Composite Hybrid Scale Fiber Matrix of Macropores and Micropores

Abstract

Disclosed herein are embodiments of nonwoven hybrid-scale fiber matrix sheets that can be used to improve wound healing. The nonwoven hybrid-scale fiber matrix sheets can be both micropores due to the hybrid-scale fiber matrix and macropores due to the addition of cuts or perforations in the hybrid-scale fiber matrix sheets. The microporous and macroporous sheets can improve biological healing at the wound site.

Description

Technical Field

[0001] Embodiments of the present disclosure generally relate to sheets of hybrid-scale fiber matrices having macropores and micropores for improving biocompatibility.

Background Art

[0002] Numerous pathological conditions and surgical procedures result in substantial defects in various organs, tissues, and anatomical structures. In most such cases, surgeons and physicians need to utilize special types of surgical meshes, materials, and / or scaffolds to repair such defects. Unfortunately, the in vivo performance of known surgical materials is adversely affected by several limiting factors. For example, existing synthetic surgical meshes typically result in excessive fibrosis or scarring, poor tissue integration, and an increased risk of postoperative pain. At the same time, known biological materials can induce strong immune responses and abnormal tissue ingrowth, which can negatively impact patient outcomes. Additionally, existing synthetic surgical meshes can cause scarring, postoperative pain, restricted mobility, restricted range of motion, adhesions, infections, ulcers, decreased biomechanical properties, and / or decreased intraoperative handling.

[0003] Nanofabrication, nanofibers, or hybrid-scale fiber matrices are meshes or materials composed of resorbable polymer fibers that are tens of thousands to thousands of times smaller than individual human cells and have recently been proposed as unique substrates for implantable surgical meshes and materials. Generally, existing nanofiber materials tend to have suboptimal mechanical performance compared to known surgical meshes. Existing nanofiber materials do not have the tensile strength, tear resistance, and burst strength required for many surgical applications or basic intraoperative procedures prior to in vivo placement. To counter this drawback, known meshes are formed using higher fiber densities as a means of improving mechanical strength. However, the use of such high-density meshes can reduce effective cell and tissue ingrowth into the mesh, reduce mesh integration with native tissue, and reduce the biocompatibility of polymer implants. As a result, there is a need for nanofiber or hybrid-scale fiber matrix materials that have increased thickness and / or strength and good cell and / or tissue integration and biocompatibility, as well as methods for manufacturing nanofiber materials.

[0004] Tissue repair can be facilitated by one or more of the materials described herein, including sheets of polymer material or treated tissue that act like the native tissue in question. For example, skin wounds, including those caused by trauma or intentionally during a medical procedure, can be repaired by the application of a material having favorable cell and tissue integration. To facilitate the repair of skin wounds, dressings and other coverings can be applied in both clinical and surgical settings to promote wound healing and protect the wound from further harm. Typical wound coverings have a variety of purposes, including absorption of exudate, drainage of exudate, management of exudate, removal of foreign and dead cell material, cessation of bleeding, protection from infection, and relief of pain, as well as generally promoting the healing process. As another example, neurosurgical repair can be performed using one or more of the materials described herein.

[0005] Furthermore, while cell microarrays can be useful in biomedical research and tissue engineering, at least some known techniques for manufacturing such cell microarrays can be costly and time-consuming and may require the use of specialized and sophisticated equipment.

SUMMARY OF THE INVENTION

[0006] Various embodiments described herein relate to sheets of hybrid scale fiber matrices having macropores and micropores for improving biocompatibility.

[0007] In particular, in some embodiments, a three-dimensional electrospun hybrid scale fiber matrix for use in repairing tissue for wound care, the flexible electrospun fiber network having a first set of electrospun fibers comprising a first bioabsorbable polymer and a second set of electrospun fibers comprising a second bioabsorbable polymer, the first bioabsorbable polymer having a composition different from that of the second bioabsorbable polymer, the flexible electrospun fiber network further having one or more macroscale pores and one or more microscale pores, the one or more macroscale pores having an opening of about 1 mm to about 20 mm, the one or more microscale pores having an opening with an area of about 10 μm 2 ~about 10,000 μm 2 and the three-dimensional electrospun hybrid scale fiber matrix is flexible enough to facilitate the application of a three-dimensional electrospun nanofiber synthetic skin graft to the uneven surface of the tissue, the three-dimensional electrospun nanofiber synthetic skin graft is flexible enough to allow movement of the three-dimensional electrospun hybrid scale fiber matrix by the tissue, and a three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft is described in which the first set of electrospun fibers and the second set of electrospun fibers are configured to degrade after application to the tissue.

[0008] In some embodiments of the three-dimensional electrospinning hybrid-scale fiber matrix, one or more macroscale pores of the three-dimensional electrospinning hybrid-scale fiber matrix are configured to allow the passage or management of exudate. In some embodiments of the three-dimensional electrospinning hybrid-scale fiber matrix, one or more microscale pores of the three-dimensional electrospinning hybrid-scale fiber matrix are configured to promote cell growth.

[0009] In some embodiments, the three-dimensional electrospinning hybrid-scale fiber matrix further has at least one protrusion arising from the surface. In some embodiments, the first biodegradable polymer of the three-dimensional electrospinning hybrid-scale fiber matrix comprises poly(lactic-co-glycolic acid), and the second biodegradable polymer comprises polydioxanone. In some embodiments of the three-dimensional electrospinning hybrid-scale fiber matrix, the perforations are evenly distributed throughout the matrix.

[0010] Also, a method of manufacturing a biomedical patch device for tissue repair, comprising depositing a first structure of fibers having electrospun nanofibers via electrospinning, the first structure of fibers being configured to promote cell growth, and depositing a second structure of fibers having electrospun nanofibers via electrospinning, the second structure of fibers being configured to promote cell growth, wherein the first structure of fibers comprises a different composition than the second structure of fibers, and the first structure of fibers and the second structure of fibers have one or more microscale pores and one or more macroscale pores, the one or more macroscale pores having an opening of about 1 mm to about 20 mm, and the one or more microscale pores having an area of about 10 μm 2 ~ about 10,000 μm 2It has an opening, the biomedical patch device has a surface, the surface has a surface pattern configured to contact tissue, and the surface pattern, the first structure of the fibers, and the second structure of the fibers are configured to promote cell growth in one or more defined directions. The biomedical patch device has sufficient flexibility to facilitate application of the biomedical patch device to the non-uniform surface of the tissue, and the biomedical patch device has sufficient flexibility to allow movement of the biomedical patch device with the tissue. A method is disclosed in which the first structure of the fibers and the second structure of the fibers are configured to degrade after application to the tissue.

