural reinforcement, poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), polyethylene terephthalate (PET), polycaprolactone (PCL), poly(lactide-co-caprolactone) (PLCL), poly(methyl methacrylate) (PMMA), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyurethane (PU), poly(glycerol-co-sebacate) (PGS), and poly(ethylene glycol) diacrylate (PEGDA), etc., or any combination thereof.

[0042] In an embodiment, the tubular vascular graft and / or the tubular support graft is formed by an electrospinning method, a three-dimensional printing method, or a bioplastic method.

[0043] In embodiments, the doped tubular support graft can contain drugs, drug-releasing microparticles and / or drug-releasing nanoparticles. In embodiments, the doped tubular support graft may contain cells and / or organoids capable of generating therapeutic agents such as cytokines and proteins such as enzymes. For example, the doped tubular support graft can contain endothelial cells. In embodiments where the doped tubular support graft is cellularized, the cells may be stem cell-derived, genetically modified, and / or have a low immunogenic profile.

[0044] In one embodiment, the tubular support graft contains pancreatic islet cells that may form pancreatic islets. In one example, the pancreatic islet-containing tubular support graft generates insulin in response to glucose, and the generated insulin diffuses into the patient's vascular structure and / or passes through the tubular vascular graft.

[0045] In embodiments, the doped tubular support graft can contain proteins (such as cytokines and enzymes, etc.) directly incorporated into the tubular support graft.

[0046] In embodiments, to promote angiogenesis of the tubular support graft after transplantation, the doped tubular support graft can contain growth factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), transforming growth factor β1 (TGFβ1), platelet-derived growth factor (PDGF), or any combination thereof.

[0047] In embodiments where the tissue-engineered construct is filled with cells at the time of transplantation, the doped tubular support graft can contain molecules such as Fas ligand, nitric oxide donor, or any combination thereof, to target activated T cells that may attack the tubular support graft or the cellularized tissue-engineered construct.

[0048] The tissue-engineered vascular graft (TEVG), which may also be referred to as such, particularly with respect to the engineered vascular graft as a tubular vascular graft of the present disclosure, different techniques can be used for the generation of TEVGs, among others, including electrospinning, decellularization, lyophilization, biotinoids, and three-dimensional (3D) bioprinting. Regarding the electrospinning method, the electrospinning method generates a porous and fibrous support from a polymer and enhances the movement of nutrients or residues through the support. By aligning nanofibers, it is possible to increase the strength of the support and promote cell alignment. Regarding decellularization, the TEVG can be decellularized to obtain an extracellular matrix. These matrices mimic the biological properties of natural blood vessels. For this reason, the TEVG contains functional proteins that can promote cell recurrence. Regarding lyophilization, lyophilization is a physical dehydration and freezing technique that reduces calcification and provides a stable graft. Regarding 3D bioprinting, 3D printing is used to manufacture the TEVG and provides an appropriate cell distribution with a high cell density.

[0049] Now, referring to the figures, FIG. 1 is a schematic diagram of the method used in the present disclosure. While FIG. 1 depicts an engineered construct that has been formed, decellularized, and reseeded with cells, it should be understood that when the tubular vascular graft is a natural blood vessel harvested from the patient's vascular structure, the same protocol may be followed starting from step C or step E. In fact, when the tubular vascular graft is a natural blood vessel harvested from the patient's vascular structure, decellularization may or may not be performed. Similarly, when the tubular vascular graft is an allograft, the allograft may be used within the protocol of FIG. 1 starting from either step C or step E.

[0050] In an embodiment, to generate an engineered tubular vascular graft, also referred to herein as an engineered construct that is tissue engineered, first, (step A) human cells that degrade to produce extracellular matrix proteins are cultured, and (step B) each tissue-engineered construct is generated in a laboratory by forming tissue. Thereafter, the cellular material is removed by a decellularization protocol, and the extracellular matrix construct remains in step C. Thereafter, the decellularized conduit may be refrigerated or stored at room temperature or by some other means of storage until needed by the patient. These cell-derived extracellular matrix protein constructs may not require cells to be injected (step D, diameter ≥ 6 mm), or (step E) may be seeded with recipient cells such as endothelial cells for small-diameter (3 - 4 mm) applications.

[0051] In an embodiment, the support of the tubular vascular graft may be a synthetic polymer such as PLA, PGA, PLGA, PLCL, PCL, etc.

