Tissue repair and sealing device having a removable graft / fastener assembly and method for using the same

Abstract

This provides a method for using tissue repair and sealing devices. [Solution] A tissue repair and sealing device and a method for using the tissue repair and sealing device are provided to rapidly repair tissue fenestration and form a pressure-resistant, watertight seal in a tissue barrier, by using the device in both minimally invasive surgical (MIS) procedures and non-MIS procedures under direct visualization. The tissue repair and sealing device comprises an applicator assembly 20 having an assembly in which a graft and a deployable fastener are integrated, and a fastener retaining and releasing member 35 slidably connected to the folded, deployable fastener. The applicator assembly repairs tissue fenestration and forms a watertight barrier by positioning the graft on the inner surface of the tissue and the deployable fastener on the outer surface of the tissue, thereby fixing the graft to the inner surface of the tissue.

Description

Technical Field

[0001] Cross-Reference to Related Applications This PCT patent application was filed on January 22, 2021 as PCT Patent Application No. PCT / US21 / 14796, and claims the benefit of U.S. Provisional Patent Application No. 62 / 965,722 filed on January 24, 2020. The contents of U.S. Provisional Patent Application No. 62 / 965,722 are incorporated herein by reference in their entirety. Background Art

[0002] Background of the Present Disclosure Technical Field The present disclosure generally relates to the field of medicine, and particularly to surgery and surgical procedures including both minimally invasive surgery (MIS) procedures and open surgery (non-MIS) procedures. Disclosed herein are a tissue repair and sealing device including a removable graft-fastener assembly for repairing tissue fenestration (e.g., those occurring during a surgical procedure, or those resulting from congenital, infectious or neoplastic processes), and a method for using the same. The tissue repair and sealing device described herein allows placement of the graft on an inner tissue surface and deployment of the fastener on an outer tissue surface. The device is deployed by moving a fastener holding and releasing member along the applicator shaft to release the deployable fastener, whereby the graft is secured to the inner tissue surface; the tissue fenestration is rapidly repaired; and a pressure-resistant watertight seal is formed.

[0003] Description of Related Art Advances in endoscopic, robotic and microsurgical technology have enabled rapid development of minimally invasive surgery (MIS) procedures that access the surgical site through small incisions. For example, MIS procedures are used to access a working space within a body cavity or interior body space (e.g., abdominal cavity, dural venous sinus, intracranial space or perispinal tissue) or a luminal pathway (e.g., cardiovascular system; gastrointestinal system; cerebrospinal fluid pathway of the skull or spinal cord; or an organ such as the uterus, bladder or kidney).

[0004] Several factors common to minimally invasive surgical (MIS) procedures, including limited workspace, restricted surgical access, poor visualization, and the fragile nature of certain tissues, make it difficult to repair and seal incisions, lacerations, or openings in subcutaneous tissue (collectively, tissue fenestrations). Failure to rapidly repair tissue fenestrations and form a watertight seal can lead to fluid leakage through the fenestrated tissue, thereby inhibiting tissue healing, promoting infection, and resulting in a significant postoperative morbidity.

[0005] In MIS procedures, various devices and methodologies are available for closing tissue fenestrations, including (a) suturing or stapling, (b) application of tissue adhesives, and (c) placement and adhesion of tissue grafts, in various combinations. However, existing devices and methodologies have limited practicality because they cannot rapidly repair tissue fenestrations or reliably form a pressure-resistant, watertight seal. As a result, healing of tissue with fenestrations is insufficient, and complications often occur due to leakage of bodily fluids, including blood (hemorrhage, hematoma, tumor effect), cerebrospinal fluid (meningitis, pneumocephalus, decreased intracranial pressure), gastrointestinal contents (infection, fistula), and urine (fistula, infection).

[0006] Direct suturing or stapling of tissue fenestrations is time-consuming and technically difficult given the limited space and access inherent in minimally invasive surgery (MIS) procedures. Consequently, rapid repair and watertight seal formation are rarely achieved in the repair of tissue fenestrations created during MIS procedures. Furthermore, certain tissues encountered during MIS procedures are unsuitable for suturing due to their fragility, insufficient tissue to allow for complete closure, and proximity to critical structures. Additionally, permanent metal implants (i.e., staples) can interfere with subsequent magnetic resonance imaging.

[0007] Absorbable and non-absorbable tissue adhesives (e.g., fibrin glue and polyglycol gel) also have limited usefulness in the rapid repair of tissue fenestrations and the formation of pressure-resistant, watertight seals. Tissue adhesives present several technical challenges that can contribute to poor surgical outcomes: (1) mixing and application of fast-curing two-component adhesives is difficult in confined spaces; (2) grafts often need to be reinforced with other tissues (e.g., fat); and (3) the bonding strength of tissue adhesives may be insufficient for forming pressure-resistant, watertight seals.

[0008] Tissue patches, including those made from the patient's own tissue (e.g., fascia and fat), other tissues (e.g., bovine or porcine tissue), or synthetic tissues (e.g., collagen matrix), require the use of sutures to remain in place and are prone to infection and tissue rejection. Overlays of stalk grafts to promote healing require glue or buttresses to ensure adhesion, do not provide immediate watertight closure, and are associated with increased surgical morbidity.

[0009] The usefulness of existing devices for attaching grafts to the outer surface of tissue fenestrations is limited in minimally invasive surgery (MIS) procedures. Devices known in the art are difficult to operate and usually require additional procedures (e.g., collecting reinforcing tissue and placing drains to reduce pressure gradients). Furthermore, tissue grafts attached to the outer surface of tissue are prone to failure, particularly susceptible to pressure differences between the inside and outside of the fenestrated tissue (e.g., blood vessels, dura mater, or gastrointestinal wall tissue). Grafts placed on the outer surface of tissue often fail to repair the tissue fenestration and form a watertight seal, leading to leakage of bodily fluids (e.g., blood, cerebrospinal fluid, or gastrointestinal contents) from the higher-pressure tissue interior. This results in poor healing, a higher incidence of infection, increased postoperative complications and morbidity, and longer hospital stays.

[0010] U.S. Patent No. 5,634,944 ("Magram") discloses a flanged graft using graft material that requires suturing to adjacent tissues such as the dura mater. PCT Patent Publication No. WO2019 / 055551 ("Sansur") discloses a thermoformable absorbent double-layer sealing device that uses a patch that is molded to fit the outer surface of a tissue fenestration and sutured in place. PCT Patent Publication No. WO2008 / 115849 ("Baird") discloses a device that uses an anchor element positioned within a tissue opening, a flexible membrane graft positioned outside the tissue opening, and a ratchet connector to fix the anchor element to the flexible membrane and close the tissue opening.

[0011] U.S. Patent Application Publication 2015 / 0164489 ("Duggal") discloses an expandable barrier that is inserted into an internal space through a defect, and subsequently expands to be positioned in contact with the internal surface. A second barrier, which may be expandable, is positioned in contact with the outer surface of the defect and connected to the inner barrier via annular or notched bridging components.

[0012] U.S. Patent No. 5,350,399 ("Erlebacher") discloses a sealing device for repairing a blood vessel (e.g., arterial puncture) that achieves repair of a fenestration by securing a bioabsorbable occluder in place inside and outside the lumen using a ratchet connector and a serrated guide.

[0013] U.S. Patent No. 7,169,168 ("Muijs Van De More") discloses a percutaneous system for sealing an arterial puncture wound, wherein an occlusion element is passed through a lumen using a guidewire and is attached to a suture-like component that secures an extraluminal element, thereby holding the occlusion element in contact with the inner surface of the puncture site.

[0014] U.S. Patent No. 8,105,352 ("Egneloev") discloses a device for sealing a puncture in a vascular wall, comprising an inner component positioned on the inner wall of the vascular vessel and an outer component positioned on the outer wall of the vascular vessel. The inner and outer components are secured by a thread-like retaining element.

[0015] U.S. Patent Application Publication 20070093840 ("Rao") discloses a device having two opposing ring-shaped plates (i.e., an inner plate bonded to an outer plate) that clamp the peripheral edge of a tissue defect to achieve watertight repair of the tissue defect. The two opposing ring-shaped plates are positioned independently on either side of the fenestration via mechanical attachments that fix their position. After the plates are joined, a ratchet-type plate connector must be cut off.

[0016] Despite the availability of existing techniques for closing tissue fenestrations in surgical procedures, there remains an unmet need in the field for devices and methods that enable rapid repair of tissue fenestrations and reliable formation of pressure-resistant, watertight seals. This disclosure meets these needs and offers further relevant advantages over existing techniques that are unsuitable for use in minimally invasive surgical (MIS) procedures. [Prior art documents] [Patent Documents]

[0017] [Patent Document 1] U.S. Patent No. 5,634,944 [Patent Document 2] International Publication No. 2019 / 055551 [Patent Document 3] U.S. Patent Application Publication No. 2015 / 0164489 [Patent Document 4] U.S. Patent No. 5,350,399 [Patent Document 5] U.S. Patent No. 7,169,168 [Patent Document 6] U.S. Patent No. 8,105,352 [Patent Document 7] U.S. Patent Application Publication No. 20070093840 [Overview of the project] [Means for solving the problem]

[0018] Summary of this disclosure Provided herein are tissue repair and sealing devices that exhibit unexpected and surprising advantages over devices and techniques currently available in the art for repairing and sealing tissue fenestrations, including tissue fenestrations occurring during minimally invasive surgery (MIS) procedures. Disclosed herein are tissue repair and sealing devices, and methods for using the devices in both MIS procedures and open (non-MIS) procedures to rapidly repair tissue fenestrations and reliably form a pressure-resistant watertight seal against pressure differentials, such as pressure differentials occurring between the inside and outside of tissue having a fenestration.

[0019] In certain specific embodiments, the tissue repair and sealing devices disclosed herein comprise, in operable combination: (1) an applicator assembly comprising a fastener retention and release member having a proximal end and a distal end, wherein the fastener retention and release member is movably attached to an applicator shaft having a proximal end and a distal end; and (2) a detachable graft and fastener assembly having a graft subassembly including a self-expanding graft that expands to its original shape after passing through a tissue fenestration, which is fixedly attached at or near the geometric center of the deployable fastener and coupler subassembly via a central coupler at or near the geometric center (also known as the center of gravity) of the deployable fastener.

[0020] Certain embodiments of the tissue repair and sealing devices disclosed herein utilize a removable graft-fastener assembly comprising a deployable fastener-coupler subassembly having a central coupler and a deployable fastener having a plurality of radial struts or spokes extending from the central coupler at or near the geometric center of the removable graft-fastener assembly. In certain embodiments of these embodiments, the removable graft-fastener assembly is attached to the applicator assembly via the central coupler at the proximal end of the applicator shaft. In further embodiments, the device is deployed by sliding a fastener retaining / releasing member along the applicator shaft toward its distal end, thereby releasing the fastener from the retaining / releasing member. In even further embodiments, once the device is deployed, the fastener secures the graft to the inner surface of the tissue and the fastener secures the outer surface of the tissue, thereby repairing tissue fenestration and forming a pressure-resistant, watertight seal.

[0021] During operation, the tissue repair and sealing device disclosed herein enables (1) placement of the graft subassembly on the inner tissue surface and (2) placement of the deployable fastener-coupler subassembly on the outer tissue surface. Prior to use, the detachable graft-fastener assembly is attached to the applicator assembly via a central coupler at the proximal end of the applicator shaft. The radial spokes or struts of the deployable fastener are folded away from the graft subassembly and inserted into the proximal end of the fastener retention and release member to hold the deployable fastener in place. Using the applicator assembly, the graft subassembly is inserted through the tissue fenestration and placed on the inner tissue surface while the deployable fastener-coupler assembly remains outside the fenestrated tissue. The tissue repair and sealing device is deployed by moving the fastener retention and release member toward the distal end of the applicator shaft to release the deployable fastener, whereby the deployable fastener opens and applies pressure to the outer tissue surface to secure the graft subassembly against the inner tissue surface, thereby allowing rapid repair of the tissue fenestration and reliable formation of a pressure-resistant watertight seal.

[0022] Further modifications of the tissue repair and sealing device that address specific technical problems encountered in minimally invasive surgery (MIS) are described herein. These include: (1) changes to the size and shape of the graft subassembly and the deployable fastener-coupler subassembly; (2) changes to the materials used for the graft subassembly and the deployable fastener-coupler subassembly; (3) arrangements that enable use of the tissue repair and sealing device in endoscopic or percutaneous procedures (e.g., use of a conical graft element and a flexible applicator assembly having a channel for receiving a guidewire); and (4) incorporation of a drug-eluting matrix material instead of or in combination with a graft component to provide sustained drug delivery at the application site.

[0023] A deployable device is illustrated herein, comprising a deployable fastener having multiple flexible spokes or struts extending radially from a coupler, wherein the deployable fastener exhibits biophysical properties, size, shape and dimensions suitable for securing a graft positioned on the inner surface of tissue and a fastener positioned on the outer surface of tissue, thereby repairing tissue fenestrations and forming a pressure-resistant, watertight seal.

[0024] In some embodiments, the tissue repair and sealing device utilizes a removable graft-fastener assembly, where one or more elements of the graft subassembly and / or deployable fastener-coupler subassembly include a biopolymer exhibiting shape memory and superelastic properties, selected from the group consisting of, for example, polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC). In certain applications, the biopolymer is a bioabsorbable material.

[0025] In further embodiments, the tissue repair and sealing devices disclosed herein utilize a removable graft-fastener assembly, wherein the graft comprises a material selected from the group consisting of autografts, syngeneic grafts, allogeneic grafts, and xenografts. In related embodiments, the graft is derived from animal tissue selected from the group consisting of human tissue, bovine tissue, and porcine tissue, and includes, for example, animal tissue selected from the group consisting of dermis, pericardium, and intestine.

[0026] In a related embodiment, the tissue repair and sealing device utilizes a removable graft-fastener assembly, wherein the graft comprises one or more synthetic materials, such as, for example, bioabsorbable materials, such as poly(ethylene terephthalate) and / or stretched polytetrafluoroethylene (ePTF).

[0027] In other related embodiments, tissue repair and sealing devices utilize a removable graft-fastener assembly, where the graft includes a dural substitute, such as, for example, a dural substitute selected from the group consisting of Duraform® dural graft implants, Biodesign® dural graft, DuraGen® Matrix, Cerafix dural graft®, PRECLUDE®, Lyoplant Onlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®, and Durepair® Regeneration Matrix.

[0028] In some embodiments, the grafts according to these embodiments may be autografts, syngrafts, allografts, or heterografts. In other embodiments, the graft comprises tissue, membrane, mesh, or matrix. In further embodiments, the graft comprises a material that is self, allograft, or heterograft. In yet another embodiment, the graft comprises one or more synthetic materials, including one or more synthetic materials selected from the group consisting of poly(ethylene terephthalate) and stretched polytetrafluoroethylene (ePTF).

[0029] In further embodiments, the graft comprises material derived from animal tissue, for example, animal tissue selected from the group consisting of human tissue, bovine tissue and porcine tissue, the animal tissue including animal tissue selected from the group consisting of dermis, pericardium and intestine. The grafts according to these embodiments may comprise one or more of the following: (1) a cell-free porous extracellular matrix skeleton; (2) collagen; (3) elastin; and (4) growth factors. In some embodiments, the grafts according to these embodiments comprise a mesh having sufficient porosity to allow cells to enter, adhere, and undergo a remodeling cycle.

[0030] In further embodiments, the grafts according to these embodiments include dural substitutes selected from the group consisting of Duraform® dural graft implants, Biodesign® Dural Graft, DuraGen® Matrix, Cerafix dural graft®, PRECLUDE®, Lyoplant Onlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®, and Durepair® Regeneration Matrix. In even further embodiments, the grafts according to these embodiments incorporate a drug-eluting matrix to continuously release drugs into the body fluids and tissues at the site of tissue repair and sealing.

[0031] In further embodiments, the tissue repair and sealing devices disclosed herein utilize a graft comprising a cell-free, porous extracellular matrix skeleton of collagen, elastin, and optionally growth factors. Such a graft may optionally comprise a mesh having sufficient porosity to allow cells to enter, adhere, and undergo a remodeling cycle. The graft may further comprise a drug-eluting matrix.

[0032] In other embodiments, the tissue repair and sealing devices disclosed herein utilize a removable graft-fastener assembly, wherein one or more elements of the graft subassembly and / or deployable fastener-coupler subassembly comprise a biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire, the wire exhibiting shape memory and superelastic properties, which enable the folding of the metal or metal alloy while retaining the ability to open to its pre-folded state. Suitable biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires include wires comprising metals or metal alloys selected from the group consisting of pure titanium; titanium-based alloys; cobalt-based alloys; platinum-based alloys; and alloys of molybdenum, tungsten, and tantalum. Suitable metals or metal alloys having shape memory and superelastic properties that are strengthened at high temperatures include, for example, nickel-titanium alloys (nitinol) and niobium-titanium alloys.

