Kink-resistant tubular graft implant

Abstract

An electrospun tubular graft implant is provided that distinguishes an electrospun tubular layer having a longitudinal axis and an outer surface. The electrospun sheet polymer layer is wrapped around the outer surface of the electrospun tubular layer and around the longitudinal axis of the electrospun tubular layer. The electrospun polymer layer is further distinguished in the electrospun sheet rolled polymer layer. Also provided is a tubular graft having a rolled electrospun polymer sheet layer wrapped around a longitudinal axis that defines the inner diameter of the tubular graft. The electrospun polymer sheet layers are configured to move independently of each other when the tubular graft is bent. A higher burst pressure is achieved compared to conventional spun grafts, and a crushing zone between the layers reduces bending stiffness and facilitates bending with excellent kink resistance.

Description

Technical Field

[0001] The present invention relates to a kink-resistant tubular graft implant and a method for manufacturing the graft implant.

Background Art

[0002] Conventional grafts are made from various biocompatible plastics and polymers. Such devices are known to cause inflammation and unwanted biological reactions in the surrounding tissues and inside the lumen. Biodegradable and absorbable materials have recently emerged as materials for medical devices. In the case of tubular vascular grafts, it is important to have sufficient mechanical properties. At the same time, it is preferable to use biodegradable materials. Therefore, a completely biodegradable composition is desirable.

[0003] U.S. Patent No. 8,057,535 describes a transplantable medical device including a fibrous polymer body, the device comprising a support filament wound around the body and an outer layer covering the filament for joining the filament to the body. The wound filament is configured to provide a certain degree of kink resistance to the device. The support filament may cause inflammation and other complications after transplantation and is not biodegradable like this graft material. U.S. Patent No. 8,057,535 shows that the support filament is fixed to the electrospun material of the graft by a coating composition, i.e., substantially all the fibers are joined to each other.

[0004] An improved artificial blood vessel requires a uniform thickness distribution over its entire length to exhibit good performance, and an additional support structure should be avoided to obtain a uniform degradation behavior. However, it is necessary that no kink occurs when the tube is bent. Standard tubes manufactured by electrospinning on a mandrel with a small diameter cannot obtain sufficient kink resistance.

Summary of the Invention

Means for Solving the Problem

[0005] An electrospun tubular graft implant is provided that defines an electrospun tubular layer having a longitudinal axis and an outer surface. One or more polymer layers of the electrospun sheet are wrapped around the outer surface of the electrospun tubular layer and around the longitudinal axis of the electrospun tubular layer. The electrospun polymer layer is further differentiated in one or more polymer layers around which the electrospun sheet is wrapped.

[0006] Also provided is a tubular graft implant comprising two or more layers of an electrospun polymer sheet wrapped around the longitudinal axis defining the inner diameter of the tubular graft implant. These two or more layers of the electrospun polymer sheet are configured to move independently of each other when the tubular graft implant is bent.

[0007] In one embodiment, the number of layers is from 10 to 20. The exact number depends on the thickness that gives a uniform result.

[0008] In still other embodiments, the implant has from 10 to 20 layers.

[0009] In still other embodiments, each of the two or more layers preferably has a thickness of from 30 μm to 50 μm, and more generally from 20 μm to 100 μm. In still other embodiments, each layer has a different fiber direction from the others.

[0010] Embodiments of the present invention have at least the following advantages. The graft has a very high burst pressure compared to a normal spun graft. The graft has a crush zone between the plurality of layers, thereby reducing the bending stiffness and facilitating bending by having excellent kink resistance. The performance is improved because the thickness of the wall body becomes more uniform. No additional support elements (such as metal stents, polymer stents, polymer filaments, etc.) are required, and the resulting device has complete bioabsorbability. Being multilayered enables the production of large sheets that can be cut to a predetermined size and then formed into roll-shaped multilayer grafts, facilitating scale-up of production.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to a tubular graft implant made of electrospinning fibers that is highly kink-resistant compared to existing graft implants. Specifically, the manufacturing method of these tubular graft implants is characterized by having the following exemplary steps.

