Improved fabric graft

Abstract

A fabric-based implant or prosthetic tubular or non-tubular product is provided that requires two materials: a fabric and an impermeable non-organic hydrophobic or super-hydrophobic material that, when built into the graft product of the invention, create three different regions. The resulting self-sealing implant or prosthetic product has super moisture resistance and is thus easier to transplant from the body. Tolerance of transplantation to electrosurgical energy, such as electrocauterization, is further improved through a surface. The implant or prosthesis product also prevents leakage and transmural communication or migration through the implant or wall while still allowing tissue to grow inwardly along at least a portion of one surface of the implant or prosthesis for secure anchoring.

Description

[0001] Inventor

[0002] Aaron Hjelle, Andover, Minnesota, United States citizen.

[0003] Robert Thatcher, Blaine, Minnesota, United States citizen.

[0004] Brian McMurray, Pine Bluff, North Carolina, United States citizen.

[0005] Stephanie B. Norris, Rocky Point, North Carolina, United States citizen.

[0006] Joseph M. Shepley, of Waynesville, Pennsylvania, is a citizen of the United States.

[0007] Savannah R. Forrester, Mauldin, South Carolina, United States citizen.

[0008] Lindsey Sanders Calcutt, Greenville, South Carolina, United States citizen.

[0009] CROSS-REFERENCE TO RELATED APPLICATIONS

[0010] This application claims priority to U.S. Provisional Application No. 63 / 362,082, filed on March 29, 2022, entitled “TEXTILE GRAFTS,” the entire contents of which are incorporated herein by reference.

[0011] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0012] not applicable Background Art Technical Field

[0013] The present invention relates generally to fabric products. More specifically, to fabric-based grafts that are stabilized and anchored after implantation, do not allow transmural communication or migration through the graft, and have improved moisture resistance on one surface, thereby preventing in vivo fusion and providing easier implantation.

[0014] Description of Related Art

[0015] The art generally describes layered grafts including fabrics, with an emphasis on vascular grafts that are self-sealing to aid repeated punctures in AV grafts in dialysis patients. Some known layered grafts include one surface covered with a semi-permeable, non-porous, water-insoluble sealing material having limited moisture resistance and a removable masking material or coating, typically initially on the opposing surface of the interstices and / or pores of the fabric (e.g., the inner luminal surface of a tubular graft), to prevent the infiltration or migration of water-insoluble materials through the fabric and ultimately prevent tissue ingrowth necessary for implant stability.

[0016] Some known implants include three layers of material, wherein a self-sealing material is sandwiched between an inner layer and an outer layer. For example, the Triplex TM The vascular graft comprises an inner layer of uncoated woven polyester (Dacron) graft and an outer layer of expanded polytetrafluoroethylene (ePTFE). The two layers are fused together by an intermediate or central layer of a self-sealing elastomeric membrane, which is a thermoplastic elastomer styrene-ethylene-propylene-styrene, an organic (styrene) copolymer. TM The graft has been shown to have a 0.68 mL / cm 2 / min of water leakage, which provides good but not complete water (or blood) impermeability. See De Paulis et al., A Third Generation of Ascending Aorta Dacron Graft: Preliminary Experience, Ann Thorac Surg 2008;85:305-09. It is important to note that De Paulis et al. stated that these three layers impart complete impermeability. However, the measured water leakage value reported by De Paulis et al. is not 0, but 0.68 mL / cm 2 / min. Therefore, Triplex TM The three-layer construction cannot be described as impermeable.

[0017] An improvement over the typical three-layer vascular graft is illustrated by the two-layer vascular graft commercialized by Vascutek Terumo, which is marketed under the name Biplex TM and provides an inner uncoated woven polyester layer coated on an outer tubular surface having a self-sealing elastomer, the self-sealing elastomer being connected to the intermediate Triplex TM The thermoplastic elastomer styrene copolymer used in the layer is the same. TM For the same reasons as described for the construction and related non-zero leakage values, BiplexTM Nor can it be accurately described as completely impermeable to water or blood.

[0018] Additionally, none of the Vascutek Terumo vascular graft products discussed above can be described as "non-porous." In other words, Biplex TM and Triplex TM Both will allow post-implantation transmural migration of cells and other materials from one side of the graft wall to and through the other side of the graft wall. Transmural communication is generally considered a requirement for effective long-term implantation of, for example, vascular grafts, whereby transmural communication results in tissue ingrowth on both sides of the graft (e.g., on both the luminal and abluminal surfaces of an exemplary vascular or tubular graft), which results in physical integration of the graft with the host tissue.

[0019] The resulting high level of integration of the graft into the body does provide anchoring stability, but it also greatly increases the difficulty of removing the graft from the ingrown tissue, both in terms of actually visualizing the graft and separating the graft from the surrounding tissue (which often requires electrocautery). Known grafts fail to present an outer layer that is not affected by electrocautery, or to allow electrocautery energy to penetrate the outer layer of the graft and damage the fabric layer.

[0020] It is therefore an object of the present invention to provide a graft having a surface and / or layer that is not affected by energy (such as but not limited to electrocautery energy) applied to the graft by an electrosurgical device.

[0021] It is another object of the present invention to provide a graft having a sealing layer that prevents exposure and / or protects the underlying fabric layer from electrocautery energy.

[0022] It is another object of the present invention to provide a graft having a sealing layer that minimizes or mitigates damage to the underlying fabric layer by electrocautery energy.

[0023] It is another object of the present invention to provide a graft having a sealing layer that minimizes, mitigates or prevents damage to the underlying fabric layer by low, medium or high power electrocautery energy.

[0024] Another object of the present invention is to provide a graft having a pressure between 0.68 mL / cm 2 / min and 0mL / cm 2 Preferably, the water leakage value or water permeability is less than 0.16 mL / cm at a pressure of 120 mm Hg. 2 Most preferably, the water leakage value or water permeability will be substantially 0 mL / cm2 at a pressure of 120 mmHg. 2 / min.

[0025] Another object of the present invention is to prevent transmural communication or migration of cells or materials from one side or surface of the graft to and / or through the other side or surface of the graft.

[0026] It is another object of the present invention to prevent complete and complete integration of an implanted graft with the body that is located on the sealant side or surface of the graft structure.

[0027] Another object of the present invention is to achieve or promote fusion of an implanted graft with a body part, wherein the fused part is easily accessible and easily separable from the body tissue.

[0028] Another object of the present invention is to allow biological tissue and / or platelets to adhere and stimulate tissue ingrowth on at least a portion of one side or surface of the graft while preventing all biological tissue and / or platelets from adhering or ingrowth on the other side or opposite surface of the graft.

[0029] Another object of the present invention is to allow biological tissue and / or platelets to adhere and stimulate tissue ingrowth on at least a portion of one side or surface of the graft, while promoting or achieving biological tissue and / or platelet adhesion or ingrowth only on selected portions of the other side or opposite surface of the graft.

[0030] Furthermore, typically, the outer coating of known vascular grafts comprises an organic polymer having a carbon-carbon bond with a binding energy of 355 kJ / mol. Thus, these organic polymer outer layers will provide limited resistance to electrocautery procedures, which are typically required during the implantation process of the implanted graft.

[0031] It is therefore another object of the present invention to provide sealing layers and surfaces for implants that are more resistant to electrocautery than sealing layers formed from known organic polymeric materials.

[0032] Another object is to provide a sealing layer that mitigates, slows and / or minimizes penetration and / or damage during electrocautery procedures at all power and voltage levels.

[0033] Another object is to provide a sealing layer that protects the underlying textile layer from penetration and / or damage during electrocautery procedures at all power and voltage levels.

[0034] Yet another object is to provide a sealing layer that protects the underlying textile layer by mitigating, slowing and / or minimizing the penetration of electrocautery energy through the sealing layer at all power and voltage levels.

[0035] Another object is to provide an outer sealing layer that is not affected by electrocautery at all power and voltage levels.

[0036] Another object of the present invention is to provide an outer sealing layer comprising a completely or partially smooth outer or exterior surface to prevent biological tissue and / or platelets from adhering thereto.

[0037] Another object of the present invention is to provide an outer sealing layer that prevents bacteria from adhering thereto and preventing infection from occurring between the outer sealing layer and the host tissue.

[0038] It is yet another object of the present invention to prevent and / or inhibit the formation of seroma between the sealant and the host tissue.

[0039] It is another object of the present invention to incorporate antibiotic materials or compounds on or within the outer sealing layer.

[0040] Known vascular grafts are also difficult to visualize during implantation and transplantation surgery when blood is present. Therefore, it is a further object of the present invention to provide an outer sealing layer or a surface of the graft that is hydrophobic to superhydrophobic and / or resistant to super resistant to moisture. In this way, blood flows out of the outer sealing layer of embodiments of the present invention, making it easier for the practitioner to see the implanted device.

[0041] It is another object of the present invention to provide certain embodiments having a colorant along at least a portion of the outer sealing layer, wherein the colorant contrasts with blood and tissue.

[0042] As discussed above, known layered grafts require the application of a removable mask or coating over the exemplary inner luminal surface of the fabric of the tubular graft to prevent the sealant from migrating through the fabric layer to reach the luminal surface, which would prevent tissue ingrowth at that surface, thereby reducing the anchoring stability of the implant. This approach reduces the thickness of the finished sealing layer, reduces the stiffness of the graft product and increases its flexibility, and requires the use of a removable mask that effectively blocks the migration of the sealant to ensure that at least a portion of the inner luminal surface is not covered by the sealant and that sufficient sealant remains on the opposite or outer surface to provide the necessary protective function.

[0043] Known layered grafts that use a removable mask or coating to protect a surface of the graft (e.g., an inner or luminal surface) from migration of sealant to the inner or luminal surface all require placement of the removable mask or coating on, for example, the luminal surface of a vascular graft, and then removal of the mask or coating to expose the underlying fabric without the sealant therein. The device allows the sealant to migrate substantially through the inner or fabric layer, thereby leaving a relatively small distance that is not touched by the sealant due to the protection of the mask or coating. In turn, the reduction in the width or thickness of the inner or fabric layer can be used for tissue ingrowth.

[0044] It is therefore another object of the present invention to retain a majority of the thickness of the inner layer or fabric layer for tissue ingrowth.

[0045] Known layered grafts also require the removal of a mask or coating applied to the inner luminal surface by active (eg, etching) or passive (eg, water-soluble) removal prior to implantation.

[0046] The present invention solves these problems, among others. Summary of the invention

[0047] A fabric-based graft product is provided that requires two materials: a fabric and a sealant. In some embodiments, the sealant is an impermeable, non-organic hydrophobic or superhydrophobic material that, when built into the graft product of the present invention, creates three separate cross-sectional areas. The resulting self-sealing graft product has super moisture resistance and is therefore easier to transplant from the body. The transplantation is further improved by the electrocautery resistance of the sealant. The graft product also prevents blood leakage and transmural communication or migration through the graft body or wall, while still allowing tissue to grow inward along at least a portion of one surface of the graft to firmly anchor within the body. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Embodiments of the present invention will now be described by way of example with reference to the following drawings.

[0049] Figure 1A and Figure 1B An end perspective view of an embodiment of the present invention is shown.

[0050] Figure 2 End or cross-sectional views of embodiments of the invention are shown.

[0051] Figure 3A A cross-sectional view of an embodiment of the present invention is shown.

[0052] Figure 3B A side view of an embodiment of the present invention is shown.

[0053] Figure 3C A side view of an embodiment of the present invention is shown.

[0054] Figure 4A A perspective view showing an embodiment of the present invention is shown.