[0052] In an embodiment, steps A - C are performed regardless of whether the implanted tubular vascular graft is acellular or cellular. The cells seeded in step A may be allogeneic, autologous, syngeneic, or xenogeneic. The cells can be seeded onto the support at about 0.5×10 6 cells per cm length of the tissue-engineered construct to about 2×10 6 cells per cm length of the tissue-engineered construct. Typically, after step B, the cells used to generate the conduit before use are killed and / or removed. In other words, the tubular vascular graft is decellularized. The killing and / or removal of cells reduces the potential for harmful immune responses. The killing and / or removal of cells leaves less than 50%, less than 75%, less than 80%, less than 85%, less than 90%, or less than 95% of viable cells, as evaluated by trypan blue staining, nucleotide incorporation, or protein synthesis. The remaining extracellular matrix is highly conserved between and among individuals and species at 40 and is less likely to cause harmful immune responses than viable cells.

[0053] In an embodiment, in step B, an extracellular matrix is generated using vascular smooth muscle cells. These vascular smooth muscle cells can be isolated from any vascular structure of a human or other mammal, including the aorta. Much of the secreted extracellular matrix contains collagen. Collagen may contain at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% of the extracellular matrix. Typically, the extracellular matrix is grown to a thickness of at least 50 micrometers, at least 100 micrometers, at least 150 micrometers, at least 200 micrometers, at least 250 micrometers, at least 300 micrometers, at least 400 micrometers or at least 500 micrometers. The diameter of the conduit may be controlled during manufacture. Typically, these conduits may have an inner diameter of at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45 or at least 50 mm.

[0054] In an embodiment, the tissue-engineered construct is re-seeded with the patient's cells prior to implantation in step E, and cell seeding promotes cell fixation and infiltration, thus improving graft endothelialization. The cells may be allogeneic or autologous. The cells may include vascular cells such as endothelial cells, fibroblasts and endothelial cells. The cells may be mesenchymal stem cells (MSCs) obtained from different sources such as adipose tissue, bone marrow and umbilical cord venous blood. MSCs are promising as cell types for TEVGs because they improve patency due to their antithrombotic properties and can also recruit endothelial cells to the site. Induced pluripotent stem cells (iPSCs) can be induced into specific lineages such as smooth muscle cells or endothelial cells, so a wide range of vascular cells can be obtained. The cells may include mononuclear cells derived from bone marrow such as MSCs with antithrombotic effects, immune-related cells and hematopoietic stem cells. Although various cell types can be used, endothelial cells are the most commonly used cells in the design of TEVGs to achieve an anticoagulant effect and improve endothelialization.

[0055] From this, the present disclosure describes a tubular support graft, also referred to herein as a sleeve, which is deposited as another tissue layer on the outer surface of a blood vessel such as a TEVG, a harvested native blood vessel segment, or an allograft, and can immediately provide physiological support within the host vascular structure. For example, the tubular support graft may contain pancreatic islets that produce insulin in response to glucose.

[0056] Figures 2-4 provide explanatory diagrams of such a tubular support graft and its manufacturing method.

[0057] The tubular support graft may be formed of fibrin gel (formed of fibrinogen and thrombin), collagen, agarose, silk, chitosan, alginate, gelatin methacryloyl, and elastin, etc., or any combination thereof. Each tubular support graft can be defined by length, inner diameter, and outer diameter, and the distance between the inner diameter and the outer diameter is called the depth or thickness.

[0058] In one embodiment, the length of the tubular support graft can be shorter than, longer than, or approximately the same as the length of the corresponding tubular blood vessel graft. In an embodiment, the length of the tubular support graft can be from about 1 cm to about 100 cm. For example, the length of the tubular support graft can be about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm, about 15 cm, about 16 cm, about 17 cm, about 18 cm, about 19 cm, about 20 cm, about 25 cm, about 30 cm, about 35 cm, about 40 cm, about 45 cm, about 50 cm, about 60 cm, about 70 cm, about 80 cm, about 90 cm, or about 100 cm. In one embodiment, the length of the tubular support graft can be from about 10 cm to about 40 cm.

[0059] In one embodiment, the inner diameter of the tubular support graft can be greater than about 1 mm. In an embodiment, the inner diameter of the tubular support graft can be about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm, about 25 mm, about 30 mm, about 35 mm, about 40 mm, about 45 mm, or about 50 mm. In one embodiment, the inner diameter of the tubular support graft is about 3 to about 20 mm.

[0060] In one embodiment, the outer diameter of the tubular support graft can be greater than about 1 mm. In an embodiment, the outer diameter of the tubular support graft can be about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm, about 25 mm, about 30 mm, about 35 mm, about 40 mm, about 45 mm, or about 50 mm. In one embodiment, the outer diameter of the tubular support graft is about 3 to about 20 mm.