[0011] In some embodiments of the method, the first portion of the biomedical patch of a particular size contains a greater number of fibers than the second portion of the biomedical patch of the same particular size. In some embodiments of the method, the surface pattern is formed by placing a mask between the collector and the spinneret, the mask being configured to prevent at least a portion of the first structure of the fibers or the second structure of the fibers from depositing on the collector. In some embodiments of the method, the surface pattern is formed by directly depositing the first structure of the fibers and the second structure of the fibers on the collector without a mask. In some embodiments of the method, the surface pattern has a plurality of organized features. In some embodiments, the surface pattern has a plurality of topographical features configured to further promote cell migration in one or more of a plurality of defined directions. In some embodiments, the macroscale pores are generated by mechanical, electronic, and / or computer-controlled cutting. In some embodiments, the cutting is laser cutting. In some embodiments, the surface pattern further has protrusions arising from the surface. In some embodiments, the surface pattern further has depressions protruding downward from the surface.

[0012] For the purposes of this summary, certain aspects, advantages, and novel features of the present invention are described herein. It should be understood that not necessarily all such advantages can be achieved in accordance with any particular embodiment of the present invention. Thus, for example, those skilled in the art will recognize that the present invention may be embodied or implemented so as to achieve one advantage or group of advantages as taught herein without necessarily achieving other advantages as may be taught or suggested herein.

[0013] All of these embodiments are intended to be within the scope of the invention disclosed herein. These and other embodiments will be readily apparent to those skilled in the art from the following detailed description when taken in conjunction with the accompanying drawings, and the invention is not to be limited to any particular disclosed embodiment.

Brief Description of the Drawings

[0014]

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DETAILED DESCRIPTION OF THE INVENTION

[0015] The embodiments provided herein facilitate the repair of biological tissues or the reinforcement of biomedical materials based on biomedical patches (e.g., grafts, nanofiber matrices, hybrid scale fiber matrices, sheets) having a plurality of fibers as shown in FIG. 1. Such fibers can have a very small cross - sectional diameter (e.g., 1 - 3000 nanometers, 1 - 1000 nanometers) and may thus sometimes be referred to as nanofibers and / or microfibers. The biomedical patches are described herein with reference to use as dura mater and surgical meshes, but the described embodiments can be applied to any living tissue. In certain embodiments, the biomedical patch can be used for the treatment of skin wounds. Further, although described as a biomedical patch, the structure having fibers may be used for other purposes. Thus, the described embodiments are not limited to biomedical patches.

[0016] The patches are described in further detail in U.S. Patent Application Publication Nos. 2017 / 0326270, 2017 / 0319323, and U.S. Patent No. 10,124,089, each of which is incorporated herein by reference in its entirety.

[0017] Advantageously, the disclosed embodiments of the hybrid scale fiber matrix sheath can be either microporous and / or macroporous (e.g., reticulated). The hybrid scale fiber matrix itself may be microporous, and additional macro cuts / slits / pores / holes may be added to the matrix to provide means for allowing exudates (e.g., liquids) to pass through the sheet. This can be particularly advantageous for wet wounds, as liquid entrapment between the sheet and the wound can be problematic. Excessive accumulation of exudate at the wound site can cause tissue damage and infection - thus, proper drainage and passage of exudate can improve the healing outcome during wound treatment.

[0018] Advantageously, the disclosed embodiments of the sheet can include important and specific cut patterns that are optimized for both intracellular and tissue ingrowth and fluid flow within the material. In addition to other properties, other physical properties can also be optimized, such as additional surface area strength, flexibility, and stretching of the sheet to cover overall conformity. Further, the embodiments of the present disclosure can enable control of the pattern, and thus, the user can modify the sheet as needed to optimize various properties.

[0019] Generally, the present disclosure relates to a nonwoven graft material comprising two or more different types of fiber compositions, each having independent mechanical, chemical, and / or biological properties. Further, the material can be either microporous or macroporous. For example, in one embodiment, including one fiber composition can stabilize the resulting nonwoven graft material, while the other fiber composition can improve the stability, free shrinkage properties, mechanical properties, and absorption rate of the nonwoven graft material.

[0020] As used interchangeably herein, "nonwoven graft material" and "nonwoven graft fabric" refer to materials that have a structure of individual fibers or yarns woven together but are not in a distinguishable way like a knitted or woven fabric. Nonwoven graft materials and nonwoven graft fabrics can be formed from many methods such as, for example, electrospinning, meltblowing, spunbonding, melt spraying, and adhesive card web methods. The basis weight of the nonwoven graft material is usually expressed in ounces per square yard (osy) of the material or grams per square meter (gsm), and the fiber diameter is usually expressed in nanometers and micrometers (μm). A suitable basis weight of the nonwoven graft material of the present disclosure can be in the range of about 50 gsm to about 300 gsm. More preferably, the basis weight of the nonwoven graft material of the present disclosure can be in the range of about 70 gsm to about 140 gsm. The tensile strength of the nonwoven graft material of the present disclosure can be in the range of about 5 Newtons (N) to about 50 Newtons (N), including about 1 N to about 10 N to about 15 N. The strength of the nonwoven graft material of the present disclosure can also be described with respect to the suture pull-out strength, which refers to the force at which a suture can be pulled out from the nonwoven graft material. A suitable suture pull-out strength can be in the range of about 1 N to about 5 N.

[0021] As used herein, the term "microfiber" refers to small-diameter fibers having an average diameter of 75 μm or less, for example, small-diameter fibers having an average diameter of about 0.5 μm to about 50 μm, or more specifically, microfibers having an average diameter of about 2 μm to about 40 μm. Another commonly used expression for fiber diameter is denier. For example, the diameter of a polypropylene fiber given in μm can be converted to denier by squaring it and multiplying the result by 0.00629. Thus, a 15-μm polypropylene fiber has a denier of about 1.42 (15 2 × 0.00629 = 1.415).

[0022] As used herein, the terms "nanosize fiber" or "nanofiber" refer to very small diameter fibers having an average diameter of 2000 nanometers or less, 1500 nanometers or less, preferably 1000 nanometers (nm) or less. Nanofibers are generally understood to have a fiber diameter range of from about 10 to about 1500 nm, more specifically from about 10 to about 1000 nm, even more specifically from about 20 to about 500 nm, and most specifically from about 20 to about 400 nm. Other exemplary ranges include from about 50 to about 500 nm, from about 100 to 500 nm, or from about 40 to about 200 nm.

