Graft device for endogenous tissue restoration between two tubular structures

Abstract

To provide a graft device which has been required for a long time of a commercial alternative blood vessel of a small diameter in order to overcome the drawbacks of currently available alternative blood vessels.SOLUTION: Graft devices are provided addressing a long need for off-the-shelf small diameter replacement vessels to overcome the drawbacks of currently available alternatives. As they are available off-the-shelf, the graft device does not require additional surgery to harvest it such as for a vein graft. A porous nature of the graft device enables restoration process, which results in new natural and patient's own tissue, in contrast to currently existing vascular prosthesis that can never fully heal. A built-in graft support device overcomes the limited kink-resistance that is typical for these kinds of (electrospun) porous devices. A zigzag pattern with alternating laminating and non-laminating areas allows the incorporation of the graft support device without the need for additional suturing or connecting the inner and outer layer for good lamination, while maintaining adequate kink-resistance.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to implant devices and methods that can enhance endogenous tissue repair or growth. [Background technology]

[0002] Off-the-shelf small diameter blood vessels have long been desired to overcome the shortcomings of currently available blood vessel replacements.

[0003] Coronary artery bypass grafting (CABG) is the most common open-heart surgery, with over one million performed annually worldwide. Eighty percent of CABG procedures use segments of native veins (an average of two to three per procedure) to reconstruct the coronary arteries, requiring an additional, painful surgical procedure to harvest veins from the patient's legs, often resulting in complications such as infection and chronic pain. Despite strenuous efforts, no suitable off-the-shelf synthetic alternatives exist for this purpose today. Commonly used ePTFE- and Dacron®-based vascular grafts are not commercially available for CABG because they cannot maintain patent patency at diameters of 4 mm or less, which are required for CABG.

[0004] Furthermore, there is a significant unmet medical need for small-diameter vessels in peripheral applications, such as dialysis access grafts and critical limb ischemia (CLI), where neither native veins nor artificial vascular prostheses can provide satisfactory long-term patency, despite their somewhat larger diameters (typically 6 mm, up to 8 mm). The problem with prosthetic grafts in these applications is that they do not heal adequately due to an inability to allow natural tissue repair. Ultimately, these grafts become clogged over time as proteins and tissues deposited from the bloodstream accumulate within these grafts, eventually causing stenosis and blockage.

[0005] Therefore, there is a need in the art to provide an implant device for repairing blood vessels by promoting endogenous tissue repair or growth while maintaining the structural and mechanical requirements required of the implant device. The present invention provides an implant device that meets this need. Summary of the Invention [Means for solving the problem]

[0006] (definition) In the present invention, the term "graft" is defined as a graft used to create a connection between two blood vessels, and may include bypass grafts, shunts, interposition grafts, end-to-end, side-to-end, end-to-side, side-to-side, snake grafts, and jump grafts (where several bypasses are created with one graft). However, devices used within existing blood vessels, such as stents and endografts, are not intended. The small diameter range of grafts provided herein is defined as 4 mm or less (for CABG), approximately 6 mm (for access grafts), and up to 8 mm (for peripheral grafts).

[0007] The present invention provides a graft device for endogenous tissue repair disposed between two tubular structures. In one embodiment, the graft device separates an electrospun inner tubular layer, an electrospun outer tubular layer, and a graft support device defined by a zigzag-patterned helical structure having inner and outer tubular surfaces. The electrospun inner tubular layer conforms to the inner tubular surface, and the electrospun outer tubular layer conforms to the outer tubular surface. The electrospun inner tubular layer and the electrospun outer tubular layer are positioned to sandwich the graft support device. In one embodiment, the zigzag-patterned helical structure occupies approximately 95% of the length of the graft device.

[0008] The implant device is configured to be deployable in a predetermined state or to remain in a predetermined state upon implantation.

[0009] The graft support device further separates a first region defined by the corners of the zigzag pattern from a second region defined by each V-shape or inverted V-shape of the zigzag pattern, excluding the first region defined by each corner.

[0010] The first regions are non-laminated regions where the electrospun inner tubular layer and the electrospun outer tubular layer are not laminated together. These first non-laminated regions prevent twisting of the graft support device while allowing bending of the graft support device. In one example, the first non-laminated regions at each corner are 0.3 to 0.5 mm apart. 2 has a surface area of

[0011] The second region is a laminated region where the electrospun inner tubular layer and the electrospun outer tubular layer are laminated together. In one example, each second laminated region within each V-shape or inverted V-shape has a width of 2.5 to 3.5 mm. 2 has a surface area of

[0012] In one embodiment, the graft support device is made from metal or polymer, the electrospun inner tubular layer and the electrospun outer tubular layer are made from polymer fibers, and the second region has a circumferential surface area ratio of polymer to helical metal or polymer to helical polymer in a ratio of 4:1 to 12:1 (8:1).