[0061] In one embodiment, the inner diameter and the outer diameter are sized according to the requirements of the application. For example, if the diameter of the segment of the vascular structure to be replaced is 3 mm, the inner diameter of the tubular vascular graft must be sized accordingly, and the inner diameter of the tubular support graft must be sized based on the outer diameter of the tubular vascular graft. Further, the outer diameter of the tubular support graft must then be sized to provide a particular thickness (i.e., wall thickness) of the tubular support graft. In an embodiment, this thickness is about 0.3 mm to about 1.5 mm, where the thickness is substantially uniform along the circumferential and longitudinal directions of the tubular support graft. In one embodiment, the thickness of the tubular support graft can be about 0.4 mm to about 0.6 mm, where the thickness is substantially uniform along the circumferential and longitudinal directions of the tubular support graft.

[0062] In embodiments, the tubular support graft may include, as structural reinforcements, poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), polyethylene terephthalate (PET), polycaprolactone (PCL), poly(lactide-co-caprolactone) (PLCL), poly(methyl methacrylate) (PMMA), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyurethane (PU), poly(glycerol-co-sebacate) (PGS), and poly(ethylene glycol) diacrylate (PEGDA), among others, or any combination thereof.

[0063] In embodiments, a cellular support structure can be doped into the tubular support graft. In embodiments, the doped tubular support graft can include, as the cellular support structure, cells and / or organoids capable of generating therapeutic agents including drugs, drug-releasing particles (i.e., microparticles, nanoparticles), and proteins such as cytokines and enzymes. For example, the doped tubular support graft can include pancreatic islet cells and / or endothelial cells. In embodiments where the doped tubular support graft is cellularized, the cells may be stem cell-derived, genetically modified, and / or have a low immunogenic profile. In embodiments, the cellular support structure within the doped tubular support graft can include induced pluripotent stem cell (IPSC)-derived pancreatic islet cells. The IPSC-derived pancreatic islet cells can include beta cells, alpha cells, F cells, and / or delta cells.

[0064] In embodiments, the doped tubular support graft can include proteins as the cellular support structure. In embodiments, the proteins can include cytokines and enzymes, among others, directly incorporated into the tubular support graft, as well as growth factors such as VEGF, HGF, FGF, TGFβ1, and PDGF, or any combination thereof, to promote angiogenesis of the support graft after transplantation.

[0065] In embodiments where the tissue-engineered construct is filled with cells at the time of implantation, the doped tubular support graft can contain molecules such as Fas ligand, nitric oxide donor, or any combination thereof, to target activated T cells that may attack the tubular support graft or the cellularized tissue-engineered construct as a cellular support structure. Fas ligand is a type II transmembrane protein belonging to the tumor necrosis family. Binding of Fas ligand to its receptor induces apoptosis. Nitric oxide is involved in the suppression of T cell proliferation.

[0066] In embodiments, the above-described tubular support graft (and / or tubular vascular graft) can be formed by electrospinning, three-dimensional printing, or bioplastic methods, casting, molding, planar cell culture, and folding / suturing methods.

[0067] As shown in FIGS. 2A and 2B, the assembly including the tubular support graft 1 may be formed by casting between a support mandrel 2 and a tubular mold 5. As shown in FIG. 2A, the inner diameter of the tubular mold 5 is larger than the outer diameter of the support mandrel 2 to ensure that the polymerized tubular support graft 1 has a desired thickness. As shown in FIG. 2B, the mixture of the hydrogel 3 and the cellular support structure 9, if present, can be injected into the space between the tubular mold 5 and the support mandrel 2. To ensure that the injected mixture is retained between the surfaces of the tubular mold 5 and the support mandrel 2, a first end cap 7' may be attached to the first end of the assembly. After injecting the mixture, a second end cap 7'' may be attached to the second end of the assembly to ensure that the injected mixture is retained between the surfaces of the tubular mold 5 and the support mandrel 2. After injecting the mixture and fixing the ends of the assembly, the polymerization of the tubular support graft 1 can proceed. The cross-sectional view of FIG. 2B shows the thickness of the tubular support graft 1 with the cellular support structure 9 embedded in the hydrogel 3. Upon polymerization, the tubular support graft 1 can be removed as needed and stored until use.

[0068] As shown in FIGS. 3A and 3B, the tubular support graft 1 may be formed by casting a mixture of the hydrogel 3 and the cellular support structure 9 on the plane of the culture dish 8, as in FIG. 3A. The volume of the mixture cast in the culture dish 8 may be such that once cured, the tubular support graft 1 has a desired thickness. Second, after the mixture of the hydrogel 3 and the cellular support structure 9 has cured, as in FIG. 3B, the tubular support graft 1 may be wrapped around the support mandrel 2. In an embodiment, both ends of the tubular support graft 1 may be connected by a bioadhesive, suturing, a polymer mesh, or other fixing means. As shown in FIG. 3B, in a particular embodiment, the cellular support structure 9 may be preferentially disposed towards the inner surface of the tubular support graft 1. The cross-sectional view of FIG. 3B shows the thickness of the tubular support graft 1 with the cellular support structure 9 embedded within the hydrogel 3. After fixing both ends of the tubular support graft 1, the tubular support graft 1 can be removed as needed and stored until use.

