Composite scaffolds for repair, reconstruction, and regeneration of soft tissues

Abstract

The disclosed composite scaffolds provide a highly porous and flexible structure that substantially maintains its three-dimensional shape under tension and provides mechanical reinforcement to the repair or reconstruction, first through the mechanical properties of the scaffold and then through the newly regenerated functional tissue as the scaffold is resorbed.

Description

Technical Field

[0001] This disclosure relates to soft tissue repair and reconstruction, and more specifically, to a composite scaffold that can be used to stabilize soft tissue injuries or defects while promoting the regeneration of new tissue. Background Technology

[0002] Biological and synthetic scaffolds are known for use in tissue engineering applications and surgical repair and reconstruction. However, few biological and synthetic scaffolds offer the optimal combination of: sufficient porosity for cell inward growth; sufficient biomatrix and surface area for cell migration and proliferation; sufficient interconnected void volume and size for meaningful extracellular matrix deposition and tissue regeneration; sufficient composite mechanical properties and mechanical load sharing with local tissues to promote functional tissue maturation while resisting collapse or compression under said mechanical loads; and a sufficient bioreabsorption timeline to support tissue repair through complete healing while promoting the regeneration of functional tissues.

[0003] Some scaffolds, such as hernia mesh, possess sufficient mechanical properties to complete surgical repairs, but lack the behavioral properties optimally suited for healing and regeneration of soft tissues and non-musculoskeletal soft tissues, including those in the knee, ankle, shoulder, elbow, and hand. Many of these scaffolds are made from permanent synthetic polymers that can cause acute or chronic adverse inflammation, pain, or complications. Furthermore, many mesh scaffolds are essentially two-dimensional, with insufficient surface area for inward cell growth and insufficient void volume for bulk tissue regeneration, thus hindering the regeneration of functional tissues. Conversely, most biological scaffolds used for repairing and reconstructing soft tissues are derived from bulk tissue harvested and processed from allogeneic or xenogeneic sources, and often heal slowly or incompletely due to any combination of bulk architecture, tissue origin, and processing methods. Highly processed biomaterials, such as collagen gels or sponges, reconstructed into entirely new architectures, can be produced with porosity suitable for inward tissue growth, but lack the appropriate strength and collapse resistance for ligament or tendon repair.

[0004] Many commercially available scaffolds made of fibers possess suitable mechanical properties, but they are unsuitable for functional tissue regeneration due to structural defects arising from existing manufacturing processes (such as braiding, knitting, and braiding) and nonwoven methods (such as electrospinning, pneumatic spinning, meltblowing, etc.). This is because the fibers do not have sufficient space between filaments and / or fiber bundles (insufficient porosity or void volume or density—e.g., typical electrospun textiles), or the surface area, void volume, and size for meaningful tissue regeneration are too small (e.g., typical planar warp-knitted textiles or braids, or fiber bundles), or when sufficient void volume is generated, the fibers are either discontinuous at cellular and biologically relevant scales or collapse as the structure is stretched.

[0005] Therefore, a scaffold and method are needed to repair or regenerate ligament tissue.

[0006] We also need a composite scaffold that mimics the mechanical properties of natural tendons and ligaments.

[0007] There is a further need for a scaffold that provides sufficient porosity and interconnected void volume for cell infiltration and tissue inward growth, while substantially maintaining its shape under load or tension.

[0008] There is still a need for a bioresorbable scaffold that supports healing for several weeks or months while promoting the regeneration of functional tissues capable of bearing mechanical loads after the scaffold is reabsorbed.

[0009] There is also a need for a scaffold that minimizes the density of the synthetic polymer and maximizes the surface area to volume ratio of the scaffold, thereby limiting foreign body response and improving tissue regeneration.

[0010] Furthermore, a support with adjustable length, width, and height is also needed for different procedures.

[0011] There is also a need for a bioresorbable scaffold that can regenerate tissue with sufficient strength and thickness after the scaffold material is fully reabsorbed.

[0012] There is also a need for a scaffold that provides a second supporting matrix that can promote cell growth separated from the scaffold to promote inward growth of tendon or ligament tissue.

[0013] This scaffold still requires engineered areas with variable size, density, porosity, material composition, fiber type, and surface properties to improve tissue regeneration and / or surgical manipulation and implantation. Summary of the Invention

[0014] A composite scaffold for ligament or tendon repair is disclosed, providing mechanical reinforcement to the repaired and healed tendon or ligament. In an embodiment, the composite scaffold includes a support structure defining a void volume. A porous material or hydrogel is disposed within the void volume of the support structure. The support structure reinforces and supports the porous material / hydrogel, enhancing the tensile strength of the scaffold and resisting compression when the scaffold is extended or subjected to elongation forces. The porous material / hydrogel has porosity and void volume that allow for sufficient extracellular matrix deposition and regeneration of new functional tissue. In an embodiment, the void volume is continuous or substantially continuous along the long axis of the scaffold, which allows for complete cell migration within the device and allows for the formation of new tissue in an axial direction of the scaffold, while being protected from significant collapse, compression, or overexpansion during mechanical loading or tension of the scaffold. Optionally, all or part of the scaffold may be hydrated with biological fluids such as blood, bone marrow aspirate, platelet-rich plasma, autologous or allogeneic cells to modulate or guide the immune response and further promote and accelerate healing and tissue regeneration.

[0015] The disclosed composite scaffold possesses a large surface area for cell proliferation and migration, and a sufficiently large interconnected void space to allow for tissue inward growth, extracellular matrix deposition, and biomechanical remodeling of functional tissue. Furthermore, the scaffold possesses the ability to maintain a highly porous structure under tension, resisting collapse, for example during surgical procedures and post-implantation, thereby maintaining cell infiltration and new tissue inward growth throughout the scaffold under physiological loads. Due to the composite mechanical properties of the device, these loads are mechanically distributed between the device and local tissues, i.e., preventing stress shielding of proximal, repair, or natural tissues, as well as developing new tissues within the scaffold itself. Furthermore, these composite mechanical properties facilitate mechanobiological signaling within the scaffold cells to differentiate and form supportive, oriented extracellular matrix and connective tissue. The disclosed composite scaffold can be manufactured using a variety of different textile and composite material manufacturing methods, and is not limited to a single manufacturing technique.

[0016] The disclosed composite scaffold provides a highly porous and flexible structure that substantially maintains its three-dimensional shape under tension, and provides mechanical reinforcement for repair or reconstruction, first through the mechanical properties of the scaffold and then through the newly regenerated functional tissue when the scaffold is reabsorbed.

[0017] The disclosed scaffold can have different regions with varying mechanical properties to facilitate fixation or different tissue regeneration. In one embodiment, the composite scaffold can be impregnated with cells, bioaspirates, or bioactive agents prior to implantation to create a biological "band-aid." In other embodiments, the bio-induced scaffold is seeded with autologous, allogeneic, or xenogeneic cells for a sustained temporary pre-culture period to allow the cells to form a collagen-rich extracellular matrix within the scaffold. The scaffold can then be processed and / or decellularized to leave a fibrous-reinforced tissue scaffold that can be subsequently implanted, or it can be implanted "as is." The disclosed scaffold is compatible with a variety of currently available fixation methods, such as sutures, suture anchors, flathead pins, staples, etc.

[0018] The disclosed composite scaffold provides a mechanism for spacing tissue fibers within the scaffold, thereby providing space for inward growth of higher-quality tissue that has not been damaged by polymers or corresponding inflammation. The microporous matrix acts as a stabilizer, helping to maintain this space and providing a larger surface area for cell growth so that tissue can mature, while the main fibers of the scaffold retain strength. If the microporous matrix is ​​reabsorbed at a faster rate than the support structure, the microporous matrix undergoes complete mass loss, allowing tissue to be recovered and remodeled within the newly generated volume in vivo, while the main support structure retains strength, allowing cells to first invade and then encapsulate the structure, and to generate functional tissue over time. Furthermore, if natural materials are used to generate a second matrix such as collagen, scaffold inflammation can be reduced and further promote inward cell growth into the scaffold without contact with any synthetic fibers including the support structure.