[0033] Other embodiments of the present disclosure include methods for rapidly repairing tissue fenestration and forming a pressure-resistant watertight seal using the tissue repair and sealing devices disclosed herein in open-vision (non-MIS) or minimally invasive surgery (MIS) procedures. Such methods include (a) selecting a tissue repair and sealing device having a removable graft-fastener assembly detachably mounted to an applicator assembly, wherein the removable graft-fastener assembly comprises a graft subassembly having a graft fixedly mounted to a deployable fastener, and a coupler subassembly having a deployable fastener having radial struts or spokes and a central coupler, and the applicator assembly comprises an applicator shaft, a fastener retaining / releasing member and an actuator rod The process includes: (b) folding the radial struts or spokes of a deployable fastener and inserting them into a fastener retaining / releasing member; (c) inserting the graft through the tissue fenestration and positioning the graft on the inner surface of the tissue; (d) positioning the deployable fastener coupler subassembly on the outer surface of the tissue; and (e) deploying the tissue repair / sealing device to release the deployable fastener from the fastener retaining / releasing member, thereby bringing it into contact with the outer surface of the tissue, fixing the graft to the inner surface of the tissue, repairing the tissue fenestration, and forming a pressure-resistant watertight seal.

[0034] The tissue repair and sealing devices and methods disclosed herein may be used in the direct, percutaneous, and / or endoscopic repair and sealing of a wide variety of human tissues. Those skilled in the art will understand that the tissue repair and sealing devices and methods described and illustrated herein may be modified without departing from the spirit and scope of this disclosure to address issues specific to the nature, condition, and surgical exposure of fenestration-affected tissue. Such modifications may include, for example, changes in the composition of materials and / or the orientation of fasteners to suit the unique characteristics of fenestration-affected tissue. Modifications may also include (1) the addition of components that allow for the replacement of various graft materials during surgery, (2) changes in the size and shape of graft-fastener units, and (3) flexible applicators with or without guidewires for percutaneous or endoscopic repair and sealing of puncture wounds or fistula sites.

[0035] These and other related aspects of the present disclosure will be better understood in light of the following drawings and detailed description illustrating certain aspects of various embodiments. The present invention provides, for example, the following items: (Item 1) A tissue repair and sealing device for use in open-visual (non-MIS) or minimally invasive (MIS) surgical procedures to rapidly repair tissue fenestration and to form a pressure-resistant watertight seal, wherein the device is a. An applicator assembly comprising an applicator shaft having a proximal end and a distal end, and a fastener retaining / releasing member having a proximal end and a distal end, wherein the fastener retaining / releasing member is movably connected to the applicator shaft, and b. A detachable graft-fastener assembly comprising, in an operable combination, a graft subassembly including a graft fixedly attached to a deployable fastener, and a coupler subassembly including a deployable fastener and a central coupler. Equipped with; i. The detachable graft-fastener assembly is configured to position the graft on the inner surface of the tissue and the deployable fastener on the outer surface of the tissue, ii. A tissue repair and sealing device wherein the detachable graft-fastener assembly is attached to the applicator assembly at the proximal end of the applicator shaft via the central coupler. (Item 2) The tissue repair and sealing device according to item 1, wherein the deployable fastener assembly is configured to assume a folded position when held by the fastener holding and releasing member, and to quickly unfold to its pre-folded state. (Item 3) The device is deployed by moving the fastener holding / releasing member toward the distal end of the applicator shaft, thereby releasing the folded, deployable fastener. When the device is deployed, the deployable fastener opens and contacts the outer surface of the tissue, fixing the graft to the inner surface of the tissue, thereby repairing tissue fenestrations and forming a pressure-resistant, watertight seal. Tissue repair and sealing devices as described in item 1. (Item 4) The deployable fastener contains a biopolymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC). The biopolymer exhibits shape memory and superelastic properties, enabling folding while retaining the ability to quickly unfold to its pre-folded state. Tissue repair and sealing devices as described in item 1. (Item 5) The deployable fastener assembly comprises a biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire selected from the group consisting of pure titanium; titanium-based alloys; cobalt-based alloys; platinum-based alloys; and alloys of molybdenum, tungsten, and tantalum. The biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire exhibits shape memory and superelastic properties, enabling folding of the wire while retaining its ability to quickly unfold to its pre-folded state. Tissue repair and sealing devices as described in item 1. (Item 6) The tissue repair and sealing device according to item 5, wherein the biocompatible, non-ferromagnetic passivated metal or passivated metal alloy is selected from the group consisting of nickel-titanium alloys (nitinol) and niobium-titanium alloys. (Item 7) The tissue repair and sealing device according to item 1, wherein the graft assembly is configured to (a) take a folded position when passing through tissue fenestration or when held by the fastener-holding / releasing member, and (b) to quickly unfold to its pre-folded state. (Item 8) The aforementioned graft is selected from the group consisting of autografts, syngeneic grafts, homogeneous grafts, and heterogeneous grafts. The graft is derived from animal tissue selected from the group consisting of human tissue, bovine tissue, and porcine tissue. Tissue repair and sealing devices as described in item 1. (Item 9) The tissue repair and sealing device according to item 1, wherein the graft material comprises one or more synthetic materials selected from the group consisting of poly(ethylene terephthalate) and stretched polytetrafluoroethylene (ePTF). (Item 10) The tissue repair and sealing device according to item 1, wherein the graft comprises a cell-free, porous extracellular matrix scaffold of collagen, elastin, and optionally growth factors. (Item 11) The aforementioned grafts include Duraform® dural graft implants, Biodesign® dural graft, DuraGen® Matrix, Cerafix dural graft®, PRECLUDE®, Lyoplant Onlay Graft®, and Neuro-Patch. A tissue repair and sealing device as described in item 1, comprising a dura mater substitute selected from the group consisting of Dural Graft®, SEAMDURA®, and Durepair® Regeneration Matrix. (Item 12) The tissue repair and sealing device according to item 1, wherein the graft comprises a drug-eluting matrix. (Item 13) The aforementioned implant comprises a biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire selected from the group consisting of pure titanium; titanium-based alloys; cobalt-based alloys; platinum-based alloys; and alloys of molybdenum, tungsten, and tantalum. The biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire exhibits shape memory and superelastic properties, enabling the wire to be folded while retaining its ability to quickly unfold to its pre-folded state. Tissue repair and sealing devices as described in item 1. (Item 14) The tissue repair and sealing device according to item 13, wherein the biocompatible, non-ferromagnetic passivated metal or passivated metal alloy is selected from the group consisting of nickel-titanium alloys (nitinol) and niobium-titanium alloys. (Item 15) A method for rapidly repairing tissue fenestration and forming a pressure-resistant, watertight seal using a tissue repair and sealing device in a direct visualization (non-MIS) procedure or a minimally invasive surgical (MIS) procedure, (a) A step of selecting a tissue repair and sealing device having a removable graft / fastener assembly that is detachably attached to an applicator assembly, The detachable graft-fastener assembly comprises a graft subassembly having a graft fixedly attached to a deployable fastener, and a coupler subassembly having a deployable fastener having a radial strut or spoke and a central coupler. The applicator assembly comprises an applicator shaft, a fastener retaining / releasing member, and an actuator rod; (b) The step of folding the radial strut or spoke of the deployable fastener and inserting it into the fastener retaining / releasing member; (c) Inserting the graft through tissue fenestration and positioning the graft on the inner surface of the tissue; (d) The step of placing the deployable fastener / coupler subassembly on the outer surface of the tissue; (e) The step of deploying the tissue repair / sealing device to release the deployable fastener from the fastener holding / releasing member, thereby bringing it into contact with the outer surface of the tissue, fixing the graft to the inner surface of the tissue, repairing the tissue fenestration, and forming a pressure-resistant watertight seal. Methods that include... (Item 16) The device is deployed by moving the fastener holding / releasing member toward the distal end of the applicator shaft, thereby releasing the folded, deployable fastener. When the device is deployed, the deployable fastener opens and contacts the outer surface of the tissue, fixing the graft to the inner surface of the tissue, thereby repairing tissue fenestrations and forming a pressure-resistant, watertight seal. The method described in item 15. (Item 17) The deployable fastener contains a biopolymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC). The biopolymer exhibits shape memory and superelastic properties, enabling folding while retaining the ability to quickly unfold to its pre-folded state. The method described in item 15. (Item 18) The deployable fastener assembly comprises a biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire selected from the group consisting of pure titanium; titanium-based alloys; cobalt-based alloys; platinum-based alloys; and alloys of molybdenum, tungsten, and tantalum. The biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire exhibits shape memory and superelastic properties, enabling the wire to be folded while retaining its ability to quickly unfold to its pre-folded state. The method described in item 15. (Item 19) The method of item 15, wherein the graft assembly is configured to (a) take a folded position when passing through tissue fenestration or when held by the fastener-retaining / releasing member, and (b) to quickly unfold to its pre-folded state. (Item 20) The aforementioned grafts include Duraform® dural graft implants, Biodesign® dural graft, DuraGen® Matrix, Cerafix dural graft®, PRECLUDE®, Lyoplant Onlay Graft®, and Neuro-Patch. The method according to item 15, comprising a dura mater substitute selected from the group consisting of Dural Graft®, SEAMDURA®, and Durepair® Regeneration Matrix. [Brief explanation of the drawing]