[0069] As shown in FIG. 4, the tubular support graft 1 may be formed by a 3D printing method or a bioplastic method. Droplets 10 of the mixture of the hydrogel 3 and the cellular support structure 9 may be dripped from the 3D biometer 12 onto the support mandrel 2. By rotating the support mandrel 9 at a predetermined speed, the droplets 10 may be dispersed along the surface of the support mandrel 9 to make the tubular support graft 1 of a predetermined thickness. For this purpose, the 3D biometer 12 includes a head that translates along the length of the support mandrel 2 based on the desired length of the tubular support graft 1. Upon polymerization, the tubular support graft 1 can be removed from the support mandrel 2 as needed and stored until use.

[0070] Figure 5 is an explanatory view of a tubular vascular graft and a tubular support graft before assembly. The closed silicone bag can contain the tissue-engineered construct or HAV3 in a sterile solution. The tubular support graft, or the sleeve containing the islets (i.e., the sleeve casting the islets) can be held in a separate sealed container and can be arranged concentrically with respect to the surface of the mandrel 4, which holds the tubular support graft 1 aseptically. The HAV3 and the tubular support graft 1 can be transferred separately to the operating room where the operator can combine the tubular support graft 1 and the HAV3 by sliding the tubular support graft 1 over the HAV3.

[0071] Regarding clinical use, FIGS. 6A and 6B illustrate and explain the process of assembling the tubular vascular graft and the support graft in the operating room. The descriptions of steps 1 to 3 are made with reference to the explanatory view of FIG. 6A and the flow diagram of FIG. 6B.

[0072] In the method 600 of FIG. 6B, the cellular support structure 9 may contain islets, the tubular support graft 1 may contain fibrin gel, and the tubular vascular graft may be a decellularized TEVG.

[0073] In step 605 or step 1, the tubular support graft 1 may be placed on the final support mandrel 2. The final support mandrel 2 can be made larger than the support mandrel used during the initial manufacture of the tubular support graft 1. The outer diameter of the final support mandrel 2 may be configured to be relatively larger than the outer diameter of the vascular mandrel 4. In practice, the outer diameter of the final support mandrel 2 may be configured to be relatively larger than the outer diameter of the tubular vascular graft 3 arranged concentrically with respect to the surface of the vascular mandrel 4. Such a geometric relationship enables the efficient concentric arrangement of the tubular support graft 1 above the tubular vascular graft 3.

[0074] In step 610 or step 2, the end of the final support axis 2 and the end of the blood vessel mandrel 4 can be in contact or opposed. In certain cases, the blood vessel mandrel 4 can be at least partially inserted into the lumen of the final support mandrel 2. In step 615, the tubular support graft 1 can slide from the final support mandrel 2 to the outside over the outer surface of the tubular blood vessel graft 3 on the tubular blood vessel graft 3.

[0075] As shown in step 3 of FIG. 6A, the assembly system includes a tubular support graft 1 disposed concentrically with respect to the outer surface of a tubular blood vessel graft 3 disposed on the blood vessel mandrel 4. The assembly system can be further understood with reference to the cross-sectional view.

Example

[0076] Example 1 One end of a glass tubular mold with an inner diameter of 8 mm was capped with a silicone plug and filled with sterile distilled water having 0.5% Pluronic® F127. After performing the Pluronic® treatment for 30 minutes, the glass tubular mold was simply washed with distilled water. A mandrel rod with an outer diameter of 7 mm was inserted into the glass tubular mold (shown in FIG. 2). Using a single silicone tube between the glass tubular mold and the mandrel rod, one end of the glass tubular mold was sealed and the mandrel mold was placed at the center of the glass tubular mold.

[0077] Fibrinogen powder from human plasma was dissolved in phosphate buffered saline (PBS) or medium at 37 ° C for 1 to 2 hours until a clear solution with a desired fibrinogen concentration ≈ 40.9 mg / ml was obtained. Next, the fibrinogen solution was filter-sterilized in a biosafety cabinet. A sterile calcium chloride (CaCl₂) solution was added to the fibrinogen solution and the mixture was placed on ice. A thrombin solution from human plasma was placed on ice in another conical tube.