[0019] According to one aspect of this disclosure, the composite scaffold includes a first matrix and an optional second matrix, the first matrix and the optional second matrix being integrally formed with each other to maximize the surface area to volume ratio of the scaffold while still maintaining mechanical and structural integrity. According to an embodiment, the first matrix can be implemented using a three-dimensional textile structure including a first support layer and a second support layer, the first and second support layers being spaced apart therebetween to define an internal space or void. A plurality of spacer elements extend between the first and second support layers to keep the support layers separated. The first and second support layers can have different geometries, fiber or material compositions. The first and second support layers and the spacer elements can be implemented as a three-dimensional textile formed from any combination of synthetic bioabsorbable polymers, natural polymers and / or additives, the three-dimensional textile comprising a multilayer woven or woven surface of multifilament fibers or monofilament fibers or any combination thereof. The second matrix is ​​disposed within the void space between the first and second support layers of the first support matrix and is adjacent to the first and second support layers. The second matrix can be implemented using a low-density, high-surface-area material, including any of the following: sponge, foam, felt, textured fibers or yarns, collagen or tissue-derived materials, or any combination thereof. The first and second matrices of the composite scaffold can have the same or different structures, compositions, and bioresorbable properties to promote optimal regeneration of functional tissues.

[0020] In one embodiment, the minimum thickness of the composite stent can be approximately greater than or equal to 1 mm. The thickness of the stent can be uniform along its length, or it can vary in a repeating or non-repetitive manner, depending on the specific application for which the stent will be used. In other embodiments, the length of the disclosed composite stent can range from approximately 2 mm to 1000 mm, depending on the specific application for which the stent will be used. The disclosed stent can be manufactured in different incremental lengths, or it can be manufactured in lengths that can be appropriately cut or customized by a practitioner as needed or according to a specific procedure.

[0021] According to one aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to an outer surface of the microporous matrix and collectively defining a void space; and a structure supporting the microporous matrix; wherein the surface area of ​​the composite scaffold is between approximately 0.6 m². 2 / gram and 1.2m 2 Between / gram.

[0022] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to an outer surface of the microporous matrix and collectively defining a void space having a measurable volume; and a structure supporting the microporous matrix; wherein the volume of the void space is between approximately 3.5 cm³. 3 / gram and 7cm 3 Between / gram.

[0023] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to the outer surface of the microporous matrix and collectively defining a void space having a measurable volume, wherein the volume of the void space is between approximately 80% and 90% of the measurable volume of the biomimetic scaffold.

[0024] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to the outer surface of the microporous matrix and collectively defining a void space having a measurable volume, and wherein the permeability of the scaffold is between approximately 1400 millidarcy and 2600 millidarcy.

[0025] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to an outer surface of the microporous matrix and collectively defining a void space having a measurable volume, wherein the tortuosity of the plurality of interconnected pores is approximately between 5 μm / μm and 45 μm / μm, wherein the tortuosity defines the ratio of the actual flow path length to the straight-line distance between a first end and a second end of the microporous matrix.

[0026] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to an outer surface of the microporous matrix and collectively defining a void space having a measurable volume; and a structure supporting the microporous matrix, wherein the ratio of the surface area of ​​the void space to the volume of the support structure is between approximately 7,000 cm². 2 / cm 3 With 14,000cm 2 / cm 3 between.

[0027] According to another aspect of this disclosure, a composite scaffold includes: a support structure defining an internal space; and a microporous matrix disposed within the internal space of the support structure, wherein the microporous matrix includes a plurality of interconnected pores with a median pore size between approximately 12 μm and 50 μm.

[0028] According to another aspect of this disclosure, a composite scaffold includes: a support structure defining an internal space; and a microporous matrix disposed within the internal space of the support structure, the microporous matrix having a plurality of interconnected pores that collectively define a void space; wherein at least about 60% of the void space comprises pores with a size of 10 μm or larger.

[0029] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and commonly defining a void space; and a structure supporting the microporous matrix; the biomimetic scaffold has a measurable dry weight value representing the weight of the biomimetic scaffold in a substantially dry state and a measurable dry volume value representing the volume of the biomimetic scaffold in a substantially dry state, wherein the weight value of the biomimetic scaffold increases by about 200% to 600% due to fluid absorption, causing the dry volume value of the biomimetic scaffold to change by about 0% to 10%.

[0030] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and commonly defining a void space; and a structure supporting the microporous matrix; the composite scaffold having a measurable dry weight value representing the weight of the composite scaffold in a substantially dry state and a measurable dry length value representing a dimensional parameter of the composite scaffold in a substantially dry state, wherein the weight value of the composite scaffold increases by approximately 200% to 600% due to fluid absorption, causing the dry length value of the composite scaffold to change by approximately 0% to 3%.

[0031] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and commonly defining a void space; and a structure supporting the microporous matrix; the composite scaffold having a measurable dry weight value representing the weight of the composite scaffold in a substantially dry state and a measurable cross-sectional profile value representing a dimensional parameter of the composite scaffold in a substantially dry state, wherein the weight value of the composite scaffold increases by approximately 200% to 600% due to fluid absorption, causing the cross-sectional profile value of the composite scaffold to change by approximately 0% to 10%.

[0032] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and commonly defining a void space; and a structure supporting the microporous matrix; wherein the minimum dimension of the composite scaffold is a thickness dimension of approximately greater than or equal to 1 mm, and wherein the swelling profile of the composite scaffold can be measured by a change in the measured wet thickness of the composite scaffold compared to the measured dry thickness of the composite scaffold being less than or equal to 10%.

[0033] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and commonly defining a void space; and a structure supporting the microporous matrix; the composite scaffold having a measurable dry weight value representing the weight of the composite scaffold in a substantially dry state, wherein the microporous matrix accounts for less than about 6% of the dry weight value of the composite scaffold.

[0034] According to another aspect of this disclosure, a support includes: a three-dimensional support structure having a length dimension extending between a first end and a second end of the support structure, the support structure including a first outer layer and a second outer layer and a plurality of spacer elements, the first outer layer and the second outer layer being spaced apart therebetween to define a thickness dimension perpendicular to the length dimension, the plurality of spacer elements connecting the first outer layer and the second outer layer to maintain the spacing therebetween; wherein when the length dimension is elongated by approximately 13%, the change in the thickness dimension of the support structure is less than approximately 35%.

[0035] According to another aspect of this disclosure, a support includes: a three-dimensional support structure having a length dimension extending between a first end and a second end of the support structure and defining a cross-sectional area perpendicular to the length dimension, the support structure including a first outer layer and a second outer layer spaced apart to define an internal space volume therebetween, and a plurality of spacer elements extending through the internal space volume between the first layer and the second layer and attached therebetween to keep the first layer and the second layer separated; wherein when the length dimension is elongated by about 13%, the change in the cross-sectional area is less than about 5%.

[0036] According to another aspect of this disclosure, a support includes: a three-dimensional support structure having a length dimension extending between a first end and a second end of the support structure and defining a width dimension perpendicular to the length dimension; the support structure includes a first outer layer and a second outer layer, and a plurality of spacer elements therebetween, the first outer layer and the second outer layer being spaced apart therebetween to define a thickness dimension perpendicular to the length dimension and the width dimension; the plurality of spacer elements connecting the first outer layer and the second outer layer to maintain the spacing therebetween; wherein when the length dimension is elongated by approximately 13%, the change in the width dimension of the support structure is less than approximately 5%.

[0037] According to another aspect of this disclosure, a support structure includes: a first outer layer and a second outer layer having a length dimension defined by their respective first and second ends and defining an internal space therebetween, each of the first and second outer layers including a plurality of interconnecting coil longitudinals extending substantially parallel to the respective length dimension; a plurality of spacer elements extending substantially perpendicular to the respective length dimension through the internal space and attached adjacent to one of the plurality of coil longitudinals to each of the first and second outer layers, the plurality of spacer elements at least partially dividing the internal space into a plurality of channels extending along the respective length dimensions of the first and second outer layers.