[0055] Figure 4B A perspective view showing an embodiment of the present invention is shown.

[0056] Figure 4C A perspective view showing an embodiment of the present invention is shown.

[0057] Figure 4D A perspective view showing an embodiment of the present invention is shown.

[0058] Figure 5 A top view of an embodiment of the present invention is shown.

[0059] Figure 6 A perspective view showing an embodiment of the present invention is shown.

[0060] Figure 7 A cross-sectional view of an embodiment of the present invention is shown.

[0061] Figure 8 A side cross-sectional view of an embodiment of the present invention is shown.

[0062] Fig. 9 A side cross-sectional view of an embodiment of the present invention is shown.

[0063] Fig.10 A top view of an embodiment of the present invention is shown. DETAILED DESCRIPTION

[0064] In general, various embodiments of the present invention relate to devices and methods for prostheses or implants (e.g., grafts, such as vascular grafts, sheets, bands, and / or patches), which may include conduits or tubular portions. Exemplary grafts may be cylindrical and various other functional shapes, some of which are described herein. However, various embodiments relate to non-tubular and / or non-conduit structures, such as flexible materials, planar structures, bands, or preformed structures, which may be easily covered with non-tubular structures, which may be flat or may include contours. Such non-tubular grafts may be used as patches, for organ repair, in pericardial surgery, etc., as will be appreciated by those skilled in the art. Prostheses or implants (e.g., the graft or patch embodiments described herein) may include fabrics, which may also include textiles, fibers, or yarns and may be woven and / or knitted or otherwise combined to form fabrics in one or more patterns. Other constructions and materials for such fabrics are known in the art, and are therefore within the scope of the present invention. In general, the following description may describe specific embodiments of a prosthesis or implant as, for example, a graft. However, as now clarified, this is not a limiting description, as the prosthesis and / or implant of the present invention includes all other embodiments described herein.

[0065] Embodiments of the present invention are intended to make the implantation of an exemplary prosthesis or implant (e.g., a transplant from a living body) easier. Generally, an outer sealing layer or a first sealing layer is provided that is not damaged by energy applied, such as electrocautery. In other embodiments, the outer sealing layer or the first sealing layer prevents the exemplary electrocautery energy from penetrating the outer sealing layer or the first sealing layer to reach the inner fabric layer or the second fabric layer, thereby preventing damage to the inner fabric layer or the second fabric layer.

[0066] In addition, the outer sealing layer or the first sealing layer can be bleeding to make visualization during implantation or removal easier, and thus the outer sealing surface or the first sealing surface can be hydrophobic, or can be super hydrophobic and / or super moisture resistant. In some embodiments, the outer sealing layer or the first sealing layer can be non-porous and have a surface roughness that helps prevent biological tissue and / or platelet adhesion, while the inner luminal tissue surface or the second opposing tissue surface allows biological tissue and / or platelets to adhere thereto.

[0067] In some embodiments, the outer or first sealing layer can include a color that contrasts with blood and tissue to aid in visualization during implantation or removal.

[0068] In some embodiments, the implant can include substantially zero water leakage or water permeability due primarily to the impermeability of the outer or first sealing layer.

[0069] In some embodiments, the first sealing surface or the outer sealing surface prevents biological tissue from growing inwardly into any portion of the first sealing surface or the outer sealing surface, while at least a portion of the inner luminal tissue surface or the second opposing tissue surface allows biological tissue and / or platelets to adhere thereto and grow into at least a portion of the inner fabric layer or the opposing fabric layer to provide anchoring stability in vivo.

[0070] In some embodiments, transmural communication of biological material or water from one side of the wall of an exemplary graft to the other side of the wall of the graft is prevented.

[0071] In some embodiments, the first or outer sealing surface prevents bacteria from adhering thereto, thereby preventing infection from occurring between the first or outer sealing surface and host tissue in contact with the first or outer sealing surface.

[0072] In some embodiments, the sealant is configured to prevent the formation of a seroma between the host tissue and the first or outer surface of the sealing layer.

[0073] In some embodiments, the antibiotic is absorbed into, embedded in, or covers at least a portion of the sealing layer prior to implantation.

[0074] In some embodiments, the antibiotic is impregnated within a portion of the sealing layer.

[0075] In some embodiments, the antibiotic may be encapsulated and embedded within or on the sealing layer, wherein the capsule is configured to be biodegradable or dissolvable.

[0076] In some embodiments, a blowing agent may be combined with the polymer or copolymer of the outer sealing layer or the first sealing layer to form a flexible structure that also includes improved self-sealing capabilities.

[0077] In some embodiments, the suture hole can self-seal to provide hemostasis within 10 minutes or less, 5 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, or 10 seconds or less of the creation of the suture hole.

[0078] In some embodiments, a dielectric polymer or dielectric copolymer can include an outer or first sealing layer to form an electrocautery resistant implant.

[0079] In some embodiments, the radiopaque material or radiopaque marker is adhered to, embedded in, impregnated in, and / or exposed within the sealing layer.

[0080] In some embodiments, the two materials forming the three cross-sectional regions may include an exemplary prosthesis or implant, such as a graft, wherein the first region is comprised solely of an exemplary woven (or knitted) fabric, the second region is comprised of a combination of woven fabrics and a sealant having some or all of the properties described above, and the third region is comprised solely of the sealant.

[0081] In some embodiments, a three-zone embodiment is achieved without the need for a removable mask or coating to achieve a first zone consisting only of an exemplary woven or knitted fabric.

[0082] In other embodiments, a removable mask or coating may be employed on an inner surface or a second opposing surface of an exemplary woven or knitted fabric to preserve a portion of the woven or knitted fabric from contamination by the sealant of Region 3 as it migrates through the woven or knitted fabric to produce Region 2.

[0083] In some embodiments, one or more structures, regions, or materials are provided on an exterior surface of the sealing layer to facilitate formation of a pseudointima on a luminal surface or a second surface of an exemplary implant or prosthesis (eg, a graft).

[0084] In some embodiments, one or more structures, regions or materials are provided on the exterior surface of the sealing layer to enable controlled communication of biological material and / or cells through the sealing layer to promote tissue ingrowth only on the fabric surface.

[0085] In some embodiments, one or more structures, regions or materials are provided on the outer surface of the sealing layer to enable controlled communication of biological materials and / or cells through the sealing layer to promote anchoring stability by fibrotic fusion with at least the outer surface or external surface of the sealing layer.

[0086] Figure 1A and Figure 1BA perspective view of an embodiment of an exemplary tubular graft or catheter graft or vascular graft is provided. The exemplary tubular graft 10 includes an inner fabric layer 12, which includes a thickness of the fabric layer 12 and defines a lumen 14 and an inner or luminal surface 16. An outer sealing layer 18 surrounds the inner layer 12, defines a thickness of the sealing layer 18 and includes an outer or abluminal surface 20.

[0087] The graft 10 shown includes an inlet I and an outlet O at opposite ends. However, it should be understood that one or more inlets or outlets may be provided in alternative embodiments. Further, the graft may include the cylindrical shape shown or may include non-cylindrical shapes, such as one or more regions having a larger outer diameter than other regions, multiple channels, a Y-shape or a T-shape, or a spherical shape, which may be used, for example, for a Valsalva aortic root graft.

[0088] The inner fabric layer 12 may include a fabric that may be woven, braided or knitted, as will be readily understood by those skilled in the art. Thus, a plurality of gaps, spaces and / or pores are provided between the fibers, yarns and / or textiles of the fabric. Some of these gaps, spaces and / or pores may allow biological tissue and / or platelets to adhere after implantation, followed by tissue ingrowth, thereby anchoring and stabilizing the implanted graft.

[0089] Electric burn resistance

[0090] Applicants have discovered that the molecular binding energies of non-organic polymers, such as silicone or silicone foam rubber, are highly advantageous in that they are virtually unaffected by the energies applied by electrosurgical techniques and / or devices, such as electrocautery energy. Due to the lower molecular binding energies of organic polymers, such materials are not unaffected by electrocautery energy.

[0091] As used herein, electrocautery refers to a well-known process by which an electric current can be passed between an electrode and a cathode, and can be monopolar or bipolar. The device can be applied to living tissue to achieve varying degrees of tissue destruction. In the case of a graft transplanted from a living body, tissue may overgrow on part or all of the graft surface. In the case of an exemplary tubular graft, electrocautery may be required to remove overlying tissue to allow visualization. It is critical to protect the exemplary graft from damage by the thermal energy of electrocautery. The description of electrocautery and eye cautery is merely exemplary. Various embodiments herein protect from any applied electrosurgical energy.

[0092] This is in contrast to ocular cautery devices and procedures that include a resistive wire through which an electric current is passed. The resistive wire is heated and can be used to pierce an implanted implant or other graft used for a variety of purposes. Thus, some embodiments of the tubular or non-tubular grafts described herein can enable ocular cautery to pierce through both the sealing layer as well as the underlying fabric layer. In this way, the graft embodiments can prevent damage to the underlying fabric layer at all power and / or voltage settings of known electrocautery devices, and as will be further described below, also allow the ocular cautery device to pierce or otherwise cut through a sealing layer, such as silicone, as well as through the underlying fabric graft.

[0093] Working Example 1

[0094] Purpose: To test the hypothesis that improved resistance can be achieved using non-organic polymer sealants over organic polymer sealants.

[0095] Materials and Methods: We evaluated and compared: (1) Gelweave commercially available from Acutek Terumo TM Tubular grafts consisting of a textile fabric (polyester) coated with gelatin, an organic polymer sealant; (2) a textile fabric graft coated with a layer of silicone.

[0096] Both tubular grafts were pre-soaked in 0.9% saline and then tightly wrapped with raw chicken to simulate the conditions after implantation in vivo, where body tissue has wrapped around or fused to the graft, thus requiring electrocautery to cut the body tissue to expose the graft for implantation or inspection. The electrocautery device was a Valleylab Force FX-C. User's Guide Force FXTM-C Electrosurgical Generator with Instant ResponseTM Technology (Copyright 2009) is hereby incorporated by reference in its entirety and is located at: 1023200.book (equippedmd.com)

[0097] The cautery parameters were set to 50% power, pure cutting mode.

[0098] Discussion: Discovering Gelweave TM The graft is very sensitive to electrocautery energy. Pre-soaked saline infiltrates the graft, providing a low resistance electrical pathway. The organic polymer gelatin (sealant) provides little protection to the inner textile fabric (polyester), resulting in damage to the fabric portion of the graft.

[0099] It was found that the silicone covered fabric graft could slow down or mitigate any damage to the sealing layer, and in fact the sealing layer was observed to be completely unresponsive to the electrocautery energy, ie completely impermeable. As a result, the fabric tubular layer was completely unaffected and undamaged by the electrocautery.

[0100] Conclusion: The non-organic polymer sealant covering or surrounding the fabric layer slows down or delays damage caused by electrocautery energy. Using the cautery parameters in this example, the sealant layer is not affected by the electrocautery energy and / or protects the fabric layer from damage by the electrocautery energy.

[0101] Working Example 2

[0102] Objective: To test the hypothesis that a non-organic polymer sealant surrounding or covering a textile graft protects a textile graft from electrocautery injury by at least delaying and / or slowing any damage caused by the electrocautery energy.

[0103] Materials and Methods: This experiment evaluated a textile fabric tubular graft coated with a layer of silicone. This is the same type of textile fabric graft discussed in Working Example 1.

[0104] The tubular graft was pre-soaked in 0.9% saline. The electrocautery device was also the same as that used in Working Example 1: Valleylab Force FX-C.