[0078] The islets (i.e., the cellular support structure) were collected from the culture flask and centrifuged at 200 rcf for 3 minutes. The supernatant was discarded, and the islet pellet was gently resuspended in the fibrinogen solution on ice. The thrombin solution was added to the fibrinogen-CaCl-islet mixture, and the fibrinogen solution was pipetted up and down on ice to mix well. The islet / fibrinogen / CaCl / thrombin mixture was pipetted into the space between the glass tubular mold and the mandrel rod (as shown in Figure 2). The second end of the glass tubular mold was sealed, and the mandrel rod was centered perfectly with the second segment of the silicone tube. The assembly and its contents were placed in a sterile sealed tray and incubated at 37 °C for 15 - 20 minutes to allow the polymerization of the fibrin gel. After gelation, the fibrin sleeve with islets (i.e., the tubular support graft) was removed by pulling out the mandrel rod from the glass tubular mold. First, the fibrin sleeve with islets was slowly slid from the original 7 mm mandrel rod to an 8 mm mandrel rod, and thus transferred to a new mandrel rod with an outer diameter of 8 mm. Transferring the fibrin sleeve with islets to a larger mandrel rod enables it to be easily slid onto a tubular vascular graft with an outer diameter of approximately 7 mm. The 8 mm mandrel rod carrying the fibrin sleeve with islets was placed in a cylindrical bottle filled with culture medium and stored at 4 °C until transplantation.

[0079] For transplantation, the tubular vascular graft was removed from its original container, and a mandrel rod with an outer diameter of 5 mm was inserted into the tubular vascular graft. The tubular vascular graft was a decellularized TEVG. Next, the 8 mm mandrel rod carrying the fibrin sleeve with islets, or the tubular support graft, was taken out of its container, and the tip of the 5 mm mandrel rod carrying the tubular vascular graft was inserted into the 8 mm mandrel rod carrying the tubular support graft. Next, the tubular support graft was transferred from the 8 mm mandrel to the tubular vascular graft as an outer jacket by slowly sliding it onto the tubular vascular graft (as shown in Figures 7A and 7B). Finally, the 5 mm mandrel rod was removed from the tubular vascular graft, and the assembly system was ready for the progress of transplantation.

[0080] As shown in FIG. 7A, the operator slides the tubular support graft 1 externally from the support mandrel over the outer surface of the tubular vascular graft 3. FIG. 7B is an image of a hematoxylin and eosin stained tissue section confirming the concentric arrangement of the tubular support graft 1 and the tubular vascular graft 3. Any visible detachment of the tubular support graft from the tubular vascular graft was caused by tissue processing for histological examination.

[0081] Example 2 FIGS. 8A - 8D relate to the performance of a non - human primate (NHP) - sized HAV covered by a sleeve graft with islets. In particular, as shown in FIG. 8A, the covered HAV was cultured in a bioreactor simulating in - vivo conditions while sufficient oxygen was supplied to the lumen of the covered HAV (i.e., 95 mmHg O2, "normoxic state"), while the oxygen level outside the covered HAV was low (i.e., 40 mmHg O2). The sealed HAV was cultured in an incubator for 6 days.

[0082] The cell viability of islet cells was evaluated using propidium iodide, a dye permeable to the included cell membranes. After 6 days of culture, as shown on day 5, 92% of the islets in the normoxic state survived, while as shown in FIG. 8B, the survival rates of the islets in the sleeve graft with islets and the hypoxic islets were 80% and 28% respectively. FIG. 8C is a graph showing cell viability under variable conditions. As shown, the viability of hypoxic free islets and islets in hypoxic fibrin decreased compared to the islets in the sleeve graft. The islet density in the sleeve graft was 125K islet equivalents (IEQ) per 40 cm and 250K IEQ per 40 cm. FIG. 8D is a graph showing insulin secretion by the sleeve graft in response to variable glucose levels. As shown, insulin secretion by free islets and sleeve grafts with islets is comparable to insulin secretion by free islets in the normoxic state.

[0083] Attempts have been made to transplant cellular tissue-engineered structures (e.g., tissue-engineered liver, pancreas, kidney, etc.), but these attempts have failed. For example, these attempts are plagued by the problem that these cells are not incorporated into the patient's bloodstream. Thus, depositing desired cells and organ pieces, etc. around blood vessels such as HAV and within tubular support grafts, as in the present disclosure, is effective for maintaining viable and functional cells because the "transplanted" cells are close to the blood supply on the outer surface of the HAV. Furthermore, these attempts are inhibited by the time-consuming and technical requirement process of coating a cellular layer onto a vascular graft in the operating room. Also, coating a tissue-engineered vascular graft before shipping it to the operating room requires removing the graft from its original packaging, which impairs its sterility and the approved and / or patented function of the packaging. Thus, according to the present disclosure, it is possible to aseptically transfer the tubular support graft to the operating room.

[0084] Incorporation by reference All references, articles, publications, patents, patent publications, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. However, no mention is made of the documents, papers, patent publications, patent publications, and patent applications cited herein, and these are not intended to affirmatively respond or suggest that they form part of the common general knowledge in any country in the world.