[0038] According to another aspect of this disclosure, a composite scaffold having a measurable volume comprises: a microporous matrix having a plurality of interconnected pores open to the outer surface of the microporous matrix and collectively defining a void space, wherein the density of the composite scaffold is approximately between 0.05 g / cc and 0.75 g / cc, wherein the density is defined as the mass of the composite scaffold per unit volume.

[0039] According to another aspect of this disclosure, a composite scaffold having a measurable volume comprises: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and collectively defining a void space; and a structure supporting the microporous matrix; wherein the total surface area to volume ratio of the composite scaffold is approximately between 160,000:1 and 190,000:1, wherein the ratio defines the ratio of the surface area of ​​the scaffold to the volume of the composite scaffold excluding the void space.

[0040] According to another aspect of this disclosure, a scaffold includes: a three-dimensional support structure extending along an axis between a first end and a second end of the support structure, the support structure including a first layer and a second layer spaced apart to define an internal space volume therebetween, and a plurality of spacer elements extending through the internal space volume between the first layer and the second layer and attached therebetween to maintain separation of the first layer and the second layer and define a cross-section perpendicular to the axis; and a microporous matrix within the internal space and having a plurality of interconnected pores that together define a void space between the first end and the second end of the support structure; wherein at least about 60% of the void space comprises pores with a size of at least 10 μm or larger; and wherein the volume of the void space is between about 3.0 cm³. 3 / gram and 9.0cm 3 Between / gram.

[0041] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening toward an outer surface of the microporous matrix and collectively defining a void space; and a structure supporting the microporous matrix; the composite scaffold has a substantially rectangular cross-section defined by an outer side, wherein the plurality of interconnected pores open toward one of the outer sides and have a maximum dimension relative to said one outer side. In one embodiment, the plurality of interconnected pores have a maximum dimension oriented at approximately 45° to 135° relative to said one outer side.

[0042] According to another aspect of this disclosure, a support includes: a three-dimensional support structure having a length dimension defined by a first end and a second end thereto, and a thickness dimension perpendicular to the length dimension defined by a first outer layer and a second outer layer separated by space; and a plurality of spacer elements extending through the space and connecting the first outer layer and the second outer layer; wherein the ratio of the surface area of ​​the void space to the measurable volume is between approximately 500 cm². 2 / cm 3 With 7,000cm 2 / cm 3 between.

[0043] According to another aspect of this disclosure, a composite scaffold occupying a measurable volume comprises: a microporous matrix having a plurality of interconnected pores that collectively define a void space having a surface area; and a structure supporting the microporous matrix; wherein the ratio of the surface area of ​​the void space to the measurable volume is between approximately 5,000 cm². 2 / cm 3 With 16,000cm 2 / cm 3between.

[0044] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores open to an outer surface of the microporous matrix and collectively defining a void space; and a structure supporting the microporous matrix; wherein the surface area of ​​the composite scaffold is approximately 0.3 m². 2 / gram and 15m 2 Between / gram.

[0045] According to another aspect of this disclosure, a method of repairing ligament or tendon injuries with a composite scaffold includes: A) providing a composite scaffold comprising: i) a first and second layer spaced apart to define an internal space therebetween, and a plurality of spacer elements extending through the internal space and attached to the first and second layers; and ii) a microporous matrix disposed within the internal space, the microporous matrix having a plurality of interconnected pores; and B) pre-tensioning the composite scaffold along its length dimension; and C) attaching the composite scaffold to an allogeneic or autologous tendon or a damaged or torn ligament or tendon.

[0046] According to another aspect of this disclosure, a method of repairing ligament or tendon injuries with a composite scaffold includes: A) providing a composite scaffold comprising: i) a first and second layer spaced apart to define an internal space therebetween, and a plurality of spacer elements extending through the internal space and attached to the first and second layers; and ii) a microporous matrix disposed within the internal space, the microporous matrix having a plurality of interconnected pores; and B) pre-tensioning the composite scaffold along its length dimension; and C) attaching the composite scaffold to an allogeneic or autologous tendon or a damaged or torn ligament or tendon.

[0047] According to another aspect of this disclosure, a method of manufacturing a composite scaffold includes: A) constructing a three-dimensional support structure extending along a length dimension between a first end and a second end therebetween and defining an inner surface within the support structure; and B) forming a microporous matrix within the inner surface, the microporous matrix having a plurality of interconnected pores in fluid communication with an outer surface of the support structure, wherein a plurality of the interconnected pores are oriented relative to dimensional characteristics of the support structure. In an embodiment, the plurality of interconnected pores are oriented radially inward from the outer surface of the support structure into the internal space. In an embodiment, the plurality of interconnected pores are oriented along the length dimension of the support structure.

[0048] According to another aspect of this disclosure, a composite scaffold includes: a support structure having an external profile defining an internal space and extending along a length dimension between a first end and a second end thereto; a microporous matrix disposed within the internal space, the microporous matrix having a plurality of interconnected pores open to the outside of the support structure; wherein a plurality of the interconnected pores are oriented relative to the dimensional characteristics of the support structure.

[0049] According to another aspect of this disclosure, a composite scaffold includes: a microporous matrix having a plurality of interconnected pores opening to an outer surface of the microporous matrix and commonly defining a void space; and a structure supporting the microporous matrix; the composite scaffold having a measurable dry weight value representing the weight of the composite scaffold in a substantially dry state, wherein the microporous matrix accounts for less than about 6% of the dry weight value of the composite scaffold.

[0050] In an embodiment, based on mass loss or molecular weight loss, the second support matrix (e.g., sponge) degrades approximately two to twelve times faster than the first support matrix. The composite scaffold may have a degradation profile in which it retains greater than or equal to 50% of its strength for at least approximately two weeks post-implantation and experiences 100% mass loss for approximately six to twelve months or longer post-implantation.

[0051] In embodiments, the support matrix, with a higher density or mass compared to a more porous matrix disposed within the support matrix, provides the primary structure and bulk structure of the disclosed scaffold. More specifically, the first and second support matrices have different density or mass compositions relative to each other. In one embodiment, the measurable mass or density of the first support structure (e.g., textile) is greater than or equal to twice the mass or density of the second support matrix (e.g., sponge).

[0052] In the disclosed embodiments, the pore structure of the microporous matrix is ​​designed to promote cell attachment, proliferation, and inward growth throughout the scaffold size. In embodiments, the surfaces of the device, the second matrix, or the pore structure can be engineered architecturally to promote cell migration in a particular direction or to promote the formation of aligned tissues such as connective tissue. In other embodiments, the surfaces of the device may differ in physical or chemical properties to reflect use in a specific anatomical location, i.e., one side promotes integration with bone while the other promotes tendon integration; or one side promotes abdominal wall regeneration while the other prevents visceral adhesions.

[0053] In the embodiments, the composite scaffold disclosed herein provides a significantly higher surface area to volume ratio compared to existing commercially available devices, to facilitate faster and greater cell infiltration and tissue growth within the composite scaffold. More specifically, based primarily on the first support matrix (e.g., textiles), the surface area of ​​the fibers, calculated using scaffold denier, polymer density, and size, is greater than 10 times the volume ratio of the device.

[0054] In one embodiment, the support may have narrowed ends that transform into suture-like dimensions, or be modified, for example, by stitching or knotting, to attach to the ends of conventional sutures used in the procedures described herein. In other embodiments, the first support matrix (e.g., textile) has ends or edges modified for heat setting, embroidery, or impregnation with other materials to facilitate better maneuverability, better integration with existing tissue, and further reduce dimensional distortion of the support under pressure, tension, or shear forces. In other embodiments, monofilament or multifilament sutures of any material may pass longitudinally through the support and exit from both ends, and be attached or secured to the support.

[0055] In other embodiments, selected sections of the stent may be repeated randomly or at a fixed frequency to increase or decrease the density of the stent by increasing or decreasing the density of the textile, for example by changing the textile pattern of the first support matrix. In still other embodiments, such repeating areas may be selected to change the surface finish of the stent by altering the smoothness or roughness of the outer surface of the stent, thereby improving the acceptability of the stent after implantation.

[0056] In one embodiment, the composite scaffold comprises only a single three-dimensional support matrix, which may be the same as or different from the first or second support matrix described herein, and may have any of the characteristics of the composite scaffold described herein.