[0105] In this series of experiments, the electrocautery device was operated in both cutting mode and coagulation mode at increasing power modes, all in monopolar mode.

[0106] result:

[0107] Table 1: Electrocautery devices in cutting mode

[0108]

[0109] 1- The sealing layer and the fabric layer are protected; the damage to the sealing layer and the fabric layer is reduced;

[0110] 2-Does not penetrate into silicone; does not damage textile fabrics

[0111] Table 2: Electrocautery devices in coagulation mode

[0112]

[0113] Additionally, Working Example 2 included saline fluid within a tubular graft that was clamped at both ends to retain the fluid therein during the electrocautery test. The temperature of the saline was again tested before and after the electrocautery test. After the electrocautery test, the temperature of the saline within the graft did not increase significantly, and therefore, the saline fluid within the graft was not affected by the electrocautery test process in terms of heat gain.

[0114] Therefore, non-organic polymer sealants (such as silicones) are excellent thermal insulators and electrical insulators. These properties allow the sealing layer to minimize and / or reduce the heat transfer and / or electrical conduction to and / or through the fabric layer below. It is very important to provide heat transfer protection. Protect the blood passing through the graft from thermal damage, such as hemolysis. In addition, protect the fabric that has grown into at least a portion of the fabric layer and / or the portion of the sealing layer from thermal damage. And, in some operations, the blood flow in the graft will be temporarily stopped, that is, it will be static, making the blood cells in the graft and especially the blood cells on the luminal surface closest to the fabric layer susceptible to thermal damage. Further, various aspects of the graft of the present invention can include therapeutic cells and / or associated therapeutic agents and / or antibiotics or other substances that adhere to or fuse to the graft. The sealing layer discussed herein provides protection against heat transfer and the resulting thermal damage to blood cells and tissues that have grown in, as well as therapeutic cells and any associated therapeutic agents and / or antibiotics or other substances that adhere to or fuse to the graft.

[0115] In each of Working Examples 1 and 2, silicone is also a strong dielectric, thus preventing a ground path, which further increases resistance to electrocautery.

[0116] Overall conclusions of working examples 1 and 2:

[0117] Thus, a graft as described above comprises a sealing layer which:

[0118] (1) Protect the underlying fabric layer from damage by the electrocautery energy of the tested device when set at all tested power levels (including the highest power level) in both the cutting mode and the coagulation mode;

[0119] (2) slowing down, delaying, minimizing and / or at least partially alleviating damage to the sealing layer itself;

[0120] (3) slowing, delaying, minimizing and / or at least partially alleviating damage to underlying fabric layers at all tested power levels (including the highest power level) in both cutting and coagulation modes;

[0121] (4) provide at least some protection to the underlying fabric from damage by electrocautery energy at all tested power levels (including the highest power level) in both cutting and coagulation modes;

[0122] (5) Provide protection against complete and / or partial penetration of electrocautery energy into and / or through the underlying fabric layer at all tested power levels (including the highest power level);

[0123] (6) slow, delay, prevent, and / or not be injured by electrocautery energy at all tested power levels (including the highest power level) in both cutting and coagulation modes; and

[0124] (7) Provide heat transfer resistance and / or thermal protection for blood cells, ingrown tissue, therapeutic cells, antibiotic agents, substances, fluids, tissues, etc. located within the fabric layer and / or on the side of the graft opposite to the sealing layer that receives electrocautery energy.

[0125] These conclusions will apply equally to both tubular and non-tubular grafts having non-organic polymer sealing layers or coatings such as silicone.

[0126] Further, the binding energy of the exemplary non-organic polymer sealant silicone is higher than the binding energy of carbon (C-C) bonds (433 kJ / mol vs. 355 kJ / mol) due to its siloxane bonds (-Si-O-Si-) forming the backbone of silicone (dimethylpolysiloxane). For the same reason, in general, inorganic polymer sealants include higher binding energies than organic polymer sealants. This property gives non-organic polymer sealants higher heat resistance than organic polymer sealants. In turn, non-organic polymer sealants therefore have higher electrical burn resistance than organic polymer sealants. Silicone is an exemplary non-organic polymer with the additional advantage that, as discussed above, it is a dielectric material, further improving its electrical burn resistance, is impermeable to water and is non-porous.

[0127] Figure 2 A cross-sectional view of an embodiment of the present invention is shown wherein two materials form an exemplary tubular graft 10, including three regions comprised or formed of the two materials as shown in the cross-section. Thus, an inner layer or fabric layer 12 comprising a fabric as described above is surrounded by an outer layer or sealing layer 18 formed of a sealing layer which, among other aspects described herein, slows, mitigates and / or prevents electrocautery from reaching the inner fabric layer 12. The concepts discussed herein are generally applicable to a prosthesis or implant in a subject.

[0128] As shown, the innermost region 1 is composed only of the exemplary fabric material. The thickness included in region 1 is less than the thickness of fabric layer 12. This is due to the sealant migrating radially inward by filling the gaps and / or pores in the fabric layer 12 to occupy a portion of the fabric layer 12. Therefore, region 2 has a combination of fabric material and sealant, and its thickness is also less than the thickness of fabric layer 12. Region 3 is composed only of sealant and includes a thickness that can be equal to the thickness of the outer sealing layer 18, or due to the loss of sealant material during the migration process to form region 2, the thickness of region 3 can be less than the thickness of the sealing layer 18. Therefore, as the sealant moves inward and radially into the adjacent fabric layer 12, the nominal outer diameter of the tubular stent will decrease over time. Alternatively, the sealant can be allowed to penetrate or migrate through the exemplary fabric all the time, thereby effectively eliminating region 1. Other embodiments can include a sealant that penetrates at least a portion of the inner luminal surface 16, leaving only other areas of the luminal surface 16 as fabric.

[0129] Region 1 is delimited on the intraluminal side by an intraluminal surface 16 .

[0130] The region 2 is delimited on the outside by a joining surface L of the fabric layer 12 , wherein the sealant of the sealing layer 18 at least initially joins with the fabric layer 12 at the joining surface L.

[0131] The transition between region 1 and region 2 is as follows Figure 2 , indicating the end point of the radially inward migration path of the sealant through the engagement surface L into the fabric layer 12. As will now become apparent, the inner fabric layer 12 is divided into inner region 1 and inner region 2 after the sealant migrates, wherein region 2 at least partially surrounds region 1.

[0132] like FIG. 3A to FIG. 3C As shown, planar grafts, sheet grafts, strips, or other non-tubular shapes are also within the scope of the present invention. As discussed herein, such non-tubular shaped grafts can be used as patches in pericardial surgery and other surgeries for organ repair, as will be readily appreciated by those skilled in the art. The exemplary planar graft 30 includes a first layer or sealing layer 32 formed of a sealant, as described herein and, among other aspects, in certain embodiments, the sealant imparts electrocautery impermeability, the sealing layer 32 defining a first surface 33. A second layer or fabric layer 34 is disposed adjacent to the sealing layer 32 and is formed of an exemplary fabric material described herein, the fabric layer 34 defining a second surface 36. Line L' illustrates the joining surface of the fabric layer 34 and marks at least an initial boundary between the sealing layer 32 and the fabric layer 34. In an alternative embodiment, and similar to Figure 2 The tubular graft embodiment may be used as Figure 3C The two materials of the first layer 32 and the second layer 34 are shown forming three regions.

[0133] Region 1 consists only of the exemplary fabric material.

[0134] Zone 2 consists of a mixture of an exemplary fabric material and a sealant.

[0135] Zone 3 consists only of sealant.

[0136] and Figure 2 Consistent with the embodiment of FIG. 1 , the thickness included in region 1 is less than the thickness of fabric layer 34 due to the intrusion and migration of the sealant of sealing layer 32 into the fabric material.

[0137] Region 2 includes a thickness extending from the engagement surface L' of the fabric layer 34 to a dashed line representing the end point of the migration of the sealant into the fabric material and the interior of the fabric layer 34 and to the second surface 36. As shown in the figure, when the fabric layer 34 is formed by the region 1 and the region 2, the thickness of the region 1 and the region 2 are both less than the thickness of the fabric layer 34, wherein the region 2 is adjacent to the region 1.

[0138] The thickness of region 3 may be the same as the thickness of sealing layer 32, and in some embodiments, may become thinner than the initial thickness of sealing layer 32 when initially applied to the fabric layer due to loss of sealant material during migration from sealing layer 32 to fabric layer 34. It is highly preferred to provide region 3, i.e., the sealant does not migrate in its entirety to produce region 2, and region 3 includes a sealant that defines the thickness of region 3.

[0139] Figure 2 as well as FIG. 3A to FIG. 3B The embodiments of FIG. 1 and FIG. 2 are all shown to include a continuous boundary between Region 1 and Region 2, marking the endpoint of the migration of the sealant into the fabric layer of each embodiment.

[0140] Among other things, this creates a strong connection between the sealing layer and the fabric layer of the exemplary tubular graft 10 and the non-tubular graft 30. In both embodiments, the sealant is prevented from migrating all the way to the inner luminal surface 16 in the tubular embodiment 10, and the sealant is prevented from reaching the second surface 36 of the non-tubular embodiment 30, thereby providing all surface area of ​​uncontaminated fabric along these uncontaminated locations 16, 36 for tissue ingrowth after implantation.

[0141] This result may be achieved by applying a mask or coating over the entire inner luminal surface 16 or the entire second surface 36 of the fabric to prevent sealant migration thereto, as disclosed in US Pat. No. 10,926,003, the entire contents of which are incorporated by reference.

[0142] Alternatively, some sealant may be allowed to reach the inner luminal surface 16 of a tubular embodiment or the second surface 36 of a non-tubular embodiment. As also disclosed in U.S. Pat. No. 10,926,003, this result may be achieved by selectively applying a mask or coating to the inner luminal surface 16 or the second surface 36 so as to selectively prevent the sealant from migrating to selected areas of the inner luminal surface 16 or the second surface 36 of the fabric while allowing the sealant to selectively migrate to other areas of the luminal surface 16 or the second surface 36 of the fabric.

[0143] According to U.S. Pat. No. 10,926,003, a sealant, removable mask or coating is prevented from completely migrating to the inner luminal surface 16 of a tubular graft by being applied to cover the entire inner luminal surface 16 of the tubular graft. Further, U.S. Pat. No. 10,926,003 teaches that some sealant can be allowed to migrate to the inner luminal surface of a tubular graft by placing an exemplary mandrel inside the lumen of the tubular graft, wherein the mandrel includes an opening therethrough. A removable mask or coating is applied to the inner lumen of the mandrel such that the applied removable mask or coating is applied radially outward through the opening of the mandrel and coats corresponding areas of the inner luminal surface 16 of the fabric tube. In addition to teaching that a mask or coating is applied to the inner luminal surface 16, it is also taught that the removable mask or coating requires an active process (such as etching or a similar active process), as opposed to a passive process (such as water-soluble), to remove the applied mask or coating.

[0144] An alternative mechanism for providing some sealant migration to selected portions of the inner luminal surface 16 of a tubular graft or the second surface 36 of a non-tubular graft includes providing a mask or coating to selected portions of the engagement surface L or L'.

[0145] Easy identification and removal of sealing layers in areas of tissue ingrowth Limited but effective integration with the body

[0146] It is desirable to provide the surface area of ​​the outer surface of the sealing layer with a material that does not promote tissue ingrowth. However, in some embodiments, portions or regions of the outer surface of the sealing layer may be configured to promote tissue ingrowth to achieve stability of the implanted graft.