[0013] In yet another embodiment, each corner of the graft support device is n-shaped or u-shaped depending on the direction of the zigzag pattern, and each corner is 0.3-0.5 mm 2 The implant support device has a uniform pitch angle.

[0014] In yet another embodiment, the electrospun inner and outer tubular layers are each a porous biodegradable polymer layer large enough to allow cellular ingrowth upon implantation to promote endogenous tissue repair or growth, and the electrospun inner and outer tubular layers are replaced over time by endogenous tissue repair or growth accompanied by cellular ingrowth.

[0015] In yet other embodiments, the implant support device has one or more separate C-shaped rings at one or both ends that are positioned at an acute angle relative to the longitudinal axis of the implant device.

[0016] In yet other embodiments, the graft support device has a closed ring at one or both ends connected to the graft support device.

[0017] In yet another embodiment, the present invention provides a graft support device comprising an electrospun inner tubular layer, an electrospun outer tubular layer, and a patterned helical structure defined by an inner tubular surface and an outer tubular surface. Similarly, as in the graft devices described above, the electrospun inner tubular layer is conformal to the inner tubular surface, and the electrospun outer tubular layer is conformal to the outer tubular surface, with the electrospun inner tubular layer and the electrospun outer tubular layer sandwiching the patterned helical structure, separating laminated and non-laminated regions. The non-laminated regions allow bending of the patterned helical structure while preventing twisting of the graft support device.

[0018] In yet another embodiment, the present invention provides a method for creating a connection between two tubular structures using a graft device, wherein the graft device separates an electrospun inner tubular layer, an electrospun outer tubular layer, and a graft support device defined by a patterned helical structure having inner and outer tubular surfaces. Similarly, as in the graft devices described above, the electrospun inner tubular layer is conformal to the inner tubular surface, and the electrospun outer tubular layer is conformal to the outer tubular surface, with the electrospun inner and outer tubular layers sandwiching the patterned helical structure separating laminated and non-laminated regions. The non-laminated regions prevent twisting of the graft support device while allowing bending of the patterned helical structure. After implantation of the graft device, the electrospun inner and outer tubular layers are substantially replaced over time by endogenous tissue restoration or growth associated with cellular ingrowth.

[0019] Advantages of embodiments of the present invention include: being off-the-shelf, they do not require additional harvesting surgery, as with vein grafts; the porosity of the vascular prosthesis allows for a repair process, resulting in new, natural, patient-specific tissue, as opposed to existing vascular prostheses, which are unable to completely heal; and incorporating a graft support device that overcomes the limited kink resistance that is a typical feature of such (electrospun) porous devices. The zigzag pattern of alternating laminated and non-laminated sections allows for the incorporation of a graft support device without additional sutures or connections between the inner and outer layers for good lamination, while maintaining sufficient kink resistance. [Brief explanation of the drawings]

[0020] [Figure 1] 1A-1C illustrate cross sections of an implant support device according to an exemplary embodiment of the present invention. [Figure 2] 1A is a side view of a portion of a zigzag pattern helix of an implant support device according to an exemplary embodiment of the present invention, also showing the definition of pitch angle relative to the side view. [Figure 3] FIG. 10 is a side view of a portion of a zigzag-patterned spiral structure of a graft support device according to an exemplary embodiment of the present invention, showing a first region (circle) that is not laminated and a second region (triangle) that is laminated when the zigzag-patterned spiral structure is sandwiched between an electrospun inner tubular layer and an electrospun outer tubular layer. [Figure 4] 10A-10C illustrate a zigzag pattern helix of an implant support device having bridges between turns of the helix, according to an exemplary embodiment of the present invention. [Figure 5] 4A-4C illustrate the actual design of the implant support device showing the first regions that are corners (ie, the n-shape and u-shape appearing in FIG. 3) according to an exemplary embodiment of the present invention. [Figure 6] 1A-1C show a graft support device having a patterned spiral structure with C-shaped rings at one or both ends thereof, according to an exemplary embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0021] There is a need in the art to provide a graft device for vascular restoration by allowing for the promotion of endogenous tissue restoration or growth while maintaining the structural and mechanical requirements required of the graft device. The present invention provides a graft device that meets this need.

[0022] In one embodiment, the graft device is a tubular implant for anastomotically connecting two tubular structures to one another. Examples of tubular implants include, but are not limited to, veins, arteries, urethras, intestines, esophagus, trachea, bronchi, ureters, or fallopian tubes. The graft devices contemplated by the present invention are not intended for endoluminal placement, i.e., placement within the lumen of an existing tubular structure.