[0013] 1. In one example, a silicon tube (SI) 120 is arranged to wrap around a rod 110 (e.g., a stainless steel rod) (FIG. 1). Broadly, reference numeral 120 may be any flexible non-metallic tube and is not limited to the exemplary silicon tube. The rod 110 is used as an electrospinning mandrel / collector. The silicon tube 120 has an outer diameter equivalent to the inner diameter of the graft implant. The silicon tube has a length equivalent to the length of the graft implant. For example, a 40 cm long graft implant will have a 40 cm long silicon tube 120. Further, the sum of the diameter of the silicon tube 120 and the thickness of the PEO layer (see below) also determines the inner diameter of the graft implant.

[0014] 2. In one embodiment, a polyethylene oxide (PEO) layer 130 is electrospun to wrap around the silicon tube 120 (Figure 2). The PEO layer is a friction-reducing water-soluble layer and is later dissolved to remove the silicon tube 120 from the tubular graft. The thickness of the electrospun PEO layer is about 50 μm. Although PEO is preferred, other water-soluble materials (applied by electrospinning or another method) may be used as can be readily understood by those skilled in the art. More generally, this step is for facilitating the removal of the silicon tube 120 from the tubular graft in a later step of the process.

[0015] 3. A polymer layer 140 is electrospun to wrap around the electrospun PEO layer 130 (Figure 3). The polymer layer 140 forms the inner surface / lumen surface of the graft implant. An example of the inner surface which is important for endogenous tissue repair (ETR) is shown in Figure 4. The polymer layer 140 aims to achieve a continuous lumen that eliminates the risk of the layers peeling off from each other. The continuous lumen is important for realizing a stable laminar flow of blood through the graft.

[0016] 4. The structure 500 is shown removed from the rod 110 (compare Figures 4 and 5).

[0017] 5. Here, a rigid pin 630 is inserted into the lumen where the rod 110, which has already been removed from the structure 500, was provided (Figure 6). The diameter of the rigid pin 630 matches the lumen of the silicon tube 120 shown as 120IL. The purpose of the rigid pin 630 is to form a ring-shaped structure by connecting the ends of the tubes to each other.

[0018] 6. The purpose of the rigid pin 630 is to shape, attach, and fix the structure so as to surround the ring-shaped (Figure 6) collector 610 that forms the ring-shaped structure 620. Other methods to achieve this purpose include, but are not limited to, stitching, adhesion, etc. The diameter of the collector 610 is, for example, 9 cm. The length of the ring-shaped structure 620 matches the circumference of the collector 610. In other words, the length of the ring-shaped structure 620 and the circumference of the collector 610 match each other, which will be equal to the length of the resulting graft implant.

[0019] For steps 1 - 6, in other embodiments, it can also be a step of creating a tube having the intended inner diameter and final length of the graft design. This tube is formed into a ring shape, attached to the second target, where a thin electrospun layer is wound up to form a roll-shaped layered graft around the tube.

[0020] 7. The layer of the polymer 710 is electrospun to surround the collector 610 (instead of the ring-shaped structure 620).

[0021] 8. As shown in Figure 7, the ring-shaped structure 620 is rolled from left to right on the collector 610. As the ring-shaped structure 620 rolls, its thickness increases as the polymer 710 is wound up on the outer surface of the ring-shaped structure 620. In other words, as the ring-shaped structure 620 rotates from left to right, its thickness is increased by the polymer 710, and as a result, a thicker ring-shaped structure 810 is obtained (Figure 8). Needless to say, by rolling and adding the polymer 710, the diameter of the ring-shaped structure 810 becomes larger than the diameter of the ring-shaped structure 620. The roll-shaped ring-shaped structure here refers to the ring-shaped structure 810. In one embodiment, immediately after the electrospinning process, that is, when the fibers are still slightly wet, winding can be performed. Thereby, it is expected that the adhesion between the roll-shaped layers is strengthened and the structural integrity is improved.

[0022] 9. Here, the ring-shaped structure 810 is cut and removed from the rigid pins 630 used to form the ring-shaped structure around the collector 610 and the collector 610, and a cut ring-shaped structure is obtained.

[0023] 10. A rod (e.g., a stainless steel rod) is placed inside the lumen of the cut ring-shaped structure to straighten the structure (not shown).

[0024] 11. Here, in a linear configuration, the polymer 1010 is electrospun onto the outer surface of the structure to obtain the structure 1000 (Figure 10).