[0147] Some embodiments may include at least one scrim area that may include textiles, fibers and / or yarns or other non-sealant materials embedded or fused along the outer surface of the sealant layer. In some embodiments, tissue growth promoting and / or antibiotic and / or immunosuppressive substances may be coated on or adhered to the scrim. Exemplary substances that may be coated on or adhered to the scrim or inoculated into the scrim are discussed below and include antibiotics, therapeutic cells, modulators, immunosuppressants, etc.

[0148] like FIG. 4A to FIG. 4D As shown, and continue to refer to Figures 1A to 3C , the exemplary scrim 50 may be circumferential (in the case of a tubular graft) or longitudinal, helical, or may be applied randomly or in a pattern to cover a portion of the outer surface of the sealing layer 18 of the exemplary tubular graft 10 while providing additional surface area that does not promote tissue ingrowth. The exemplary scrim 50 may be applied to tubular or non-tubular grafts. See Figure 5 , see an exemplary scrim 50 configuration in the sealing layer 32 of an exemplary non-tubular graft 30.

[0149] Generally, the scrim 50 can be embedded within the sealing layer 18 or 32 so as not to significantly increase the outer diameter of the tubular graft 10 or the non-tubular graft 30. In some of these embodiments, the scrim 50 can be applied to the engagement surface L or L' so that the scrim and the fabric layer are in contact without the intervening sealant, and wherein the scrim is effectively surrounded by the sealant. In other embodiments, the scrim can be adhered to the outer surface of the sealing layer of the tubular graft 10 or the non-tubular graft 30, and thus can slightly increase the outer diameter of the graft 10, 30.

[0150] Other embodiments may include textiles, fibers, yarns, and / or non-sealant materials that may be knitted or woven or otherwise braided and may cover or sleeve at least a portion of the outer sealing layer of an implanted tubular or non-tubular graft. These solutions may also include antibiotics and / or tissue growth promoting substances as described above. Figure 6 An exemplary embodiment of an exemplary tubular graft 10 is provided that includes a textile cover 52 that partially covers and is attached and / or adhered to the sealing layer 18. In some embodiments, the textile cover 52 can be water soluble or otherwise biodegradable.

[0151] In some embodiments, the scrim and / or textile, fiber, yarn and / or non-sealant material covering or sleeve may include a color, such as blue or other color that provides contrast with tissue and blood to aid in locating the implanted graft and the scrim and / or textile covering or sleeve.

[0152] In some embodiments, the scrim and / or textile, fiber, yarn and / or non-sealant material covering or sleeve may be water soluble or biodegradable.

[0153] In some embodiments, the scrim and / or textile, fiber, yarn and / or non-sealant material covering or sleeve may include at least a partial covering of a water soluble layer or film to at least partially cover and thereby protect that portion of the scrim and / or textile covering, fiber, yarn and / or non-sealant material or sleeve, and / or any protection and / or prevention of premature loss of any substance that may be coated, adhered or inoculated on or in the scrim and / or textile covering, fiber, yarn and / or non-sealant material or sleeve. In addition, such a water soluble film may be used to create a timed release structure or framework for exposing the scrim to blood and / or any substance that may be coated, adhered or inoculated on or in the scrim and / or textile, fiber, yarn and / or non-sealant material covering or sleeve. Figure 7 A cross-sectional view of an exemplary tubular graft 10 is provided that includes an exemplary circumferential scrim 50 embedded within or adhered to the outer sealing layer 18 and a water soluble film 60 disposed at least on the scrim 50. It should be understood that the scrim 50 may include the substances described herein, which may be coated on, adhered to, and / or inoculated on or within the scrim 50.

[0154] Achievement and / or maintenance of self-sealing and hemostasis

[0155] Certain embodiments of prostheses, implants (such as, but not limited to, tubular or non-tubular grafts, patches, sheets, or bands) as described herein may include improvements that assist in achieving and / or maintaining hemostasis.

[0156] Continuing with reference to the drawings, the sealing layer 18 (tubular example) or 32 (non-tubular example) may include a sealant formed from a polymer, copolymer, dielectric material, or organic or non-organic polymer or copolymer, any of which may be combined with a foaming agent in some embodiments to improve the self-sealing function of the graft. The sealant of the present invention is selected to provide one or more of the following, in particular: impermeability to electrocautery injury; improved blood drainage; improved visibility in the body; improved resistance to adhesion of the material to the outer surface; improved resistance to bacterial adhesion to the outer surface of the sealant; seroma formation and / or infection between the surface of the graft and the biological tissue in contact with the graft surface; improved self-sealing strength after puncture; and improved water leakage or water permeability.

[0157] Preferred sealants in various embodiments of the present invention are non-organic polymers, and a preferred non-organic polymer is silicone. When combined with a blowing agent, silicone forms silicone foam rubber, and most preferably, in some embodiments, forms closed-cell silicone foam rubber. The method of forming silicone foam rubber (closed-cell) is well known to those skilled in the art. For example, azodicarbonide blowing agents for producing many types of polymer and elastomer closed-cell foams will be easily recognized by those skilled in the art. Alternatively, perfluoroelastomer ("PFE") or variants of PFE can be used to replace non-organic polymers, such as silicone, because it has excellent self-sealing properties when puncturing or cutting. More alternatively, non-organic polymers can be layered in combination with PFE or its variants. In alternative embodiments, exemplary silicones can be layered on top of the fabric layer below, wherein a layer or region of PFE or its variants covers at least a portion of the silicone bottom layer. More alternatively, the bottom layer disposed on the fabric layer can be PFE and it can be covered by an exemplary silicone layer.

[0158]

[00136] Some of the embodiments discussed herein that provide self-sealing improvements due to puncture (eg, suture hole puncture) may be implemented using organic or inorganic polymers or copolymers.

[0159] Generally, the self-sealing improvement is provided by the properties of the sealing layer. The sealing layer may comprise in whole or in part an organic or inorganic polymer or copolymer which, when combined with the blowing agent described above, may produce an open or closed cell structure formed by the resulting organic or inorganic polymer or copolymer foam rubber.

[0160] The sealing layer may include a tissue-facing layer that includes one or both of an open-cell or closed-cell structure. At the bonding surface, the sealing layer 18 may include an inorganic or organic polymer or copolymer sealant. In this embodiment, the sealant covering and / or adhering to the bonding surface is a polymer or copolymer and may be organic or inorganic, but is not combined with a foaming agent. Closed-cell and / or open-cell foam rubber formed by an organic or inorganic polymer or copolymer may be disposed or layered on the sealant to form the sealing layer 18.

[0161] Any combination of closed cell and / or open cell configurations may be used in combination with inorganic or organic polymer or copolymer sealants.

[0162] In some embodiments, the tissue-facing surface 20 (tubular), 33 (non-tubular) may include one or both of open-cell and closed-cell organic or inorganic polymer or copolymer foam rubber.

[0163] In some embodiments, the preferred polymer or copolymer is inorganic, and in some embodiments, the preferred inorganic polymer may include silicone. When used in combination with the polymer or copolymer foam rubber described herein, self-sealing of a graft puncture (e.g., a suture hole) occurs within one or more of the following: 10 minutes or less; 5 minutes or less; 2 minutes or less; 1 minute or less; 30 seconds or less; and / or 10 seconds or less.

[0164] The sealing layer configurations described above provide improved closure of punctures through the sealing layer and / or fabric layer, with improved time to restore hemostasis to the implanted graft. For example, but not limited to, a self-sealing layer comprising a polymer or copolymer foam rubber can enable restoration of hemostasis after graft puncture, for example, self-sealing of a suture hole within one or more of the following: 10 minutes or less; 5 minutes or less; 2 minutes or less; 1 minute or less; 30 seconds or less; and / or 10 seconds or less.

[0165] Similarly, the sealing layer configuration includes, for example, an inorganic sealant layer or region within the sealing layer 18, wherein the sealing layer also includes a closed-cell foam rubber layer as described herein, which can be capable of restoring hemostasis after graft puncture, for example, self-sealing of a suture hole within one or more of the following: 10 minutes or less; 5 minutes or less; 2 minutes or less; 1 minute or less; 30 seconds or less; and / or 10 seconds or less.

[0166] The sealing layer configuration includes an organic or inorganic polymer or copolymer sealant layer covering and / or adhered to the engaging surface of the fabric layer, wherein the sealant layer is covered by or integrated with a closed-cell foam rubber as described herein, which can restore hemostasis after graft puncture, for example, self-sealing of a suture hole within one or more of the following: 10 minutes or less; 5 minutes or less; 2 minutes or less; 1 minute or less; 30 seconds or less; and / or 10 seconds or less.

[0167] The sealing configuration includes a closed-cell foam rubber layer as described herein and covering and adhered to the bonding surface, wherein the closed-cell foam rubber layer is covered by an organic or inorganic polymer or copolymer sealant covering and adhered to the bonding surface of the fabric layer, wherein the sealant layer is covered by or integrated with it, which can restore hemostasis after graft puncture, for example, self-sealing of the suture hole within one or more of the following: 10 minutes or less; 5 minutes or less; 2 minutes or less; 1 minute or less; 30 seconds or less; and / or 10 seconds or less.

[0168] In some embodiments, a hydrogel can be provided along a portion of the graft, wherein the hydrogel is configured to swell when exposed to water and / or blood to stop any bleeding that may occur. Thus, the hydrogel can be embedded in the graft at points that are prone to bleeding. In some embodiments, the hydrogel can be embedded between the textile and the outer sealing layer, within the textile, along the outer surface of the sealing layer, or at any point between the textile and the sealing layer.

[0169] In some embodiments, a cuff may be provided where anastomosis may be performed. In other embodiments, the number of suture holes may be minimized, such as 1 suture hole / mm, or 1 suture hole / 2 to 3 mm.

[0170] Infection prevention or mitigation

[0171] Implant described herein or prosthesis (such as but not limited to tubular or non-tubular graft, patch, sheet and / or band) certain embodiments can be configured to prevent and / or alleviate infection.Techniques for preventing or alleviating bacteria or other materials from adhering to the tissue-facing surface of the embodiment of the graft are described above, and it can help prevent or alleviate the infection formed on the tissue-facing surface.

[0172]

[0013] Additional infection prevention and mitigation structures are now described with reference to the accompanying drawings.

[0173] In general, an infection prevention or mitigation mechanism may be provided on the various implant or prosthesis embodiments described herein, and may include (1) an applied infection prevention or mitigation mechanism; and / or (2) an embedded or impregnated infection prevention or mitigation mechanism.

[0174] The infection prevention or mitigation mechanism may include one or more or at least one antibiotic or antibiotic compound. When present, the at least one antibiotic compound may be applied immediately prior to implantation into the outer surface or tissue-facing surface of the subject tubular or non-tubular graft. Application of the at least one antibiotic compound may include spraying, brushing, dipping or other equivalent application and / or coating methods to provide a coating of at least one antibiotic on the tissue-facing surface and / or may be applied to the scrim 50 or the textile cover 52 as described above.

[0175] At least one antibiotic or antibiotic compound can be combined with one or more materials to form a composition, and the composition can be applied to the tissue-facing surface as described above.Such a composition can include a carrier or other materials, which provide the viscosity or adhesion to the enhanced tissue-facing surface, so that even if there is the super-hydrophobicity or moisture-resistant tissue-facing surface of some embodiments, it is also ensured that the tissue-facing surface has at least a portion of the layer of the composition at least loaded with antibiotic.In addition, at least one antibiotic can be provided in a microcapsule form, wherein the capsule can adhere to the sealing layer at the tissue-facing surface.Alternately, microencapsulated antibiotics can be maintained in place by at least partially embedding in the sealing layer at the tissue-facing surface and / or being pressed therein.Microcapsule is preferably biodegradable and / or water-soluble, so that the capsule can be broken, thereby allowing the release of the encapsulated antibiotic.Can be by providing a certain range of capsule thickness, biodegradability, water-soluble and / or material, with a timed release method to control the decomposition of the encapsulated antibiotic, whereby some capsules decompose faster, and other capsules need longer time to decompose.