[0057] A method for treating ligament or tendon injuries is also disclosed, wherein a scaffold is attached to an allogeneic or autologous tendon for replacement of the damaged ligament or tendon, or the scaffold is used to reinforce a damaged or torn ligament or tendon. The method of use may include: preparing the scaffold with a solution to improve its performance; pre-tensioning the scaffold; and / or fixing the distal femur; and independently tensioning and fixing the tendon and graft in the tibial tunnel.

[0058] In use, the composite scaffold can be used in a wide range of medical procedures, including reinforced suture repair, independent repair or reconstruction, or reconstruction using tissue grafts and for fixation purposes. Reinforced repair or reconstruction using the composite scaffold can be applied to the knee, ankle, shoulder, hip, elbow, foot, and hand, as well as non-musculoskeletal soft tissues.

[0059] According to another aspect of this disclosure, the graft preparation stage provides a surface and fixation mechanism that allows for the independent tensioning of tissues (e.g., tendons or ligaments) and composite scaffolds before or during the implantation procedure.

[0060] According to another aspect of this disclosure, the fixation device allows tissue (e.g., tendon or ligament) and composite scaffold to attach to each other, thereby avoiding the need for cross-sutures. Such a device may include a clamp with a leg that passes through the graft and tendon. Attached Figure Description

[0061] The various features and advantages of the invention can be more readily understood by referring to the following detailed description taken in conjunction with the accompanying drawings, wherein similar reference numerals denote similar structural elements, and wherein:

[0062] Figure 1A This is a conceptual diagram of a composite stent based on this disclosure;

[0063] Figure 1B These are photographs of the composite scaffold according to this disclosure;

[0064] Figure 1C These are photographs of the composite scaffold according to this disclosure;

[0065] Figure 2A This is a conceptual diagram of a braided pattern that can be used for the outer layer of a composite scaffold, based on this disclosure;

[0066] Figure 2B This is a conceptual diagram of an alternative braided pattern that can be used for the outer layer of a composite scaffold, based on this disclosure;

[0067] Figure 2C It is based on the provisions of this disclosure, including Figure 2A -Conceptual diagram of the outer layer yarn component pattern of -B;

[0068] Figure 2D This is a perspective view of a textile pattern for a pair of composite supports that can be used in ACL and rotator cuff procedures, according to this disclosure.

[0069] Figure 3A It is based on the provisions of this disclosure. Figure 2A A photograph of a plan view of at least one outer layer of a composite scaffold made with a pattern;

[0070] Figure 3B yes Figure 3A A photograph of the side view of the composite support;

[0071] Figure 4A It is based on the provisions of this disclosure. Figure 2A SEM image of a plan view of at least one outer layer of a composite scaffold made with a pattern;

[0072] Figure 4B yes Figure 4A SEM image of the side view of the composite scaffold;

[0073] Figure 4C It is along Figure 4A Seen from axis 4A-4A in the middle Figure 4A SEM image of a perspective cross-sectional view of the composite scaffold;

[0074] Figure 5A This is a perspective view of a mold that can be used to manufacture a composite support according to this disclosure;

[0075] Figure 5B -C are top and side plan views, respectively, of another mold that can be used to manufacture composite supports according to this disclosure;

[0076] Figure 5D The relationship between temperature, time, and pressure during the freeze-drying process is illustrated in the form of a graph according to this disclosure;

[0077] Figures 6A-6C It is based on the provisions of this disclosure. Figure 1C The line AA in the middle is intercepted Figure 1C SEM images of a sagittal cross-sectional view of the microporous matrix of the composite scaffold;

[0078] Figure 6D It is based on the provisions of this disclosure. Figure 1C The line BB in the middle is cut off Figure 1C SEM images of the coronal cross-sectional view of the microporous matrix of the composite scaffold;

[0079] Figure 6E It is based on the provisions of this disclosure. Figure 1C The line BB in the middle is cut off Figure 1C SEM images of the cross-sectional view of the microporous matrix of the composite scaffold;

[0080] Figure 6F It is based on the provisions of this disclosure. Figure 1C The line AA in the middle is intercepted Figure 1C SEM images of a sagittal cross-sectional view of the microporous matrix of the composite scaffold;

[0081] Figure 6G It is based on the provisions of this disclosure. Figure 1C The line BB in the middle is cut off Figure 1C SEM images of the coronal cross-sectional view of the microporous matrix of the composite scaffold;

[0082] Figure 6H It is based on the provisions of this disclosure. Figure 1C The line BB in the middle is cut off Figure 1CSEM images of the cross-sectional view of the microporous matrix of the composite scaffold;

[0083] Figure 6I It is based on the provisions of this disclosure. Figure 1C The line AA in the middle is intercepted Figure 1C SEM images of a sagittal cross-sectional view of the microporous matrix of the composite scaffold;

[0084] Figure 7A These are SEM images of a typical microporous matrix of a fiber support structure attached to a composite matrix according to this disclosure;

[0085] Figure 7B These are SEM images of a typical microporous matrix of a fiber support structure attached to a composite matrix according to this disclosure;

[0086] Figure 7C These are SEM images of the outer surface of a typical microporous matrix of a composite scaffold according to this disclosure;

[0087] Figure 8 Test data showing the relationship between the cumulative total pore surface area and the pore size as defined in this disclosure are presented in graphical form.

[0088] Figure 9 The cumulative total pore volume relative to the pore size is shown in the form of graphs for several composite scaffold samples according to this disclosure and textile support structures only.

[0089] Figure 10 The relationship between mercury pressure and several composite scaffold samples according to this disclosure and composite scaffolds with only textile support structures is shown in the form of charts.

[0090] Figure 11 The relationship between the aperture distribution and the logarithmic differential volume according to this disclosure is illustrated in graphical form.

[0091] Figure 12 The load-to-extension relationship of both individual tendons and tendons reinforced with composite scaffolds according to this disclosure is illustrated in graphical form.

[0092] Figure 13A Based on this disclosure Figure 1C A cross-sectional microscopic view of the composite scaffold, which shows the relationship between the porous matrix and the supporting matrix;

[0093] Figure 13B It is based on the hydration of blood according to this disclosure. Figure 1C A cross-sectional microscopic view of the composite scaffold, showing how red blood cells completely infiltrate the collagen sponge porous matrix;

[0094] Figure 14The image shows a composite stent for MPFL repair or reconstruction according to this disclosure.

[0095] Figure 15 A conceptual illustration shows a circular textile structure at various stages of manufacturing according to this disclosure.

[0096] Figure 16 This conceptually demonstrates how the composite materials disclosed in this disclosure can be used to enhance ACL repair, stabilization, or reconstruction; and

[0097] Figure 17 The relationship between pore size distribution and porosity percentage, as measured according to this disclosure, is presented in graphical form. Detailed Implementation

[0098] Embodiments of the system and method will now be described in detail with reference to the accompanying drawings, in which similar reference numerals refer to the same or corresponding elements in each of the several views. Throughout this specification, the phrase “in an embodiment” and variations thereof are generally understood to mean that a particular feature, structure, system, or method described includes at least one iteration of the disclosed technique. Such phrases should not be construed as indicating or interpreted as indicating that a particular feature, structure, system, or method described is the best or only way in which the embodiments can be implemented. Rather, such phrases should be understood to indicate instances of ways in which the described technique can be implemented, but not necessarily the only way. Furthermore, terms indicating orientation such as “top,” “bottom,” “side,” “lower,” and “upper,” as well as references on specific axes in three-dimensional space, are used only to help describe the position of components relative to each other. No terms indicating orientation are used to describe absolute orientation, i.e., the “upper” portion must always be at the top.