[0023] In one embodiment, as shown in FIG. 1, an implant device 100 includes an electrospun inner tubular layer 110 and an electrospun outer tubular layer 120. In an exemplary cross-section shown in FIG. 2, a graft support device formed from a zigzag-patterned helical structure 130 is sandwiched between the electrospun inner tubular layer 110 and the electrospun outer tubular layer 120. As shown in FIG. 2, the zigzag-patterned helical structure 130 has a uniform pitch angle 132, an inner tubular surface, and an outer tubular surface. The electrospun inner tubular layer 110 is coincident with the inner tubular surface, and the electrospun outer tubular layer 120 is coincident with the outer tubular surface. The inner tubular layer 110 is in contact with the outer tubular layer 120 except where the zigzag-patterned helical structure 130 is disposed.

[0024] Embodiments of the present invention are not limited to graft support devices with a zigzag-patterned helical structure, as long as the patterned helical structure achieves the objective of the graft device having laminated and non-laminated regions for the purpose of preventing easy bending and kinking. The device has electrospun inner and outer tubular layers of a patterned helical structure having inner and outer tubular surfaces. The electrospun inner tubular layer is coincident with the inner tubular surface, and the electrospun outer tubular layer is coincident with the outer tubular surface. The electrospun inner and outer tubular layers are arranged to sandwich the patterned helical structure, separating the laminated and non-laminated regions. The non-laminated regions allow the patterned helical structure to bend while preventing the zigzag-patterned helical structure from kinking.

[0025] Returning to the example of the zigzag patterned spiral structure, as shown in Figures 3 and 5, the pattern separates first regions 310 defined by the corners of the zigzag pattern. The first regions are non-laminated regions where neither the inner electrospun tubular layer nor the outer electrospun tubular layer is laminated due to the relatively high density of material at the corners of the zigzag pattern. The electrospun material is not connected to each other in narrow spaces such as the first regions 310, enhancing kink resistance while allowing the zigzag patterned spiral structure to bend. In one example, the first non-laminated regions at each corner are each 0.3 to 0.5 mm. 2 has a surface area of

[0026] The spiral structure of the zigzag pattern separates second regions 320 defined by the area within each V-shape or inverted V-shape in the zigzag pattern, excluding the first regions defined as the respective corners, as shown in Figures 3 and 5. The second regions are laminated regions where the electrospun inner tubular layer and the electrospun outer tubular layer are laminated or adhered together. In one example, the second laminated region within each V-shape or inverted V-shape is 2.5 to 3.5 mm. 2 has a surface area of

[0027] The zigzag patterned helical structure may be made from a metal (e.g., nitinol) or a polymer, and the electrospun inner and outer tubular layers may be made from polymer fibers. In one embodiment, the circumferential / cylindrical surface area ratio of the electrospun polymer to the metal (or polymer) is 4:1 to 12:1 (as defined for the implant device). In one exemplary embodiment, this ratio is approximately 8:1. The circumferential / cylindrical surface area is measured on the outer surface of the implant support device.

[0028] In embodiments, it is important that the electrospun inner and outer tubular layers each be a biodegradable polymer layer with sufficient porosity to allow cellular ingrowth upon implantation to promote endogenous tissue repair or growth, such that the electrospun inner and outer tubular layers are replaced over time by endogenous tissue repair or growth associated with cellular ingrowth.

[0029] In a specific design of the graft support device of the present invention, each corner in the zigzag patterned helix is ​​either n-shaped 330 or u-shaped 340, depending on its orientation within the zigzag pattern, as shown in Figure 3. The reason for this shape is that V-shaped or inverted V-shaped corners are prone to polymer damage due to metal abrasion and do not maximize the initial non-laminated area required for mobility of the zigzag patterned helix.

[0030] The narrow width of the N- or U-shapes prevents the electrospun inner and outer polymer fibers from locally adhering / bonding to each other, i.e., they become delaminated. Rather, these N- or U-shapes function as "hinge regions" where the relatively high metal density allows for relative movement between the helical structures and electrospun layers, and where localized electrospun polymer fibers are not connected to each other through the metal / polymer U- or N-shaped structures (i.e., first regions).

[0031] The zigzag pattern helical structure can be fabricated from laser-cut tubing. Some embodiments may include connecting struts ("bridges") 410 to improve manufacturing yield, as shown in FIG. 4. The connectors can be designed to not compromise the structure's ability to recover from heavy clamping or its fatigue life durability. As such, the number of bridge connectors can vary from zero to multiple bridges per revolution. The bridge configuration can be used to adjust the axial compliance of the implant device.