[0023] As used herein, the term "spunbond fiber" refers to small diameter fibers formed by extruding a molten thermoplastic material through a plurality of fine, usually circular, capillaries of a spinneret and rapidly reducing the diameter of the extruded filaments, such as, for example, as described in U.S. Patent No. 4,340,563 to Appel, U.S. Patent No. 3,692,618 to Dorschner, U.S. Patent No. 3,802,817 to Matsuki, U.S. Patents Nos. 3,338,992 and 3,341,394 to Kinney, U.S. Patents Nos. 3,502,763 and 3,909,009 to Levy, and U.S. Patent No. 3,542,615 to Dobo, each of which is hereby incorporated by reference in its entirety.

[0024] As used herein, the term "meltblown fiber" refers to a fiber formed by extruding a molten thermoplastic material through a plurality of fine and usually circular die capillaries as a melt stream or filament into a converging high velocity gas (e.g., air) stream that attenuates the filaments of the molten thermoplastic material to reduce its diameter (which may be the diameter of microfibers). The meltblown fibers are then carried by the high velocity gas stream and deposited on a collection surface to form randomly dispersed meltblown fibers. Such a method is disclosed, for example, in U.S. Patent No. 3,849,241, which is hereby incorporated by reference in its entirety. Meltblown fibers may be continuous or discontinuous and are generally microfibers having a diameter of less than 10 μm.

[0025] As used herein, the term "electrospinning" refers to a technique that uses the interaction between hydrodynamics and a charged surface to produce nano-sized fibers called electrospun fibers from a solution. Generally, the formation of electrospun fibers involves supplying a solution to an orifice within a body that is in electrical communication with a voltage source, and the electrical force aids in the formation of fine fibers that are deposited on a surface that may be grounded or at a lower voltage than the body. In electrospinning, a polymer solution or melt supplied from one or more needles, slots, or other orifices is charged to a high voltage relative to a collection grid. The electrical force overcomes the surface tension and moves the fine jets of the polymer solution or melt towards the grounded or oppositely charged collection grid. The jets may be drawn out into even finer fiber streams before reaching the target and are collected as interconnected small fibers. Specifically, when the solvent is evaporating (in processes that use a solvent), this liquid jet is stretched to many times its original length to produce continuous ultrathin fibers of the polymer. The dried or solidified fibers can have a diameter of about 40 nm, or about 10 to about 100 nm, although fibers of 100 to 500 nm are commonly observed. Various forms of electrospun nanofibers include branched nanofibers, tubes, ribbons, and split nanofibers, nanofiber yarns, nanofibers coated on the surface (e.g., with carbon, metal, etc.), nanofibers produced in a vacuum, and the like. The production of electrospun fibers is shown in many publications and patents, including, for example, P.W. Gibson et al., "Electrospun Fiber Mats: Transport Properties," AIChE Journal, 45(1):190-195 (January 1999), which is hereby incorporated by reference in its entirety.

[0026] As used herein, the term "type", such as when referring to "various fibers" or "different types of fibers", refers to fibers having "substantially different overall material compositions" with measurably different properties outside of differences in "average diameter" or other "size". That is, two fibers can be of the same "type" as defined herein but can have different "average diameters" or "average diameter ranges". Fibers are of different "types" if they have substantially different overall material compositions, although they may still have one or more common components. For example, electrospun fibers made from a polymer blend having a first polymer component present at a level of at least 10% by weight are considered a different type of fiber from electrospun fibers made from a polymer blend that substantially does not contain the first polymer element. Different "types" of fibers can also have completely different contents, each being made from, for example, different polymers, or one being made from polymer fibers and the other being made from titania fibers, or being made from, for example, ceramic fibers and titania fibers.

[0027] As used herein, the term "polymer" generally includes, but is not limited to, homopolymers, copolymers such as block, graft, random and alternating copolymers, terpolymers, etc., as well as blends and modifications thereof. Further, unless specifically limited otherwise, the term "polymer" shall be taken to include all possible geometric configurations of the material. These configurations include, but are not limited to, isotactic symmetry and atactic symmetry.

[0028] Hybrid scale fiber graft material

[0029] The nonwoven graft material of the present disclosure typically includes at least two different types of fiber compositions, including a composition comprising a hybrid-scale fiber matrix, each having independent mechanical, chemical, and / or biological properties. However, in some embodiments, the fibers may be the same. The fiber composition is preferably made from a synthetic absorbent polymer material. As used herein, the term "absorbent polymer material" refers to a material formed from an absorbent (also referred to as "biodegradable") polymer. That is, the polymer has the property of decomposing into degradation products that can be removed from the site within a period substantially coinciding with the period of postoperative healing when the material is exposed to conditions typical of those present at the postoperative site. Such degradation products can be absorbed into the patient's body. It should be understood that the period of postoperative healing is the period measured from the application of the nonwoven graft material of the present disclosure until the postoperative site is substantially healed. This period can range from several days to several months, depending on the invasiveness of the surgery and the healing rate of a particular individual. It is intended that the nonwoven graft material of the present invention can be prepared such that the time required for resorption of the nonwoven graft material can be controlled to coincide with the time required for healing or tissue reformation and regeneration. For example, in some nonwoven graft materials of the present disclosure, the fiber composition is selected to decompose within a period of about one week, while in other nonwoven graft materials, the composition is selected to decompose within a period of three years or, if desired, even longer.

[0030] The fiber compositions used in the present disclosure can be manufactured from any absorbent material that meets the criteria of the material, as their criteria are described above. The fiber composition can be formed from absorbent polymers such as, but not limited to, polymers of lactic acid and glycolic acid, copolymers of lactic acid and glycolic acid, poly(ether-co-ester), poly(hydroxybutyrate), polycaprolactone, copolymers of lactic acid and ε-aminocaproic acid, lactide polymers, copolymers of poly(hydroxybutyrate) and 3-hydroxyvalerate, polyesters of succinic acid, poly(N-acetyl-D-glucosamine), polydioxanone, cross-linked hyaluronic acid, cross-linked collagen, etc., and combinations thereof. Suitable synthetic polymers include, for example, polycaprolactone (poly(ε-caprolactone), PCL), polydioxanone (PDO), poly(glycolic acid) (PGA), poly(L-lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(L-lactide) (PLLA), poly(D,L-lactide) (P(DLLA)), poly(ethylene glycol) (PEG), montmorillonite (MMT), poly(L-lactide-co-ε-caprolactone) (P(LLA-CL)), poly(ε-caprolactone-co-ethyl ethylene phosphate) (P(CL-EEP)), poly[bis(p-methylphenoxy)phosphazene] (PNmPh), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(urethane ester) urea (PEUU), poly(p-dioxanone) (PPDO), polyurethane (PU), polyethylene terephthalate (PET), poly(ethylene-co-vinyl acetate) (PEVA), poly(ethylene oxide) (PEO), poly(phosphazene), poly(ethylene-co-vinyl alcohol), polymer nanoclay nanocomposite, poly(ethyleneimine), poly(ethylene oxide), polyvinylpyrrolidone, polystyrene (PS), and combinations thereof. Particularly suitable polymers include poly(lactic acid-co-glycolic acid), polydioxanone, polycaprolactone, and combinations thereof.