[0176] Still alternatively, the at least one antibiotic may be at least partially in a granular, powdered or other non-liquid form, which may be configured to adhere to or be partially embedded or pressed into the sealing layer at the tissue-facing surface.

[0177] Other infection prevention and / or mitigation mechanisms may include impregnating the sealing layer with and / or embedding at least one antibiotic compound or composition within the sealing layer.

[0178] In some cases, the sealing layer may include, for example, at least a partial layer of an open-cell foam rubber as described herein at the engaging surface. At least one antibiotic compound or a composition thereof may then be disposed in at least some of the open cells along or near the engaging surface. The antibiotic compound or composition disposed in the open cells may be liquid, non-liquid, encapsulated or unencapsulated, and may be capable of timed release as described herein.

[0179] In some embodiments, the infection prevention and / or reduction mechanism is configured to provide an antibiotic material to prevent or reduce any infection between the tissue engaging surface and the host tissue.

[0180] Antibiotic preparations

[0181] As discussed, various embodiments of the present invention may also include an effective amount of at least one antibiotic or antibiotic compound along and / or embedded in and / or fused to the outer sealing layer of the tubular or non-tubular graft or coated along other regions or portions. The at least one antibiotic may be encapsulated and / or non-encapsulated, or a combination of encapsulated and non-encapsulated, and may be applied to or within the scrim 50 or textile cover 52 as described above.

[0182] The degradability or solubility of any capsule surrounding the antibiotic can be modified to produce a timed release of the encapsulated antibiotic, wherein some capsules dissolve or degrade faster than other capsules. Further, some antibiotics may not be encapsulated and therefore fully available at the time of implantation. In addition, a biodegradable or water-soluble film layer may be provided on the antibiotic (whether encapsulated or not) to provide an additional mechanism for modifying the release of the antibiotic over time.

[0183] Exemplary antibiotics for use in embodiments of the present invention may include mupirocin, defensins, gentamicin, geneticin, cefminoxime, penicillin, streptomycin, xylitol, rampafin, or other antibiotics.

[0184] Therapeutic cells

[0185] "Therapeutic cells" are defined herein to include at least one cell or cell type, such as but not limited to neural stem cells, which is applied to, embedded in, or otherwise fused to a tubular or non-tubular graft of the present invention.

[0186] The therapeutic cells may be from any source and may be at various stages of development and differentiation, so long as the therapeutic cells are sufficient to stimulate tissue growth into a designated portion of the graft, along a textile or fabric surface as described above (such as scrim 50 or textile sleeve 52), or along a portion of the outer surface of the sealing layer. In addition, it should be recognized that the therapeutic cells may be allogeneic or autologous to the host. With allogeneic, the therapeutic cells are intended to be derived from a mammal other than the patient subject, while autologous therapeutic cells are derived from the patient subject, manipulated ex vivo, and transported back into the patient by implanting the graft of the present invention.

[0187] As used herein, "modulator" refers to any molecule that has a growth, proliferation, differentiation or nutritional effect on the implanted therapeutic cells of the present invention. Any modulator that can modulate the development of transplanted donor cells can be administered by the methods of the present invention. See, for example, Mackay-Sim et al. (2000) Prog. Neurobiol. 62: 527-559, incorporated herein by reference. Modulators are further discussed below, and each such aspect is included in the definition of "modulator".

[0188] As used herein, the terms "differentiation" and "maturation" refer to cells that develop into specialized cells from the stage with the potential to differentiate into at least two different cell lineages. For the purposes of the present invention, such terms can be used interchangeably. The term "lineage" refers to all stages of developmental cell types, from the earliest precursor cells to fully mature cells (i.e., specialized cells). Therefore, the implanted therapeutic cells of the present invention can be derived from a pluripotent cell lineage, preferably a neural lineage, and can be in any differentiation stage. Therefore, the present invention includes therapeutic cells that are naturally programmed to differentiate into only one type of lineage. These types of cells can include some types of fibroblasts or simply differentiated astrocytes, neurons, oligodendrocytes, microglia or endothelial cells, and they can be derived from or only separated from donor tissue or amniotic tissue.

[0189] As used herein, the term "pluripotent stem cell" refers to a cell that can be differentiated into multiple lineages. The characteristics of multipotent therapeutic cells (e.g., stem cells) are that they carry out continuous cell proliferation, regenerate an exact copy of themselves (self-renewal), generate a large number of regional cell offspring, and respond to damage or disease to make (elaborate) the ability of new cells. "Pluripotent cell group" refers to a cell composition that can be differentiated into less than all cell lineages but at least differentiated into two cell lineages. Current research has shown that the pluripotent stem cell lineage from non-neural regions is not limited to its developmental origin, but can generate region-specific neurons when exposed to appropriate environmental cues (Lamga et al. (2001) J. Neurosci. 20: 8727-8735).

[0190] The therapeutic cells of the present invention can be derived from any fetal, amniotic or adult mammalian tissue, including bone marrow or neural tissue. In addition, the therapeutic cells can include but are not limited to pluripotent stem cells, progenitor cells, genetically engineered cells, T cells and / or autologous cells.

[0191] Methods for isolating and transplanting various progenitor cells derived from different tissues at different developmental stages are known in the art and include, for example: striatal cortex (Winkler et al. (1998) Mol. Cell. Neurosci. 11:99-116; Hammang et al. (1997) Exp. Neural. 147:84-95); cortex (Brustle et al. (1998) Nat. Biotechnol 16:1040-1044 and Sabate et al. (1995) Nat. Genet 9:256-260); human telencephalon (Flax et al. (1998) Nature 392:18-24 and Vescovi et al. (1999) Neuron 11:951-966); hippocampus (Gage et al. (1995) J. Neurobiol. 36:249-266 and Suhonen et al. (1996) Nature 383:624-627); basal forebrain (Minger et al. (1996) Exp. Neurol. 141:12-24); ventral midbrain (Winkler et al. (1998) Mol. Cell. Neurosci. 11:99-116; Svendsen et al. (1996) Exp. Neural 137:376-388; Hammang et al. (1997) Exp. Neurol. 147:84-95; Studer et al. (1997) Nat. Neurosci. 1:290-295; Milward et al. (1997) J. Neurosci. Res. 50:862-871); and subventricular zone (Milward et al. (1997) Milward et al. (1997) J. Neurosci. Res. 50:862-871). Each of these references is incorporated herein by reference.

[0192] Additionally, methods for isolating stem cell progeny and methods for promoting differentiation thereof can also be found in US Pat. No. 6,071,889 and US Pat. No. 6,103,530, both of which are incorporated herein by reference.

[0193] The therapeutic cells of the present invention can be altered to enhance tissue growth stimulation. For example, a preferred cell type is human foreskin fibroblasts, which are easily obtained and cultured (see, e.g., U.S. Pat. No. 6,060,048). Such cells are preferably genetically altered using methods known in the art to express growth factors, neurotransmitters, neuropeptides, or enzymes involved in metabolism or tissue generation. See, e.g., Gage et al. (1987) Neurosci. 23: 795-807; Rosenberg et al. (1988) Science 242: 1575-1578; Shimohama et al. (1989) Mol. Brain Res. 5: 271-278; incorporated by reference. Alternatively, therapeutic cells derived from non-neuronal sources (such as epidermal cells) can be transformed or transdifferentiated into different types of therapeutic cells. See, e.g., U.S. Pat. No. 6,087,168.

[0194] As discussed, the therapeutic cells of the present invention can be genetically altered before being implanted into a host tissue having a graft structure. As used herein, the term "genetically altered" refers to cells into which exogenous nucleic acids (e.g., DNA) have been introduced. Exogenous nucleic acids can be introduced by a variety of techniques, including but not limited to calcium phosphate-mediated transfection, DEAE-mediated transfection, microinjection, viral transformation, protoplast fusion, and lipofection. Genetically altered cells can express exogenous nucleic acids in a transient or long-term manner. In general, transient expression occurs when exogenous DNA cannot be stably integrated into the chromosomal DNA of the transfected cells. On the contrary, long-term expression of exogenous DNA occurs when exogenous DNA has been stably integrated into the chromosomal DNA of the transfected cells.

[0195] Such genes of interest include neurotransmitter synthases (i.e., tyrosine hydrolase (TH) and choline acetyltransferase). Such methods are well known in the art. For example, therapeutic donor cells from different regions and different developmental stages of the brain have been isolated and immortalized by genetic alteration. For example, olfactory and cerebellar cells have been immortalized using viral myc (v-myc) oncogenes to generate cell lines with neuronal and glial phenotypes (Ryder et al. (1990) J. Neurobiol. 21: 356). Similar studies by Snyder et al. ((1992) Cell 68: 33) have produced multipotent neuronal cell lines that were transplanted into rat cerebellum to form neurons and glial cells. In other studies, mouse neuroepithelial cells were immortalized with a retroviral vector containing c-myc and cultured with growth factors to form differentiated cell types resembling astrocytes and neurons (Barlett et al. (1988) Proc. Natl. Acad. Sci. USA 85:3255).

[0196] Immunosuppressants

[0197] Alternative embodiments of the present invention may also include an effective amount of at least one immunosuppressant to enhance the viability of the graft, which may or may not include therapeutic cells, by protecting against inflammatory responses and / or activating host immune activity. The immunosuppressant may be applied along the graft or embedded or fused therein and / or applied to or otherwise fused to the scrim 50 or textile, fiber and / or yarn and / or non-sealant material (including a sleeve as described above).

[0198] When the immunocompetent cells of the host tissue detect the implanted graft of the present invention, an inflammatory response and / or activation of the host immunocompetent cells can be caused. When present along the implanted graft or in the graft, this series of events may also reduce the survival of the therapeutic cells. Therefore, the immunosuppressant can be coated on the graft and / or embedded or fused therein, not only to the implanted graft itself, but also to the survival and vitality of any therapeutic cells coated on the implanted graft or fused therein play a vital role. Conventional and well-known immunosuppressants that can be used alone or in combination in the present invention include cyclosporin A, tacrolimus, prednisolone, azathioprine, methylprednisolone, mycophenolate mofetil (mycophenylate) and sirolimus. Another immunosuppressant includes applying genetically engineered cells expressing Fas ligand.

[0199] Conditioner

[0200] When present along or within an implanted exemplary prosthesis or implant (such as a graft, patch, sheet and / or band), certain modulators, particularly for regulating the growth and differentiation of the delivered therapeutic cells, fall within the scope of the invention and include, for example, modulators in an effective amount to promote the survival of donor cells by regulating immune and inflammatory responses. Such modulators include, for example, cyclosporin and various other immunomodulators, including interleukins (i.e., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10); tumor necrosis factor (i.e., TNF-α and TNF-β); and interferons (i.e., IFN-α, IFN-β, IFN-γ, IFN-Ω, and IFN-τ); and any biologically active variants thereof. Further details regarding the administration of these immunomodulators by the methods of the present invention can be found in U.S. Patent No. 09 / 733,168, entitled "Methods for Administering a Cytokine to the Central Nervous System and the Lymphatic System," filed December 9, 2000, which is incorporated herein by reference.