[0099] refer to Figure 1A-6D The composite scaffold 10 includes a first three-dimensional support matrix and a second matrix integrally formed to form the composite scaffold 10, wherein the first matrix and the second matrix maximize the surface area to volume ratio and surface area to weight ratio of the scaffold. (Reference) Figure 1AIn one embodiment, the first substrate may be implemented using a support structure 5 comprising a first outer layer 12 and a second outer layer 14, spaced apart to define an internal void space 16 therebetween. A plurality of spacer elements 18 extend between the first outer layer 12 and the second outer layer 14 to maintain the separation of the layers. In one embodiment, each of the layers 12, 14 and spacer elements 18 may be implemented as a three-dimensional textile structure, each having a different geometry, fiber, or material composition. For example, any one of the outer layers 12, 14, and spacer elements 18 may be implemented using a textile of multifilament fibers and / or monofilament fibers. The support layers 12 and 14 may be implemented as a substantially planar three-dimensional textile comprising multiple woven surfaces, and the spacer elements 18 may be implemented using interconnected yarns in a “Z” direction perpendicular to the planes of layers 12 and 14 to provide support and prevent collapse.

[0100] The support structure 5 is designed to provide mechanical support and resistance to compression for the growing new tissue, thereby maintaining the area intended for new tissue formation during patient movement and activity. Thus, the support structure 5 provides tensile strength along its long axis and stiffness in the "z-direction" to resist compression.

[0101] In embodiments, the support structure 5 may be formed from any of the following and may optionally be coated with an anti-adhesion material: 30-150 denier multifilament fibers, 30-150 denier monofilament fibers, or 30-150 denier composite yarns, or any combination thereof, such as a combination of multifilament fibers and monofilament fibers. Methods including, but not limited to, heat setting or embroidery may be used to seal or secure the rough-finished edges of the support 10. In one embodiment, the support structure 5 is made of poly-L-lactic acid (PLLA) of 75 denier 30 filaments with a polymer density of 1.25 g / cc. The yarn may be woven onto twisted fiber yarns to provide a higher stiffness yarn for use as a lining yarn as described below.

[0102] In the embodiment, one or both outer layers 12 and 14 of the support structure 5 can be constructed via, for example... Figure 2A and 2C The demonstrated implementation uses a warp-knitted open chain structure 22 made of double yarns, thereby producing Figure 3A The textile layers shown in the image. (As from...) Figure 2A and 3A As can be seen, the outer layer comprises a series of loops connected by a single weft-oriented insert yarn 26 and having two 0° straight insert yarns 24 inserted into columnar structures on both sides, such as... Figure 2AAs shown, the patterns of the first outer layer 12 and the second outer layer 14 may be the same or different. In one embodiment, outer layers 12 and 14 may have the same number of coil rows, wherein spacer elements 18 connect similar corresponding coil rows in each of layers 12 and 14. In another embodiment, outer layers 12 and 14 may have different numbers of coil rows, wherein spacer elements 18 connect coil rows in each of layers 12 and 14.

[0103] As used herein, a loop warp is a "row" of loops longitudinally inserted into a fabric. Each loop warp can be a single fiber or a double fiber, with the double fibers used to increase strength but also increasing volume. Increasing the number of loop warps, or the number of yarns per loop warp, will increase the ultimate tensile strength of the fabric. By adjusting the number of loop warps, the width of the fabric can be varied, allowing the same textile design to be applied to: narrow applications, such as for ACL reinforcement, for example, 5 mm wide; medium-width applications, such as for shoulder sleeves, for example, 23 mm wide; and very wide applications, such as for hernias, for example, 200 mm wide. Ultimate tensile strength, elongation, and initial stiffness can be improved by adding 0° straight insert yarns to the technical surface of the fabric. These insert yarns are incorporated linearly into each loop warp.

[0104] The machine used to manufacture the support 10 is a Karl Mayer Double NeedleBar Warp Knitting Machine. These machines are computer-controlled and allow modification of many parameters to alter the properties of the textile. Key variables include the number of wales, the number of yarns per wale, the addition of insert yarns to the wales, the insert yarn design, and the number of yarns per insert yarn. The fabric's stretch under tensile loads can be affected, for example, by knitting two wales together instead of three wales together.

[0105] refer to Figure 3B and 4B The spacer element 18 can be implemented using multiple yarns in a "Z" direction perpendicular to the plane of layers 12 and 14, the yarns connecting layers 12 and 14 and providing support to prevent collapse. In one embodiment, each of layers 12 and 14 can have the same number of wales, and the spacer element 18 can connect corresponding wales in each of layers 12 and 14. In other embodiments, the spacer element 18 can cross diagonally between different wales of layers 12 and 14. The spacer element 18 can comprise yarns that can be monofilaments, multifilaments, or multifilaments and / or textured yarns.

[0106] One or both of layers 12 and 14 can be used Figure 2BThe textile patterns shown in the diagram are used for implementation. Other textile patterns applicable to layers 12 and 14 may include full tricot, locknit, queenscord, single atlas, jersey, reverse jersey, Milan interlock, Milano, half Milano, etc. Variations in the warp-knitted surface design can be used to adjust the dimensions, density, and mechanical properties of layers 12 and 14, including any of the following: surface design, number of loops, number of yarns per loop, addition of insert yarns to the loops, insert yarn design, number of yarns per insert yarn, extension or reduction of mass (machine parameters), or extension or reduction of gap (machine parameters).

[0107] Alternative methods for warp knitting include using V-bed knitting machines such as whole garment knitting machines, or using double rapier looms or fly-shot looms to produce woven 3D spacer fabrics.

[0108] Adding tension threads between the knitted panels of a mobile phone disperses tension and keeps the panels together during the manufacturing process until the threads are removed, preventing them from tearing or getting stuck. These threads can be removed mechanically or dissolved during washing.

[0109] In an illustrative embodiment, the No. 5 support structure implemented with three-dimensional textiles may have physical parameters as shown in Figure 1 below.

[0110] textiles only <![CDATA[Surface area (m 2 / g)]]> 0.2315 Mass (g) 0.0684 <![CDATA[Sample SA (m 2 )]]> 0.0158 Skeletal density (g / cc) 1.24 <![CDATA[Skeleton volume (cm 3 )]]> 0.0552 <![CDATA[SA:Vol(cm 2 :cm 3 )]]> 2871

[0111] A support having the aforementioned physical values ​​and defining a plurality of spacer elements 18 extending through between the first outer layer 12 and the second outer layer 14 can be calculated to have a gap space between approximately 500 cm. 2 / cm 3 With 7,000cm 2 / cm 3 The ratio of the measurable void space surface area to volume between them.

[0112] After manufacturing, the scaffold textiles can be scrubbed to clean them and remove any finishing agents that may have been used. Scrubbing methods can involve the use of water, solvents, and water-solvent mixtures. The fabric can be washed with or without restraint. The fabric can also be treated with reagents to modify its surface properties, such as altering its hydrophilicity. Various reagents can be used for this purpose, including polyethylene glycol. The surface can also be treated with reagents such as fibrin to improve cell adhesion. When a portion of the scaffold is intended to be placed in contact with a bone region, the surface of the fibers can be coated with calcium phosphate, hydroxyapatite, or bioactive glass, or growth factors such as bone morphogenetic proteins and demineralized bone matrix.

[0113] In embodiments, the composite scaffold 10 or any portion thereof comprising layers 12 and 14 or spacer element 18 may comprise any combination of synthetic bioresorbable polymers, natural polymers, and / or additives. Synthetic bioresorbable polymers suitable for use as part of the composite scaffold may comprise homopolymers, copolymers, or polymer blends of any of the following: polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, polyhydroxyalkanoates, polyanhydrides, poly(orthoesters), polyphosphazenes, poly(amino acids), polyalkyl cyanoacrylates, poly(propylene glycol fumarate), poly(trimethylene carbonate), poly(glycerol sebate), poly(gluconate), poly(ethylene glycol), poly(vinyl alcohol), and polyurethane, or any combination thereof. Natural polymers suitable for use as part of the composite scaffold may comprise silk, collagen, chitosan, hyaluronic acid, alginate, and amniotic membrane-derived matrices.

[0114] Composite support dimensions

[0115] In embodiments, the thickness of the composite support 10 (i.e., the vertical height dimension of the support relative to its larger length and width dimensions) can be between approximately 0.5 mm and 5 mm, or even more preferably between approximately 1 mm and 3 mm. Even more preferably, the minimum thickness of the support can be approximately greater than or equal to 1 mm. In embodiments, the thickness of the support 10 can be uniform along its length, or it can vary in a repeating or non-repetitive manner, depending on the specific application for which the support will be used.