[0036] Certain aspects of this disclosure will become clearer by reference to the drawings presented, which are presented for illustrative purposes rather than limitation. [Figure 1A-B] Figure 1 is a drawing illustrating an exemplary tissue repair and sealing device according to one embodiment of the present disclosure. Figure 1A shows an applicator assembly comprising an applicator shaft and a fastener retainer / release member, the fastener retainer / release member being slidably connected to the applicator shaft. Figure 1B shows a detachable graft-fastener assembly comprising a graft subassembly and a deployable fastener-coupler subassembly, which includes a central coupler for attaching the detachable graft-fastener assembly to the applicator assembly at the proximal end of the applicator shaft. Figure 1C is a CAD drawing showing a perspective view of an exemplary tissue repair and sealing device as described in further detail herein. [Figure 1C] Same as above. [Figure 2]Figure 2 is a diagram illustrating the spatial arrangement of components of an exemplary detachable graft-fastener assembly, where the graft subassembly is fixedly attached at its center to a deployable fastener-coupler subassembly via a central coupler. In Figure 2, a particular embodiment of the detachable graft-fastener assembly includes a deployable fastener-coupler subassembly comprising a deployable fastener having a plurality of struts or spokes that (1) extend radially from the central coupler and (2) are in contact with the surface of the graft subassembly. In the particular graft subassembly shown in Figure 2, the struts or spokes of the deployable fastener extend beyond the outer edge of the graft subassembly to facilitate the folding of the deployable fastener and its retention by the fastener retaining / releasing member on the applicator assembly. [Figure 3A] Figure 3A is a diagram showing the retention of the deployable fastener / coupler subassembly (shown in Figures 1 and 2) by the fastener retention / release member of the applicator assembly. The deployable fastener / coupler subassembly folds at each of the multiple radial struts or spokes that extend radially from the central coupler and is inserted into the proximal end of the fastener retention / release member, thereby holding the deployable fastener in a folded position until the tissue repair / sealing device is deployed. [Figure 3B-C]Figures 3B–3E are drawings illustrating the use of tissue repair and sealing devices according to various embodiments of the present disclosure for rapidly repairing tissue fenestrations and ensuring the formation of a pressure-resistant, watertight seal. Figure 3B shows the tissue repair and sealing device before insertion of a graft subassembly through a tissue fenestration. This tissue repair and sealing device comprises an applicator assembly attached to a removable graft and fastener assembly, where the struts or spokes of a deployable fastener and coupler subassembly are folded away from the graft subassembly and inserted into the proximal end of a fastener retaining and releasing member. Figure 3C shows the tissue repair and sealing device of Figure 3B after insertion of a graft subassembly through a tissue fenestration. This graft subassembly is positioned on the inner surface of the tissue, with the deployable fastener and coupler subassembly remaining outside the tissue having the fenestration, before the tissue repair and sealing device is deployed. Figure 3D shows the deployment of the tissue repair and sealing device by releasing the deployable fastener by sliding the fastener holding and release member toward the distal end of the applicator shaft. Figure 3E shows how the tissue fenestration is repaired and a pressure-resistant watertight seal is formed by separating the detachable graft-fastener assembly from the applicator assembly, positioning the deployable fastener-coupler assembly in contact with the outer surface of the tissue, and fixing the graft subassembly to the inner surface of the tissue. [Figure 3D-E] Same as above. [Figure 3F-3G]Figures 3F and 3G are photographs of exemplary deployable fastener / coupler prototypes according to the embodiments shown in Figures 3A-3E, fabricated from polyglycolic acid using a 3D stereolithography (SLA) printer with a resolution of 25-50 microns. Figure 3F shows the deployable fastener / coupler prototype in an open configuration, and Figure 3G shows the deployable fastener / coupler in a closed configuration, with multiple radial struts or spokes folded for insertion into the proximal end of the fastener retaining / releasing member. For illustrative purposes only, the struts or spokes of the deployable fastener are bound together with plastic tape to highlight the configuration of the deployable fastener that is inserted into and held by the fastener retaining / releasing member, which is movably connected to the applicator shaft. [Figure 4] Figure 4 is a drawing illustrating a freely selectable embodiment of various tissue repair and sealing devices disclosed herein, in which a central coupler is configured to be rotatably attached to a deployable fastener, thereby enabling angular rotation of the graft. In one exemplary embodiment shown in Figure 4B, the central coupler is fabricated in a ball-and-socket arrangement that allows for the orientation of a detachable graft-fastener assembly over a range of angles relative to the applicator shaft Figure 4A, as may be required during MIS procedures. [Figure 5A-B]Figure 5 illustrates embodiments of the tissue repair and sealing device of the present disclosure configured for use in surgical procedures (e.g., lumbar puncture and gastrostomy) to seal the site of large-diameter needle puncture or percutaneous fistula creation. Figure 5A shows a tissue repair and sealing device comprising an applicator assembly having an applicator shaft and a fastener-retaining and releasing member, and a removable graft-fastener assembly having a graft subassembly and a deployable fastener-coupler assembly, wherein the graft is a conical occluding graft, the applicator shaft is made of a flexible material, and the applicator shaft, central coupler and graft are configured to have a central channel for housing a guidewire. In certain embodiments, the conical occluding graft comprises a bioabsorbable material. Figure 5B shows the deployment of a tissue repair and sealing device according to the embodiment shown in Figure 5A, in which a conical occluding graft is positioned on the inner surface of the tissue, and radial struts or spokes of a deployable fastener are positioned on the outer surface of the tissue, thereby applying pressure to the outer surface of the tissue to fix the conical occluding graft, thereby repairing the tissue fenestration (i.e., the puncture wound or fistula site) and forming a pressure-resistant, watertight seal. [Figure 5C-E]Figures 5C–5G illustrate an exemplary method of repairing a puncture site using a tissue repair and sealing device, as shown in Figure 5A, in conjunction with the use of a guidewire. As shown in Figure 5C, the guidewire is passed through a large-bore needle inserted through the tissue barrier for fluid drainage. In an alternative embodiment of this method, the guidewire may be passed through an indwelling catheter before removal. After the large-bore needle or indwelling catheter is removed, the guidewire remains in place (Figure 5D). Figure 5E illustrates the passage of the distal (lateral) end of the guidewire through a conical occluder graft, a central coupler, and a central channel within the applicator shaft. The tissue repair and sealing device advances along the guidewire to the puncture site, the conical occluder graft passes through the puncture hole and is positioned in contact with the inner surface of the punctured tissue, and the tissue repair and sealing device is deployed by moving the fastener-holding and releasing member toward the distal end of the applicator shaft, releasing the deployable fastener-coupler subassembly (Figure 5F). The deployable fastener is positioned in contact with the outer surface of the tissue and, by applying pressure to the outer surface of the tissue, secures the conical occlusive graft, repairs the puncture wound, and forms a pressure-resistant, watertight seal. The applicator assembly is removed from the removable graft-fastener assembly that remains at the puncture site, and the applicator assembly is removed by sliding along the guidewire, after which the guidewire is removed (Figure 5G). [Figure 5F-G] Same as above. [Figure 6]Figure 6 is a drawing illustrating various freely selectable embodiments of the tissue repair and sealing devices disclosed herein. Figure 6A shows an applicator assembly comprising an applicator shaft and a fastener retainer / release member, the fastener retainer / release member being slidably connected to the applicator shaft. Figure 6B shows a removable graft-fastener assembly comprising a graft subassembly in which a foam ring is bonded to one surface of the graft, the foam ring having sufficient flexibility to allow the graft to fold while being inserted through tissue fenestration and sufficient rigidity to allow the graft to open (and take its original shape) before being placed on the inner surface of the tissue. In some embodiments of this disclosure, which are described in further detail herein, the foam ring comprises a bioabsorbable material. [Figure 7] Figure 7 is a diagram illustrating a freely selectable configuration of the tissue repair and sealing device shown in Figures 1-5, where the applicator assembly (Figure 7A) further comprises an actuator rod attached to one end of the fastener retaining and releasing member, the actuator rod extending beyond the applicator shaft, thereby allowing the fastener retaining and releasing member from the detachable graft-fastener assembly from a considerable distance from the deployable fastener (Figure 7B). [Figure 8] Figure 8 is a drawing showing a freely selectable embodiment of the tissue repair and sealing device shown in Figures 1-4 and 6-7, comprising an applicator assembly (Figure 8A) and a removable graft-fastener assembly (Figure 8B), wherein the removable graft-fastener assembly comprises a graft subassembly including a foam ring fixed and bonded to the graft, the foam ring having sufficient flexibility to allow the graft to fold while being inserted through tissue fenestration and sufficient rigidity to allow the graft to unfold before being placed on the inner surface of the tissue (as shown in Figure 19), the graft spreading beyond the foam ring to improve adhesion of the graft to the inner surface of the tissue. [Figure 9] Figure 9 is a drawing showing the spatial arrangement of components of an exemplary graft subassembly, which includes a foam ring fixed and bonded to the inner surface of the graft. The exemplary foam ring is shown in combination with a ring stabilizing member and a central coupler receiving member. An exemplary graft subassembly is shown with an orifice from which the central coupler receiving member protrudes. [Figure 10] Figure 10 is a diagram showing the spatial arrangement of components of an exemplary removable graft-coupler assembly, which includes a graft subassembly (as shown in Figure 9) attached to a deployable fastener-coupler subassembly. The graft subassembly comprises a graft fixed and bonded to a foam ring having a ring stabilizing member and a central coupler receiving member on its inner surface. In this exemplary removable graft-coupler assembly, the graft extends beyond the outer circumference of the foam ring to improve contact and adhesion with the inner surface of the tissue. A deployable fastener-coupler subassembly is shown, which has a deployable fastener having multiple radial spokes or struts extending from the central coupler. The deployable fastener-coupler subassembly is fixedly attached to the central coupler of the graft subassembly via the central coupler receiving member. [Figure 11] Figure 11 is a diagram showing a deployable fastener / coupler subassembly, with a recess in the central coupler for attaching the center of the deployable fastener / coupler subassembly to the center of the graft subassembly in the central coupler receiving member as shown in Figure 10. [Figure 12] Figure 12 is a drawing showing a typical arrangement of a detachable graft-fastener assembly, which comprises a graft subassembly (with or without a foam ring or one or more ring stabilizing members) and a deployable fastener-coupler subassembly having a central coupler and a deployable fastener having multiple radial spokes or struts extending radially from the central coupler. [Figure 13]Figure 13 is a drawing showing various free-choice configurations of a removable graft-fastener assembly that includes a deployable fastener-coupler subassembly having multiple radial spokes or struts, which allows for the optimization of the deployable fastener-coupler subassembly for use in fastening tissue fenestrations of various sizes and in various different tissues to secure the graft subassembly to the tissue surface in order to ensure the formation of a watertight seal. [Figure 13A] Figure 13A is a drawing showing a removable graft-fastener assembly that includes (1) a graft subassembly with a graft (with or without a foam ring or ring stabilizing member), and (2) a deployable fastener-coupler subassembly having a central coupler and a deployable fastener having six radial spokes or struts. [Figure 13B] Figure 13B is a drawing showing a removable graft-fastener assembly comprising (1) a graft subassembly with a graft (with or without a foam ring or ring stabilizing member), and (2) a deployable fastener-coupler subassembly having a deployable fastener with 12 radial spokes or struts and a central coupler to enhance the force exerted by the deployable fastener when fixing the graft to the tissue surface. [Figure 13C] Figure 13C is a drawing showing a removable graft-fastener assembly comprising (1) a graft subassembly with a graft (with or without a foam ring or ring stabilizing member), and (2) a deployable fastener-coupler subassembly having a deployable fastener with 6 radial spokes or struts and a central coupler, where each radial spoke or strut further comprises a lateral extension to improve the stability of the deployable fastener-coupler subassembly.[Figure 13D] Figure 13D is a drawing showing a removable graft-fastener assembly comprising (1) a graft subassembly having a graft (with or without a foam ring or ring stabilizing member), and (2) a deployable fastener-coupler subassembly having a deployable fastener and a central coupler having six radial spokes or struts, where each radial spoke or strut further comprises two to six lateral extensions to improve the stability of the deployable fastener-coupler subassembly. [Figure 14A-B] Figure 14 illustrates a particular aspect of a removable graft-fastener assembly according to a particular embodiment of the tissue repair and sealing device described herein. Figure 14A is a line drawing showing a removable graft-fastener assembly comprising (1) a graft subassembly having a graft (with or without a foam ring or ring stabilizing member), and (2) a deployable fastener-coupler subassembly having a deployable fastener and a central coupler having six radial spokes or struts, where each radial spoke or strut is fabricated to thicken, curve away from the graft subassembly, and include one or more returns at each end of the radial spoke or strut. Figure 14B is a CAD drawing showing various aspects of the removable graft-fastener assembly shown in Figure 14C. Figures 14D–14F are photographs of prototypes of detachable implant / fastener assemblies according to various embodiments disclosed herein (including those shown in Figures 14A and 14B, which were fabricated using a 3D SLA printer as described in further detail herein). [Figure 14C] Same as above. [Figure 15]Figure 15 is a drawing illustrating the spatial arrangement of components of an exemplary graft subassembly according to an alternative embodiment of the present disclosure, enabling the use of autologous tissue grafts or the surgical replacement of other non-rigid natural or synthetic graft materials in tissue repair and sealing devices. In certain aspects of this embodiment, the graft subassembly comprises a graft having a central orifice at or near its geometric center for receiving a central coupler. The graft is attached to a foam ring across its entire inner surface, the foam ring comprising a plurality of ring stabilizing members extending radially from the central coupler, and graft stabilizing projections for securing the graft subassembly. [Figure 16] Figure 16 is a drawing illustrating the spatial arrangement of components of a particular embodiment of an exemplary removable graft-fastener assembly according to an alternative embodiment of the present disclosure, wherein a second foam ring has a plurality of graft stabilization projection alignment rings radially arranged along its inner outer circumference, and the second foam ring is positioned on the outer surface of the graft to receive graft stabilization projections that protrude from the foam ring and are attached to the inner surface of the graft. [Figure 17] Figure 17 is a drawing showing the spatial arrangement of components of a particular embodiment of an exemplary detachable graft-fastener assembly according to an alternative embodiment of the present disclosure (see Figures 15 and 16), where the deployable fastener comprises a central coupler receiving ring and a plurality of radial spokes or struts extending from the central coupler receiving ring. [Figure 18] Figure 18 is a drawing showing the folding of radial spokes or struts extending from one end of the central coupler receiving member of a deployable fastener / coupler subassembly, which is intended for attachment to an applicator assembly and fastening with a fastener retaining / releasing member, according to the embodiments shown in Figures 15-17. [Figure 19]Figure 19 is a schematic diagram of an alternative embodiment of a tissue repair and sealing device disclosed herein, configured to provide continuous drug delivery to fluids, tissues, or spaces within body cavities, blood vessels, tubules, or other structures within the body. [Figure 20] Figure 20 illustrates an embodiment of a graft assembly, in which the graft comprises multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires, the wires enabling the folding of the metal or metal alloy while retaining the ability to open to its pre-folded state by exhibiting shape memory and superelastic features. Figure 20A illustrates one aspect of this embodiment in which the multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires extend radially from a central coupler. As shown in Figure 20B, the multiple radially biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires allow the graft to fold away from the central coupler in an umbrella or parasol arrangement. As shown in Figure 20C, the multiple radially biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires also allow the graft to be further folded in a helical arrangement to reduce its diameter for insertion into a fastener retaining / releasing member. [Figure 21]Figure 21 illustrates a tissue repair and sealing device of the present disclosure, in which an applicator assembly having (a) an applicator shaft, an elongated fastener retaining / releasing member and an actuator rod is connected to a removable graft-fastener assembly having (b) a graft subassembly and a deployable fastener-coupler subassembly (Figure 21A). According to this embodiment, the removable graft-fastener assembly utilizes a graft assembly as shown in Figure 20, wherein the graft comprises a plurality of biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires, the wires enabling the folding of the metal or metal alloy while retaining the ability to open to a pre-folded state by exhibiting shape memory and superelastic properties. Figure 21B illustrates the tissue repair and sealing device of Figure 21A, in which both the radial strut or spokes and the graft subassembly are folded and inserted into the fastener retaining / releasing member. Figure 21C illustrates further compression of the graft subassembly by folding, allowing the radially biocompatible, non-ferromagnetic passivated metal wire or passivated metal alloy wire to be arranged in a helical configuration, which is beneficial for repairing fenestrations in tissues where space beneath the tissue barrier is limited. [Figure 22A-C]Figure 22 illustrates a method for rapidly repairing tissue fenestrations and forming a pressure-resistant, watertight seal using a tissue repair and sealing device comprising a graft subassembly and a deployable fastener / coupler subassembly, as illustrated in Figures 20A-20C and 21A-21C. These tissue repair and sealing devices offer particular advantages in repairing fenestrated tissue, especially in tissues with small tissue fenestrations and / or brittle nature. In this embodiment, the graft subassembly is configured to comprise multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires that extend radially from the center of the graft and exhibit shape memory and superelastic properties. Thus, the graft subassembly is configured to deform easily to fit within the fastener-retaining / releasing member and to re-expand to its original shape when the fastener-retaining / releasing member is moved inside the tissue. Figure 22A illustrates an exemplary tissue repair and sealing device before deployment. A removable graft-and-fastener assembly is attached to the applicator assembly at the proximal end of the applicator shaft, and the folded radial struts or spokes of a deployable fastener-and-coupler subassembly are held at the proximal end of a fastener-retaining-and-releasing member. Before inserting the graft subassembly through tissue fenestration, the radial struts or spokes of the deployable fastener-and-coupler subassembly are folded away from the graft subassembly along the axis center through the central coupler and inserted into the proximal end of the fastener-retaining-and-releasing member. This embodiment shows an elongated fastener-retaining-and-releasing member for accommodating a graft subassembly including a graft comprising multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires extending radially from the center of the graft, and folded away from the central coupler in an umbrella or parasol arrangement and held by a fastener-retaining-and-releasing member. Figure 22B shows the tissue repair and sealing device from Figures 20A-20C and 21A-21C after the proximal end of the fastener retention and release member and the graft subassembly have passed through tissue fenestration.Figure 22B shows the deployment of the graft subassembly by moving the fastener retaining / releasing member along the applicator shaft toward its distal end and stopping when the proximal end of the fastener retaining / releasing member reaches the outside of the tissue with the fenestration. The graft subassembly is then pulled back so that the graft contacts the inner surface of the tissue with the fenestration, with the deployable fastener / coupler subassembly remaining within the fastener retaining / releasing member outside the tissue with the fenestration. Figure 22D shows the deployable fastener / coupler subassembly released from the fastener retaining / releasing member by sliding the fastener retaining / releasing member toward the distal end of the applicator shaft, thereby releasing the struts or spokes of the deployable fastener, which rapidly return to their original positions and apply pressure against the outer surface of the tissue with the fenestration, thereby securing the graft in the optimal position and sealing the fenestration. Figure 22E illustrates how a detachable graft-fastener assembly is separated from the applicator assembly, and a deployable fastener-coupler assembly is positioned in contact with the tissue's outer surface to secure the graft subassembly to the tissue's inner surface, thereby rapidly repairing tissue fenestration and reliably forming a pressure-resistant, watertight seal. [Figure 22D-E] Same as above. [Figure 23A]Figure 23 illustrates various embodiments of a pressure chamber used to test the physical parameters of a graft subassembly for use in a tissue repair and sealing device according to the present disclosure, the pressure chamber enabling the establishment of internal fluid pressure waves corresponding to fluids in various human body compartments. Figure 23A is a photograph of an in vitro pressure chamber used to test the ability of a graft subassembly for use in a tissue repair and sealing device to maintain a watertight seal at supernormal pressure, and Figure 23B is a CAD drawing thereof. As shown in Figure 23B, the pressure chamber 160 comprises a waveform generator 141, an opening 143 for positioning a graft sample, an acrylic plate 145 for securing the graft sample, a pressure sensor 147, and a water inlet 149. [Figure 23B] Same as above. [Figure 23C] This in vitro pressure chamber enables the generation of internal fluid pressure waves corresponding to fluid pressure waves in various human body compartments. In this example, a pig or sheep dura mater is held between two acrylic plates, with a pressure sensor placed at the opening and embedded to record continuous pressure within the chamber. Waveforms are generated in the chamber's fluid to reproduce the pulsatile pressure waves found in various human tissue compartments. Figure 23C shows the in vivo pressure waveform of human CSF, and Figure 23D shows the in vitro pressure chamber waveform obtained using the pressure chambers shown in Figures 23A-23B. [Figure 23D] Same as above. [Figure 24]Figure 24 is a graph of pressure-resistance data obtained using the in vitro pressure chamber shown in Figure 23, testing a graft subassembly containing DuraSecure graft material. This graph shows typical pressure measurements over time from an in vitro chamber replicating human cerebrospinal fluid (CSF) within the dura mater. In this case, the chamber pressure was first brought to normal human CSF pressure (10 cmH2O), then gradually increased by 2 cmH2O increments until it reached pathologically high pressure (>20 cmH2O), and then maintained for a further 2 minutes without pressure decay, demonstrating a watertight seal. These data demonstrate that this graft subassembly maintained pressure over the time it took to gradually increase from normal pressure for human cerebrospinal fluid (i.e., 10 cmH2O) in vivo, and withstood a high pressure of 25 cmH2O for 2 minutes. [Modes for carrying out the invention]

[0037] Detailed explanation of this disclosure This disclosure provides a tissue repair and sealing device and a method for using it in both MIS and non-MIS procedures to rapidly repair tissue fenestrations and to reliably form a pressure-resistant, watertight seal. In certain embodiments, the tissue repair and sealing device according to this disclosure comprises (1) an applicator assembly having a fastener-retaining and releasing member (having a proximal and distal end) movably connected to an applicator shaft (having a proximal and distal end), and (2) a detachable graft-fastener assembly having a graft subassembly fixedly attached to a deployable fastener-coupler subassembly for positioning a graft subassembly on the inner surface of the tissue and a deployable fastener-coupler subassembly on the outer surface of the tissue. By moving the fastener holding and release member along the applicator shaft toward its distal end, the tissue repair and sealing device is deployed, releasing the deployable fastener and coupler subassembly. This positions the fastener on the outer surface of the tissue and secures the graft to the inner surface of the tissue, thereby achieving rapid repair of tissue fenestration and reliable formation of a pressure-resistant, watertight seal.

[0038] This disclosure will be better understood with respect to the following definitions, which are provided for clarification purposes and are not intended to limit the scope of the subject matter disclosed herein.

[0039] definition Unless otherwise defined herein, each term has the same meaning as it has to those skilled in the art in the relevant field.

[0040] As used herein, the terms “minimally invasive surgery” and “MIS” are used interchangeably to refer to surgical techniques that avoid the use of open invasive surgery, supporting non-surgical or local surgery, which shorten wound healing time, reduce associated pain, and lower the risk of infection compared to conventional “non-MIS” techniques by limiting the size of the incision. MIS techniques (e.g., endoscopy, laparoscopy, arthroscopy) require the use of laparoscopic devices and the operation of those devices remotely while indirectly observing the surgical field through an endoscope or similar device (e.g., neuroendoscopy). MIS procedures include the use of subcutaneous injections and interventional radiology (e.g., angioplasty), coronary catheterization, permanent placement of spinal and brain electrodes, stereotactic brain surgery, Nuss procedures, pneumatic injections, subdermal implants, refractive surgery, percutaneous surgery, cryosurgery, microsurgery, keyhole surgery, and endovascular surgery, as well as radioactivity-based medical imaging techniques (e.g., gamma cameras, positron emission tomography, and SPECT). Related procedures include image-guided surgery and robot-assisted surgery.

[0041] As used herein, the term “tissue barrier” refers to a layer of tissue within the body that separates two compartments of the body. In vivo, the “tissue barrier” functions as both a protective barrier and a gatekeeper between different compartments (e.g., between blood and tissues), and is formed by specialized membrane-bound proteins located on the plasma membrane outside epithelial and endothelial cells. Such barriers prevent the free diffusion of solutes and molecules across the epithelial and endothelial monolayers by blocking paracellular spaces, thereby creating an organ-specific homeostatic environment. Tissue barriers include meninges, dura mater of the nervous system, abdominal wall, fascia, blood vessels, esophagus, oropharynx, stomach, small and large intestines, rectum, trachea, bronchi, heart, bladder, ureters, urethra, uterus, peritoneum, pleura, fallopian tube, sclera of the eye, synovial membrane, tympanic membrane, or capsules of parenchymal organs (e.g., kidneys, liver and pancreas), and tissues containing bodily fluids or spaces enclosed by tissue barriers (blood, cerebrospinal fluid, gastrointestinal contents, pleural cavity, peritoneal cavity, vitreous fluid, inner ear, fallopian tube, or joint cavity).

[0042] As used herein, the term “meninges” refers collectively to the three membranes (dura mater, arachnoid mater, and pia mater) that line the skull and spinal canal, surround the brain and spinal cord, and protect the central nervous system. “Meningitis” is inflammation of the meninges, usually caused by infectious agents.

[0043] As used herein, the terms “dura” and “dura mater” are interchangeable and refer to the outermost layer (i.e., the layer closest to the skull and vertebrae) of the three layers of membranes called meninges (i.e., the meningeal layers), which are made up of dense, irregular connective tissue. The “dura mater” (also known as “pachymeninx”) is primarily derived from a population of neural crest cells, with paraxial mesoderm contributing after birth. The “dura mater” protects the central nervous system by surrounding the brain and spinal cord.