[0031] The fibers for the fiber composition can be of various sizes as would be considered suitable by one of ordinary skill in the art for the ultimate purpose of the nonwoven graft material. In some embodiments, the fibers for the fiber composition may be a hybrid scale fiber matrix. Typically, the fibers of the hybrid scale fiber matrix have an average fiber diameter of less than 5 μm (including less than 2 μm, including less than 1.5 μm, and including less than 1.0 μm). For example, in some embodiments, the fibers can have an average fiber diameter in the range of about 10 nm to about 5 μm, more specifically about 10 nm to about 1.0 μm, more specifically still about 20 nm to about 500 nm, and most specifically about 20 nm to about 400 nm. Other exemplary ranges include about 50 nm to about 500 nm, about 100 nm to about 500 nm, and about 40 nm to about 200 nm.

[0032] A suitable ratio of the first fiber composition to the second fiber composition resulting in the nonwoven graft material can range from about 10 to 1 to about 1 to 10.

[0033] In some embodiments, the nonwoven graft material is made from a first nonwoven fiber composition prepared from poly(lactic-co-glycolic acid) and a second nonwoven fiber composition prepared from polydioxanone. The resulting nonwoven graft material is a non-biological tissue substitute designed to provide optimal strength, handling, and sutureability while reducing local inflammation and improving wound healing and tissue regeneration. In an exemplary embodiment, the nonwoven graft material can be synthesized by electrospinning a first fiber composition comprising a copolymer of glycolide and L-lactide and a second fiber composition comprising polydioxanone (100 mol%) to create a structure that evokes a natural extracellular matrix. The mol% of glycolide relative to the mol% of L-lactide can range from about 100 mol% glycolide to 0 mol% L-lactide to 0 mol% glycolide to about 100 mol% L-lactide. A particularly preferred nonwoven graft material comprises a first fiber composition comprising 90 mol% glycolide and 10 mol% L-lactide, the mol% of glycolide relative to the mol% of L-lactide. This synthesis method produces a mechanically strong material while providing the appearance and feel of natural tissue. The structure of this non-biological graft material further supports in-growth and neoduralization of cells and tissues while minimizing inflammation.

[0034] The nonwoven graft material can typically be prepared to be of any of a variety of sizes, shapes, and thicknesses. The wet and dry nonwoven graft materials can be suitably cut and trimmed to any desired size and shape. In a particularly preferred embodiment, the nonwoven graft material has a size in the range of about 0.55 inches in diameter to about 0.5 inches × 1 inch to about 2.5 cm × 2.5 cm (1 inch × 1 inch) to about 25.5 cm × 50 cm (10 inches × 20 inches) and includes, for example, about 2.5 cm × 2.5 cm (1 inch × 1 inch), about 5.0 cm × 5.0 cm (2 inches × 2 inches), about 7.5 cm × 7.5 cm (3 inches × 3 inches), includes about 12.5 cm × 17.5 cm (5 inches × 7 inches), and includes about 10 cm × 12.5 cm (4 inches × 5 inches).

[0035] The non-woven graft material typically has a thickness in the range of about 0.1 mm to about 5 mm, including about 0.3 mm to about 0.8 mm, about 0.3 mm to about 0.7 mm, and about 0.3 mm to about 0.5 mm.

[0036] The non-woven graft material is typically microporous and has interconnected pores with a pore size in the range of about 10 μm 2 to about 10,000 μm. 2 Particularly preferred embodiments have a pore size of less than 300 μm. 2 Pores in this size range are thought to be able to accept cell invasion and support cell growth and proliferation, subsequent angiogenesis, and tissue development.

[0037] Furthermore, as shown in FIG. 2, the material can be macro-porous and micro-porous. Thus, the non-woven hybrid scale fiber matrix graft material sheet 200 can have one or more perforations (e.g., holes, cuts, slots, slits, openings) 202 in the sheet 200. In some embodiments, the perforations 202 can be found throughout the sheet 200. In some embodiments, the perforations 202 can be formed only in a portion of the sheet 200, such as 25%, 50%, or 75% of the sheet 200. The portions having the perforations 202 can be separated or connected. In some embodiments, the perforations 202 can be uniform, while in other embodiments they can be non-uniform. In some embodiments, the perforations 202 are distributed substantially evenly throughout the sheet 200, thereby providing an even distribution of fluid transport. In some embodiments, the perforations 202 can be concentrated in a particular region of the sheet 200, resulting in making that particular region more fluid-transportable than other regions. In some embodiments, the density of the slits in the non-woven hybrid scale fiber matrix graft material sheet can range from 1 to 400 slits per square inch. In some embodiments, the slits in the non-woven hybrid scale fiber matrix graft material can include a density of about 1 slit per square inch, about 5 slits per square inch, about 10 slits per square inch, about 15 slits per square inch, about 20 slits per square inch, about 40 slits per square inch, about 60 slits per square inch, about 80 slits per square inch, about 100 slits per square inch, about 150 slits per square inch, about 200 slits per square inch, about 250 slits per square inch, about 300 slits per square inch, about 350 slits per square inch, about 400 slits per square inch, and / or can include a density within the range defined by two of the foregoing values. In some embodiments, the length of the perforations in the non-woven hybrid scale fiber matrix graft material sheet can range from 1 to 20 mm.In some embodiments, the length of the perforation may be about 1 mm, about 2 mm, about 3 mm, about 5 mm, about 10 mm, about 15 mm, about 20 mm, and / or may include slits having lengths within the range defined by two of the foregoing values. In some embodiments, the perforations may be separated into columns, and the distance between each column may be in the range of 0.5 - 20 mm. In some embodiments, the distance between each column may be about 0.5 mm, about 1 mm, about 2 mm, about 3 mm, about 5 mm, about 10 mm, about 15 mm, about 20 mm, and / or may include distances within the range defined by two of the foregoing values. In some embodiments, the distance between individual perforations within a column may be in the range of 1 - 20 mm. In some embodiments, the distance between individual perforations may be about 1 mm, about 2 mm, about 3 mm, about 5 mm, about 10 mm, about 15 mm, about 20 mm, and / or may include distances within the range defined by two of the foregoing values.