[0116] In embodiments, the width of the disclosed composite stent 10 can range from approximately 2 mm to 1000 mm, depending on the specific application for which the stent will be used. In embodiments, the width of the disclosed stent can be uniform or can vary in a repeating or non-repetitive manner, depending on the specific application for which the stent will be used. For example, the stent 10 may have ends that narrow within the width of the stent and dimensionally transform into suture-like dimensions, or may be modified to attach to the ends of conventional sutures used in the procedures described herein.

[0117] In embodiments, the length of the disclosed composite stent can range from approximately 2 mm to 1000 mm, and even more preferably greater than or equal to approximately 10 inches, depending on the specific application for which the stent will be used. In embodiments, the disclosed stent can be manufactured in different incremental lengths, or in lengths that can be cut or customized by a practitioner as needed. Figure 4B This is a SEM image of a side view of a composite support 10, which may have a length dimension and is formed by an outer pair of layers 12 and 14 separated by a plurality of spacer elements 18. Figure 4B The images were taken using a Philips / FEI XL30 ESEM scanning electron microscope (SEM), where a 1 mm scale is shown and the distance between the spacer yarns along the length dimension axis is represented by reference lines 1-23. Table 1 shows each reference line and its corresponding distance value in micrometers, as well as the average distance. As can be seen from Table 1, the average distance between the spacer yarns along the length dimension axis is between approximately 200 μm and 300 μm.

[0118] Table 1

[0119]

[0120] Figure 4C yes Figure 4A SEM images of the perspective cross-sectional view of the composite scaffold. Figure 4C The photographs were taken using SEM, and the images show a 1mm scale diagram. The distance between the spacer yarns along the width axis perpendicular to the length dimension axis is represented by reference lines 1-17. Table 2 shows each reference line and its corresponding distance value in micrometers, as well as the average distance. As can be seen from Table 2, the average distance between the spacer yarns along the width axis is between approximately 300μm and 400μm (along the axis).

[0121] Table 2

[0122]

[0123] In the disclosed composite scaffold 10, the corresponding distances between the spacer elements 18 (e.g., spacer yarns) create a series of substantially parallel channels of similar size that extend through the gap between outer layers 12 and 14. As described herein, these channels provide space within the support structure in which a microporous matrix 15 can be formed. Importantly, these channels are formed along the axis of the device, thus creating a continuous channel between the two ends of the scaffold. When replaced by a new tissue, the new tissue is substantial and therefore load-bearing along the axis of the device, and thus a functional tissue.

[0124] Supporting structural additives

[0125] The composite scaffold 10, made from any of the aforementioned materials, can be combined with additives to enhance various properties of the scaffold, including those promoting cell growth and regeneration. Such additives suitable for use as part of the composite scaffold may contain biological products, including seeded cells, bioaspirates, and bioactive agents. Seeded cells suitable for use as part of the composite scaffold may contain adipose-derived stem cells, mesenchymal stem cells, and induced pluripotent stem cells, or any combination thereof. Bioaspirates suitable for use as part of the composite scaffold may contain whole blood, platelet-rich plasma, and bone marrow aspirate concentrate, or any combination thereof.

[0126] Bioactive agents suitable for use as part of the composite scaffold 10 may include growth factors, extracellular matrix molecules and peptides, therapeutic agents and osteoinducing or osteoconductive agents or any combination thereof, and may be added to the support structure 5 before or after the formation of the microporous matrix 15.

[0127] Growth factors suitable for use as part of a composite scaffold may include the transforming growth factor-β superfamily (e.g., transforming growth factor-β, bone morphogenetic protein), insulin-derived growth factors, platelet-derived growth factors, epidermal growth factor, interleukin-1 receptor antagonists, fibroblast growth factor, and vascular endothelial growth factor, or any combination thereof.

[0128] Extracellular matrix molecules and peptides suitable for use as part of a composite scaffold may include tendinin-C, hyaluronic acid, glycosaminoglycans (e.g., chondroitin sulfate, dermatan sulfate, and heparan sulfate), fibrin, thrombin, leucine-rich small peptides (e.g., core proteoglycans and disaccharide proteoglycans), fibronectin, elastin, and arginine-glycine-aspartic acid (RGD) peptides or any combination thereof.

[0129] Suitable therapeutic agents for use as part of a composite scaffold may include nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, indomethacin, nabumetone, naproxen, and diclofenac), steroidal anti-inflammatory drugs (e.g., cortisone and hydrocortisone), antibiotics, or antimicrobial agents, or any combination thereof.

[0130] Suitable osteoinducing or osteoconductive agents for use as part of a composite scaffold may contain tricalcium phosphate, hydroxyapatite, and bioactive glass, or any combination thereof.

[0131] microporous matrix

[0132] Optional microporous matrix 15 can be formed within the internal void spaces 16 of the composite scaffold 10. The microporous matrix 15 is supported and held by the support structure 5, providing support for cell colony and proliferation. The microporous matrix 15 is reabsorbable or biodegradable and is designed to be rapidly replaced by new tissue. The microporous matrix made from the materials described herein does not inherently possess usable mechanical strength properties, either in terms of tensile strength or compressive strength.

[0133] In one embodiment, a method for manufacturing a composite scaffold is disclosed, the method comprising: constructing a three-dimensional support structure extending along a length dimension between a first end and a second end therebetween and defining an inner surface within the support structure; and forming a microporous matrix within the inner surface, the microporous matrix having a plurality of interconnecting pores 60 in fluid communication with an outer surface of the support structure. The microporous matrix is ​​formed such that the plurality of interconnecting pores 60 are oriented relative to the dimensional characteristics of the support structure. For example, those pores closest to the outer surface of the composite matrix may extend substantially perpendicularly or radially inward relative to said closest outer surface of the support structure. Additionally, other pores among the plurality of interconnecting pores 60 may be oriented along the length dimension of the support structure in a manner that simulates the orientation of the spacer elements 18 (e.g., spacer yarns) separating outer layers 12 and 14.

[0134] In an embodiment, the microporous matrix 15 may be implemented using a high surface area material, such as any of the following: sponge, foam, or textured fiber or yarn, or any combination thereof. Methods for producing the microporous matrix 15 may include any of the following: freeze-drying, particle leaching, open-cell extrusion, solvent casting, solid-state foaming, and crosslinking. In one embodiment, the sponge / foam that can be used as the microporous matrix may include any of the following: freeze-dried sponge, open-cell extruded foam, and particle leaching sponge, or any combination thereof.

[0135] Suitable materials for implementing the micropores 15 are collagen, including bovine type I collagen. Other materials that can be used instead of collagen, or in addition to collagen, for the porous matrix 15 include hydrogels based on polyethylene glycol (PEG), polycaprolactone (PCL), or poly(glycolic acid-co-caprolactone) (PGCL), or combinations thereof. The collagen solution can be impregnated into the support structure 5 with the aid of a mold used to hold the scaffold in place. The auxiliary scaffold material can also be coated onto the outer surface of the support structure 5 in an encapsulating manner. The mold containing the textile and collagen solution can be placed in a shelf freeze dryer, also known as a lyophilizer, which uses temperature-controlled shelves to freeze the contents of the mold to very cold temperatures, such as as low as -55°C. This creates a crystalline structure in the collagen solution, thereby forming a matrix of interconnected pores within the collagen structure occupying the internal void spaces 16 of the support structure 5. A vacuum is drawn in the freeze dryer chamber, and the shelf temperature is gradually increased to provide energy to the frozen solvent, thereby causing a sublimation process. The sublimated solvent was collected in a separate condenser and completely removed from the inflammation. After a period of heating and vacuum, a highly porous, low-density collagen matrix was formed within the textile.

[0136] During this process, the porosity of collagen in the microporous matrix 15 can be affected in several ways. The volumetric porosity can be increased or decreased by decreasing or increasing the weight percentage of the collagen solution, respectively. The pore size can be adjusted by changing the freezing rate in the mold. Increasing the freezing rate decreases the average size, while decreasing the freezing rate increases the average size.