[0044] As used herein, the terms “arachnoid” and “pia mater” refer to the two inner meningeal layers enclosed by the “dura” or “dura mater.” The “arachnoid” is sandwiched between the considerably thick “dura” and the deeper “pia mater.” The “arachnoid” is separated from the “pia mater” by the subarachnoid space and is involved in the retention of cerebrospinal fluid ("CSF") within the subarachnoid space ("SAS"). The “pia mater” is a thin, permeable fibrous tissue that allows blood vessels to pass through to the brain and nourish it. The “arachnoid” and “pia mater” together are known as the “lepimeninges” and have a complex function as barriers and facilitators for the movement of fluids, solutes, and cells on the surface of the CNS, as well as for the movement of fluids and solutes within the parenchyma of the CNS. This is outlined in Weller et al., Acta Neuropathologica 135:363-385 (2018). Both the arachnoid membrane and the pia mater originate from the neural crest.

[0045] As used herein, the term “fenestration” refers to an opening in a body tissue barrier, such as a laceration, tear, puncture, defect, or other tear. Fenestrations can be spontaneous (e.g., cerebrospinal fluid leakage due to a congenital defect); secondary (e.g., damage to the tissue barrier due to a tumor or infection); planned (e.g., an incision or puncture in the outer wall of a blood vessel, dura mater, or body organ); or unplanned (e.g., an accidental dural incision, a tear in the intestine, or a laceration of the wall of a body organ during a surgical procedure). Fenestrations in tissue barriers usually require repair and sealing to prevent serious complications (e.g., infection, bleeding, and wound breakdown). However, in MIS procedures, direct repair and sealing by conventional methods (e.g., suturing or stapling) is severely limited due to the combination of limited workspace and access vectors, restricted field of view, and the nature and robustness of the tissue barrier with the fenestration.

[0046] As used herein, the terms “dural incision,” “unintentional dural incision,” and “accidental dural incision” refer to unintentional tears of the dura mater (dural lacerations) that typically occur during minimally invasive spinal surgery (MIS) procedures performed on the spine (e.g., microscopic lumbar discectomy). The complexity of MIS procedures on the spinal cord contributes to the occurrence of “dural incisions.” Dural incisions require prompt repair and watertight sealing to prevent postoperative complications, including cerebrospinal fluid leakage with subsequent meningitis, or, most commonly, the accumulation of air in the spinal canal in the epidural or subarachnoid space where the surrounding dura mater has been destroyed (i.e., pneumorachis, aerorachia, or epidural emphysema).

[0047] As used herein, the term “graft” generally refers to tissues, membranes, meshes, matrices, etc., that exhibit favorable biophysical properties and are of a size, shape, and other dimensions suitable for adhesion to tissue surfaces, repair of tissue fenestrations, and formation of pressure-resistant watertight seals. “Grafts” may originate from natural sources, such as animal organ tissues and tissue barriers, and grafts include tissues from donors that exhibit a defined genetic relationship to the tissue from the recipient, e.g., autografts (tissue obtained from a patient), syngeneic grafts (tissue obtained from identical twins), allografts (tissue obtained from another person), or xenografts (tissue obtained from a non-human animal species). Such grafts from natural sources may be autologous, allogeneic, or xenografts and may incorporate one or more synthetic materials.

[0048] As used herein, the term “drug-eluting graft” refers to a graft material that incorporates a drug-eluting matrix to provide controlled, localized drug release. (Han and Lelkes, Focal Controlled Drug Delivery, Advances in Delivery Science and Technology (Springer, Boston, 2014)). As used herein, the term “non-absorbable” refers to a material intended for long-term structural use because it is not broken down and absorbed by the body. “Non-absorbable” materials include implanted polymers, such as polyethylene and polyketones (PEEK), and phase-pure tricalcium β-phosphate (TCP) and hydroxyapatite (HA).

[0049] As used herein, the term “bioabsorbable” refers to materials that do not need to be removed manually because they are broken down and absorbed by the body. Bioabsorbable materials include polymers containing biomacromolecules and their copolymers, such as polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC), which can be customized to meet mechanical performance parameters, biocompatibility, and absorption rates.

[0050] As used herein, the terms “passivated metal” or “passivated metal alloy” refer to metals and metal alloys that are more corrosion-resistant and exhibit higher biocompatibility compared to natural metals or metal alloys. Passivation can be achieved by applying a shielding outer layer as a microcoating to the exposed surface of a metal or metal alloy.

[0051] Words and phrases using singular or plural forms also include their singular and plural forms. For example, terms such as "a" or "an," and phrases such as "at least one" and "one or more," include both singular and plural forms. Terms intended to be "open" (including the words "comprise," "comprising," "include," "including," "have," and "having") should be interpreted in an inclusive rather than exclusive or exhaustive sense. That is, the term "including" should be interpreted as "including but not limited to," and "includes" should be interpreted as "including but not limited to." It should be interpreted as "but is not limited to," and "to have ~" should be interpreted as "to have at least ~."

[0052] The use of the term “or” in a claim is used to mean “and / or” unless it is expressly indicated that it refers only to the options, or unless the options are mutually exclusive; however, this disclosure supports the definitions of “and / or” as referring only to the options.

[0053] Furthermore, the terms “in this specification,” “above,” and “below,” as well as words of a similar nature, when used in this Application, refer to the entire Application and not to any particular part thereof.

[0054] Where a feature or aspect of this disclosure is described in terms of a group of Markush members, it will be further understood that this disclosure is also intended to be described in terms of any individual member or subgroup of a member of that group of Markush members. Similarly, all scopes disclosed herein also encompass all possible subscopes and combinations of subscopes, and phrases such as “between,” “maximum,” “at least,” “greater than,” and “less than” include the number described in that scope and each individual member.

[0055] The implementation of this disclosure will involve the adoption of conventional methods and methodologies commonly used in the field of medicine, particularly minimally invasive (MIS) and non-minimally invasive (non-MIS) surgical techniques. Such methods and methodologies are well described in academic papers, medical literature, scientific literature, and patent documents relating to surgical techniques. For example, Hunter and Spight, “Atlas of Minimally Invasive Surgical Operations” (McGraw-Hill Education, Inc., 2018); Jones and Schwaltzberg, “Operative Endoscopic and Minimally Invasive Surgery” (CRC Press, 2019); and Nahai, “The Art of Aesthetic Surgery” (2 nd See Ed., Thieme, 2010.

[0056] All documents cited herein, including but not limited to patents, patent applications and patent publications (whether U.S., PCT, or other foreign), and all technical, medical, and / or scientific publications, whether preceding or following, are incorporated herein by reference in their entirety.

[0057] Tissue repair and sealing devices This specification provides a tissue repair and sealing device that exhibits unexpected and remarkable advantages over devices and technologies currently available in the art for repairing and sealing tissue fenestrations, including tissue fenestrations occurring during minimally invasive surgical (MIS) procedures. During operation, the tissue repair and sealing device of this disclosure fixes the graft to the tissue surface by (1) placing a graft subassembly on the inner surface of the tissue and (2) placing a deployable fastener on the outer surface of the tissue, thereby repairing the tissue fenestration and forming a pressure-resistant, watertight seal.

[0058] In a particular embodiment, the tissue repair and sealing device disclosed herein comprises an applicator assembly having (1) a fastener retaining and releasing member having a proximal and distal end, the fastener retaining and releasing member being movably mounted on an applicator shaft having a proximal and distal end, and (2) a detachable graft-fastener assembly having a graft subassembly fixedly mounted at or near the geometric center of a fastener-coupler subassembly that is deployable via a central coupler at or near the geometric center (also known as the centroid) of a deployable fastener.

[0059] Certain embodiments of the tissue repair and sealing devices disclosed herein utilize a removable graft-fastener assembly comprising a deployable fastener-coupler subassembly having a central coupler and a deployable fastener having a plurality of radial struts or spokes extending from the central coupler at or near the geometric center of the removable graft-fastener assembly. In certain embodiments of these embodiments, the removable graft-fastener assembly is attached to the applicator assembly via the central coupler at the proximal end of the applicator shaft. In further embodiments, the device is deployed by sliding a fastener retaining / releasing member along the applicator shaft toward its distal end, thereby releasing the fastener from the retaining / releasing member. In even further embodiments, once the device is deployed, the fastener secures the graft to the inner surface of the tissue and the fastener secures the outer surface of the tissue, thereby repairing tissue fenestration and forming a pressure-resistant, watertight seal.

[0060] During operation, the tissue repair and sealing device disclosed herein allows (1) the placement of a graft subassembly on the inner surface of the tissue, and (2) the placement of a deployable fastener / coupler subassembly on the outer surface of the tissue. Before use, the detachable graft / fastener assembly is attached to the applicator assembly via a central coupler at the proximal end of the applicator shaft. The radial spokes or struts of the deployable fastener are folded away from the graft subassembly and inserted into the proximal end of the fastener retaining / releasing member to hold the deployable fastener in place. The graft subassembly is inserted through the tissue fenestration using the applicator assembly, and the deployable fastener / coupler assembly is placed on the inner surface of the tissue, while the fenestration remains outside the tissue. The tissue repair and sealing device is deployed by moving the fastener holding and release member toward the distal end of the applicator shaft, thereby releasing the deployable fastener. This opens the deployable fastener, applying pressure to the outer surface of the tissue and securing the graft subassembly to the inner surface of the tissue, thereby enabling rapid repair of tissue fenestration and ensuring the formation of a pressure-resistant, watertight seal.

[0061] Further modifications to tissue repair and sealing devices to address specific technical issues encountered in MIS surgery are described herein. These include (1) changes in the size and shape of the graft subassembly and the deployable fastener / coupler subassembly; (2) changes in the materials used for the graft subassembly and the deployable fastener / coupler subassembly; (3) rotation of the connecting component so that the graft is oriented so as not to be perpendicular to the applicator shaft, thereby improving the line of sight visualization of fenestration during graft insertion; (4) arrangements that enable the use of the tissue repair and sealing device in endoscopic or percutaneous procedures (e.g., the use of a conical graft element and a flexible applicator assembly having a channel for accommodating a guidewire); and (5) incorporating a drug-eluting matrix material in place of or in combination with the graft component to provide continuous drug delivery at the application site.

[0062] A deployable device is illustrated herein, comprising a deployable fastener having multiple flexible spokes or struts extending radially from a coupler, wherein the deployable fastener exhibits biophysical properties, size, shape and dimensions suitable for securing a graft positioned on the inner surface of tissue and a fastener positioned on the outer surface of tissue, thereby repairing tissue fenestrations and forming a pressure-resistant, watertight seal.

[0063] Figure 1 illustrates an exemplary tissue repair and sealing device according to one embodiment of the present disclosure. Figure 1A shows an applicator assembly 20 comprising a fastener retainer / release member 35 having a proximal end 37 and a distal end 39, the fastener retainer / release member 35 being slidably connected to an applicator shaft 25 having a proximal end 27 and a distal end 29. Figure 1B shows a detachable graft-fastener assembly 50 comprising a graft subassembly 55 and a deployable fastener-coupler subassembly 65, the deployable fastener-coupler subassembly 65 comprising a central coupler 67 for attaching the detachable graft-fastener assembly 50 to the applicator assembly 20 at the proximal end 27 of the applicator shaft 25, and radial spokes or struts 77.

[0064] The removable graft-and-fastener assembly 50 shown in Figure 1 is configured to position the graft subassembly 55 on the inner surface of the tissue and the deployable fastener-and-coupler subassembly 65 on the outer surface of the tissue. The tissue repair and sealing devices according to these embodiments are deployed by sliding the fastener-holding-and-releasing member 35 toward the distal end 29 of the applicator shaft 25, thereby releasing the deployable fastener-and-coupler subassembly 65 from the proximal end 37 of the fastener-holding-and-releasing member 35. The graft subassembly 55 is fixed to the inner surface of the tissue and the coupler subassembly 65 to the outer surface of the tissue via the deployable fastener, thereby repairing tissue fenestration and forming a pressure-resistant, watertight seal.

[0065] In a particular embodiment of the embodiment shown in Figure 1, the applicator shaft 25 is a flattened, bayonetted, and / or cylindrical applicator shaft. In another embodiment of the embodiment shown in Figure 1, the fastener retaining / releasing member 35 is a cylindrical fastener retaining / releasing member having a proximal end 37 and a distal end 39, where the proximal end 37 is configured to receive and hold a deployable fastener / coupler subassembly 65 in a folded position (shown in Figure 3). In a further embodiment of the embodiment shown in Figure 1, the graft subassembly 55 comprises an integrated graft. In yet another embodiment of the embodiment shown in Figure 1, the deployable fastener / coupler subassembly 65 is fabricated from one or more bioabsorbable materials.

[0066] During use, the graft subassembly is selected based on a visual assessment of the size of the tissue fenestration and the physical characteristics of the surrounding tissue (e.g., brittleness). The graft subassembly 55 is inserted through the tissue fenestration into the space inside the tissue barrier and pulled back against the inner surface of the tissue. The deployable fastener / coupler subassembly 65 is released from the applicator assembly 20 by sliding the fastener retaining / releasing member 35 toward the distal end 29 of the applicator shaft 25, thereby contacting the outer surface of the tissue and fixing the graft subassembly 55 to the inner surface of the tissue, repairing the tissue fenestration and forming a pressure-resistant, watertight seal.

[0067] Figure 2 illustrates the spatial arrangement of components of an exemplary detachable graft-fastener assembly 50, where the graft subassembly 55 is fixedly attached at its center 59 to the deployable fastener-coupler subassembly 65 at the proximal end 69 of the central coupler 67. Figure 2 shows a particular embodiment of the exemplary detachable graft-fastener assembly 50, which includes a deployable fastener-coupler subassembly 65 having a plurality of struts or spokes 77 extending radially from the proximal end 69 of the central coupler 67, each in contact with the inner surface of the graft 57 and optionally extending beyond the outer edge of the graft subassembly 55.

[0068] Figure 3A illustrates the retention of the radial struts or spokes 77 of the deployable fastener / coupler subassembly 65 (shown in Figures 1 and 2) at the proximal end 37 of the fastener retaining / releasing member 35. The deployable fastener / coupler subassembly 65 folds at each of the multiple radial struts or spokes 77 that extend radially from the distal end 71 of the central coupler 67. The folded radial struts or spokes 77 of the deployable fastener / coupler subassembly 65 are inserted into the proximal end 37 of the fastener retaining / releasing member 35, thereby holding the deployable fastener / coupler subassembly 65 in its folded position until the tissue repair / sealing device is deployed.

[0069] Figures 3B–3E illustrate the use of a tissue repair and sealing device for rapidly repairing tissue fenestrations and forming a pressure-resistant, watertight seal, comprising (a) an applicator assembly 20 having a fastener retaining / releasing member 35 movably mounted on an applicator shaft 25 and an actuator rod 45, and (b) a removable graft-fastener assembly 50 having a graft subassembly 55 fixedly mounted to a deployable fastener-coupler subassembly 65 having a central coupler 67 and a plurality of radial struts or spokes 77, as illustrated in Figures 1 and 2. Figure 3B shows the tissue repair and sealing device before insertion of the graft subassembly 55 through the tissue fenestration. The tissue repair and sealing device comprises an applicator assembly mounted on a removable graft-fastener assembly, where the struts or spokes 77 of the deployable fastener-coupler subassembly are folded away from the graft subassembly and inserted into the proximal end of the fastener retaining / releasing member 35.

[0070] Figure 3C shows the tissue repair and sealing device of Figure 3B after insertion of the graft subassembly 55 through the tissue fenestration. Before the tissue repair and sealing device is deployed, the graft subassembly 55 is positioned on the inner surface of the tissue, with the deployable fastener / coupler subassembly remaining outside the tissue with the fenestration.

[0071] Figure 3D shows the deployment of the tissue repair and sealing device by using an actuator rod 45 to slide the fastener holding and release member 35 toward the distal end 29 of the applicator shaft 25, thereby releasing the deployable fastener strut or spoke 77.

[0072] Figure 3E shows how tissue fenestration is repaired and a pressure-resistant, watertight seal is formed by separating the detachable graft-fastener assembly from the applicator assembly, positioning the deployable fastener-coupler assembly in contact with the tissue's outer surface, and securing the graft subassembly to the tissue's inner surface.

[0073] Figures 3F and 3G are photographs of exemplary deployable fastener / coupler prototypes according to the embodiments shown in Figures 3A-3E, fabricated from polyglycolic acid using a 3D stereolithography (SLA) printer with a resolution of 25-50 microns. Figure 3F shows a prototype of a deployable fastener 65 and central coupler 67 having struts or spokes 77 in an open arrangement, while Figure 3G shows a deployable fastener / coupler 65 in a closed arrangement, with multiple radial struts or spokes 77 folded for insertion into the proximal end of the fastener retaining / releasing member.

[0074] Figure 4 illustrates a freely selectable configuration of various tissue repair and sealing devices disclosed herein, in which a central coupler 67 is configured to be rotatably attached to a deployable fastener 75 having a plurality of radial struts or spokes 77, thereby enabling angular rotation of the graft subassembly 55. In one exemplary embodiment shown in Figure 4B, the central coupler 67 is fabricated in a ball-and-socket arrangement that allows the detachable graft-fastener assembly 50 to be oriented over a range of angles with respect to the applicator shaft 25 of the applicator assembly 20 (Figure 4A) in order to rotate the detachable graft-fastener assembly 50, which may be required during MIS procedures (where access and visibility are restricted).