[0085] Numbered embodiments of the present invention Regardless of the appended claims, the present disclosure describes the following numbered embodiments.

[0086] (1) A system for replacing a segment of a vascular structure, comprising a tubular vascular graft disposed concentrically with respect to the outer surface of a first mandrel, and a tubular support graft disposed concentrically with respect to the outer surface of a second mandrel and slidable on the outer surface of the tubular vascular graft, wherein the outer diameter of the second mandrel and the outer diameter of the tubular vascular graft are sized such that the tubular support graft can slide on the outer surface of the tubular vascular graft when the segment of the vascular structure is replaced.

[0087] (2) The system according to (1), wherein the tubular vascular graft is a construct comprising a three-dimensional proteinaceous extracellular matrix.

[0088] (3) The system according to (1) or (2), wherein the three-dimensional proteinaceous extracellular matrix is decellularized, and the construct is formed by seeding cells on a substrate and maintaining the cells under conditions suitable for cell growth, whereby the proteinaceous extracellular matrix is formed around the cells.

[0089] (4) The system according to any one of (1) to (3), wherein the substrate is polyglycolic acid.

[0090] (5) The system according to any one of (1) to (4), wherein the proteinaceous extracellular matrix comprises collagen.

[0091] (6) The system according to any one of (1) to (5), wherein the tubular vascular graft comprises smooth muscle cells.

[0092] (7) The system according to any one of (1) to (6), wherein the tubular vascular graft comprises endothelial cells.

[0093] (8) The system according to any one of (1) to (7), wherein the tubular vascular graft comprises smooth muscle cells directed towards the outer surface of the tubular vascular graft and endothelial cells directed towards the inner surface of the tubular vascular graft.

[0094] (9) The system according to any one of (1) to (8), wherein the tubular vascular graft contains autologous cells.

[0095] (10) The system according to any one of (1) to (9), wherein the tubular support graft is a construct comprising a three-dimensional hydrogel matrix and a cellular support structure.

[0096] (11) The system according to any one of (1) to (10), wherein the cellular support structure contains at least one of a drug, drug-releasing microparticles, and drug-releasing nanoparticles.

[0097] (12) The system according to any one of (1) to (11), wherein the cellular support structure contains at least one of cells, organoids, and tissues.

[0098] (13) The system according to any one of (1) to (12), wherein the cells are pancreatic islet cells.

[0099] (14) The system according to any one of (1) to (13), wherein the tubular support graft further contains pancreatic islets.

[0100] (15) The system according to any one of (1) to (14), wherein the cellular support structure contains at least one protein.

[0101] (16) The system according to any one of (1) to (15), wherein the cellular support structure contains at least one of vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and hepatocyte growth factor.

[0102] (17) The system according to any one of (1) to (16), wherein the cellular support structure contains at least one of Fas ligand and nitric oxide donor.

[0103] (18) The system according to any one of (1) to (17), wherein the cellular support structure contains endothelial cells.

[0104] (19) The tubular support graft is formed by one of molding, casting, planar tissue culture, electrospinning, and three-dimensional printing, and the system according to any one of (1) to (18).

[0105] (20) The system according to any one of (1) to (19), wherein the length of the tubular support graft is shorter than the length of the tubular blood vessel graft.

[0106] (21) The system according to any one of (1) to (20), wherein the length of the tubular support graft is longer than the length of the tubular blood vessel graft.

[0107] (22) The system according to any one of (1) to (21), wherein the length of the tubular blood vessel graft is 1 cm to 100 cm.

[0108] (23) An apparatus comprising a tubular support graft including a three-dimensional hydrogel matrix and a cellular support structure, the tubular support graft being configured to be concentrically located around a tubular blood vessel graft, the apparatus.

[0109] (24) The apparatus according to (23), wherein the cellular support structure includes at least one of a drug, drug-releasing microparticles, and drug-releasing nanoparticles.

[0110] (25) The apparatus according to (23) or (24), wherein the cellular support structure includes at least one of cells, organoids, and tissues.

[0111] (26) The apparatus according to any one of (23) to (25), wherein the cells are pancreatic islet cells.

[0112] (27) The apparatus according to any one of (23) to (26), wherein the tubular support graft further includes pancreatic islets.

[0113] (28) The apparatus according to any one of (23) to (27), wherein the cellular support structure includes at least one protein.

[0114] (29) The device according to any one of (23) to (28), wherein the cellular support structure contains at least one of vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and hepatocyte growth factor.

[0115] (30) The device according to any one of (23) to (29), wherein the cellular support structure contains at least one of Fas ligand and nitric oxide donor.