[0137] Since the total surface area of ​​pores is related to the pore size, for example, a large number of small pores will have a larger surface area than a few large pores. Therefore, increasing the freezing rate will reduce the average pore size, thereby increasing the total surface area, while decreasing the freezing rate will increase the average size, thereby reducing the total surface area of ​​the microporous matrix. Figure 5D It is a graph showing the relationship between temperature, pressure, and time during the freeze-drying process.

[0138] Variations in mold materials (including Delrin, aluminum, stainless steel, or others) transfer heat in different ways and can create different microporous matrix structures by altering the crystallization of the collagen solution upon freezing. For example, molds made of Delrin, a thermoplastic used in the manufacture of precision parts, transfer heat more slowly, resulting in larger pore sizes in the collagen solution. Conversely, molds made of aluminum transfer heat very quickly, producing a microporous matrix with relatively small pore sizes. Molds made of stainless steel transfer heat more slowly than aluminum and produce pores larger than those produced using aluminum molds, but smaller than those produced using Delrin molds.

[0139] Furthermore, adjusting the mold thickness between the bottom surface of the mold and the bottom of the cavity has a similar effect of increasing or decreasing the heat transfer rate, which can produce different microporous matrix structures. In the embodiments, or Figure 5A and 5B The mold shown is made of stainless steel and has the cavity dimensions listed in Table 2 below, where the 5×260mm column refers to... Figure 5A The mold shown is 50, and the 23×30mm column refers to... Figure 5B The mold 57 is shown. The mold 50 defines a plurality of rectangular cavities 52 and has a clamp 54 with pins 55 that can be fixed at its ends. The mold 57 includes an array of rectangular cavities 59 and through holes 53.

[0140] Table 2

[0141] 5×260mm 23×30mm Cavity width 5.21 23.20 Cavity length 260.00 30.20 cavity depth 4.09 8.00 Distance from the bottom of the cavity to the bottom of the mold 4.70 4.70

[0142] Figure 5A The mold shown utilizes end clips made of Delrin, which can be fixed to the main mold body and can be used to hold textile supports during the freeze-drying process.

[0143] In the illustrative embodiment, the cavity 52 of the mold 50 has a substantially rectangular cross-sectional shape. Other cross-sectional shapes can be used to maximize the contact between the surface areas of the support structure during the process of forming a microporous matrix in the support structure 5. Specifically, a support having any of the following shapes—D-shaped, U-shaped, O-shaped, or C-shaped—can be used during freeze-drying to maximize the surface area of ​​the support shape and further promote the orientation of the pores within the microporous matrix during the freeze-drying process. Specifically, for the support structure 5 having a cylindrical or tubular shape, a tubular mold, whether horizontally or vertically oriented, can be used during the freeze-drying process.

[0144] Alignment of the apertures with respect to the support dimensions can be achieved through contact with the mold surface. For example... Figure 6D -E、 Figure 6G The cross-sectional SEM image of -H shows that the pores within the microporous matrix 15 are formed adjacent to the mold surface and perpendicular to the plane in contact with the mold. In the embodiment, the applicant has found that the pores can be oriented proximally at 45° to 135° relative to the plane in contact with the mold. In the embodiment, for the... Figure 5A The mold shown is similar to a traditional mold, with numerous pores oriented perpendicular to the contact surface inside the mold towards the center of the support structure 5. This orientation further promotes faster inward growth of cells into the composite scaffold 10.

[0145] Alternative mold designs utilize cavities similar to those described above, but add a robustly molded and airtight top cover. Similar to injection molding, a vacuum, pressure, or other means can be used to fill the mold with collagen solution from one end and release trapped gas at the other end, thereby facilitating further alignment of collagen fibers during the injection process.

[0146] Alternative mold designs utilize cavities where textiles are placed on the sides, with the textile surface perpendicular to the bottom of the mold. Other alternative mold designs can use cavities with a "U"-shaped cross-sectional profile or another shape, which will produce finished scaffolds with a shape more suitable for specific types of implants.

[0147] Various manufacturing methods are available for creating microporous matrices within the void spaces of textile support structures, including salt leaching, gas extrusion, and other methods using high pressure or vacuum and gases.

[0148] The reabsorption and mechanical properties of the microporous matrix can be further modified through crosslinking. Typically, the materials used for crosslinking are potentially cytotoxic, so the ability to use lower levels is highly beneficial. The advantage of the disclosed procedure is that the use of the support structure 5 allows the microporous matrix 15 to utilize low levels of crosslinking. A 3D textile filled with a dry, highly porous, and low-density collagen microporous matrix is ​​removed from the mold cavity and placed on a permeable shelf, such as a wire frame, in a sealed chamber. A formaldehyde and ethanol solution is poured into a tray, which is placed under the frame of the support, and the chamber door is sealed. The tray completely covers the basic dimensions (L×W) of the chamber, and vapor from the solution is used to crosslink the collagen within the 3D textile. After a set time, the tray is removed, and the product is moved to an aeration chamber where clean, dry air, or alternatively, another gas such as nitrogen, is pumped through and exits the chamber, effectively terminating the crosslinking process. The crosslinking of collagen can be increased by increasing the time in the chamber, increasing the concentration of formaldehyde in the ethanol solution, or decreasing the aeration. Similarly, crosslinking can be reduced by decreasing the time spent in the chamber and lowering the concentration of formaldehyde in the ethanol solution.

[0149] Alternatively, chemical crosslinking agents can be added to the collagen solution. These agents can include, but are not limited to, various concentrations of aldehydes such as glutaraldehyde, genipin, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and EDC / N-hydroxysuccinimide (EDC / NHS). Another alternative crosslinking mode can be photochemically activated crosslinking, which may involve triggering the crosslinking process with or without a crosslinking initiator using UV or visible light.

[0150] Mechanical properties of composite stents

[0151] The mechanical properties of the composite stent 10 disclosed herein make it optimal for a wide range of medical procedures, including reinforced suture repair, independent repair or reconstruction, or reconstruction using tissue grafts and for fixation purposes. Tensile tests were performed on the composite stent 10 manufactured according to the description herein and in Examples 1, 2, and 3 using a Mark-10 tensile testing machine at a crosshead speed of 20 mm / min, and the results are listed in Table 3.

[0152] Table 3

[0153]

[0154]

[0155] As disclosed herein, the composite support 10, and specifically the support structure 5, has the advantage of its ability to resist compression when stretched. In the embodiments, as can be seen from the values ​​in Table 3 above, the width, height, and cross-sectional area of ​​the three-dimensional textile including the support structure 5 resist compression under considerable forces. Specifically, for a surface with approximately 9.92 mm... 2 A support structure 5 has a cross-sectional area, a thickness (height) of approximately 2.17 mm, and a width of approximately 4.57 mm. The length of the support structure 5 is extended by approximately 13% due to a force of 35 N along its length axis. In an embodiment, the change in the thickness of the support structure is less than approximately 31% when the length is extended by approximately 13%. In an embodiment, the change in the cross-sectional area is less than approximately 35% when the length is extended by approximately 13%. In an embodiment, the change in the width of the support structure is less than approximately 5% when the length is extended by approximately 13%.

[0156] In an embodiment, a support structure 5 of a certain length implemented using a three-dimensional textile scaffold as disclosed herein can have an ultimate load at an elongation percentage between approximately 30% and 125% of its length dimension. In an embodiment, the scaffold can yield at an elongation percentage between approximately 5% and 15% of its length dimension. In an embodiment, the toughness of the scaffold can be between approximately 0.073 g-f / denier and 1.102 g-f / denier. In an embodiment, the stiffness of the scaffold can be between approximately 2.5 N / mm and 25 N / mm, wherein stiffness defines the degree to which the scaffold resists deformation in response to an applied force. In an embodiment, the failure strain of the scaffold can be between approximately 20% and 70%. In an embodiment, the failure toughness of the scaffold can be between approximately 0.3 g-f / denier and 2 g-f / denier.