[0032] In one example, as shown in FIG. 2, a uniform pitch angle 132 is defined between two adjacent patterns of zigzag helical (metallic) supports, spaced apart to allow for strong polymer fiber attachment between the inner and outer electrospun layers. The pitch is approximately 2 mm. To prevent twisting, it is preferable that the pitch not be too large. On the other hand, if the value is too small, collapse will occur. A preferred value is 1.5 to 2.5 mm, but it can also be 1 to 3 mm.

[0033] The uniform pitch angle 132, as shown in Figure 2, is approximately the same along the length of the zigzag patterned spiral. The preferred ratio of cell-to-cell distance to pitch is 1:1. Ratios between 2:1.5 and 1:1.5 work as well, but ratios lower than 1:1.5 and higher than 2:1 compromise kink resistance. A distance of 2 mm between adjacent cells is preferred, and a pitch of 2 mm is optimal. This provides an optimal opening and a support structure with excellent kink resistance.

[0034] The graft manufacturing process begins with electrospinning the inner layer onto a tubular mandrel. The inner layer is spun so that its outer diameter matches the inner diameter of the graft support device, creating sufficient friction between the two. The graft support device is then expanded and filled into a tube. The inner diameter of the tube is larger than the outer diameter of the spun inner layer, acting as an expansion tool to expand the graft support device axially to the desired location within the inner layer. The outer layer is then electrospun using a special process designed to ensure optimal adhesion (i.e., lamination) of the outer layer fibers and the inner layer fibers in the non-metallic coating. This process ensured complete lamination of the second region, and was tested and validated on the benchtop. The support specifications described above (polymer and support density, cell spacing) were designed to achieve optimal fiber lamination.

[0035] In yet another embodiment, as shown in FIG. 6, a graft support device 600 defines a longitudinal axis. The body of the graft support device is fabricated with a patterned helical structure, as shown in FIGS. 2-3, for example. In one embodiment, 90-95% of the length 612 of the graft support device defined along the longitudinal axis is the patterned helical structure. For another approximately 5-10% portion 622, one or more free-standing C-shaped rings 620 are positioned at an acute orientation angle α relative to the longitudinal axis of the graft device at one end of the support element, and optionally at the other end of the graft support device (not shown). The C-shaped rings are embedded between an electrospun inner tubular layer and an electrospun outer tubular layer. Depending on the application, the acute orientation angle may be 15-90 degrees, preferably 30-60 degrees, and nominally 45 degrees.

[0036] A C-shaped ring is defined as a circular or oval ring that is not completely closed, i.e., has an opening large enough to accommodate standard surgical scissors to create an axial slit without cutting through the ring struts. In one embodiment, the openings of the C-shaped ring are aligned with each other. In other embodiments, the C-shaped ring may be a closed ring.

[0037] The C-shaped ring is embedded between the inner and outer tubular layers to prevent delamination of the layers. In one embodiment, the orientation angle is nominally about 45 degrees. In a preferred embodiment, the C-shaped ring is made of Nitinol.

[0038] In one embodiment, the patterned spiral portion of the graft support device 612 has oval or circular end rings 624 attached to (and part of) the patterned spiral portion. These so-called end rings 624 are aligned generally parallel to two or more separate C-shaped rings. In a preferred embodiment, the end rings are made of Nitinol.

[0039] Note that the end rings are physically connected to the graft support device. They are always fully closed. This is important because it prevents the graft from collapsing and stabilizes the ends of the graft. It also prevents the graft support device from expanding, distinguishing it from intraluminal devices such as stents.

[0040] The electrospun materials referred to herein may contain a polymer backbone selected from the group consisting of ureido-pyrimidinone (UPy) quadruple hydrogen-bonding motifs (see Sijbesma (1997), Science 278, 1601-1604 for a pioneering example) and biodegradable polyesters, polyurethanes, polycarbonates, poly(orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinyl alcohols, and polypropylene fumarates. Examples of polyesters include polycaprolactone, poly(L-lactide), poly(DL-lactide), poly(valerolactone), polyglycolide, polydioxanone, and their copolyesters. Examples of polycarbonates include poly(trimethylene carbonate), poly(dimethyltrimethylene carbonate), and poly(hexamethylene carbonate).