[0116] (31) The device according to any one of (23) to (30), wherein the cellular support structure contains endothelial cells.

[0117] (32) The device according to any one of (23) to (31), wherein the tubular support graft is formed by one of molding, casting, planar tissue culture, electrospinning, and three-dimensional printing.

[0118] (33) The device according to any one of (23) to (32), wherein the length of the tubular support graft is shorter than the length of the tubular blood vessel graft.

[0119] (34) The device according to any one of (23) to (33), wherein the length of the tubular support graft is longer than the length of the tubular blood vessel graft.

[0120] (35) The device according to any one of (23) to (34), wherein the length of the tubular blood vessel graft is 1 cm to 100 cm.

[0121] (36) A method for exchanging a segment of a vascular structure, comprising providing a tubular support graft disposed concentrically with respect to the outer surface of a support mandrel, contacting at least a planar end of the support mandrel with at least a planar end of a blood vessel graft mandrel, and sliding the tubular support graft on the outer surface of a tubular blood vessel graft disposed concentrically with respect to the outer surface of the blood vessel graft mandrel.

[0122] (37) A method of forming a tubular support graft, comprising: placing a support mandrel within a tubular mold, wherein a first end of the support mandrel and a first end of the tubular mold are fluid-sealed by a first end cap; injecting a mixture of a hydrogel and a cellular support structure into a volume formed between a surface of the support mandrel and a surface of the tubular mold; fluid-sealing a second end of the support mandrel and a second end of the tubular mold by a second end cap; and removing the second end cap and a tubular sleeve after the mixture has cured to form the tubular support graft.

[0123] (38) A method of forming a tubular support graft, comprising: injecting a mixture of a hydrogel and a cellular support structure into a culture dish; after the mixture has cured, wrapping the cured mixture around a support mandrel; and fixing an open end of the wrapped cured mixture to form the tubular support graft.

[0124] (39) A method of forming a tubular support graft, comprising: rotating a support mandrel at a predetermined speed; depositing droplets of a mixture of a hydrogel and a cellular support structure onto a surface of the rotating support mandrel via a three-dimensional printer; and removing the cured mixture from the rotating support mandrel after curing to form the tubular support graft.

[0125] (40) An apparatus comprising a tubular support graft comprising a three-dimensional hydrogel matrix and a cellular support structure, wherein the tubular support graft is configured to be concentrically positioned around a vascular segment harvested from a patient's vascular structure.

[0126] (41) The apparatus according to (40), wherein the cellular support structure comprises at least one of a drug, drug-releasing microparticles, and drug-releasing nanoparticles.

[0127] (42) The device according to (40) or (41), wherein the cellular support structure comprises at least one of cells, organoids, and tissues.

[0128] (43) The device according to any one of (40) to (42), wherein the cells are pancreatic islet cells.

[0129] (44) The device according to any one of (40) to (43), wherein the tubular support graft further comprises pancreatic islets.

[0130] (45) The device according to any one of (40) to (44), wherein the cellular support structure comprises at least one protein.

[0131] (46) The device according to any one of (40) to (45), wherein the cellular support structure comprises at least one of vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and hepatocyte growth factor.

[0132] (47) The device according to any one of (40) to (46), wherein the cellular support structure comprises at least one of Fas ligand and nitric oxide donor.

[0133] (48) The device according to any one of (40) to (47), wherein the cellular support structure comprises endothelial cells.

[0134] (49) The device according to any one of (40) to (48), wherein the tubular support graft is formed by one of molding, casting, planar tissue culture, electrospinning, and three-dimensional printing.

[0135] (50) The device according to any one of (40) to (49), wherein the length of the tubular support graft is shorter than the length of the tubular vascular graft.

[0136] (51) The device according to any one of (40) to (50), wherein the length of the tubular support graft is longer than the length of the tubular vascular graft.

[0137] (52) The device according to any one of (40) to (51), wherein the length of the tubular vascular graft is 1 cm to 100 cm.

[0138] (53) The device according to any one of (40) to (52), wherein the vascular segment is taken from the patient's vascular structure.

[0139] (54) A method for expanding a segment of a patient's vascular structure, comprising: taking a segment of the patient's vascular structure; sliding the taken segment of the patient's vascular structure on the outer surface of a vascular graft mandrel such that the taken segment is concentrically arranged; providing a tubular support graft concentrically arranged with respect to the outer surface of a support mandrel; bringing at least a planar end of the support mandrel into contact with at least a planar end of the vascular graft mandrel; and sliding the tubular support graft on the outer surface of the taken segment to expand the taken segment.