[0038] Figures 3 - 10 show various non - limiting perforation patterns that may be used in embodiments of the present disclosure.

[0039] Furthermore, while the above figures show the perforations as straight cuts, other types of perforations may be used as well. Figures 11A - 11B show some examples of alternating perforations using circles (Figure 11A) and diamonds (Figure 11B). These are not limiting shapes, and other shapes such as triangles, rectangles, ellipses, irregular polymers, etc. may also be used for perforations. Furthermore, combinations of different types of perforations may also be used. Figures 13A - 13E also disclose non - limiting exemplary perforation patterns including combinations of perforations to form zigzags and stars, as well as irregular shapes.

[0040] Figures 12A - 12D show embodiments of the macro - and microporous matrices discussed herein. Figure 12A shows a representative plan view of an embodiment of a macro - and microporous matrix having dimensions of 3 ± 0.05 inches by 1 ± 0.05 inches. In Figure 12A, the matrix is composed of two fiber assemblies produced by electrospinning, where the first fiber assembly is a copolymer between glycolide and L - lactide and the second fiber assembly is a polymer of para - dioxanone. Figure 12A is further characterized by a repeating pattern featuring circular protrusions and perforations represented as white lines repeated over a significant portion of the matrix. Figure 12B is a depth - representation side view of an embodiment of a macro - and microporous matrix showing the overall thickness of the matrix in the range of 0.2 - 0.95 mm. Figure 12C shows a representative plan view of an embodiment of a macro - and microporous matrix having dimensions of 3 ± 0.05 inches by 1 ± 0.05 inches. Figure 12C is characterized in that it is composed of two fiber assemblies produced by electrospinning, where the first fiber assembly is a copolymer between glycolide and L - lactide and the second fiber assembly is a polymer of para - dioxanone. Figure 12D is a depth - representation side view of an embodiment of a macro - and microporous matrix where the surface is substantially flat or otherwise has no surface pattern. Figures 14A - 14B, Figure 15, and Figure 16 show non - limiting embodiments of the hybrid - scale fiber matrix when applied to tissue. Figures 14A and 14B show non - limiting embodiments where a non - woven graft material is laid over a wound site.

[0041] In some embodiments, the non-woven graft material may be surface-modified with biomolecules such as (but not limited to) hyaluronic acid, collagen, laminin, fibronectin, growth factors, integrin peptides (Arg-Gly-Asp, i.e., RGD peptides), or sodium hyaluronate and / or chitosan nicotinic amide ascorbate, which are thought to enhance cell migration and proliferation, or any combination thereof. The material may also be impregnated with these and other bioactive agents such as drugs, vitamins, growth factors, therapeutic peptides, etc. Additionally, drugs that relieve pain may also be incorporated into the material.

[0042] In another embodiment, the disclosure relates to a laminate comprising a non-woven graft material comprising a first non-woven fiber composition and a second non-woven fiber composition.

[0043] In some embodiments, the non-woven graft material of the laminate comprises a first non-woven fiber composition comprising poly(lactic-co-glycolic acid) and a second non-woven fiber composition comprising polydioxanone, as described herein.

[0044] In some embodiments, the non-woven graft material may have at least one protrusion arising from the surface of the non-woven graft material. A protrusion is a projection or elevation arising from the surface of the non-woven graft material. The protrusions can arise from the upper surface of the non-woven graft material, the bottom surface of the non-woven graft material, and from both the upper and bottom surfaces of the non-woven graft material. The protrusions can be of any desired shape, such as, for example, circular, spherical, square, rectangular, rhomboidal, star-shaped, irregular, and combinations thereof. The protrusions can be of any desired height measured from the surface of the material to the top of the protrusion. In one embodiment, the protrusions can have a substantially uniform height from the surface of the material. In another embodiment, the protrusions can be formed gradually from the surface of the material to the highest measurable surface of the protrusion. In some embodiments, the surface of the non-woven graft material includes a plurality of protrusions. The plurality of protrusions can be patterned on the surface of the non-woven graft material or can be randomly distributed. In another embodiment, the method includes forming at least one indentation in the surface of the non-woven graft material. An indentation is a recess or depression in the surface of the non-woven graft material. The indentations can be on the upper surface of the non-woven graft material, the bottom surface of the non-woven graft material, and on both the upper and bottom surfaces of the non-woven graft material. The indentations can be of any desired shape, such as, for example, circular, spherical, square, rectangular, rhomboidal, star-shaped, irregular, and combinations thereof. The indentations can be of any desired depth measured from the surface of the material to the bottom of the indentation. In one embodiment, the indentations can have a substantially uniform depth from the surface of the material to the deepest depth of the indentation. In another embodiment, the indentations can be formed gradually from the surface of the material to the deepest depth of the indentation. In some embodiments, the surface of the non-woven graft material includes a plurality of indentations. The plurality of indentations can be patterned on the surface of the non-woven graft material or can be randomly distributed. In another embodiment, the non-woven graft material can have at least one protrusion arising from at least one indentation in the surface of the non-woven graft material and the surface of the non-woven graft material. In another embodiment, the non-woven graft material can have at least one protrusion arising from the upper surface of the non-woven graft material and at least one indentation in the upper surface of the non-woven graft material.In another embodiment, the non-woven graft material may have at least one protrusion arising from the bottom surface of the non-woven graft material and at least one indentation in the bottom surface of the non-woven graft material. In another embodiment, the non-woven graft material may have at least one protrusion arising from the top surface of the non-woven graft material, at least one protrusion arising from the bottom surface of the non-woven graft material, at least one indentation in the top surface of the non-woven graft material, and at least one indentation in the bottom surface of the non-woven graft material. The plurality of indentations and the plurality of indentations may be patterned or randomly distributed on the surface of the non-woven graft material. Suitable methods for forming the protrusions and indentations include pressing, stamping, and other methods known to those skilled in the art.

[0045] Electrospinning

[0046] In some embodiments, the present disclosure relates to a method of preparing a non-woven graft material. This method generally includes preparing an aqueous solution of the above polymers. In particular, fibers obtained from separate polymer solutions are brought into contact with each other using one or more methods such as electrospinning, electrospraying, meltblowing, spunbonding, etc. to form a non-woven graft material, and the non-woven graft material is dried.