[0075] Figure 5 illustrates embodiments of the tissue repair and sealing device of the present disclosure configured for use in surgical procedures (e.g., lumbar puncture and gastrostomy) to seal the site of large-diameter needle puncture or percutaneous fistula creation. Figure 5A shows a tissue repair and sealing device comprising (a) an applicator assembly 20 having an applicator shaft 25 and a movable-mounted fastener-retaining-release member 35, and (b) a removable graft-fastener assembly 50 having a graft subassembly 55 fixedly attached to a deployable fastener-coupler assembly 65, wherein the graft 57 is a conical occluding graft, the applicator shaft 25 is made of a flexible material, and the applicator shaft 25, central coupler 67 and graft 57 are configured to have a central channel 123 for housing a guidewire. In certain embodiments, the conical occluding graft 57 comprises a bioabsorbable material. Figure 5B shows the deployment of a tissue repair and sealing device according to the embodiment shown in Figure 5A, in which a conical occluding graft 57 is positioned on the inner surface of the tissue, and radial struts or spokes 77 of a deployable fastener 75 are positioned on the outer surface of the tissue, thereby applying pressure to the outer surface of the tissue to fix the conical occluding graft 57, thereby repairing the tissue fenestration (i.e., the puncture wound or fistula site) and forming a pressure-resistant, watertight seal.

[0076] Figure 6 illustrates a freely selectable embodiment of various tissue repair and sealing devices disclosed herein, in which a removable graft and fastener assembly 50 comprises a graft subassembly 55 including a foam ring 61 fixed to and bonded to a graft 57, the foam ring 61 having sufficient flexibility to allow the graft 57 to fold while being inserted through the tissue fenestration, and having sufficient rigidity to allow the graft 57 to open after passing through the tissue fenestration to be positioned on the inner surface of the tissue. In some embodiments of this disclosure, the foam ring 61 comprises a bioabsorbable material.

[0077] Figure 7 illustrates an optional embodiment of the tissue repair and sealing device shown herein, including Figures 1-4 and 6, the tissue repair and sealing device comprising an applicator assembly 20 (Figure 7A) and a removable graft-fastener assembly 50 (Figure 7B), the applicator assembly 20 further comprising an actuator rod 45 having a proximal end 47 and a distal end 49, the actuator rod 45 being attached at its proximal end 47 to the distal end 39 of a fastener retaining / releasing member 35. During operation, the actuator rod 45, extending beyond the distal end 29 of the applicator shaft 25, allows the radial spokes or struts 77 (as shown in Figure 3) of a deployable fastener 75 to be released from the proximal end 37 of the fastener retaining / releasing member 35 from a considerable distance from the removable graft-fastener assembly.

[0078] Figure 8 illustrates a freely selectable embodiment of the tissue repair and sealing device shown herein, including Figures 1-4 and 6-7, the tissue repair and sealing device comprising an applicator assembly 20 (Figure 8A) and a removable graft-fastener assembly 50 (Figure 8B), the removable graft-fastener assembly 50 comprising a graft subassembly 55 including a foam ring 61 fixed and bonded to the graft 57, the foam ring 61 having shape memory and superelastic properties sufficient to allow the graft 57 to fold while being inserted through tissue fenestrations and sufficient to allow the graft 57 to unfold (as shown in Figures 3B-3E) after passing through tissue fenestrations to position on the inner surface of the tissue, the graft 57 spreading beyond the foam ring 61 to improve adhesion of the graft 57 to the inner surface of the tissue.

[0079] Figure 9 illustrates the spatial arrangement of components of an exemplary graft subassembly 55, which includes a foam ring 61 fixedly bonded to the inner surface 91 of the graft 57. The exemplary foam ring 61 is shown in combination with a ring stabilizing member 62 and a graft stabilizing projection 63. The exemplary graft subassembly 55 also shows an orifice 60 from which the graft stabilizing projection 63 protrudes.

[0080] Figure 10 illustrates the spatial arrangement of components of an exemplary removable graft-coupler assembly 50, which includes a graft subassembly 55 (as shown in Figure 9) attached to a deployable fastener-coupler subassembly 65. As shown in Figure 10, the graft subassembly 55 includes a graft 57 fixed and bonded to a foam ring 61, a foam ring stabilizing member 62, and graft stabilizing projections 63 on its inner surface. In this exemplary removable graft-coupler assembly 50, the graft 57 extends beyond the outer periphery of the foam ring 61 to improve contact and adhesion to the inner surface of the tissue. A deployable fastener-coupler subassembly 65 is shown, which has a deployable fastener 75 having multiple radial spokes or struts 77 extending from the proximal side 69 of a central coupler 67. The deployable fastener-coupler subassembly 65 is fixed and attached to the graft subassembly 55 via the graft stabilizing projections 63 on the proximal side 69 of the central coupler 67 (shown in Figure 11).

[0081] Figure 11 shows a diagram of the deployable fastener / coupler subassembly 65, with the center of the deployable fastener / coupler subassembly 65 showing a recess 70 in the proximal side 69 of the central coupler 67 for mounting to the center of the graft subassembly 55 at the graft stabilizing projection 63 as shown in Figure 10.

[0082] Figure 12 illustrates a typical configuration of a removable graft-fastener assembly 50, comprising a graft subassembly 55 (with or without a foam ring 61 or ring stabilizing member 62) and a deployable fastener-coupler subassembly 65 having a central coupler 67 and a deployable fastener 75 having multiple radial spokes or struts 77 extending radially from the central coupler 67. Thanks to the various sizes, shapes, and materials used in the fabrication of the graft subassembly 55 and the deployable fastener-coupler subassembly 65, a selection of removable graft-fastener assemblies is possible, where the graft subassembly 55 can safely pass through tissue fenestration, completely cover the defect on the inner surface of the tissue, and exhibit desirable bioabsorption capacity, drug elution, and other biophysical properties for repairing tissue fenestration and forming a pressure-resistant watertight seal.

[0083] Regardless of the size, shape, and material used in the graft subassembly 55 and the deployable fastener / coupler subassembly 65, the detachable graft / fastener assembly 50 is designed to be interchangeably attached to the applicator assembly 20 at the proximal end 27 of the applicator shaft 25, and each of the detachable graft / fastener assemblies 50 is configured to be held by a fastener retaining / releasing member 35 of the applicator assembly 20 (as depicted herein), and to be released from the fastener retaining / releasing member 35 when the applicator assembly 20 is deployed.

[0084] Those skilled in the art will understand that the interchangeability of the detachable graft-and-fastener assembly 50 allows surgeons to quickly assess the suitability of various graft subassemblies for repairing a given tissue fenestration when placing the graft subassembly 55 on the tissue surface and the deployable fastener-and-coupler subassembly 65 on the tissue surface during a surgical procedure.

[0085] Figure 13 illustrates various free-choice arrangements of a removable graft fastener assembly 50, which includes a deployable fastener coupler subassembly 65 having multiple radial spokes or struts 77 (e.g., ranging from 6 radial spokes or struts to 12 radial spokes or struts) to enable optimization of the deployable fastener coupler subassembly 65 for use in securing the graft subassembly 55 to the tissue surface in order to rapidly repair tissue fenestrations of various sizes in various different tissues and thereby ensure the formation of a pressure-resistant watertight seal.

[0086] Figure 13A illustrates a removable graft-fastener assembly 50 comprising (1) a graft subassembly 55 having a graft 57 (with or without a foam ring 61 or ring stabilizing member 62), and (2) a deployable fastener-coupler subassembly 65 having a central coupler 67 and a deployable fastener 75 having six radial spokes or struts 77.

[0087] Figure 13B illustrates a removable graft-fastener assembly 50 comprising (1) a graft subassembly 55 having a graft 57 (with or without a foam ring 61 or ring stabilizing member 62), and (2) a deployable fastener-coupler subassembly 65 having a deployable fastener 75 with 12 radial spokes or struts 77 and a central coupler 67, which may be required in situations where there is a large pressure difference between compartments on the inside and outside of the tissue having fenestrations, thereby increasing the force exerted by the deployable fastener 75 when fixing the graft 57 to the inner surface of the tissue.

[0088] Figure 13C illustrates a removable graft-fastener assembly 50 comprising (1) a graft subassembly 55 having a graft 57 (with or without a foam ring 61 or ring stabilizing member 62), and (2) a deployable fastener-coupler subassembly 65 having a deployable fastener 75 having six radial spokes or struts 77 and a central coupler 67, wherein each radial spoke or strut 77 further comprises a lateral extension 79 that improves the stability of the deployable fastener-coupler subassembly 65, which may be required when the fenestrated tissue is brittle or exhibits multiple fenestrations at the attachment site.

[0089] Figure 13D illustrates a removable graft-fastener assembly 50 comprising (1) a graft subassembly 55 having a graft 57 (with or without a foam ring 61 or ring stabilizing member 62), and (2) a deployable fastener-coupler subassembly 65 having a deployable fastener 75 having six radial spokes or struts 77 and a central coupler 67, wherein each radial spoke or strut 77 further comprises two to six lateral extensions 79 that improve the stability of the deployable fastener-coupler subassembly 65, which may be required when the fenestrated tissue is brittle or exhibits multiple fenestrations at the attachment site.

[0090] Figure 14A illustrates a removable graft-fastener assembly 50 comprising (1) a graft subassembly 55 having a graft 57 (with or without a foam ring 61 or ring stabilizing member 62), and (2) a deployable fastener-coupler subassembly 65 having a deployable fastener 75 having six radial spokes or struts 77 and a central coupler 67, wherein each of the radial spokes or struts 77 is fabricated to be thicker, curve away from the graft subassembly 55, and include a return 81 at the distal end 80 of each radial spoke or strut 77 in order to improve adhesion of the structure to the underlying tissue. Figure 14B is a CAD drawing of a removable graft-fastener assembly 50 (as illustrated in Figure 14A) which has arched spokes or struts and a dura mater lock channel and can be fabricated from PLGA or other suitable biocompatible and / or bioresorbable material exhibiting one or more of the desired mechanical properties shown in Table 1. It will be recognized by those skilled in the art that increasing the thickness and curvature of the radial spokes or struts 77 and / or adding the return 81 may be beneficially employed in less collatenous tissues with fenestrations (e.g., intestinal mucosa) (in which tissue the curved struts exert greater pressure against the tissue outer surface, and the return 81 allows the strut tips of the radial spokes or struts 77 to slightly penetrate the tissue at the application site). Figure 14C is an exemplary removable graft-curved fastener assembly 50 fabricated using PLGA with a 3D printer.

[0091] Figure 15 illustrates the spatial arrangement of components of an exemplary graft subassembly 55 according to an alternative embodiment of the present disclosure, which allows for the use of autologous tissue grafts or the replacement of other non-rigid natural or synthetic graft materials in tissue repair and sealing devices during surgery. With non-rigid grafts, particularly autologous grafts, it can be difficult to precisely position the graft 57 in contact with the inner surface of the tissue having a fenestration and to completely cover the entire opening, as the graft 57 may fold or deform after passing through the fenestration.

[0092] In certain aspects of this embodiment, the graft subassembly 55 comprises a graft 57 having a central orifice 60 at or near its geometric center for receiving a central coupler 67. The graft 57 is attached to a foam ring 61 over its entire inner surface 91, the foam ring 61 comprising a plurality of ring stabilizing members 62, each of which (1) extends radially from the central coupler 67, and (2) each of which has a graft stabilizing projection 64 at its distal end. It will be understood that the foam ring 61 is flexible enough to allow the graft 57 to fold while passing through tissue fenestration, and rigid enough to return to its original flat shape so that the graft 57 can be positioned on the inner surface of the tissue.

[0093] Figure 16 illustrates the spatial arrangement of components in a particular embodiment of an exemplary detachable graft-fastener assembly 50 according to an alternative embodiment of the present disclosure, in which a second foam ring 61 has a plurality of graft stabilization projection alignment rings 68 radially arranged along its inner outer circumference, and the second foam ring 61 is positioned on the outer surface 92 of the graft 57 so as to receive graft stabilization projections 64 that project from the foam ring 61 and adhere to the inner surface 91 of the graft 57.

[0094] Figure 17 illustrates the spatial arrangement of components in a particular embodiment of an exemplary detachable graft-fastener assembly 50 according to an alternative embodiment of the present disclosure (see Figures 15 and 16), where the deployable fastener 75 comprises a central coupler receiving ring 95 and a plurality of radial spokes or struts 77, each having a distal end 80 extending from the central coupler receiving ring 95.

[0095] The removable graft-fastener assemblies 50 shown in Figures 15-17 find particular utility in the form of the tissue repair and sealing devices of this disclosure in clinical applications where it is desirable to replace one graft 57 (e.g., a first graft 57 containing autologous, allogeneic, xenogeneic, or synthetic graft material) with a second graft 57 (e.g., a second graft 57 containing autologous, allogeneic, xenogeneic, or synthetic graft material) during the course of a surgical procedure. Autologous grafts may include, for example, patient tissue collected concurrently with the surgical procedure. Thus, the graft subassembly 55 may use a graft 57 fabricated from tissue collected from the patient's fascia, cranial periosteum, mucosa, or skin. Alternatively, the graft 57 may include allogeneic, xenogeneic, or synthetic graft material that can be replaced in the device in the manner described for autologous grafts, depending on the clinical situation.

[0096] When in use, the graft 57 is cut into a circular shape and formed to have a central orifice 60 to accommodate a passage for the central coupler 67 passing through the center of the graft 57. The graft is then attached to a foam ring 61 having a plurality of graft stabilizing protrusions 64 on the outer circumference of its inner surface 91. A second foam ring 61 having a plurality of graft stabilizing protrusion alignment rings 68 is attached to the outer surface 92 of the graft along its outer circumference. A deformable fastener 75 is then positioned on the second foam ring 61, thereby securing the deformable fastener 75 to the central coupler 67 in the central coupler receiving member 101.

[0097] Figure 18 illustrates the folding of radial spokes or struts 77 that extend from the central coupler receiving member 101 to the proximal end of a deployable fastener / coupler subassembly 65, in preparation for attachment to the applicator assembly 20 and fastening with the fastener retaining / releasing member 35.

[0098] Figure 19 is a schematic diagram of an alternative embodiment of a tissue repair and sealing device disclosed herein, configured to provide continuous drug delivery into bodily fluids, tissues, or spaces within a body cavity, blood vessel, lumen, or other structure within the body. In this embodiment, the graft 57 is replaced by or incorporates a drug-eluting matrix (e.g., a bioabsorbable drug-eluting matrix for delivering a drug or active substance to the tissue surface and / or for continuous release into blood, bodily fluids, or tissue parenchyma in contact with the matrix).

[0099] Figure 20 illustrates an embodiment of a graft assembly 55, in which the graft 57 comprises multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64, the wires exhibiting shape memory and superelastic properties, thereby enabling the graft 57 to fold while retaining its ability to open to its pre-folded state. Figure 20A illustrates one aspect of this embodiment in which the multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64 extend radially from a central coupler 67. As shown in Figure 20B, the multiple radially extending biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64 allow the graft 57 to fold away from the central coupler 67 in an umbrella or parasol configuration. As shown in Figure 20C, the multiple radially biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64 also allow the implants 57 to be further (or alternatively) folded in a helical arrangement to reduce their diameter for insertion into the fastener retaining / releasing member 35.

[0100] Figure 21A illustrates a tissue repair and sealing device of the present disclosure, in which an applicator assembly 20 having (a) an applicator shaft 25, an elongated fastener retaining / releasing member 35 and an actuator rod 45 is connected to (b) a removable graft-fastener assembly 50 having a graft subassembly 55 and a deployable fastener-coupler subassembly 65. According to this embodiment, the removable graft-fastener assembly 50 uses a graft assembly 55 as shown in Figure 20, where the graft 57 comprises a plurality of biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64, the wires enabling the folding of their metal or metal alloy while retaining the ability to open to a state before folding by exhibiting shape memory and superelastic features. Figure 21B illustrates the tissue repair and sealing device of Figure 21A, in which both the radial strut or spoke 77 and the graft subassembly 55 are folded and inserted into the fastener retaining / releasing member 35. Figure 21C illustrates further compression of the graft subassembly 55 by folding, allowing the non-ferromagnetic passivated metal wire or passivated metal alloy wire 64 to be arranged in a helical configuration with radial biocompatibility, which is beneficial for repairing fenestrations in tissues where space beneath the tissue barrier is limited.

[0101] 1. Grafts for use in tissue repair and sealing devices In certain embodiments, the tissue repair and sealing devices disclosed herein comprise a graft that is directly incorporated into (i.e., “integrated) with) a removable graft-fastener assembly, or a graft that is replaced surgically using a foam ring as described herein. The tissue repair and sealing devices according to this disclosure may employ a fixed central coupler that maintains the removable graft-fastener assembly in an orientation perpendicular to the applicator assembly, or an adjustable central coupler that allows movement of the removable graft-fastener assembly relative to the applicator assembly for use in tissue fenestration and improved visibility of nearby structures.