[0201] Additional modulators useful in the methods of the invention include CAP23 (a major cortical cytoskeleton-associated and calmodulin-binding protein) and GAP43 (a neural growth-associated protein). See, e.g., Frey et al. (2000) J. Cell. Biol. 7: 1443-1453. Other agents of interest include osteogenic protein-1 (OP-1), a morphogenic protein that stimulates growth, differentiation, and maintenance of differentiation (U.S. Pat. No. 6,153,583); sonic hedgehog, a polypeptide that has been shown to promote survival of dopaminergic neurons (Miao et al. (1996) Cell Transplant 55: 2-17); various other glial growth factors (U.S. Pat. Nos. 5,716,930, 6,147,190, and 5,530,109); and any biologically active variants thereof. All of these references are incorporated herein by reference.

[0202] Other modulators of interest and within the scope of the invention include growth factors. As used herein, "growth factor" refers to a polypeptide that is capable of regulating the development of therapeutic cells on or within an implanted graft. Growth factors that can be used in the methods of the invention include, but are not limited to, members of the neurotrophin family (i.e., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4, also known as NT-4 / 5 or NT-5); fibroblast growth factor (FGF, i.e., basic fibroblast growth factor); epidermal growth factor family (i.e., EGF, TGF.α, amphiregulin, heparin-binding EGF-like growth factor (HB-EGF), cytokines (BTC), and neuromodulin group); platelet-derived growth factor; insulin; insulin-like growth factor (i.e., IGF-I and IGF-2); ciliary neurotrophic factor (CNTF), glial cell-derived neurotrophic factor family (GDN F) (i.e., GDNF and facial neurons (NTN), Persephin (PSP) and artemin (ART)); Transforming growth factor β superfamily (i.e., subfamily includes TGFβ1, TGFβ2, TGFβ3, TGFβ4, TGFβ5, activin, inhibin, growth factor of biological skin); Growth differentiation factor (GDF) (i.e., GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, GDF8, GDF9, GDF9B, GDF10, GDF11 and GDF15); Glial-derived microtubule-linked proteins; Activity-dependent neurotrophic factor (ADNF); Glial growth factor (GGF); etc. It is also recognized that any biologically active variants of these growth factors can also be used in the methods of the present invention.

[0203] The modulators of the present invention may be from any animal species, including but not limited to rodents, avian, canine, bovine, porcine, equine, and preferably human. Preferably, the modulator administered is from the same species as the animal being treated.

[0204] The various methods and pharmaceutical compositions of the present invention also encompass biologically active variants of regulatory polypeptides (i.e., growth factors, such as IGF-I, NGF and basic FGF, cytokines, etc.). Such variants should retain the biological activity of the regulator, particularly the ability to regulate donor cell development (i.e., promote survival, maintain desired phenotypes, and / or regulate developmental cues produced by donor cells). For example, when the regulatory polypeptide is a growth factor, such as a member of the IGF-I, NGF-I or FGF family, the ability to bind to their corresponding receptor sites will be retained. Such receptor binding activity can be measured using standard bioassays.

[0205] One such modulator (growth factor) useful in the present invention is IGF-I. The term "IGF-I" as used herein refers to insulin-like growth factor I (IGF-I), a single-chain peptide having 70 amino acids and a molecular weight of about 7,600 Daltons. Insulin-like growth factor I stimulates mitosis and growth processes associated with cell development. The amino acid and nucleotide sequences of IGF-I are known in the art. See, e.g., U.S. Pat. No. 5,324,639, which discloses the sequence of human IGF-I; Genbank Accession No. X15726, which discloses the sequence of bovine IGF-I; and Genbank Accession No. X06043, which discloses the sequence of rat IGF-I. Each of these references is incorporated herein by reference.

[0206] In another embodiment of the present invention, regulator can include the member of the FGF family of somatomedin and / or its biologically active variant.The fibroblast growth factor family encompasses a group of structurally related proteins, which bind heparin with high affinity.FGF family members have mitogen activity and induce the proliferation of various cell types.FGF family members also participate in angiogenesis, differentiation, cell migration, embryonic development and neuron maintenance / survival.Term " FGF " as used herein refers to the member of the fibroblast growth factor family, including for example FGF-1 (acidic FGF), FGF-2 (basic FGF), FGF-3, FGF-4, FGF-5, FGF-6, FGF-8, FGF-9, FGF-98 or its biologically active fragment or variant.Amino acid sequences and methods for preparing many FGF family members are well known in the art.

[0207] In another embodiment of the present invention, the regulator may include nerve growth factor (NGF) or a biologically active variant thereof. NGF was initially isolated as a complex with a molecular weight of 130 kDa and a sedimentation coefficient of 7S. The 7S complex includes three types of subunits, of which "β" is a subunit that carries all the biological activities of NGF. Nerve growth factor stimulates the mitosis and growth processes of cells (particularly nerve cells) and regulates development (i.e., affects repair, survival and differentiation). Preferred amino acid sequences of human prepro-NGF and human mature NGF are provided in U.S. Patent No. 5,288,622, which is incorporated herein by reference.

[0208] The NGF used in the present invention can be in a substantially purified, natural, recombinantly produced form or a chemically synthesized form. For example, NGF can be isolated directly from cells that naturally express NGF. NGF can also be recombinantly produced in a eukaryotic or prokaryotic cell expression system, as described in Edwards et al. (1988) Mol. Cell. Biol. 8: 2456; U.S. Pat. No. 5,986,070; and U.S. Pat. No. 6,005,081, all of which are incorporated herein by reference. Alternatively, the modulators of the present invention may include erythropoietin (EPO), brain-derived neurotrophic factor (BDNF) and epidermal growth factor (EGF). Each of the modulators described herein plays a key role in the in vivo survival and differentiation of the therapeutic cells of the methods and pharmaceutical compositions of the present invention.

[0209] By administering an effective amount of at least one modulator by the methods of the present invention, i.e., coating or fused or embedded along the sealing layer or other area of ​​an implanted prosthesis, implant (such as a graft, patch, sheet and / or band), and also including but not limited to being fused into a scrim 50 or a textile, fiber or yarn or other non-sealant material sleeve 52, in combination with therapeutic cells, it will modulate the development of the therapeutic cells of the transplant. The phrase "modulate development" herein particularly means that the modulator enhances the survival, differentiation, axonal development, dendritic development and / or proliferation of the transported therapeutic cells; improves the adhesion of the transported therapeutic cells to the surrounding tissue (i.e., fusion into the parenchymal tissue); improves the ability of the transported therapeutic cells to establish synaptic connections with host neurons (i.e., enhances neurofibril formation in donor cells; increases the neurofibril projection distance of donor cells; or enhances the neurofibril fate of donor cells); and / or directs the transported therapeutic cells to commit to a specific neural lineage (i.e., adopts a neuron (GABAergic neuron, dopaminergic neuron, cholinergic neuron, hippocampal neuron, etc.), an astrocyte or an oligodendrocyte fate). It is also recognized that modulators can enhance the survival of transplanted donor cells by modulating the subject's immune response. "Modulate" means downregulation of the immune or inflammatory response (i.e., affecting systemic immune function, antigen presentation, cytokine production, lymphocyte proliferation, and entry of lymphocytes and macrophages).

[0210] Furthermore, it is known to administer modulators to "modulate the development of implanted therapeutic donor cells" (i.e., promote the release of neurotransmitters (such as dopamine, acetylcholine, GABA or other neuroprotective factors) by affecting the developmental cues released by the transplanted cells. Thus, the function and repair of surrounding host tissue (i.e., enhanced nerve fiber formation, nerve fiber projection distance, and / or nerve fiber density) can be enhanced by the non-invasive methods of the present invention.

[0211] Pharmaceutical composition

[0212] Pharmaceutical composition can be applied to or fused in tubular or non-tubular prosthesis or implant (such as but not limited to graft, patch, sheet or band), and it can include one or more in antibiotic, therapeutic cell, regulator and / or immunosuppressant.For example, except at least one therapeutic cell of effective dose, such pharmaceutical composition can also include at least one regulator as described above, at least one delivery enhancer as described above, at least one antibiotic and / or at least one immunosuppressant, all as described herein.In addition, all these materials, no matter as composition or as independent material applied or fused to graft or its, can be encapsulated as described herein, and / or can be coated or covered with degradable or water-soluble film.In all cases, the timed release of various materials can be realized by method described herein.

[0213] Further, any of the antibiotics, therapeutic cells, modulators and / or immunosuppressants and / or pharmaceutical compositions of any of the listed substances may include any pharmaceutically acceptable additives, carriers and / or adjuvants that can promote or enable the retention of the substance along or within the graft, and also facilitate the release of the substance from the graft at a designed time point.

[0214] "Pharmaceutically acceptable carrier" means a carrier conventionally used in the art to facilitate the storage, administration and / or biological activity of therapeutic cells, modulators, antibiotics and / or therapeutic cells, modulators, antibiotics and / or in the pharmaceutical composition of the present invention. The carrier may also reduce any undesirable side effects of the components of such pharmaceutical composition. A suitable carrier should be stable, i.e., not react with the other ingredients in the formulation. It should not produce significant local or systemic adverse effects on the recipient at the dosage and concentration used for treatment. Such carriers are well known in the art.

[0215] Suitable carriers for various embodiments of the present invention include conventional carriers for large stable macromolecules, such as albumin, gelatin, collagen, polysaccharides, monosaccharides, polyvinyl pyrrolidone, polylactic acid, polyglycolic acid, polymeric amino acids, fixed oils, ethyl oleate, liposomes, glucose, sucrose, lactose, mannose, dextrose, dextran, cellulose, mannitol, sorbitol, polyvinyl alcohol (PEG) etc. Other pharmaceutical compositions may include microparticles, organic and inorganic compounds or other substances (such as antibiotics or immunosuppressants for the transplant itself) used as adhesion materials for cells and cell aggregates. These compounds may include components and organic and / or inorganic particles of multiple adhesive molecules, gels (encapsulation / embedding materials for cells), extracellular matrix, such as fibrin or fibronectin carbon or clay and dextran particles and compositions thereof.

[0216] Water, saline, aqueous glucose and glycol are preferred liquid carriers, particularly for (when isotonic) solutions. Carriers can be selected from various oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Suitable pharmaceutical excipients include starch, cellulose, talcum powder, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can be subjected to conventional drug treatment, such as sterilization, and can contain conventional pharmaceutical additives, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for regulating osmotic pressure, buffers, etc. In the case where the carrier is a liquid, it is preferred that the carrier is hypotonic or isotonic with body fluids and has a pH in the range of 4.5 to 8.5.

[0217] Other acceptable components in the pharmaceutical composition include, but are not limited to, isotonicity regulators, such as water, saline, and buffers, including phosphates, citrates, succinates, acetic acid, and other organic acids or salts thereof. Typically, pharmaceutically acceptable carriers also include one or more stabilizers, reducing agents, antioxidants, and / or antioxidant chelators. The use of buffers, stabilizers, reducing agents, antioxidants, and chelators in the preparation of protein-based compositions, particularly pharmaceutical compositions, is well known in the art. See Wang et al. (1980) J. Parent. Drug Assn, 34(6):452-462; Wang et al. (1988) J. Parent. Sci. Tech. 42:S4-S26 (Supplement); Lachman et al. (1968), Drug and Cosmetic Industry 102(1):36-38, 40, and 146-148; Akers (1988) J. Parent. Sci. Tech. 36(5):222-228; and Methods in Enzymology, Volume XXV, Colowick and Kaplan, eds., "Reduction of Disulfide Bonds in Proteins with Dithiothreitol," Konigsberg, pp. 185-188.