[0047] The non-woven graft material is dried to remove the solvent used to prepare the aqueous polymer solution. Drying can be carried out using methods generally known in the art, including but not limited to Yankee dryers, vacuum chambers, vacuum ovens, and through-air dryers. Preferably, a non-compressive drying method that tends to preserve the bulk or thickness of the non-woven graft material is used. Suitable through-drying apparatuses and through-drying fabrics are conventionally well-known. Those skilled in the art can readily determine the optimal drying gas temperature and residence time for a particular through-drying operation.

[0048] In some embodiments, a first fiber composition obtained from a first aqueous polymer solution and a second fiber composition obtained from a second aqueous polymer solution are mixed and an electrospun graft material is formed using the electrospinning method as described above. The electrospinning method generally involves applying a high voltage (e.g., about 1 kV to about 100 kV, including about 3 kV to about 80 kV depending on the configuration of the electrospinning apparatus) to a polymer fiber solution to generate a polymer jet. As the jet moves through the air, the jet elongates under repulsive electrostatic forces and nanofibers or hybrid-scale fibers are produced from the polymer fiber solution. The high voltage is applied between a ground plane (or an oppositely charged surface) and a conductive capillary into which the polymer fiber solution is injected. If the capillary is a non-conductor such as a glass pipette, a high voltage can also be applied to the solution or melt through wiring. First, the solution at the open tip of the capillary is pulled into a conical shape (so-called "Taylor cone") by the interaction of the electric force and the surface tension. In a specific voltage range, a fine jet of the polymer fiber solution is formed at the tip of the Taylor cone and is emitted towards the target. The force from the electric field accelerates and stretches the jet. This stretching, together with the evaporation of the solvent molecules, makes the jet diameter smaller. As the jet diameter decreases, the charge density increases until the electrostatic force within the polymer overcomes the cohesive force that holds the jet together (e.g., surface tension), splitting or "spraying" the jet into multifilaments of polymer nanofibers or hybrid-scale fibers. The fibers continue to expand until they reach the collector, where they are collected as non-woven nanofibers or hybrid-scale fibers and optionally dried.

[0049] Solvents suitable for preparing the aqueous polymer solution include, for example, hexafluoroisopropanol (HFIP), dichloromethane (DCM), dimethylformamide (DMF), acetone, and ethanol.

[0050] In some embodiments, the method may further include forming at least one protrusion arising from the surface of the non-woven graft material, forming at least one indentation on the surface of the non-woven graft material, and combinations thereof. A protrusion is a projection or elevation arising from the surface of the non-woven graft material. The protrusion can arise from the upper surface of the non-woven graft material, the bottom surface of the non-woven graft material, and from both the upper and bottom surfaces of the non-woven graft material. The protrusion can be of any desired shape, such as circular, spherical, square, rectangular, rhombic, star-shaped, irregular, and combinations thereof. The protrusion can have any desired height measured from the surface of the material to the top of the protrusion. In one embodiment, the protrusion can have a substantially uniform height from the surface of the material. In another embodiment, the protrusion can be formed gradually from the surface of the material to the highest measurable surface of the protrusion. In some embodiments, the surface of the non-woven graft material includes a plurality of protrusions. The plurality of protrusions can be patterned on the surface of the non-woven graft material or can be randomly distributed. In another embodiment, the method includes forming at least one indentation on the surface of the non-woven graft material. An indentation is a recess or depression in the surface of the non-woven graft material. The indentation can be on the upper surface of the non-woven graft material, the bottom surface of the non-woven graft material, and on both the upper and bottom surfaces of the non-woven graft material. The indentation can be of any desired shape, such as circular, spherical, square, rectangular, rhombic, star-shaped, irregular, and combinations thereof. The indentation can have any desired depth measured from the surface of the material to the bottom of the indentation. In one embodiment, the indentation can have a substantially uniform depth from the surface of the material to the deepest depth of the indentation. In another embodiment, the indentation can be formed gradually from the surface of the material to the deepest depth of the indentation. In some embodiments, the surface of the non-woven graft material includes a plurality of indentations. The plurality of indentations can be patterned on the surface of the non-woven graft material or can be randomly distributed. In another embodiment, the non-woven graft material can have at least one protrusion arising from at least one indentation on the surface of the non-woven graft material and the surface of the non-woven graft material. In another embodiment, the non-woven graft material can have at least one protrusion arising from the upper surface of the non-woven graft material and at least one indentation on the upper surface of the non-woven graft material.In another embodiment, the nonwoven graft material may have at least one protrusion resulting from at least one indentation on the bottom surface of the nonwoven graft material and the bottom surface of the nonwoven graft material. In another embodiment, the nonwoven graft material may have at least one protrusion arising from the upper surface of the nonwoven graft material, at least one protrusion arising from the bottom surface of the nonwoven graft material, at least one indentation on the upper surface of the nonwoven graft material, and at least one indentation on the bottom surface of the nonwoven graft material. The plurality of indentations and the plurality of indentations may be patterned or randomly distributed on the surface of the nonwoven graft material. Suitable methods for forming protrusions and indentations include pressing, stamping, and other methods known to those skilled in the art.

[0051] In some embodiments, when the material is electrospun, the above-described macroperforations can be incorporated into the sheet of material, such as by a cutting step. This can be done mechanically, electronically, and / or under computer control in some embodiments to provide consistency. Also, laser cutting can be used to form perforations in the material.

[0052] In some embodiments, perforations can be incorporated into the material during the electrospinning process, such that an additional cutting step may not be used. For example, when the fibers are electrospun onto a substrate, the substrate pattern can be prepared such that the fibers leave a specific perforation pattern in the material. For example, the substrate may be metal, and the fibers may adhere to the metal substrate to form the desired cutting pattern.

[0053] In some embodiments, the sheet can be manufactured to have regions of higher or lower fiber density that can provide the macro-porous capabilities discussed herein.

[0054] Tissue repair

[0055] In some embodiments, the present disclosure relates to a method of tissue repair in an individual in need of tissue repair. The method can include applying to a surgical site a nonwoven graft material that includes a first fiber composition and a second fiber composition. The method is particularly suitable for repairing tissues such as, for example, dura mater, pericardium, small intestinal submucosa, dermis, epidermis, tendon, trachea, cardiac valve leaflet, gastrointestinal tract, and cardiac tissue. Suitable tissue repair procedures include, for example, neurosurgical procedures such as dura mater repair, skin grafting, trachea repair, gastrointestinal tract repair (e.g., abdominal hernia repair, ulcer repair), cardiac defect repair, head and neck surgery, application to fractures, and burn repair.