[0102] As used herein, the term “graft” generally refers to tissues, membranes, meshes, matrices, etc., that exhibit favorable biophysical properties and are of a size, shape, and other dimensions suitable for adhesion to tissue surfaces, repair of tissue fenestrations, and formation of pressure-resistant watertight seals. “Grafts” may originate from natural sources, such as animal organ tissues and tissue barriers, and grafts include tissues from donors that exhibit a defined genetic relationship to the tissue from the recipient, e.g., autografts (tissue obtained from a patient), syngeneic grafts (tissue obtained from identical twins), allografts (tissue obtained from another person), or xenografts (tissue obtained from a non-human animal species). Such grafts from natural sources may be autologous, allogeneic, or xenografts and may incorporate one or more synthetic materials.

[0103] As used herein, the term “synthetic mesh” refers to grafts made from non-biological materials, including poly(ethylene terephthalate) (also known as Dacron®) or expanded polytetrafluoroethylene (ePTFE, Goretex®), as described in Patera and Schoen, Biomaterials Science pp.470-494 (Elsevier Academic Press, San Deieto, CA (2004)). “Synthetic mesh” is often permanent, non-absorbable, and associated with chronic inflammation and foreign body reactions, stiffness and fibrosis, and infection. Schmatz, Cureus 10(1):e2127 (2018) provides a report on surgical experience with FDA-approved synthetic bioabsorbable graft materials.

[0104] As used herein, the term “biological mesh” refers to a graft derived from animal tissue, typically human or porcine dermis, processed into a cell-free, porous extracellular matrix skeleton of collagen and elastin. “Biological mesh” often contains tissue-derived growth factors that attract endothelial cells and fibroblasts, and releases further chemotaxis that signal the migration of other structural cells. The three-dimensionality and porosity of “biological mesh” allow cells (primarily fibroblasts and inflammatory cells) to invade, adhere to, and undergo a remodeling cycle consisting of degradation of the biological mesh and regeneration of the collagen skeleton by the host tissue. The balance of this degradation and reconstruction process, and the rate at which it occurs, influences the final strength and structure of the repaired tissue. “Biological mesh” can be crosslinked to increase the stiffness of the graft; however, greater cell infiltration is usually observed in uncrosslinked biological mesh. Crosslinking can also prevent collagen degradation and inhibit macrophage migration (which poses and increases the risk of infection).

[0105] As used herein, the term “dural substitute” refers to a synthetic or biological graft used to seal dural tissue fenestrations by absorbing and integrating with the patient’s tissue in order to prevent CSF leakage and enable healing of dural openings after surgery. Examples of “dural substitutes” that may be usefully used in the tissue repair and sealing devices disclosed herein include Duraform® dural graft implants (Natus, Medical Inc., Middleton, WI), a high-tensile-strength, collagen-based biocompatible material manufactured from processed bovine tendon; and Biodesign® Dural Graft, which utilizes the natural extracellular matrix (ECM) derived from the submucosa (SIS) of the porcine small intestine. Examples include Duraplasty graft (Cook Medical, Bloomington, IN); DuraGen® Matrix (Integra LifeSciences, Princeton, NJ), a collagen matrix; Cerafix dural graft®, a synthetic absorbent material; PRECLUDE Dura Substitute®, an inert elastomer fluoropolymer (ePTFE); Lyoplant Onlay Graft®, an absorbent collagen bilayer; Neuro-Patch Dural Graft®, a microporous fleece; SEAMDURA®, a copolymer membrane with layered PGA; and Durepair® Regeneration Matrix (Medtronic, Minneapolis, MN), a non-synthetic collagen matrix derived from type III bovine fetal tissue.

[0106] As used herein, the term “drug-eluting graft” refers to a graft material that incorporates a drug-eluting matrix to provide controlled, localized drug release. (Han and Lelkes, Focal Controlled Drug Delivery, Advances in Delivery Science and Technology (Springer, Boston, 2014)). As used herein, the term “non-absorbable” refers to a material intended for long-term structural use because it is not broken down and absorbed by the body. “Non-absorbable” materials include implantable polymers, such as polyethylene and polyketones (PEEK), and phase-purity tricalcium β-phosphate (TCP) and hydroxyapatite (HA).

[0107] In one embodiment, the unsupported graft material is not only flexible enough to pass through the tissue defect, but also rigid enough to maintain its shape during placement. In another embodiment, a thin bioabsorbable foam ring is bonded to the outer circumference of the graft 5, which is flexible enough to deform as it passes through the defect and then return to its original shape on the inner surface of the tissue. A connecting component 6 is attached to the center of the graft, allowing for the attachment and detachment of the applicator shaft.

[0108] In certain deployable devices according to these embodiments, the deployable fastener is made from a flexible, bendable, and compressible material. In further embodiments, the flexible, bendable, and compressible material is a bioabsorbable material comprising one or more biopolymers, including one or more biopolymers selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC).

[0109] A deployable device is illustrated herein that comprises a deployable fastener having multiple flexible spokes or struts extending radially from a coupler, the deployable fastener exhibiting biophysical properties, size, shape and dimensions suitable for repairing tissue fenestration and forming a pressure-resistant, watertight seal by securing a graft positioned on the inner surface of the tissue to a fastener positioned on the outer surface of the tissue.

[0110] In certain deployable devices according to these embodiments, the graft comprises a flexible, bendable, rigid, and compressible material. In some embodiments of these embodiments, the graft exhibits shape memory and superelastic properties. When used in combination with a deployable fastener, the graft according to these embodiments is suitably used for repairing tissue fenestrations and forming a pressure-resistant, watertight seal, when the graft is positioned on the inner surface of the tissue and secured to the outer surface of the tissue using the deployable fastener.

[0111] In certain embodiments, the grafts according to these embodiments may be autologous grafts, syngeneic grafts, allogeneic grafts, or xenografts. In other embodiments, the graft comprises tissue, membrane, mesh, or matrix. In further embodiments, the graft comprises material that is autologous, allogeneic, or heterogeneous. In yet another embodiment, the graft comprises one or more synthetic materials, including one or more synthetic materials selected from the group consisting of poly(ethylene terephthalate) and stretched polytetrafluoroethylene (ePTF). In yet another embodiment, the graft comprises material derived from animal tissue, e.g., animal tissue selected from the group consisting of human tissue, bovine tissue, and porcine tissue, or animal tissue selected from the group consisting of dermis and intestine. The grafts according to these embodiments may comprise a cell-free, porous extracellular matrix skeleton of collagen, elastin, and optionally growth factors. In some embodiments, the grafts according to these embodiments comprise a mesh having sufficient porosity to allow cells to enter, adhere, and undergo a remodeling cycle.

[0112] In other embodiments, the grafts according to these embodiments are made from a flexible, pliable, rigid, compressible material, which is a bioabsorbable material, including bioabsorbable materials that contain one or more biopolymers (for example, biopolymers selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC)).

[0113] In further embodiments, the grafts according to these embodiments are dura mater substitutes, such as Duraform® dural graft implants, Biodesign® Dural Graft, DuraGen® Matrix, Cerafix dural graft®, PRECLUDE®, and Lyoplant. This includes dura mater substitutes selected from the group consisting of Onlay Graft®, Neuro-Patch Dural Graft®, SEAMDURA®, and Durepair® Regeneration Matrix.

[0114] The devices and methods described herein may be applied to the direct, percutaneous, or endoscopic repair and sealing of multiple tissues within the body. Furthermore, the devices and methods described herein may be modified to address issues specific to the nature, condition, and surgical exposure of tissues having fenestrations, such as changes in the material and orientation of the fasteners, components that allow for substitution with different graft materials during surgery, changes in the size and shape of the graft-fastener units, and percutaneous or endoscopic repair and sealing of puncture wounds or fistula sites using flexible applicators with or without guidewires.

[0115] Before using the repair and sealing device, the deployable fastener is folded and inserted into a slidably mounted fastener retaining and releasing member. After positioning the graft on the tissue inner surface of the tissue with the fenestration and the fastener on the tissue outer surface, the device is deployed by sliding the fastener retaining and releasing member along the applicator shaft toward its distal end. Once the device is deployed, the struts or spokes of the fastener are released from the fastener retaining and releasing member and come into contact with the tissue outer surface of the tissue with the fenestration, thereby securing the graft and fastener in place, repairing the tissue fenestration, and forming a watertight seal.

[0116] Further modifications to tissue repair and sealing devices addressing specific technical challenges encountered in MIS surgery are described herein. These include modifications to the size and shape of the graft-fastener unit, rotational attachment in coupling devices that allow the graft to be positioned relative to the applicator to improve visibility and access, modifications to the material and arrangement of struts, the use of flexible applicator-guidewire channels for use in endoscopic or percutaneous procedures, and the provision of continuous drug delivery at the application site by incorporating drug-eluting matrix material into the graft component.

[0117] Accordingly, in certain embodiments, the tissue repair and sealing devices described herein incorporate a drug-eluting matrix that provides continuous drug release into bodily fluids and tissues at the site of tissue repair and sealing. Figure 19 illustrates an exemplary tissue repair and sealing device in which a graft 57 incorporates or is replaced by a bioabsorbable drug-eluting matrix for providing continuous drug delivery into bodily fluids, tissues, or spaces within a body cavity, blood vessel, lumen, or other intrabodily structure. By placing the drug-eluting matrix on the inner surface of the tissue, many types of drugs or active agents can be locally and continuously released into the blood, bodily fluids, or tissue parenchyma in contact with the matrix. The device may be rigid or flexible as described above and can be passed through under direct visualization, by endoscopy, or by a percutaneous approach using a guidewire.

[0118] The above-described tissue repair and sealing devices may be adapted for use in fixing a drug-eluting matrix, or a graft incorporating a drug-eluting matrix, to an internal tissue surface (including, but not limited to, tissues selected from the dura mater, blood vessels, esophageal wall, gastric or intestinal wall, bladder wall, ureter, peritoneum, pleura, uterus, Fallopian canal, sclera of the eye, synovial membrane, tympanic membrane, or capsule of a parenchymal organ). The drug incorporated into the drug-eluting matrix may be designed to be released into a fluid or space enclosed by a tissue barrier (blood, cerebrospinal fluid, gastrointestinal contents, pleural cavity, peritoneal cavity, vitreous fluid, inner ear, Fallopian canal, or joint cavity) and disperse the drug at a predetermined rate and concentration based on the properties of the drug, the target tissue, and the chemical composition of the drug-eluting matrix in order to achieve the intended therapeutic effect.

[0119] In certain embodiments, tissue repair and sealing devices such as those disclosed herein may be useful for continuously delivering therapeutic drugs into the bloodstream via arteries or veins for systemic distribution, or for continuously delivering therapeutic drugs into arterial bloodstream supplying tissue distal to the implant to produce a localized effect in downstream tissue while minimizing systemic distribution, or for continuously delivering therapeutic drugs to bodily fluids and / or tissues within cavities or spaces. In certain applications, the released drug may act locally and directly on the tissue to which the drug-eluting matrix or graft containing the drug-eluting matrix is ​​fixed. Thus, this disclosure intends to use the tissue repair and sealing devices disclosed herein for use in local delivery of active ingredients to promote healing, prevent local cell proliferation (e.g., intimal proliferation or excessive scarring), provide local anesthesia, inhibit fertilization, or treat infection with an antimicrobial agent. In any embodiment, the bioabsorbable nature of the repair and sealing device and the drug matrix may eliminate the need to remove the device at the end of treatment.

[0120] Drug-eluting matrices and grafts that may be adapted for use in the tissue repair and sealing devices of this disclosure are described in the art. For example, Alvarez-Lorenzo, Journal of Pharmacology and Experimental Therapeutics 370:544 (2019) (described implantable smart drug-release devices and materials); Concheiro, Advanced Drug Delivery Review 65(9):1188 (2013) (described chemically crosslinked and implantable cyclodextrin hydrogels for use in drug-eluting medical devices); Nie, Journal of Materials Chemistry 7:6515 (2019) (described integrated grafts containing biologically generated cartilage-bone interfaces for osteochondral defect repair); Zilberman, 299 (Springer-Verlag 2010) (outlined drug-eluting medical implants including drug-eluting matrices and grafts); Zilberman, Journal of Controlled Release 130(3):202(2008) (Describes antibiotic-eluting medical devices including drug-eluting matrices and grafts); Zuckerman, Gels 6:9(2020) (Describes affinity-based release from cyclodextrin hydrogel); Richter, U.S. Patent No. 7,048,714 (Describes a drug-eluting medical device having an expandable portion for drug release); Ding, U.S. Patent No. 7,758,909, Lye, U.S. Patent Publication No. 2005 / 0070989 and Feng, U.S. Patent Publication No. 2008 / 0051881 (Describes a medical device having a porous surface / layer for controlled drug release); Fennimore, U.S. Patent No. 8,007,737 (Describes antioxidants for preventing drug oxidation and degradation in drug-eluting medical devices); Atanasoska, U.S. Patent No. 8,815,273 (Describes a drug-eluting medical device having a porous layer); Jennings, U.S. Patent No. 9,605,175 and U.S. Patent No. 10, See Patent No. 314,912 (describes polymer coating compositions for use in medical devices); Gemborys, U.S. Patent No. 9,801,983 and U.S. Patent No. 10,159,769 (describes medical devices for delivering bioactive substances to treatment points); Speck, U.S. Patent Publication No. 2011 / 0295200, Zilberman, U.S. Patent Publication No. 2016 / 0082161 and Hoffmann, U.S. Patent Publication No. 2011 / 0301697 (describes drug-eluting medical devices); Wong, PCT Patent Publication No. 2006 / 135609 (describes an asymmetric drug-eluting hemodialysis graft); Hanson, PCT Patent Publication No. 2008 / 156487 and Peck, PCT Patent Publication No. 2014 / 144188 (describes drug-eluting grafts for local drug delivery to tissue). Each of these scientific and medical papers, patents, and patent publications is incorporated herein by reference in whole.

[0121] The drug-eluting matrices and grafts for use with the tissue repair and sealing devices disclosed herein may contain one or more drugs or therapeutic agents, such as, for example, anti-infective agents, anti-cancer agents, biologics, cardiovascular agents, central nervous system agents, and coagulation modifiers, which are well known and readily available in the art. Examples of modifiers include gastrointestinal agents, genitourinary agents, hormones, immunological agents, and metabolites.

[0122] 2. Biocompatible materials for use in tissue repair and sealing devices The tissue repair and sealing device of this disclosure comprises several biocompatible and / or bioabsorbable elements configured to position a graft, composed of a natural or synthetic material, onto the inner surface of a tissue fenestration, wherein the graft is secured in place by a biodegradable fastening mechanism being released onto the outer surface of the tissue during placement. More specifically, after the graft has passed through the tissue and is positioned to completely cover the inner end of the defect, a sliding, cylindrical release mechanism on the applicator releases a flexible, bioabsorbable fastener, which is deployed onto the outer surface of the tissue, thereby securing the graft in place and providing rapid watertight repair and sealing of the defect. The graft-fastening unit is applied using a detachable applicator shaft, which is connected to the graft-fastening unit during graft placement and then removed after the graft is secured.

[0123] The connecting devices and fasteners are composed of flexible, bioabsorbable materials and may be designed to secure the graft in place by applying radial struts of the required tensile strength, and to be completely absorbed by the tissue over time to allow for graft healing.

[0124] As used herein, the term “bioabsorbable” refers to materials that do not need to be removed manually because they are broken down and absorbed by the body. Examples of bioabsorbable materials include (1) metals or their alloys, typically magnesium-based and iron-based alloys, and (2) polymers including biomacromolecules and their copolymers, such as polylactide (PLA), polyglycolide (PGA), polylactide-co-D,L lactide (PDLLA), polylactide-co-glycolide (PLGA), polylactide-co-caprolactone (PLCL), polycaprolactone (PCL), polydioxanone (PDO), and polylactide-co-trimethylene carbonate (PL-TMC), which can be customized to meet mechanical performance parameters, biocompatibility, and absorption rates.

[0125] Bioabsorbable materials can be processed by conventional manufacturing methods, including injection molding, extrusion molding, compression molding, and machining. These polymers can also be used in novel manufacturing methods such as electrospinning, selective laser sintering, and fusion deposition modeling.

[0126] Biomacromolecules that exhibit good biocompatibility and produce degradation products that are excreted from the body through metabolic pathways are available. PLA-based substrates are non-toxic and allow cells to differentiate and produce, for example, extracellular matrix components.

[0127] Due to their mechanical properties and ability to extend the degradation time of bioabsorbable materials, polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and poly(L-lactide-co-D,L-lactide) (PDLLA) are particularly beneficial material options. Similar to suture anchors, the addition of calcium phosphate helps promote bone growth while being absorbed at a rate slow enough to allow for proper functioning of the implant. This controlled degradation is highly beneficial to the present invention because complete degradation of the bioabsorbable screw allows for inward growth of bone tissue into the interfering screw area, resulting in natural tissue fixation of the transplanted tendon and better patient outcomes.

[0128] Poly-L-lactide-co-D,L-lactide (PDLLA) possesses good tensile strength and excellent mechanical and thermal properties. Since most of these applications do not require implants to be subjected to high mechanical loads, the bioabsorbable materials used in these procedures have focused on improving the biological response and the ability to promote healthy bone regeneration without causing harmful side effects during degradation.