[0140] (55) A method for expanding a segment of a patient's vascular structure, comprising: obtaining a vascular allograft; sliding the vascular allograft on the outer surface of a vascular graft mandrel such that the vascular allograft is concentrically arranged; providing a tubular support graft concentrically arranged with respect to the outer surface of a support mandrel; bringing at least a planar end of the support mandrel into contact with at least a planar end of the vascular graft mandrel; and sliding the tubular support graft on the outer surface of the vascular allograft to expand the vascular allograft.

Claims

1. A device The apparatus comprises a tubular support graft including a three-dimensional hydrogel matrix and a cellular support structure, wherein the tubular support graft is configured to be concentrically positioned around a tubular vascular graft.

2. The apparatus according to claim 1, wherein the cellular support structure contains at least one of a drug, drug-releasing fine particles, or drug-releasing nanoparticles.

3. The apparatus according to claim 1, wherein the cellular support structure includes at least one of cells, organoids, or tissues.

4. The apparatus according to claim 3, wherein the cells are islet cells or islet cells derived from induced pluripotent stem cells.

5. The apparatus according to claim 1, wherein the tubular support graft further comprises pancreatic islets.

6. The apparatus according to claim 1, wherein the cellular support structure comprises at least one protein.

7. The apparatus according to claim 1, wherein the cellular support structure includes at least one of vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, or hepatocyte growth factor.

8. The apparatus according to claim 1, wherein the cellular support structure includes endothelial cells.

9. A tubular support graft for use in a method of replacing or expanding a segment of a vascular structure, wherein the method is To provide the tubular support graft piece that is arranged concentrically with respect to the outer surface of the support mandrel, To bring at least the planar end of the support mandrel and at least the planar end of the vascular graft mandrel into contact, The tubular support graft comprises sliding the tubular support graft on the outer surface of a tubular vascular graft that is arranged concentrically with respect to the outer surface of the vascular graft mandrel.

10. The apparatus according to claim 1, wherein the cellular support structure comprises one or more therapeutic agents or therapeutic agent generating components.

11. The apparatus according to claim 1, wherein the cellular support structure comprises at least one of primary cells, stem cell-derived cells, or genetically modified cells.

12. The apparatus according to claim 3, wherein the cellular support structure includes the cells, and the cells are configured to produce one or more therapeutic agents.

13. The apparatus according to claim 6, wherein the at least one protein comprises at least one of cytokines, enzymes, growth factors, or peptides.

14. The apparatus according to claim 1, wherein the three-dimensional hydrogel matrix comprises at least one of fibrin gel, collagen, agarose, silk, chitosan, alginate, gelatin methacryloyl, or elastin.

15. The apparatus according to claim 1, wherein the tubular support graft further comprises a structural reinforcing material.

16. The apparatus according to claim 15, wherein the structural reinforcing material comprises at least one polymer selected from the group consisting of poly(glycolic acid), poly(lactic acid), poly(lactic acid-coglycolic acid), polycaprolactone, polyethylene terephthalate, polytetrafluoroethylene, or polyurethane.

17. A tubular blood vessel graft, A tubular support graft according to claim 9, wherein the tubular support graft is positioned on the outer surface of the tubular blood vessel graft and A system that includes this.

18. The system according to claim 17, wherein the tubular vascular graft comprises at least one of a tissue-manipulated vascular graft, an autologous graft, or an allogeneic graft.

19. The system according to claim 17, wherein the tubular blood vessel graft is a synthetic material.

20. The system according to claim 17, wherein the tubular support graft comprises pancreatic islet cells.

21. The system according to claim 17, wherein the tubular support graft is manufactured separately from the tubular vascular graft.

22. The system according to claim 17, wherein the tubular support graft is configured to be housed in a sterile container separate from the tubular vascular graft before use.

23. The system according to claim 17, wherein the tubular support graft is configured to be assembled with the tubular blood vessel graft at the site of use by sliding it.

24. The system according to claim 17, wherein the tubular support graft is not attached to the tubular vascular graft before being placed around the tubular vascular graft.

25. The tubular support graft according to claim 9, for use in a method of replacing or expanding a segment of the vascular structure, wherein the tubular support graft and the tubular vascular graft are provided separately before assembly.

26. The tubular support graft according to claim 9, for use in a method of replacing or dilating a segment of a vascular structure, wherein the sliding is performed at a surgical site.

27. ​​The apparatus according to claim 1, wherein the cellular support structure is embedded in the three-dimensional hydrogel matrix.

28. A method for forming a tubular support graft, Forming a tubular body containing a hydrogel matrix on a supporting mandrel, and Incorporating one or more cellular support structures within the hydrogel matrix. Includes, A method comprising: the tubular body being removed from the support mandrel and subsequently configured to slide on the vascular graft.

29. The method according to claim 28, wherein forming the tubular body includes casting, winding, or three-dimensional printing.

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