[0056] Preferably, the nonwoven graft material includes a first fiber composition, and examples of the first fiber composition include polycaprolactone (poly(ε-caprolactone), PCL), polydioxanone (PDO), poly(glycolic acid) (PGA), poly(L-lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(L-lactide) (PLLA), poly(D,L-lactide) (P(DLLA)), poly(ethylene glycol) (PEG), montmorillonite (MMT), poly(L-lactide-co-ε-caprolactone) (P(LLA-CL)), poly(ε-caprolactone-co-ethyl ethylene phosphate) (P(CL-EEP)), poly[bis(p-methylphenoxy)phosphazene] (PNmPh), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(urethane ester) urea (PEUU), poly(p-dioxanone) (PPDO), polyurethane (PU), polyethylene terephthalate (PET), poly(ethylene-co-vinyl acetate) (PEVA), poly(ethylene oxide) (PEO), poly(phosphazene), poly(ethylene-co-vinyl alcohol), polymer nanoclay nanocomposite, poly(ethyleneimine), poly(ethylene oxide), polyvinyl pyrrolidone, polystyrene (PS), and polymers selected from combinations thereof. Particularly suitable polymers include poly(lactic acid-co-glycolic acid), polydioxanone, polycaprolactone, and combinations thereof.

[0057] Preferably, the nonwoven graft material comprises a second fiber composition, and examples of the second fiber composition include polycaprolactone (poly(ε-caprolactone), PCL), polydioxanone (PDO), poly(glycolic acid) (PGA), poly(L-lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(L-lactide) (PLLA), poly(D,L-lactide) (P(DLLA)), poly(ethylene glycol) (PEG), montmorillonite (MMT), poly(L-lactide-co-ε-caprolactone) (P(LLA-CL)), poly(ε-caprolactone-co-ethyl ethylene phosphate) (P(CL-EEP)), poly[bis(p-methylphenoxy)phosphazene] (PNmPh), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(urethane ester) urea (PEUU), poly(p-dioxanone) (PPDO), polyurethane (PU), polyethylene terephthalate (PET), poly(ethylene-co-vinyl acetate) (PEVA), poly(ethylene oxide) (PEO), poly(phosphazene), poly(ethylene-co-vinyl alcohol), polymer nanoclay nanocomposite, poly(ethyleneimine), poly(ethylene oxide), polyvinylpyrrolidone, polystyrene (PS), and polymers selected from combinations thereof. Particularly preferred polymers include poly(lactic acid-co-glycolic acid), polydioxanone, polycaprolactone, and combinations thereof.

[0058] In a particularly preferred embodiment, the nonwoven graft material comprises a first fiber composition containing poly(lactic acid-co-glycolic acid) and a second fiber composition containing polydioxanone.

[0059] As used herein, "an individual in need of tissue repair" refers to an individual having tissue defects, tissue damage, tissue that is missing due to injury or removal, and tissue damaged by an incision. The method is particularly suitable for use in an individual or subset of individuals having a dural defect that requires repair of the dura mater. An individual having a dural defect can be an individual having a perforation in the dura mater, an individual from whom the dura mater has been removed, an individual in whom the dura mater has been damaged, and an individual having a dura mater with a surgical incision. An individual in need of tissue repair can be an adult individual, an infant, and a pediatric individual. Particularly suitable individuals can be human. Other particularly suitable individuals can be animals such as primates, pigs, dogs, cats, rabbits, rodents (e.g., mice and rats).

[0060] In some embodiments, the nonwoven graft material is secured to the surgical field, for example, by suturing the nonwoven graft material to the surgical field. In other embodiments, the nonwoven graft material is secured to the surgical field by a surgical adhesive or the like.

[0061] From the above description, it will be understood that the nanofibers and hybrid-scale fiber matrices of the present invention, as well as the manufacturing methods and usage methods, have been disclosed. Although some components, techniques, and aspects have been described with a certain degree of particularity, it is clear that many changes can be made to the specific designs, structures, and methodologies described herein without departing from the spirit and scope of the present disclosure.

[0062] The specific features described in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, the various features described in the context of a single embodiment can also be implemented separately or in any suitable partial combination in multiple embodiments. Furthermore, although the features can be described as acting in a particular combination, one or more features from the claimed combination can, in some cases, be deleted from the combination, and the combination can be claimed as any partial combination or variation of any partial combination.

[0063] Furthermore, the methods may be depicted in the drawings or described herein in a particular order, but such methods need not be performed in the particular order or sequence shown, and not all methods need to be performed to achieve the desired result. Other methods not shown or described may be incorporated into the exemplary methods and processes. For example, one or more additional methods may be performed before, after, simultaneously with, or between any of the described methods. Further, the methods may be rearranged or the order changed in other embodiments. Also, the separation of the various system components in the above embodiments should not be understood to require such separation in all embodiments, and it should be understood that the described components and systems may generally be integrated together into a single product or packaged into multiple products. Further, other embodiments are within the scope of the present disclosure.

[0064] Conditional language such as “can,” “could,” “might,” or “may” is generally not intended to convey that a particular embodiment necessarily includes or does not include a particular feature, element, or step, unless specifically stated otherwise or otherwise interpreted within the context in which it is used. Thus, such conditional language generally is not intended to imply that a feature, element, and / or step is required in any way for one or more embodiments.

[0065] Conjunctive language such as “at least one of X, Y, and Z” is generally used in contexts where it is to be understood that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not necessarily intended to imply that a particular embodiment requires that it include at least one of at least one of X, at least one of Y, and at least one of Z.

[0066] Degree expressions used in this specification, such as the terms "about", "approximately", "generally", and "substantially", refer to values, amounts, and characteristics that are close to the recited values, amounts, and characteristics, and that can still perform the desired function or achieve the desired result. For example, the terms "about", "approximately", "generally", and "substantially" may refer to amounts within a range of 10% or less, 5% or less, 1% or less, 0.1% or less, and 0.01% or less of the recited amount. When the recited amount is 0 (e.g., none, having none), the ranges listed above may be specific ranges and not within a specific percentage of the value. For example, it is 10 wt. / vol.%. or less, 5 wt. / vol.%. or less, 1 wt. / vol.%. or less, 0.1 wt. / vol.%. or less, 0.01 wt. / vol.%. or less of the recited amount. Further, all values in the tables within the present disclosure are understood to be the recited values, or alternatively, approximately the recited values.