[0025] 12. The next step is to remove the silicon tube (SI) 120 from the structure 1000, which is achieved by dissolving the polyethylene oxide (PEO) layer 130 from the structure 1000. By submerging the structure 1000 in water, it becomes possible to remove the silicon tube (SI) 120 from the structure 1000, and as a result, the structure 1100 is obtained. The fact that the three polymer layers overlap allows these layers to slide on top of each other, preventing kinking of the tubular graft implant. Note that the middle polymer layer is configured to be helically wound, while the inner and outer layers are configured to be continuous cylinders.

[0026] 13. The structure 1100 is annealed linearly in a vacuum oven at approximately 37 degrees Celsius. The goal here is to finally complete a straight cylindrical tubular graft implant.

[0027] The point of the present invention is the step of rolling over a thin layer of an electrospun polymer sheet and winding up and collecting the sheet around a ring, thereby creating a more kink-resistant laminated graft. The step of creating the ring structure is an example for achieving this, but there are other approaches for reliably removing the target, and the present invention is not limited to the specific examples provided herein.

[0028] The essential requirements of the ring are as follows. Define the inner diameter and the final length of the final graft device. Require a degree of flexibility to be able to form the ring. Require sufficient adhesiveness of the electrospun polymer layer so that the polymer can be collected when rolling over the electrospun polymer layer. Require that it can be easily removed from the inside of the wound-up tube.

[0029] In still other embodiments, it is considered that there may be a continuous inner tube (created in step 3) and a continuous outer tube (created in step 11) that prevent the roll from unwinding.

[0030] This method and its final structure have the following advantages.

[0031] Breaking pressure

[0032] Roll-shaped tubes were manufactured according to steps 1 to 13 and compared with other tubes of the same material and the same thickness manufactured by conventional electrospinning, that is, by directly depositing polymer fibers on a rotating cylindrical target. In the breaking pressure test, they showed breaking pressures of 2000 mmHg and 800 mmHg, respectively. In other words, the tubular graft implant has significantly higher breaking pressure resistance (about 2000 mmHg) compared to a normal spun graft (about 800 mmHg).

[0033] By manufacturing the tube in the described method, considering the circumferential direction, the fiber orientation within the scaffold rotates by 90° (Figure 15). Therefore, the fiber arrangement reverses from a strong arrangement in the longitudinal direction (i.e., the polymer is stronger in the axial direction than in the circumferential direction) to a strong arrangement in the circumferential direction. In the conventional method of spinning a polymer on a cylindrical target, usually, a gentle axial orientation (e.g., with an axial-to-circumferential tensile modulus ratio of about 2:1) is obtained. After winding the main direction of the fiber in the described method, a strong alignment ratio is oriented in the circumferential direction. This improves the kink resistance and burst pressure resistance of the tube, as well as the radial force of the scaffold.

[0034] Multiple layers

[0035] The tubular graft implant has multiple layers. Instead of a single thick scaffold layer, with a layout composed of different layers, the tubular graft has crushing regions between the multiple layers. These crushing regions enable the squeezing of the material. When the tubular graft is bent, the different layers slide or move relative to each other, reducing the bending stiffness of the scaffold and facilitating bending with excellent kink resistance compared to the standard method of electrospinning artificial blood vessels.

[0036] An important point regarding the crushing regions is that since the layers can move relative to each other, they operate as a bundle of semi-independent thin structures. This improves the bending stiffness of the composite structure and significantly enhances the bendability. The main purpose of obtaining these so-called crushing regions is to keep the layers unconnected to each other.

[0037] In one embodiment, the method of the present invention relates to a graft in which each layer has a different fiber orientation. This can be obtained when two different sheets are spun, laid on top of each other (such that the fiber directions are different from each other), and then the two sheets are wound together to form a graft / tube. Multilayer grafts can be obtained using only one sheet, but all layers have the same orientation. Thus, in one embodiment, the method includes the step of achieving different fiber orientations by rolling the layers.

[0038] Porosity

[0039] The tubular graft implant has an acceptable / desirable porosity for ETR. This is in contrast, for example, to ePTFE tubular grafts which have pore sizes that are insufficient to allow for cell infiltration and ETR.