[0129] Polydioxanone (PDO) polymers can be fabricated to provide materials with a desired degree of flexibility, good mechanical properties, and a fast to moderate degradation profile ranging from about 6 to about 12 months. Polydioxanone (PDO) polymers are suitable for use in the manufacture of grafts, fasteners, and central couplers according to this disclosure, which can fix the regenerating tissue system in place for a long enough period to allow for complete healing, after which the grafts and sutures degrade and are absorbed by the body. Their degradation profile depends on several factors, including the crystallinity of the polymer, molecular weight, sterilization method, and in vivo environment.

[0130] Biopolymers that may be advantageously used in tissue repair and sealing devices disclosed herein exhibit one or more of the mechanical properties shown in Table 1.

[0131] [Table 1]

[0132] Bioabsorbable materials can be processed by conventional manufacturing methods, including injection molding, extrusion molding, compression molding, and machining. These polymers can also be used in novel manufacturing methods such as electrospinning, selective laser sintering, and fusion deposition modeling.

[0133] Biocompatible and bioabsorbable materials that may be adapted for use in the tissue repair and sealing devices of this disclosure are described in the art. For example, AZoM, Biomaterials, 2630 (2004) (describes the classification and physical characteristics of biomaterials for use in medical devices); Evonik, Medical Plastics News (describes the applications of bioabsorbable materials in medical devices); Gilding, Polymer 20(12):1459 (1979) (describes biodegradable polymers, including homopolymers and copolymers of polyglycolic acid (PGA) and polylactic acid (PLA), for use in medical devices, particularly surgical devices); Kadam, Medical Plastics News 15:22 (2020) (considers the applications of medical polymers for developing efficient medical device technologies); Middleton, Biomaterials 21(23):2335 (2000) (considers synthetic biodegradable polymers for use in orthopedic devices); Santos, Tissue Engineering 225 (Ed. Daniel See Eberli, 2010 (outline of bioabsorbable polymers for use in tissue engineering); and Sheikh, Materials 8:5744 (2015) (outline of biodegradable materials for use in bone repair and tissue engineering). Each of these scientific and medical papers is incorporated herein by reference in its entirety.

[0134] In certain embodiments, the tissue repair and sealing devices disclosed herein may utilize a removable graft-fastener assembly in which the graft subassembly and / or deployable fastener-coupler subassembly incorporate a biocompatible, non-ferromagnetic passivated metal or passivated metal alloy into the graft 57, foam ring 61, central coupler 67, and / or deployable fastener 75, thereby providing or enhancing the shape memory and superelastic properties of those components of the tissue repair and sealing device.

[0135] Suitable biocompatible, non-ferromagnetic passivated metals or passivated metal alloys for use in tissue repair and sealing devices disclosed herein include, but are not limited to, cobalt-based alloys, pure titanium, titanium-based alloys, platinum-based alloys, and alloys of molybdenum, tungsten, and tantalum. Passivated metal wires or passivated metal alloy wires suitable for use in removable implant and fastening assemblies exhibit desirable shape memory and superelastic properties, such as those exhibited by nickel-titanium (nitinol) and / or niobium-titanium.

[0136] Biocompatible, non-ferromagnetic passivated metals or metal alloys suitable for use in the tissue repair and sealing devices of this disclosure are described in the art. See, for example, U.S. Patent No. 8,349,249 ("Wachter") and U.S. Patent No. 8,992,761 ("Lin"), which are incorporated herein by reference.

[0137] Methods for using tissue repair and sealing devices This disclosure provides a method for using a tissue repair and sealing device in both MIS and non-MIS procedures to achieve rapid repair of fenestration-affected tissue and reliable formation of a pressure-resistant, watertight seal. The tissue repair and sealing device disclosed herein comprises (1) an applicator assembly having a proximal and distal end fastener-retaining and releasing member having a proximal and distal end, movably mounted on an applicator shaft having a proximal and distal end, and (2) a detachable graft-fastener assembly comprising a graft subassembly and a deployable fastener-coupler subassembly fixedly mounted to the center of the graft, in an operable combination.

[0138] Accordingly, in a particular embodiment, a method for using the tissue repair and sealing device disclosed herein includes: (1) selecting a removable graft-fastener assembly as disclosed herein; (2) attaching the removable graft-fastener assembly to an applicator assembly comprising an applicator shaft and a fastener retaining / releasing member; (3) folding the fastener and inserting it into the fastener retaining / releasing member; (4) positioning the graft on the inner surface of the tissue; (5) positioning the deployable fastener on the outer surface of the tissue; (6) fixing the graft to the inner surface of the tissue by releasing the deployable fastener onto the outer surface; (7) repairing the tissue fenestration; and (8) forming a pressure-resistant watertight seal.

[0139] Figures 3B–3E illustrate a method for using a tissue repair and sealing device, as illustrated in Figures 1 and 2, which comprises a graft subassembly and a deployable fastener / coupler subassembly, to rapidly repair tissue fenestrations and form a pressure-resistant, watertight seal.

[0140] Figure 3B illustrates the steps for preparing an exemplary tissue repair and sealing device for use in the repair and sealing of tissue fenestrations. A removable graft-fastener assembly 50 is attached to the applicator assembly 20 at the proximal end 27 of the applicator shaft 25, and the folded radial struts or spokes 77 of a deployable fastener-coupler subassembly 65 are held at the proximal end 37 of a fastener-retaining-release member 35. Before inserting the graft subassembly 57 through the tissue fenestration, the radial struts or spokes 77 of the deployable fastener-coupler subassembly 65 are folded away from the graft subassembly 55 and along the center of the axis passing through the central coupler 67, and inserted into the proximal end of the fastener-retaining-release member 35.

[0141] To determine the optimal size and shape of the graft subassembly 55 in relation to the size and shape of the fenestration, the graft is brought close to the defect while viewing it directly, microscopically, or endoscopically. Thanks to the central coupler 67 on the deployable fastener / coupler assembly 65, the surgeon can quickly replace and select the removable graft / fastener assembly 55 to provide the graft with the optimal size, shape, and material for sealing the tissue fenestration.

[0142] Figure 3C shows the tissue repair and sealing device of Figure 3B after insertion of the graft subassembly 57 through the tissue fenestration, where the graft subassembly 57 covers the entire inner opening of the defect and is then pulled back to contact the inner surface of the tissue with the fenestration, while the deployable fastener / coupler subassembly 65 remains outside the tissue with the fenestration before the tissue repair and sealing device is deployed. Re-expansion of the graft after passing through the fenestration can be facilitated by using a flexible, semi-rigid graft material or by incorporating a flexible ring of bioabsorbable material around the outer circumference of the graft (as shown in Figures 6-8 and 13C-13D). Thus, the graft subassembly 55 is configured to deform easily to somehow pass through the tissue fenestration and re-expansion to its original shape once inside the tissue.

[0143] Figure 3D shows the deployment of the tissue repair and sealing device. Once the graft subassembly 55 is positioned on the inner surface and the deployable fastener / coupler subassembly 65 is positioned on the outer surface of the tissue, the device is deployed by sliding the fastener retaining / releasing member 35 toward the distal end 29 of the applicator shaft 25, thereby releasing the struts or spokes 77 of the deployable fastener, which rapidly return to their original positions and apply pressure against the outer surface of the tissue with the fenestration, thereby securing the graft in the optimal position and sealing the fenestration.

[0144] Figure 3E shows how tissue fenestration is rapidly repaired and a pressure-resistant, watertight seal is reliably formed by separating the detachable graft-fastener assembly 50 from the applicator assembly 20, positioning the deployable fastener-coupler assembly 65 in contact with the tissue's outer surface, and securing the graft subassembly 55 to the tissue's inner surface.

[0145] Figure 5 illustrates an alternative embodiment of a tissue repair and sealing device disclosed herein, configured to seal a large-diameter needle puncture (e.g., arterial puncture or lumbar puncture) or fistula (surgical opening) associated with the drainage of body fluids into a hollow body organ or cavity, or the placement of an infusion or drainage tube or cannula made for an infusion or drainage tube (e.g., lumbar drain, gastrostomy tube, thoracentesis drain, paracentesis, arterial catheter, suprapubic cystostomy). In this embodiment, the applicator shaft 25 is made of a flexible material that allows the tissue repair and sealing device to pass through an endoscope or via a percutaneous route using a removable graft / fastener assembly 50 and a guidewire passed through an internal channel in the applicator shaft 25.

[0146] Figures 5C–5G illustrate exemplary methods for repairing tissue fenestrations (e.g., defects caused by large-diameter needle punctures, including puncture wounds in the arterial wall, dura mater, stomach, or pleura) using tissue repair and sealing devices as shown in Figures 5A and 5B. In these tissues, punctures (with or without the placement of a drain or cannula through the needle) can lead to persistent leakage through the puncture site, causing serious complications (e.g., hematoma formation, cerebrospinal fluid leakage, peritonitis, or pneumothorax). As shown in Figures 5A and 5B, the occluder graft 57 has a conical shape and is deformable along a guidewire to pass through a small puncture wound in the tissue barrier, and the deformable conical occluder graft 57 base material re-expands to completely cover the puncture wound on the inner surface of the tissue. The occluding graft may be selected in size based on the size of the defect to be sealed, may contain a bioabsorbable polymer as described herein, and may further comprise a drug-eluting component for delivering the drug to the site of tissue fenestration.

[0147] Figure 5C illustrates a large-bore needle 121 positioned through a tissue barrier 125 (e.g., arterial wall, dura mater, stomach, or pleura) with its tip positioned in a lumen or cavity 127 inside the tissue barrier. A flexible guidewire 123 is then inserted through the large-bore needle 121 into the lumen or cavity. It will be understood that the guidewire may be positioned with a tube or cannula placed by a percutaneous approach (e.g., arterial catheter, lumbar spinal drain, ventriculofensis, pleurocytosis, gastrostomy, or suprapubic cystotomy). In an alternative embodiment of this method, the guidewire may be passed through an indwelling catheter before its removal (not shown).

[0148] As shown in Figure 5D, once the guide 123 is inserted, the large-diameter needle 121 is removed, leaving the guidewire 123 in place after passing through the tissue fenestration. Figure 5E illustrates the placement of the tissue repair and sealing device, by inserting the outer end of the guidewire 123 into the opening at the tip of the conical occlusal graft 57 and passing the guidewire 123 through the conical occlusal graft 57, the central coupler 67, and the central channel of the flexible applicator shaft 25 of the applicator assembly 20, exiting from the distal end 29 of the flexible applicator shaft 25. Before passing the tissue repair and sealing device along the guidewire 123, several radial spokes or struts 77 are folded away from the conical occlusal graft 57 and inserted into the proximal end 37 of the fastener retaining and releasing member 35.

[0149] The tissue repair and sealing device advances along the guidewire 123 to the puncture site, and the conical occluding graft 57 passes through the puncture hole and is positioned in contact with the inner surface of the punctured tissue. The tissue repair and sealing device is deployed by moving the fastener retaining and releasing member 35 toward the distal end 29 of the applicator shaft 25, thereby releasing the deployable fastener and coupler subassembly 65 (Figure 5F). Multiple radial struts or spokes 77 of the deployable fastener 75 are positioned in contact with the outer surface of the tissue, and by applying pressure to the outer surface of the tissue, they secure the conical occluding graft 57, repair the puncture wound, and form a pressure-resistant watertight seal. The applicator assembly 20 is removed from the removable graft and fastener assembly 50 that remains at the puncture site, and the applicator assembly 20 is removed by sliding along the guidewire 123, after which the guidewire 123 is removed (Figure 5G).

[0150] Figures 22A–22E illustrate a method for rapidly repairing tissue fenestrations and forming a pressure-resistant, watertight seal using a tissue repair and sealing device comprising a graft subassembly 55 and a deployable fastener / coupler subassembly 65, as illustrated in Figures 20A–20C and 21A–21C. These tissue repair and sealing devices offer particular advantages in repairing fenestrated tissue, especially in tissues with small tissue fenestrations and / or brittle nature. In this embodiment, the graft subassembly 55 is configured to comprise multiple biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64 that extend radially from the center of the graft 57 and exhibit shape memory and superelastic properties. Thus, the graft subassembly 55 is configured to deform easily to fit within the fastener retaining / releasing member 35, and to enter the tissue and re-expand to its original shape when the fastener retaining / releasing member 35 is moved.

[0151] Figure 22A illustrates an exemplary tissue repair and sealing device before deployment. The removable graft-fastener assembly 50 is attached to the applicator assembly 20 at the proximal end 27 of the applicator shaft 25, and the folded radial struts or spokes 77 of the deployable fastener-coupler subassembly 65 are held at the proximal end 37 of the fastener-retaining-release member 35. Before inserting the graft subassembly 57 through the tissue fenestration, the radial struts or spokes 77 of the deployable fastener-coupler subassembly 65 are folded away from the graft subassembly 55 along the axis center through the central coupler 67 and inserted into the proximal end of the fastener-retaining-release member 35. This embodiment shows an elongated fastener-retaining / releasing member 35 for housing a graft subassembly 55, which includes a graft 57 comprising a plurality of biocompatible, non-ferromagnetic passivated metal wires or passivated metal alloy wires 64 extending radially from the center of the graft 57, and which is folded away from the central coupler 67 in an umbrella or parasol arrangement and held by the fastener-retaining / releasing member 35.

[0152] To determine the optimal size and shape of the graft subassembly 55 in relation to the size and shape of the fenestration, the graft is brought close to the defect while viewing it directly, microscopically, or endoscopically. Thanks to the central coupler 67 on the deployable fastener / coupler assembly 65, the surgeon can quickly replace and select the removable graft / fastener assembly 55 to provide the graft with the optimal size, shape, and material for sealing the tissue fenestration.

[0153] Figure 22B shows the tissue repair and sealing device of Figures 20A-20C and 21A-21C after the proximal end of the fastener-holding / releasing member 35 and the graft subassembly 55 have passed through the tissue fenestration. Figure 22C shows the deployment of the graft subassembly 55 by moving the fastener-holding / releasing member 35 along the applicator shaft 25 toward its distal end and stopping when the proximal end of the fastener-holding / releasing member 35 reaches the outside of the fenestrated tissue at the site of the central coupler 67. Then, in Figure 22C, the graft subassembly 55 is pulled back so that the graft 57 contacts the inner surface of the fenestrated tissue, with the deployable fastener-coupler subassembly 65 remaining inside the fastener-holding / releasing member 35 outside the fenestrated tissue.

[0154] Figure 22D shows a deployable fastener coupler subassembly 65 released from the fastener retaining / releasing member 35 by sliding the fastener retaining / releasing member 35 toward the distal end 29 of the applicator shaft 25, thereby releasing the deployable fastener struts or spokes 77, which rapidly return to their original positions, applying pressure against the outer surface of the tissue having the fenestration, thereby securing the graft in an optimal position and sealing the fenestration.

[0155] Figure 22E shows how tissue fenestration is rapidly repaired and a pressure-resistant, watertight seal is reliably formed by separating the detachable graft-fastener assembly 50 from the applicator assembly 20, positioning the deployable fastener-coupler assembly 65 in contact with the tissue's outer surface, and securing the graft subassembly 55 to the tissue's inner surface.

[0156] 1. Method for repairing and sealing fenestrations in the dura mater In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to repair and seal cerebrospinal fluid (CSF) leakage resulting from fenestration in the dura mater covering the brain and spine. The integrity of the dura mater is essential for containing CSF within the central nervous system. The pressure of CSF is higher than the pressure of adjacent tissues or internal spaces.

[0157] This pressure difference causes even small fenestrations to leak cerebrospinal fluid (CSF) through them, hindering their natural healing. CSF leakage can lead to numerous complications, including wound infection, meningitis, brain herniation, intracranial hemorrhage, and headaches due to decreased intracranial pressure. Openings in the dura mater can occur spontaneously (e.g., congenital defects, tumors, infections), intentionally (e.g., dural incision for craniotomy or spinal surgery, lumbar puncture, etc.), or accidentally (dural tears in spinal surgery or endoscopic sinus surgery, trauma, etc.). Because CSF is under pressure and continues to leak outward through unrepaired fenestrations as described above, overlay grafts or adhesives tend to detach from the outer surface of the dura mater, impairing the healing of the fenestration. Therefore, spontaneous healing of dural openings that were not repaired in the initial surgery is insufficient, and subsequent measures to stop cerebrospinal fluid leakage often require readmission, further surgery, and / or the collection of additional tissue grafts or other procedures such as lumbar drainage catheterization.