[0218] Additionally, some embodiments of the exemplary prostheses or implants described herein (such as tubular or non-tubular grafts, patches, sheets or strips) may include a sealing layer having silver or colloidal silver, which is a known antibiotic agent, wherein the silver or colloidal silver is embedded, doped and / or coated on the sealing layer. The sealing layer may include silicone having silver or colloidal silver.

[0219] In some embodiments, a layered approach can be employed to reduce seromas and / or infections of implanted tubular or non-tubular grafts. For example, an inner or outer coating of a carrier and an antibiotic operably attached to the carrier can be provided.

[0220] Radiopaque and / or visual markers

[0221] Certain embodiments of tubular or non-tubular prostheses and implants, such as the grafts, patches, sheets, and bands described herein, may include radiopaque markers that assist medical practitioners with the aid of imaging instruments and techniques to locate the position of the graft, ensure proper placement, assess the condition of the implanted graft, and / or help prevent occlusion of branch arteries and veins. A non-limiting list of imaging instruments and / or techniques includes X-rays, fluoroscopy, CT scans, and MRIs.

[0222] Visual indicia may also be provided to assist a medical practitioner in determining if a subject's graft is twisted or otherwise deformed, and may indicate the length or other dimensions of the graft under physiological pressure. For example, indicia indicating 1 cm length increments will measure at 1 cm under physiological pressure and may measure at greater or less than 1 cm length under non-physiological pressure. As defined herein, a visual indicia is a indicia that is visible to the unaided eye of a practitioner and is enhanced only by a magnifying glass without the aid of an imaging device or other enhancement technology.

[0223] Reference now Figure 8 And continue to refer to Figure 1 to Figure 7 , the radiopaque markers may include one or more radiopaque areas disposed at one or more locations along the graft. One or more radiopaque areas may be located at the engagement surface of the fabric layer, i.e., below the sealant layer 18. Other radiopaque areas may be embedded within the sealing layer 18 without being structurally connected to the engagement surface of the fabric layer 18.

[0224] Figure 8 Exemplary radiopaque markers are shown fused into a Valsalva graft as rings at the sinotubular junction and aortic root to serve as a "landing zone" for future fluoroscopically guided valve surgery. A first radiopaque marker ring is shown located between the collar and the Valsalva skirt, and a second radiopaque marker ring is shown located at the upper end of the Valsalva skirt. Radiopaque markers may be used in other tubular or non-tubular grafts described herein. For example, but not limitation, the radiopaque material or marker may include a complete or partial or discontinuous ring around a branch location (e.g., a native vessel or graft) to enable identification during fluoroscopically guided intervention. See Figure 8 , for example branch locations of radiopaque markers or rings.

[0225] In some embodiments, the radiopaque area or marking can be visible to the naked eye of a medical practitioner without the need for imaging equipment or other vision enhancement aids. In this embodiment, the visible radiopaque area can also be used as the visual marking described above.

[0226] In other embodiments, the radiopaque areas or markings are not visible to the naked eye of the physician and must be visualized using imaging techniques.

[0227] As described above, visual markings facilitate quick assessment of a subject's graft for distortion or other deformities and may indicate the length or other dimensions of the graft under physiological pressure. For example, markings indicating 1 cm length increments would measure at 1 cm under physiological pressure and could measure at greater or less than 1 cm length under non-physiological pressure.

[0228] In an exemplary tubular graft, two or more visual markings may be provided at or near the tissue-facing surface of the sealing layer. In certain embodiments, the two or more visual markings may be aligned with the non-deformed longitudinal axis of the tubular graft and may be radially spaced apart from one another. In certain embodiments, the two or more radially spaced apart visual markings may be visually distinct from one another to assist the practitioner in, among other things, assessing whether the graft is distorted. For example, the markings may differ in color, or may be continuous versus intermittent or dashed, discrete dots versus dashed or continuous, to provide visual distinguishing characteristics between the markings.

[0229] Various embodiments of tubular or non-tubular grafts described herein can be used as dissection planes. Generally, the surface of the graft comprising a woven fabric is well anchored to the tissue adjacent thereto and does not allow any tissue growth into the surface when the woven fabric is completely covered on the opposite surface with a non-organic polymer or copolymer (such as silicone). See, for example, FIGS. 1 to 3. Figure 3C . Preferred materials and designs such as Fig. 9 and Fig.10 As shown, an exemplary non-tubular graft 70 is included, which has an outer sealing layer 18 that forms a complete cover relative to an embedded polyester mesh woven material 72 that is partially exposed on the opposite surface. A portion of the polyester mesh woven material 72 is embedded in or covered by the outer sealing layer 18, which can include an organic or inorganic polymer or copolymer. Preferred polymers include silicone, but other polymers can also be used as long as tissue is not allowed or enabled to grow inward through or into the outer sealing layer material. In some cases, such as Fig. 9As shown, the pocket of exemplary silicone can be exposed on the tissue-facing surface so that tissue ingrowth occurs in a manner corresponding to the exposed polyester mesh braid. In other embodiments, the exemplary silicone is prevented from reaching the tissue-facing surface, and the entire tissue-facing surface is therefore available for tissue ingrowth. However, the opposite surface of the outer sealing layer 18 is not available for tissue ingrowth, which is useful for providing a surgical dissection plane for surgery after implantation. As noted, such a surgical dissection plane can be provided in both tubular grafts and non-tubular grafts as described herein.

[0230] The surgical dissection plane implementation may be used for, but is not limited to, the following purposes.

[0231] Encompasses ventricular assist devices ("VAD"), including right ventricular assist devices and left ventricular assist devices.

[0232] Heart valve leaflets.

[0233] The base or commissure of a heart valve.

[0234] Extracorporeal membrane oxygenation (“ECMO”).

[0235] Guide tissue regeneration.

[0236] Venous surgery.

[0237] Rotator cuff support.

[0238] Knee pads.

[0239] Leg ligaments.

[0240] Skull pad.

[0241] Dental implants.

[0242] Rhinoplasty.

[0243] Burning.

[0244] Heart valve reinforcement.

[0245] The selected embodiments of the invention are as follows:

[0246] 1. A tubular or non-tubular implant or prosthesis configured to be easily transplanted from a living body, comprising: a textile fabric layer including a plurality of gaps and / or pores and defining an engagement surface and an opposing surface; and a sealing layer of a non-porous, non-organic polymer adhered to the engagement surface and defining a tissue-facing surface, wherein the non-porous, non-organic polymer is configured to partially penetrate at least some of the plurality of gaps and / or pores at the opposing surface of the textile fabric layer;

[0247] wherein the non-porous, non-organic polymer of the sealing layer does not penetrate to an opposing surface of the textile fabric layer, and wherein the heat resistance of the non-porous, non-organic polymer of the sealing layer is greater than the heat resistance of the organic polymer or organic copolymer, whereby the outer layer is configured to resist and / or mitigate damage caused by applied electrosurgical energy,

[0248] As such, the inner fabric layer is protected and resists and / or mitigates damage thereto by the applied electrosurgical energy.

[0249] 2. A tubular or non-tubular implant or prosthesis according to item 1, wherein the non-porous, non-organic polymer of the sealing layer comprises molecular bonds having a binding energy higher than that of carbon bonds.

[0250] 3. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer is hydrophobic.

[0251] 4. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer is superhydrophobic and comprises a sliding angle of <10 degrees.

[0252] 5. A tubular or non-tubular implant or prosthesis according to the item, wherein the sealing layer has ultra-resistance to moisture, including a sliding angle of <10 degrees and blood flow therefrom.

[0253] 6. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer does not include gaps or pores therethrough.

[0254] 7. Tubular or non-tubular implants or prostheses according to item 1, including 0 mL / cm 2 / min water permeability value.

[0255] 8. A tubular or non-tubular implant or prosthesis according to item 1, wherein the tissue-facing surface of the outer layer includes a surface roughness having a root mean square average value of 35 nm or less, wherein the surface roughness of the tissue-facing surface is configured to prevent body tissue or platelets from adhering to at least a portion of the tissue-facing surface after implantation of the tubular implant or prosthesis.

[0256] 9. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer is configured to prevent biological tissue and / or platelets from adhering to at least a portion of the tissue-facing surface.

[0257] 10. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer is configured to prevent bacterial adhesion to the tissue-facing surface.

[0258] 11. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer is configured to prevent the formation of seromas along the tissue-facing surface.

[0259] 12. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer is configured to prevent infection from forming along the tissue-facing surface.

[0260] 13. A tubular or non-tubular implant or prosthesis according to item 1, wherein at least a portion of the opposing surfaces of the fabric layer allow tissue ingrowth.

[0261] 14. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer prevents transmural communication or migration from the luminal surface to the outer layer.

[0262] 15. A tubular or non-tubular implant or prosthesis according to item 1, wherein at least a portion of the sealing layer comprises a color that contrasts with blood and tissue.

[0263] 16. Tubular or non-tubular implants or prostheses according to item 1, comprising three cross-sectional areas:

[0264] a region 1 defined on a first side by an opposite surface of the fabric layer and wherein the plurality of gaps and / or pores do not include any non-porous, non-organic polymer of the sealing layer;

[0265] a region 2 located within the fabric layer and adjacent to region 1 and bounded on a first side by the region and on an opposite side by the engaging surface, wherein at least some of the plurality of interstices and / or pores comprise a non-porous, non-organic polymer; and

[0266] A region 3, adjacent to the bonding surface and bounded on the inside by the bonding surface and on the outside by the tissue-facing surface defined by the sealing layer, wherein region 3 consists only of a non-porous, non-organic polymer, wherein region 3 defines a thickness.

[0267] 17. A tubular or non-tubular implant or prosthesis according to item 16, wherein the non-porous, non-organic polymer of region 3 prevents biological tissue from growing in or communicating through the wall into region 3 through the joining surface.

[0268] 18. A tubular or non-tubular implant or prosthesis according to item 17, wherein ingrowth of biological tissue into at least a portion of region 2 and into region 1 is not prevented.

[0269] 19. A tubular or non-tubular implant or prosthesis according to item 1, wherein the non-porous, non-organic polymer comprises a blowing agent that forms a polymer foam rubber.

[0270] 20. The tubular or non-tubular implant or prosthesis according to item 19, wherein the polymer foam rubber forms a polymer foam rubber closed-cell structure.

[0271] 21. A tubular or non-tubular implant or prosthesis according to item 19, wherein at least the tissue-facing surface of the sealing layer comprises one or both of an open-cell polymer foam rubber structure and a closed-cell polymer foam rubber structure.

[0272] 22. A tubular or non-tubular implant or prosthesis according to item 1, wherein the implant is tubular and configured to be connectable to one or both of an inlet or outlet of a left ventricular assist device or a right ventricular assist device.

[0273] 23. A tubular or non-tubular implant or prosthesis according to item 1, wherein the graft is tubular and is configured to include a Valsalva aortic root graft.

[0274] 24. A tubular or non-tubular implant or prosthesis according to item 1, wherein the sealing layer provides protection and insulation during intravascular surgery to prevent heat transfer to and / or through the fabric layer and / or electrical energy transfer to and / or through the fabric layer.

[0275] 25. A tubular or non-tubular implant or prosthesis according to item 24, wherein the sealing layer protects blood cells in or near the textile fabric from thermal or electrical damage.

[0276] 26. A tubular or non-tubular implant or prosthesis according to item 24, wherein the sealing layer prevents therapeutic cells, therapeutic agents and / or antibiotics or other substances adhered to or fused within the textile fabric from thermal or electrical damage.

[0277] 27. A tubular or non-tubular implant or prosthesis according to item 24, wherein the sealing layer protects tissue on or adjacent to the textile fabric from thermal or electrical damage.