[0067] The disclosure in this specification of any particular feature, aspect, method, characteristic, trait, property, attribute, component, etc. regarding various embodiments is applicable to all other embodiments shown in this specification. Further, it is recognized that any method described in this specification can be implemented using any device suitable for implementing the recited steps.

[0068] Although numerous embodiments and variations of the present disclosure are described in detail, other variations and methods of using them will be apparent to those skilled in the art. Therefore, it should be understood that various applications, variations, materials, and alternatives can be made from equivalents without departing from the unique and inventive disclosure in this specification or the claims.

Claims

1. A three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft for use in repairing tissue for wound care, having a flexible electrospun fiber network having a first set of electrospun fibers comprising a first bioabsorbable polymer and a second set of electrospun fibers comprising a second bioabsorbable polymer, wherein the first bioabsorbable polymer has a different composition from the second bioabsorbable polymer, wherein the flexible electrospun fiber network further has a plurality of macroscale pores and a plurality of microscale pores, the plurality of macroscale pores having openings of about 1 mm to about 20 mm, and the plurality of microscale pores having an area of about 10 μm ２ or more and less than 300 μm ２ having openings, and the distance between individual macroscale pores being about 1 mm to about 20 mm, wherein the three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft has sufficient flexibility to facilitate application of the three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft to the non-uniform surface of the tissue, wherein the three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft has sufficient flexibility to allow movement of the three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft by the tissue, A three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft, wherein the first set of electrospun fibers and the second set of electrospun fibers are configured to degrade after application to the tissue.

2. The three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft according to claim 1, wherein the plurality of macroscale pores of the three-dimensional electrospun hybrid scale fiber matrix synthetic skin graft are configured to allow passage of exudate.

3. The three-dimensional electrospinning hybrid scale fiber matrix synthetic skin graft of claim 1, wherein the plurality of microscale pores of the three-dimensional electrospinning hybrid scale fiber matrix synthetic skin graft are configured to promote cell growth.

4. The three-dimensional electrospinning hybrid scale fiber matrix synthetic skin graft of claim 1, wherein the first biodegradable polymer comprises poly(lactic-co-glycolic acid) and the second biodegradable polymer comprises polydioxanone.

5. The three-dimensional electrospinning hybrid scale fiber matrix synthetic skin graft of claim 1, wherein the perforations are evenly distributed throughout the matrix.

6. A method of manufacturing a biomedical patch device for tissue repair, comprising: depositing a first structure of fibers having hybrid scale fibers electrospun via electrospinning, the first structure of the fibers being configured to promote cell growth; depositing a second structure of fibers having hybrid scale fibers electrospun via electrospinning, the second structure of the fibers being configured to promote cell growth, wherein the first structure of the fibers comprises a different composition than the second structure of the fibers, wherein the first structure of the fibers and the second structure of the fibers have a plurality of macroscale pores and a plurality of microscale pores, the plurality of macroscale pores having an opening of about 1 mm to about 20 mm, and the plurality of microscale pores having an area of about 10 μm ２ or more and 300 μm ２ or less, and the distance between individual macroscale pores is about 1 mm to about 20 mm. The biomedical patch device has a surface, and the surface has a surface pattern configured to contact tissue. The surface pattern, the first structure of the fiber, and the second structure of the fiber are configured to promote cell growth in one or more defined directions. The biomedical patch device has sufficient flexibility to facilitate application of the biomedical patch device to the non-uniform surface of the tissue. The biomedical patch device has sufficient flexibility to allow movement of the biomedical patch device with the tissue. A method in which the first structure of the fiber and the second structure of the fiber are configured to decompose after application to the tissue.

7. The method according to claim 6, wherein a first portion of the biomedical patch of a specific size contains a greater number of fibers than a second portion of the biomedical patch of the specific size.

8. The method according to claim 6, wherein the surface pattern is formed by placing a mask between a collector and a spinneret, and the mask is configured to prevent at least a portion of the first structure of the fiber or the second structure of the fiber from depositing on the collector.

9. The method according to claim 6, wherein the surface pattern is formed by directly depositing the first structure of the fiber and the second structure of the fiber on the collector without a mask.

10. The method according to claim 9, wherein the surface pattern has a plurality of organized features.

11. The method according to claim 9, wherein the surface pattern has a plurality of topographic features configured to further promote cell movement in one or more of the plurality of defined directions.

12. The method according to claim 6, wherein the macroscale pores are generated by mechanical, electronic, and / or computer-controlled cutting.

13. The method according to claim 12, wherein the cutting is laser cutting.

14. The three-dimensional electrospun hybrid-scale fiber matrix synthetic skin graft according to claim 1, wherein the first set of electrospun fibers has an average diameter of 2,000 nm or less.

15. The three-dimensional electrospun hybrid-scale fiber matrix synthetic skin graft comprises a plurality of protrusions originating from the bottom surface of the flexible electrospun fiber network and a plurality of depressions formed on the upper surface of the flexible electrospun fiber network, wherein the plurality of protrusions have a substantially uniform height, the plurality of depressions have a substantially uniform depth, the plurality of protrusions and the plurality of depressions are spherical, the plurality of protrusions are patterned over the entire bottom surface, The three-dimensional electrospun hybrid-scale fiber matrix synthetic skin graft according to claim 1, wherein the plurality of depressions are patterned over the entire upper surface.

16. The method according to claim 6, wherein the first structure of the fibers has an average diameter of 2,000 nm or less.

17. The surface of the biomedical patch device includes an upper surface and a bottom surface, the biomedical patch device comprises a plurality of protrusions originating from the bottom surface and a plurality of depressions formed on the upper surface, wherein the plurality of protrusions have a substantially uniform height, the plurality of depressions have a substantially uniform depth, the plurality of protrusions and the plurality of depressions are spherical, the plurality of protrusions are patterned over the entire bottom surface, The method according to claim 6, wherein the plurality of depressions are patterned over the entire upper surface. **Claim 18** The plurality of macroscale pores include slits that penetrate the entire thickness of the three-dimensional electrospinning hybrid-scale fiber matrix synthetic skin graft, The three-dimensional electrospinning hybrid-scale fiber matrix synthetic skin graft according to claim 1, wherein the density of the slits is about 5 slits per square inch. **Claim 19** The method according to claim 6, further comprising the step of forming the plurality of macroscale pores as slits that penetrate the entire thickness of the hybrid-scale fibers at a density of about 5 slits per square inch.

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