[0158] Methods for sealing dural fenestrations include several approaches; one or a combination of direct suturing, placement of natural or synthetic grafts, tissue sealants, auxiliary tissue grafts to reinforce overlay graft repair, epidural blood injection ("blood patch"), or lumbar drainage. Several commercially available dural substitutes exist, including human cadaveric dura mater, bovine and / or porcine pericardium, and various synthetic matrix preparations. These are typically applied as overlay grafts, sometimes with sutures or glue. The frequency of cerebrospinal fluid leakage due to improperly sealed dural openings varies considerably depending on the nature and location of the procedure, ranging from 1-2% in spinal surgery (higher in reoperations) to 10-15% in pituitary and certain posterior fossa surgeries. The future development of MIS approaches to the brain and spine is largely limited by the difficulty of re-establishing dural integrity. A major limitation in the repair and sealing of dura mater opened intentionally or unintentionally for MIS procedures is the difficulty of suturing the dura mater. This is generally due to the difficulty of reaching the site of the dural incision with conventional suturing and / or the fragility of the dura mater in certain locations. Furthermore, suturing is dangerous in many situations because critical nerve structures (nerve roots, cranial nerves, spinal cord, brain, blood vessels) are nearby, and the needle could inadvertently damage these structures by passing through the dura mater. Another application of the present invention described herein for dural closure may be for craniotomy and spinal open-vision (non-MIS) procedures in which underlying nerve structures are exposed during craniotomy or laminectomy procedures by making a planned incision of the dura mater. Typically, suture closure is employed for such dural incisions, but this is time-consuming and often not watertight. Furthermore, this device can facilitate fenestration and visualization of nearby structures by utilizing a vertically oriented graft-fastener unit fixed on the applicator shaft, or an adjustable coupling device that allows rotation of the graft-fastener unit.

[0159] 2. Method for repairing and sealing puncture wounds of the spinal dura mater In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to repair and seal puncture sites of the spinal dura mater for lumbar puncture and spinal drainage. Such punctures can cause persistent leakage of cerebrospinal fluid into adjacent perispinal tissues, leading to decreased intracranial pressure, which can manifest as headaches so severe that they impair normal daily life. For example, the incidence of headaches due to cerebrospinal fluid leakage can be as high as 80% after dural puncture for spinal anesthesia. Current methods for closing dural puncture leakage include bed rest and / or the use of an epidural blood patch. Percutaneous repair and sealing of spinal dura mater puncture wounds using the tissue sealing devices described herein is achieved by passing the device, which has a flexible applicator shaft, along a guidewire during spinal drainage or removal of the spinal puncture needle. The device is passed along the guidewire until a conical, bioabsorbable occluder graft passes through the puncture opening and reaches the space within the dura mater. The occluding graft is withdrawn, and after its base material covers the inner surface of the puncture fenestration, the applicator is withdrawn along the guidewire. As the binding cylinder is withdrawn together with the applicator, the gripping strut is released and the graft is fixed in place and immediately provides a watertight seal by unfolding on the outer surface of the dura mater of the puncture fenestration. Since this occluding graft is bioresorbable, it will not need to be removed.

[0160] 3. Method for repairing and sealing fenestrations in hollow internal organs In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to repair and seal fenestrations in the walls of hollow internal organs (including, but not limited to, the esophagus, stomach, small and large intestines, rectum, bladder, ureters, uterus, and vagina). Such fenestrations may occur spontaneously (e.g., tumors, infections), intentionally (e.g., incision or biopsy of an organ in surgery), or accidentally (tears or punctures in surgery). Fenestrations in the walls of such hollow organs typically require repair to prevent intraperitoneal leakage of intestinal contents or urine, or bacterial invasion through the uterus or vagina, which could lead to peritonitis or fistula formation. Rapid and watertight repair and sealing of such organs can be achieved using the tissue repair and sealing devices described herein during the procedure, thereby preventing leakage and subsequent infection, or eliminating the need for reoperation. In any of these situations, the graft may consist of autologous, allogeneic, heterogeneous, or synthetic materials, either directly incorporated as an integrated graft-fastener unit or replaced surgically using a bioabsorbable graft frame / holder device. Furthermore, in any of these situations, the device can facilitate fenestration and visualization of nearby structures by utilizing a vertically oriented graft-fastener unit fixed on an applicator shaft, or an adjustable coupling device that allows rotation of the graft-fastener unit.

[0161] 4. Methods for repairing and sealing puncture wounds, perforations, or fistulas. In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to repair and seal puncture wounds, perforations, or fistulas in hollow abdominal organs after biopsy or removal of a tube or cannula. Examples of use related to biopsy include perforations of the esophagus, stomach, small or large intestine, or rectum that occur during oral or transanal endoscopic biopsy, or perforations of the vagina and uterus or bladder and ureters, respectively, during transvaginal and transurethral endoscopic procedures. In another related embodiment, the tissue repair and sealing devices described herein may be used for percutaneous repair of fistulas or needle puncture wounds in the wall of hollow organs after removal of a drainage tube. In this embodiment, a flexible repair and sealing device advanced through an endoscope or along a guidewire may be used for extracorporeal percutaneous tubes, drains, or cannulas removed from the esophagus, stomach, small or large intestine, rectum, or bladder (suprapubic canal). Graft components in these applications may include flat grafts made of natural or synthetic materials, or conical occlusive grafts. As described above, the advantage of immediate sealing of the tubulation site is the prevention of leakage of fluid into the peritoneum or through the skin via the percutaneous conduit.

[0162] 5. Methods for repairing and sealing fenestrations in body cavities In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to repair and seal fenestrations of body cavities, including but not limited to the peritoneum, pleural cavity, inner ear, or joint cavity. Drainage of the pleural cavity via thoracentesis can result in pneumothorax due to air entering through the puncture site in the pleura. Similarly, percutaneous or endoscopic puncture of the peritoneum or paracentesis for surgical access (e.g., for drainage or dialysis) may later leak through the skin incision. Likewise, surgical procedures on the ear or joint may form fenestrations in the tympanic membrane or synovial membrane, respectively. In these situations, the tissue repair and sealing devices described herein, having a flat or conical graft and in a rigid or flexible form, can immediately seal the puncture site and prevent subsequent complications. Furthermore, this device can facilitate fenestration and visualization of nearby structures by utilizing a vertically oriented graft-fastener unit fixed on the applicator shaft, or an adjustable coupling device that allows rotation of the graft-fastener unit.

[0163] 6. Methods for repairing and sealing defects in the body's fascia. In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to repair and seal fenestrations of defects in the fascia of the body, including but not limited to the abdominal wall, chest wall, or muscle and ligament fascia. Defects in these fascial structures can lead to hernia formation or wound collapse of the underlying tissue. Repair of fascia of the body using the devices described herein may include directly closing the fascia in a direct visualization (non-minimally invasive surgery) procedure using one or more graft clamp components applied to the edge of the fascia, or, in the case of large defects, incorporating a free graft of natural or synthetic material circumferentially fixed to the edge of the defect using multiple graft-fastener units. Furthermore, fenestrations in the fascia may be closed via an endoscopic or percutaneous approach using flexible or rigid tissue repair and sealing devices. In any of these situations, the devices can facilitate visualization of the fenestration and surrounding structures by utilizing vertically oriented graft-fastener units fixed on an applicator shaft, or adjustable coupling devices that allow rotation of the graft-fastener units.

[0164] 7. Methods for local delivery of drugs and other active substances In certain embodiments, the tissue repair and sealing devices disclosed herein are configured to continuously deliver drugs and other active ingredients locally from a drug-eluting matrix incorporated into a graft component or a drug-eluting matrix that replaces a graft component. Local drug delivery offers several advantages: (a) the drug concentration is maximized at the application site, minimizing adverse effects from systemic distribution of the drug; (b) the drug can be delivered at sufficient concentration to body compartments that are relatively difficult to reach by intravenous or oral routes (e.g., poorly perfusing compartments such as cerebrospinal fluid and abscess cavities due to limitations by the blood-brain barrier); (c) continuous delivery ensures a steady-state therapeutic concentration of the drug without the peak and trough fluctuations that occur with intermittent administration; (d) patient adherence to medication is not an issue; and (e) the drug-eluting matrix may be biodegradable and can be manipulated to release specific drugs at known rates and times depending on the delivery site. Currently, many drug-eluting matrices are used clinically, but most require the implantation of the matrix into subcutaneous or solid tissue. In this embodiment, depending on the clinical situation and the intended therapeutic effect, a modified tissue repair and sealing device can be used to implant and fix any category of drug or bioactive substance to any site in the body.

[0165] The distribution of a drug may depend on the application site of the matrix. For example, a matrix placed on the inner surface of a blood vessel may provide systemic distribution in the case of a venous implant site, or provide local distribution of the drug to downstream tissues perfused by the artery (e.g., a neoplasm or a single organ). Furthermore, a matrix placed on the inner surface of a tissue barrier may provide drug delivery to the fluids or cavities surrounded by that barrier (e.g., a dural implant releasing a drug into the cerebrospinal fluid, a peritoneal implant releasing a drug into the peritoneal cavity, or a gastrointestinal implant releasing a drug into the intestines). Also, a matrix placed inside a barrier may release a drug to modulate the barrier itself (e.g., promoting healing, inhibiting scarring or hyperplasia, or managing local pain). Finally, a matrix implant placed in contact with the parenchyma inside the capsule of a parenchymal organ or inside a tumor may provide local drug delivery to a portion of that organ or tumor (e.g., the kidney, pituitary gland, malignant or benign tumor). As described above, the applications of this repair and sealing device can be applied to almost all categories of drugs as well as all types of body organs and tissues.

[0166] While various embodiments have been disclosed herein, other embodiments will be apparent to those skilled in the art. The various embodiments disclosed herein are for illustrative purposes only and are not intended to be limiting, and the true scope and spirit are as shown by the claims. This disclosure is provided to illustrate certain embodiments and is further described by the following embodiments, which are not intended to limit the scope of this disclosure or the subject matter claimed. [Examples]

[0167] Example 1 In vitro model for testing tissue repair and sealing devices This embodiment provides in vitro model systems that can be adapted and used to test various embodiments of the tissue repair and sealing devices disclosed herein. Various physical properties and other parameters of the tissue repair and sealing devices disclosed herein can be tested in in vitro model systems, including those described in scientific, medical, and patent literature, as well as in vitro model systems that can be configured to test the repair and sealing of tissue fenestrations using the devices disclosed herein. See Dafford, The Spine Journal 15(5):1099(2015); Chauvet, Acta Neurochirurgica 153(12):2465(2011); and Wang, MATEC Web of Conferences 119:01044(2017).

[0168] Van Doormaal, Operative Neurosurgery 15(4):425 (2018) and Kinaci, Expert Review of Medical Devices 16(7):549 (2019) disclose in vitro model systems using fresh porcine dura mater to test resistance to acute rupture pressure and intracranial pressure, and to evaluate cerebrospinal fluid leakage in repaired and sealed tissue fenestration.

[0169] In Megyesi, Neurosurgery 55(4):950(2004); Chauvet, Acta Neurochir (Wien) 153(12):2465(2011); and Kizmazoglu, Br.J. Neurosurgery 33(6):655(2019), an in vitro model system is disclosed that uses human cadaveric dura mater attached to a cylindrical metallic glass filled with colored saline to measure the watertightness of repaired and sealed tissue fenestrations and to evaluate the pressure at which repaired and sealed tissue fenestrations leak.

[0170] Lin, International Forum of Allergy and Rhinology 6(10):1034(2016); Lin, International Forum of Allergy and Rhinology 5(7):633(2015); Chorath, Allergy & Rhinology 10:1(2019); and Chen, American Journal of Rhinology and Allergy 33(6):757(2019) disclose an in vitro model system for porcine dura mater that utilizes saline injection to provide unidirectional pressure to measure the mean rupture pressure of repaired and sealed tissue fenestration. This in vitro model system employs a polyvinyl chloride (PVC) tube with one end capped. A small hole is provided on the end cap side, which is configured to have a three-way stopcock for injecting saline and monitoring chamber pressure, thereby simulating an increase in intracranial pressure (ICP). A silicone brain is placed beneath a simulated cribriform plate within a cylindrical tube. Following a computed tomography scan of a real skull base (Able, Lexington, MA), a section of the cribriform plate with a 30mm-25mm opening was modeled, imported into CAD (computer-aided design) software (3D Systems, Rockhill, SC), and printed in polycarbonate (Airwolf, Costa Mesa, CA). A second dura mater support disc with the same opening was prepared and positioned to align with the opening of the simulated cribriform plate excision. The cavity pressure was monitored using a pressure transducer (AMTEK, Inc, Ajman, UAE), and its output was directly transcribed into an Excel spreadsheet using WindaqXL (DATAQ, Akron, OH). The transducer was calibrated in mmHg, and all measurements were converted to centimeters of water (cmH2O). Pig dura mater was used because its mechanical properties are similar to those of human dura mater. Pig dura mater and fascia lata were collected from euthanized pigs, placed in saline solution, and stored at 4°C. To avoid dura mater degradation, experiments were conducted within 5 days of collection. The dura mater was uniformly cut into sections measuring 24mm-19mm.

[0171] The pressure chamber is designed to be adjustable to meet the requirements of various test procedures. The body is made of Schedule 80 PVC and is equipped with two flanges and end caps. It is made of a T-joint. The left end cap is perforated and plugged for a push-connect tube fitting that acts as an inlet for the inventors' test fluid. This fluid flow is passed through a three-way valve, allowing for two different ways to control the fluid flow, one end controlled by a solenoid valve and the other by a syringe. To the right of the T-joint is a flange, on which a membrane is securely fixed with an acrylic piece. This acrylic is designed to accommodate a 6.5" speaker that can test pressure changes produced by sound waves that mimic the body's natural respiratory cycle and other human functions. Above the T-joint is another flange that will hold the test stand. The test stand consists of two pieces of acrylic that will sandwich a commercially available synthetic hard membrane material piece. On the underside of the lower acrylic plate is a pressure transmitter that monitors the pressure changes of the test while controlling the solenoid valve.

[0172] The pressure chamber used to test the graft subassemblies of this disclosure is shown in Figures 23A and 23B. Figure 23C is the pressure waveform of human CSF, and Figure 23D is the in vitro chamber pressure waveform obtained using the pressure chamber shown in Figure 23A. For testing, the closure device comprises a probe that is controlled and operated with one hand. This device delivers a bioabsorbable base membrane under the incision. Upon insertion, a pressure network is applied externally, forming a watertight seal. If the placement is successful, the delivery probe is removed. It is important that the sealant device can be adjusted or removed if adjustment of placement is required.

[0173] Pressure distribution by an external speaker creates waveforms similar to the natural rhythm of CSF flow, patient movement, and waveforms naturally produced by the body, including coughs and sneezes. This seal is formed by the overlapping of the dura mater and the substrate. The physical forces on which the watertight seal depends are the back pressure of the CSF, the uniform load from the tension arm, and the coefficient of friction between the two surfaces. The back pressure of the CSF constantly fluctuates depending on the patient's body and movement. The load on the dura mater varies depending on the size of each device due to the material properties of PLGA. The coefficient of friction helps to keep the device in place. Leakage resulting from any of these forces is overcome in testing.

[0174] Example 2 In vivo model for testing tissue repair and sealing devices This embodiment provides in vivo model systems that can be adapted and used to test various embodiments of the tissue repair and sealing devices disclosed herein. Various physical properties and other parameters of the tissue repair and sealing devices disclosed herein can be tested in in vivo model systems, including those described in scientific literature, medical literature and patent literature, as well as in vivo model systems that can be configured to test the repair and sealing of tissue fenestrations using the devices disclosed herein.

[0175] de Almeida, Otolaryngology Head Neck Surgery 141(2):184 (2009) and Seo, Journal of Clinical Neuroscience 58:187 (2018) describe an in vivo pig craniotomy model system that can be adapted to test the repair of tissue fenestrations by evaluating cerebrospinal fluid (CSF) leakage. In de Almeida's craniotomy, pigs are subjected to craniotomy to create a fistula that passes through the cribriform plate into the nasal cavity. CSF leakage can be evaluated endoscopically before and after the repair of tissue fenestrations. Inflammation and bone reformation can also be evaluated by histopathological analysis.

[0176] Dafford, Spine Journal 15(5):1099 (2015) describes a comparison of hydrostatic pressure intensity for dural repair methods in a hydrostatic model system of calf vertebrae. Dural leakage is measured as a function of hydrostatic pressure and leakage area. Analysis of variance (ANOVA) is used to determine the leakage velocity and the rate of reduction of the leakage area.

[0177] Deng, Neurological Research 38(9):799(2016); Preul, Neurosurgery 53(5):1189(2003); and Zerris, Journal of Biomedical Materials Research 83(2):580(2007) describe in vivo canine dura mater and arachnoid model systems for evaluating CSF leakage. Deng also reports macroscopic and microscopic observations at 30 and 90 days after dural repair. Preul reports the results of the Valsalva test and histopathological analyses of control and treated animals at 1, 4, 7, and 56 days after surgery.

[0178] Cosgrove, Journal of Neurosurgery 106:52 (2007); Osbun, World Neurosurgery 78(5):498 (2012); and Weinstein, Journal of Neurosurgery 112(2):219 (2010) describe in vivo craniotomy and craniectomy methodologies that may be adapted to test the repair of tissue fenestration by evaluating CSF leakage in humans. The neurological procedure used by Cosgrove was performed infratentorial or supratentorially using suboccipital, temporal, and frontal surgical approaches with dural incision lengths ranging from 1.0 to 19.0 cm. Osbun evaluated complications leading to unplanned postoperative intervention or reoperation after dural closure, comparing the incidence of surgical site infection, CSF leakage, and other neurological complications in both the treated (dural repair) group and the control group.

[0179] Therefore, the scope of this disclosure is indicated by the appended claims rather than by the foregoing description, and all changes that fall within the meaning and equivalence of the claims are intended to be incorporated herein.

Claims

[Claim 1] The invention as shown in the drawings.

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