[0040] Uniform thickness profile

[0041] The wall thickness profile of the tubular graft implant according to the method described herein is more uniform than the profile achieved by standard electrospinning because potential thickness variations at the tip of the spun scaffold are eliminated. This allows for a relatively long graft length to be achieved in the case of small diameter blood vessels (i.e., coronary artery bypass grafts).

[0042] In a conventional electrospinning process, electrospun devices may sometimes be slightly thicker in the center compared to the outer edge. This effect is eliminated when the material is rolled because the thickness is symmetric along the circumference of the spun tube. The thickness range of the device as a whole is preferably 0.1 mm to 2 mm, particularly 0.4 mm to 1 mm. The diameter range is 2 to 8 mm, and the small diameter may usually be 6 mm or less, but may be up to 8 mm depending on the application. The length of the device is preferably 5 cm to 100 cm.

[0043] For the individual layers of the device, in certain embodiments, a thickness of 30 μm to 50 μm is preferred. In other embodiments, the thickness may be 20 μm to 100 μm. From the perspective of kink resistance, a thinner thickness is preferred, but since uniform reproduction becomes difficult, it is better not to be too thin.

[0044] Metal-free solution

[0045] The tubular graft implant according to the method described herein does not include a support element (such as a metal) that is common in the art to prevent kinking. Incorporating support elements for the purpose of kink resistance and radial support is very costly for mass production, has a large burden on quality and regulation, and also involves the risk of long-term breakage / failure in the clinical setting.

[0046] The tubular graft implant according to the method described herein focuses on significantly increasing the circumferential strength and reducing the bending stiffness to achieve acceptable kink resistance. Therefore, a support element for such a tubular graft implant is redundant. Another important design goal is to obtain a tubular graft implant that is completely bioabsorbable, which is achieved by the final structure 1100.

[0047] Kink

[0048] When testing the kink resistance of the tubular graft implant by the method described in this specification, it showed substantially improved kink resistance compared to unsupported grafts. As shown in FIG. 12, prototypes with a wall thickness of about 600 μm or less and a diameter of about 3.2 mm or less were used. Since the roll-shaped PEO layer was used as the mandrel for the inner diameter, the desired inner diameter of 4.0 mm was not achieved. This prototype causes kinking at a radius of 1.25 cm, while the unsupported graft causes kinking before reaching a radius of 3 cm. FIG. 13 is a diagram showing a prototype with a diameter of 4.0 mm defined by a fixed silicon tube. The wall thickness was 500 μm or less. This prototype caused kinking at 1.75 cm, which is still a significant improvement compared to a standard electrospun graft (without a metal support) that had already caused kinking before reaching 3 cm. As shown in FIG. 13, the bending radius of this prototype was 1.75 cm. The kink radius of an equivalent single-layer device was 3 cm. This difference is important and is a very meaningful difference for applications targeted at embodiments of the present invention. Physically explaining this large difference is that as the thickness increases, the bending stiffness of the material increases cubically. When multiple layers can move relative to each other, they act to some extent like several thin beams rather than one thick beam. This significantly reduces the bending force and makes it easier to bend the device, improving kink resistance.

[0049] Scalability

[0050] Embodiments of the present invention may also offer the advantage of enabling easier scalability. For example, in other embodiments, it can be considered that an electrospun sheet for winding (step 7) is separately manufactured using a very large target, cut to a predetermined size immediately before being rolled (step 8), and then mounted on the target.

[0051] As yet another embodiment, it is assumed that the rotation is performed on a linear target. For example, Step 1: Manufacture the inner layer by spinning on a linear cylindrical target having a desired inner diameter. Step 2: Separately manufacture a thin electrospun sheet for forming a roll-shaped inner spiral layer. Step 3: Wrap the sheet manufactured in Step 2 around the target together with the inner layer manufactured in Step 1. Step 4: Spin a thin outer layer around the roll-shaped structure created in Step 3.

[0052] Furthermore, any embodiment in which the winding is performed in two separate operations can also be assumed. After the first winding step, a reinforcing structure may be applied around the roll-shaped structure, and then a second sheet may be wrapped around it, and then the outer layer may be spun. This facilitates the expansion and automation of the process.