[0041] Similar results can be achieved with non-supramolecular polymers by carefully selecting their properties and engineering the materials to ensure the desired surface characteristics. These polymers may include biodegradable or non-biodegradable polyesters, polyurethanes, polycarbonates, poly(orthoesters), polyphosphoesters, polyanhydrides, polyphosphazenes, polyhydroxyalkanoates, polyvinyl alcohol, and polypropylene fumarate. Examples of polyesters include polycaprolactone, poly(L-lactide), poly(DL-lactide), poly(valerolactone), polyglycolide, polydioxanone, and their copolyesters. Examples of polycarbonates include poly(trimethylene carbonate), poly(dimethyltrimethylene carbonate), and poly(hexamethylene carbonate).

Claims

1. 1. A graft device for endogenous tissue repair disposed between two tubular structures, comprising: (a) an electrospun inner tubular layer; (b) an electrospun outer tubular layer; (c) a graft support device defined by a zigzag patterned helical structure having an inner tubular surface and an outer tubular surface; the electrospun inner tubular layer conforms to the inner tubular surface; the electrospun outer tubular layer conforms to the outer tubular surface; the electrospun inner tubular layer and the electrospun outer tubular layer are positioned to sandwich the graft support device; the graft support device defines a first region defined by a corner formed by the zigzag pattern; the graft support device defines a second region defined by a region within the V-shape or inverted V-shape of the zigzag pattern, excluding the first regions defined as the corners of each of the V-shape or inverted V-shape; the first region is configured to be a non-laminated region in which neither the electrospun inner tubular layer nor the electrospun outer tubular layer is laminated; the first non-laminated region prevents kinking of the graft support device while allowing the graft support device to flex; The device, wherein the second region is configured as a laminated region in which the electrospun inner tubular layer and the electrospun outer tubular layer are laminated.

2. the implant support device is made of metal or polymer; the electrospun inner tubular layer and the electrospun outer tubular layer are made from polymer fibers; The device of claim 1 , wherein the second region is configured such that the circumferential surface area ratio of polymer to metal or polymer strand is between 4:1 and 12:1 (8:1).

3. The first non-laminated region at each corner is 0.3 to 0.5 mm ２ 10. The device of claim 1 having a surface area of

4. The second lamination region in each V-shape or each inverted V-shape is 2.5 to 3.5 mm ２ 10. The device of claim 1 having a surface area of

5. 10. The device of claim 1, wherein the electrospun inner tubular layer and the electrospun outer tubular layer are each configured to be a porous biodegradable polymer layer of sufficient size to allow cellular ingrowth upon implantation to promote endogenous tissue repair or growth.

6. 6. The device of claim 5, wherein the electrospun inner and outer tubular layers are replaced over time by endogenous tissue restoration or growth associated with cellular ingrowth.

7. Each corner in the graft support device has an n-shape or a u-shape depending on the direction of the zigzag pattern, and each corner has a width of 0.3 to 0.5 mm ２ 10. The device of claim 1 having a surface area of

8. The device of claim 1 , wherein the graft support device has a uniform pitch angle.

9. The device of claim 1 , wherein the implant support device has one or more independent C-shaped rings at one or both ends spaced apart at an acute orientation angle relative to the longitudinal axis of the implant device.

10. The device of claim 1 , wherein the graft support device has a closed ring at one or both ends connected to the graft support device.

11. The device of claim 9 , wherein approximately 95% of the implant device has the zigzag patterned helical structure.

12. The device of claim 1 , wherein the implant device is deployable in a predetermined state or configured to maintain a predetermined state upon implantation.

13. 1. An implant device comprising: (a) an electrospun inner tubular layer; (b) an electrospun outer tubular layer; (c) a graft support device defined by a zigzag patterned helical structure having an inner tubular surface and an outer tubular surface; the electrospun inner tubular layer conforms to the inner tubular surface; the electrospun outer tubular layer conforms to the outer tubular surface; the electrospun inner tubular layer and the electrospun outer tubular layer are arranged to sandwich a patterned spiral structure separating laminated and non-laminated regions; The non-laminated regions prevent kinking of the graft support device while allowing the graft support device to flex.

14. 1. A method of forming a connection between two tubular structures using a graft device, comprising: The implant device comprises: (a) an electrospun inner tubular layer; (b) an electrospun outer tubular layer; (c) a graft support device defined as a zigzag patterned helical structure having an inner tubular surface and an outer tubular surface; the electrospun inner tubular layer conforms to the inner tubular surface; the electrospun outer tubular layer conforms to the outer tubular surface; the electrospun inner tubular layer and the electrospun outer tubular layer are arranged to sandwich the patterned spiral structure separating laminated and non-laminated regions; the non-laminated regions prevent kinking of the graft support device while allowing the graft support device to flex; The method, wherein after implantation, the electrospun inner tubular layer and the electrospun outer tubular layer are replaced over time by endogenous tissue restoration or growth associated with cellular ingrowth.

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