[0278] 28. A tubular or non-tubular implant or prosthesis configured for easy transplantation from a living body with controlled tissue ingrowth and in vivo integration of the implanted graft, comprising:

[0279] a fabric layer including a plurality of gaps and / or pores and defining an engagement surface and an opposing surface; and a sealing layer of a non-porous, non-organic polymer adhered to at least a portion of the engagement surface and defining a tissue-facing surface, wherein the non-porous, non-organic polymer is configured to partially penetrate at least some of the plurality of gaps and / or pores at the opposing surface of the fabric layer;

[0280] wherein the sealing layer is interrupted by at least one textile scrim configured to promote tissue ingrowth.

[0281] 29. An implant or prosthesis according to item 28, wherein at least one textile scrim is operably connected to the fabric layer at the engagement surface.

[0282] 30. The implant or prosthesis according to item 28, wherein at least one textile scrim is embedded in the sealing layer, wherein the at least one textile scrim is separated from the fabric layer by the non-porous, non-organic polymer of the sealing layer.

[0283] 31. The implant or prosthesis according to item 28, wherein at least one of the group consisting of antibiotics, therapeutic cells, modulators and immunosuppressants is embedded in at least one scrim and / or operably connected thereto.

[0284] 32. An implant or prosthesis according to item 31, wherein at least one of the Markush group of item 28 is encapsulated with a water-soluble or biodegradable or bioerodible material.

[0285] 33. The implant or prosthesis according to item 28, further comprising a water-soluble, biodegradable or bioerodible film covering the at least one scrim.

[0286] 34. The implant or prosthesis of item 28, wherein at least a portion of at least one scrim comprises a color that contrasts with blood and / or tissue.

[0287] 35. An implant or prosthesis according to item 34, wherein at least a portion of at least one scrim is blue.

[0288] 36. A tubular or non-tubular implant or prosthesis configured to be radiopaque, comprising:

[0289] a fabric layer including a plurality of gaps and / or pores and defining an engaging surface and an opposing surface;

[0290] a sealing layer of a non-porous, non-organic polymer adhered to at least a portion of the engagement surface and defining a tissue-facing surface, wherein the non-porous, non-organic polymer is configured to partially penetrate at least some of the plurality of gaps and / or pores at an opposing surface of the fabric layer; and

[0291] One or more radiopaque regions include a radiopaque material, wherein the radiopaque material is embedded within the sealing layer and / or attached to the engaging surface of the fabric layer.

[0292] 37. An implant or prosthesis according to item 36, wherein the implant or prosthesis comprises a Valsalva graft and wherein the one or more radiopaque regions comprise a radiopaque ring configured to be located at a junction with the aortic root and / or the sinotubular junction.

[0293] 38. An implant or prosthesis according to item 36, wherein the radiopaque ring is a complete ring or a partially interrupted ring.

[0294] 39. An implant or prosthesis according to item 36, wherein one or more radiopaque regions are also visible to the practitioner's eye and are configured to enable evaluation and diagnosis of the position and condition of the implant.

[0295] 40. A tubular or non-tubular implant or prosthesis comprising:

[0296] a fabric layer including a plurality of gaps and / or pores and defining an engaging surface and an opposing surface;

[0297] a sealing layer of a non-porous, non-organic polymer adhered to at least a portion of the engagement surface and defining a tissue-facing surface, wherein the non-porous, non-organic polymer is configured to partially penetrate at least some of the plurality of gaps and / or pores at an opposing surface of the fabric layer; and

[0298] One or more areas of the fabric layer are exposed within the sealing layer, wherein the one or more areas of the fabric layer are not covered by the sealing layer and are at least partially surrounded by the sealing layer.

[0299] 41. An implant or prosthesis according to item 40, wherein one or more areas of the exposed fabric layer are configured to allow tissue ingrowth.

[0300] 42. An implant or prosthesis according to item 41, wherein one or more areas of the exposed fabric layer are configured to serve as a dissection plane.

[0301] The description of the present invention and its application set forth herein is illustrative and is not intended to limit the scope of the present invention. The features of various embodiments can be combined with other embodiments within the concept of the present invention. Variations and modifications of the embodiments disclosed herein are possible, and those of ordinary skill in the art will understand the actual alternatives and equivalents of the various elements of the embodiments after studying this patent document. These and other variations and modifications may be made to the embodiments disclosed herein without departing from the scope and spirit of the present invention.

Claims

1. A tubular or non-tubular implant or prosthesis configured to prevent or reduce infection when implanted in a living body, comprising: a fabric layer including a plurality of gaps and / or pores and defining an engaging surface and an opposing surface; a sealing layer comprising a polymer and / or copolymer, wherein the sealing layer is adhered to the engagement surface and defines a tissue-facing surface, wherein the polymer and / or copolymer is configured to at least partially penetrate at least some of the plurality of gaps and / or pores at the engagement surface of the fabric layer; and At least one infection prevention or mitigation mechanism is disposed on the tissue-facing surface or embedded within the sealing layer.

2. A tubular or non-tubular implant or prosthesis according to claim 1, wherein: The at least one infection prevention or reduction mechanism comprises at least one antibiotic compound disposed on the tissue-facing surface of the sealing layer.

3. A tubular or non-tubular implant or prosthesis according to claim 2, wherein: At least a portion of the sealing layer is configured to absorb the at least one antibiotic compound.

4. A tubular or non-tubular implant or prosthesis according to claim 1, wherein: The at least one infection prevention or reduction mechanism comprises at least one antibiotic compound embedded within the sealing layer.

5. A tubular or non-tubular implant or prosthesis according to claim 4, wherein: The at least one antibiotic compound is embedded at or on the tissue-facing surface.

6. A tubular or non-tubular implant or prosthesis according to claim 5, wherein: The at least one antibiotic compound is encapsulated in a water-soluble or biodegradable or bioabsorbable capsule.

7. A tubular or non-tubular implant or prosthesis according to any one of claims 1 to 6, wherein: At least a portion of the tissue-facing surface of the sealing layer comprises an open-cell foam rubber structure formed by the polymer and / or copolymer in combination with a foaming agent, and wherein the at least one antibiotic compound is disposed within at least one open cell of the open-cell foam rubber structure.

8. A tubular or non-tubular implant or prosthesis according to any one of claims 1 to 7, wherein: The sealing layer includes one or more of an impermeable, non-porous, non-organic polymer, a non-organic open-cell foam rubber structure, and a non-organic closed-cell foam rubber structure.

9. A tubular or non-tubular implant or prosthesis according to any one of claims 1 to 7, wherein: The sealing layer includes one or more of an organic polymer, a non-organic or organic open-cell foam rubber structure, and a non-organic or organic closed-cell foam rubber structure.

10. A tubular or non-tubular implant or prosthesis according to claim 9, wherein: The non-organic or organic open-cell foam rubber structure comprises at least a portion of the tissue-facing surface, and wherein an impermeable, non-porous, non-organic polymer is adhered to the engaging surface of the fabric layer.

11. A tubular or non-tubular implant or prosthesis according to any one of claims 1 to 10, wherein: The at least one antibiotic compound is configured for timed release from the sealing layer and / or the tissue-facing surface and / or the encapsulation.

12. A tubular or non-tubular implant or prosthesis according to any one of claims 1 to 11, wherein The at least one antibiotic compound is selected from one or more of the group consisting of mupirocin, defensins, gentamicin, geneticin, cefminox, penicillin, streptomycin, xylitol and rapamycin.

13. A tubular or non-tubular implant or prosthesis having improved self-sealing function, comprising: a fabric layer including a plurality of gaps and / or pores and defining an engaging surface and an opposing surface; and a self-sealing layer comprising a polymer or copolymer foam rubber adhered to at least the engaging surface of the fabric layer, the self-sealing layer defining a tissue-facing surface, wherein the self-sealing layer is adhered to at least a portion of the opposing surface of the fabric layer and is configured to at least partially penetrate at least some of the plurality of gaps and / or pores of the fabric layer; and wherein the sealing layer is configured to provide hemostasis after suture puncture through the tubular or non-tubular implant or prosthesis within one or more time ranges to achieve post-suture puncture hemostasis, the time range being in the group consisting of: 10 minutes or less, 5 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, and 10 seconds or less.

14. A tubular or non-tubular implant or prosthesis according to claim 13, wherein: At least a portion of the self-sealing layer comprises a polymer or copolymer foam rubber having a closed-cell structure.

15. The tubular or non-tubular graft according to claim 13, wherein: At least the tissue-facing surface of the sealing layer includes one or both of an open-cell polymer foam rubber structure and a closed-cell polymer foam rubber structure.

16. The tubular or non-tubular graft according to claim 13, wherein: The polymer or copolymer of the polymer or copolymer foam rubber is non-organic.

17. The tubular or non-tubular graft according to claim 13, wherein: The polymer or copolymer foam rubber includes silicone foam rubber selected from one or both of a closed-cell structure and an open-cell structure.

18. A tubular or non-tubular implant or prosthesis having improved visible and / or radiopaque markings, comprising: a fabric layer including a plurality of gaps and / or pores and defining an engaging surface and an opposing surface; and a self-sealing layer comprising a polymer or copolymer foam rubber adhered to at least the engaging surface of the fabric layer, the self-sealing layer defining a tissue-facing surface, wherein the self-sealing layer is adhered to at least a portion of the opposing surface of the fabric layer and is configured to at least partially penetrate at least some of the plurality of gaps and / or pores of the fabric layer; and One or more radiopaque regions are disposed at one or more locations along and / or around the tubular or non-tubular implant or prosthesis, wherein the one or more radiopaque regions are located at the engagement surface of the fabric layer and / or embedded within the sealing layer.

19. A tubular or non-tubular implant or prosthesis according to claim 18, wherein The one or more radiopaque regions are configured to be visible to the eye of a medical practitioner without the aid of an imaging instrument.

20. A tubular or non-tubular implant or prosthesis according to claim 18 and / or 19, wherein: The one or more radiopaque regions are configured to be invisible to the eye of a medical practitioner without the aid of an imaging instrument.

21. A tubular or non-tubular implant or prosthesis according to any one of claims 18 to 20, wherein The graft is tubular and further includes at least two markers disposed at or near the tissue-facing surface of the sealing layer along a longitudinal axis of the tubular graft, wherein the at least two markers are radially spaced from one another around the tubular implant or prosthesis.

22. A tubular or non-tubular implant or prosthesis according to claim 21, wherein At least one of the at least two markings comprises a continuous linear marking.

23. A tubular or non-tubular implant or prosthesis according to claim 21, wherein: At least one of the at least two markings comprises a discontinuous or dashed linear marking.

24. A tubular or non-tubular implant or prosthesis according to any one of claims 18 to 23, wherein The at least two markings are configured to be visible to the naked eye of a medical practitioner.

25. A tubular or non-tubular implant or prosthesis configured to resist or delay injury resulting from application of electrocautery energy, comprising: a fabric layer including a plurality of gaps and / or pores and defining an engaging surface and an opposing surface; and a sealing layer of a non-porous, non-organic polymer adhered to the engagement surface and defining a tissue-facing surface, wherein the non-porous, non-organic polymer is configured to partially penetrate at least some of the plurality of gaps and / or pores at the opposing surface of the fabric layer; wherein the non-porous, non-organic polymer of the sealing layer does not penetrate to the opposite surface of the textile fabric layer, and wherein the outer layer is configured to resist and / or delay damage from applied electrosurgical energy, Thereby, damage to the inner fabric layer caused by the applied electrosurgical energy is resisted and / or delayed.

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