[0053] Furthermore, any embodiment in which the winding is performed using a sheet cut at an angle with respect to a preferred fiber orientation may also be assumed (Figure 14). After cutting, by wrapping the sheet around a mandrel, a tube having a preferred fiber orientation at an arbitrary angle with respect to the spindle can be obtained. In yet another embodiment, before wrapping a plurality of sheets around a mandrel, it is conceivable to stack the plurality of sheets at different preferred angles. In this way, it becomes possible to produce a graft having a plurality of preferred fiber orientations, such as two symmetric preferred fiber orientations with respect to the longitudinal axis, such as the collagen fiber orientation of a natural blood vessel.

[0054] Regarding Figure 14, Step 1: Manufacture an electrospun sheet having a preferred fiber orientation (as marked with a line). Step 2: Cut into rectangular sheets having different preferred fiber orientations. Step 3: Rotate the sheet in alignment with the axis of rotation. Step 4: Wrap the sheet around a cylindrical mandrel to produce a multilayer graft having a fiber orientation inclined with respect to the main axis of the graft. Step 5: Remove the inner mandrel.

[0055] For the purposes of the present invention, the term "graft" refers to a graft used to connect two blood vessels to each other, and may be a bypass graft, shunt, interposition graft, end-to-end, side-to-end, end-to-side, side-to-side, or may be a snake or jump graft (where multiple bypasses are created with one graft). It does not mean a device used within an existing blood vessel, such as a stent or endograft. The diameter range of the small graft devices provided here is 4 mm or less (for CABG), around 6 mm (for access grafts), and up to 8 mm (for peripheral grafts).

[0056] In one embodiment, the tubular graft implant is a pre-bend graft. In an example, by rotating a flexible thin tube on a large-diameter mandrel, a curved graft having a radius similar to that of the large mandrel can be obtained. Thus, the graft is pre-bent or pre-curved, which may be an advantage in some applications.

[0057] The electrospinnable materials referred to in the present application may include a ureido-pyrimidinone (UPy) quadruple hydrogen bonding motif (pioneered by Sijbesma (1997), Science 278, 1601-1604), and may include a polymer backbone selected from the group consisting of 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 copolyesters thereof. Examples of polycarbonates include poly(trimethylene carbonate), poly(dimethyltrimethylene carbonate), poly(hexamethylene carbonate), and the like.

[0058] Even for polymers other than supramolecules, similar results can be obtained by carefully selecting properties and processing the materials to ensure the required surface properties. 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 copolyesters thereof. Examples of polycarbonates include poly(trimethylene carbonate), poly(dimethyltrimethylene carbonate), poly(hexamethylene carbonate), and the like.

Claims

1. An electrospun tubular graft implant, (a) an electrospun, continuous lumen-providing tubular layer having a longitudinal axis and an outer surface, (b) one or more roll-shaped polymer layers of an electrospun sheet wound in a roll shape on the outer surface of the electrospun tubular layer and around the longitudinal axis, (c) an electrospun outer polymer layer covering the one or more roll-shaped polymer layers, A graft implant, wherein the tubular layer, the one or more roll-shaped polymer layers, and the outer polymer layer are slidable on one another.

2. The graft implant according to claim 1, comprising 10 to 20 layers.

3. The graft implant according to claim 1, wherein each of the one or more layers has a thickness of 30 μm to 50 μm, or a thickness of 20 μm to 100 μm.

4. The graft implant according to claim 1, comprising two or more layers, wherein the layers have different fiber directions from one another.

5. The graft implant according to claim 1, wherein the one or more roll-shaped polymer layers are wound in a roll shape around the longitudinal axis and form a helically wound configuration.

6. A tubular graft implant, comprising two or more layers of an electrospun polymer sheet wound in a roll shape around a longitudinal axis defining an inner diameter of the tubular graft implant, and configured such that when the tubular graft implant is bent, the two or more layers of the electrospun polymer sheet move independently of one another.

7. The graft implant according to claim 6, comprising 10 to 20 layers.

8. The graft implant according to claim 6, wherein each of the two or more layers has a thickness of 30 μm to 50 μm or a thickness of 20 μm to 100 μm.

9. The graft implant according to claim 6, wherein the layers have different fiber directions from each other.

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