[0157] In illustrative embodiments, the ultimate load displacement, implemented using a three-dimensional textile scaffold with a width of 5 mm, a length of 40 mm, and a thickness of approximately 1 mm, or as disclosed herein, can be approximately between 5 mm and 50 mm. The ultimate load displacement defines the change in displacement under a load applied to the bionic scaffold, beyond which the bionic scaffold will fail. Such tests are performed using a 40 mm gauge length and according to standards established by the American Society for Testing and Materials (ASTM). In the illustrated embodiments, the yield displacement of the scaffold can be approximately between 1 mm and 8 mm. The yield displacement defines the change in displacement at which the bionic scaffold begins to deform. In the illustrated embodiments, the yield force of the scaffold can be approximately between 20 N and 70 N. The yield force defines the force at which the bionic scaffold begins to deform. In the illustrated embodiments, the stiffness of the scaffold can be approximately between 2.5 N / mm and 25 N / mm. The stiffness defines the degree to which the bionic scaffold resists deformation in response to an applied force. In the illustrative embodiments, the ultimate strain of the scaffold can be approximately between 20% and 70%, where ultimate strain defines the deformation of the bionic scaffold due to stress. In the illustrated embodiments, the ultimate load of the scaffold can be approximately between 100 N and 200 N, where ultimate load is defined as the amount of load applied to the bionic scaffold, exceeding which the scaffold fails. In the illustrative embodiments, the ultimate strength of the scaffold can be approximately between 2.5 MPa and 20 MPa, where ultimate strength is defined as the ability of the bionic scaffold to withstand a load that tends to elongate the bionic scaffold. In the illustrative embodiments, the ultimate stress of the scaffold can be approximately between 2.5 MPa and 20 MPa, where ultimate stress is defined as the maximum stress that the structure can resist, exceeding which the structure fails. In the illustrated embodiments, the modulus of the scaffold can be approximately between 2.5 MPa and 70 MPa, where modulus defines a measure of the stiffness of the bionic scaffold with void spaces. In the illustrative embodiment, the modulus of the scaffold can be approximately between 150 MPa and 600 MPa, where modulus defines a measure of the stiffness of the biomimetic scaffold without void space, and the modulus is calculated using only the cross-sectional area of ​​the material comprising the composite scaffold.

[0158] According to embodiments, the composite scaffold disclosed herein provides greater support for a larger amount of regenerating tissue through staggered degradation rates of the scaffold components. More specifically, the first support matrix 5 and the second support matrix 15 of the scaffold 10 have different degradation rates. In one embodiment, the second support matrix 15 (e.g., a sponge) degrades 2 to 12 times faster than the first support structure 5, based on mass loss or molecular weight loss. For example, a sponge including the second support matrix may have mass loss 3 to 6 months after implantation, while a textile fabric including the first support matrix may have mass loss 12 months after implantation. This difference in degradation rates allows the large amount of tissue growth facilitated by the internal voids of the scaffold 10 to continue to be supported by the textile fabric for a longer period of time. As indicated, parameters of material degradation can be measured by mass loss or molecular weight loss. In one embodiment, the composite scaffold may have a degradation profile in which strength retention is greater than or equal to 50% for at least approximately four weeks after implantation and mass loss is 100% for approximately six to twelve months after implantation.

[0159] According to embodiments, the composite scaffold disclosed herein can have features that enhance usability and improve performance once implanted. In embodiments, the scaffold 10 may have narrowed ends that transform into suture-like dimensions, or be modified, for example, by stitching or knotting, to attach to the ends of conventional sutures used in the procedures described herein. In embodiments, the support structure 5 (e.g., textile) has ends or edges modified for heat setting, embroidery, or impregnation with other materials to facilitate better maneuverability, better integration with existing tissue, and further reduce dimensional distortion of the scaffold 10 under pressure, tension, or shear forces. In embodiments, selected sections of the scaffold 10 may be repeated randomly or at a fixed rate to increase or decrease the density of the textile, for example, by changing the textile pattern of the first support structure 5. In embodiments, such repeated areas may be selected to alter the surface finish of the scaffold by varying the freeze-drying, smoothness, or roughness parameters of the scaffold's outer surface, thereby improving post-implantation acceptability.

[0160] In an embodiment, the spacer element 18 may be located only in a portion of the internal space 16 of the support 10, such as a hollow cavity, as shown below. Figure 2D As shown. In other embodiments, the spacer element 18 may have any regular or irregular repeating pattern in the internal space 16 between layers 12 and 14 of the support 10. In other embodiments, the spacer element 18 itself may be implemented using textiles or tissues or tissue-derived materials such as felt, or as otherwise described herein.

[0161] According to embodiments, the composite scaffold can also be seeded with cells for a sustained temporary pre-culture period to allow the cells to form a collagen-rich extracellular matrix on the sponge and textile components. The scaffold can then optionally be decellularized to leave a matrix template with native extracellular matrix proteins on the textile structure, and the scaffold can subsequently be implanted to repair tendons or ligaments in vivo.

[0162] Characteristics of the pore size of the support

[0163] Tests were conducted on multiple samples of composite scaffolds fabricated according to Examples 1 and 2 and the process described herein to determine various behavioral properties as described below. Each sample composite scaffold contained a microporous matrix with numerous interconnected pores open to the outer surfaces of both the microporous matrix and the composite scaffold. Various properties of the pores within the microporous matrix and correspondingly within the composite scaffold were measured using mercury infiltration porosimetry (MIP) or gas adsorption. Mercury is a non-wetting liquid that does not actively fill porous structures. However, by applying pressure using MIP, mercury can be forced into the pores of the microporous matrix, with higher pressures allowing mercury to enter smaller pores. Pore size (diameter) and pore volume can be accurately measured by precisely monitoring the volume of mercury while progressively increasing the applied pressure. Pore size and volume measurements are commonly used to determine a variety of properties of the microporous matrix and the composite scaffold.

[0164] surface area

[0165] A key characteristic of the disclosed composite scaffold is the following ratio: scaffold surface area per unit weight of scaffold. Due to the numerous interconnected pores within the microporous matrix supported by a 3D textile support structure, the disclosed composite scaffold possesses a large surface area on which cell migration and subsequent neotissue development can occur. Using a microporous infiltration process (MIP), rather than simply geometric dimensions and image quantification, allows for more precise measurement of the total surface area of ​​the interconnected pores and the exterior of the composite scaffold. The surface area can be calculated by assuming the pores are spheres, using the following formula from the known diameter of the pores measured by the MIP:

[0166] A = 4πr 2

[0167] Thus, the surface area parameter can be expressed as square meters per gram (m²). 2 The quantity measured in units of / g is the composite scaffold surface area per unit weight of the composite scaffold region. Figure 8 Figure 80 shows the test data, illustrating the relationship between the cumulative total pore surface area and the pore size measured in micrometers for several composite scaffold samples and for samples containing only the 3D textile with support structure 5. Figure 8In the samples, the 3D textile support structure 5, whether alone or filled with a microporous matrix 15, comprises PLLA fibers. All samples were produced according to the methods described herein and Examples 1 and 2. In the embodiments, the surface area per unit weight of the disclosed composite scaffold can be between approximately 0.3 m². 2 / gram and 1.5m 2 The surface area per unit weight of the disclosed composite scaffold can be between / gram and 0.6m². 2 / gram and 1.2m 2 The surface area per unit weight of the disclosed composite stent can be between / gram and 0.71m². 2 / gram and 1.0m 2 Between / gram.

[0168] Using gas adsorption, such as with krypton, allows for more precise measurement of the total surface area of ​​interconnected pores and the exterior of the composite scaffold, rather than just geometric dimensions and image quantification. The table below shows two samples with a width of 5 mm and a length of 40 mm. As measured by krypton adsorption for pores with a diameter less than 1 μm, the surface area of ​​the composite scaffold is approximately 0.3 m². 2 / gram and 15m 2 Between / gram.

[0169] sample <![CDATA[BET SA(m 2 / g)]]> 5mm 0.5826 5mm 0.5558

[0170] Total pore volume

[0171] Another important characteristic of composite scaffolds is their high porosity, which is partly due to the number, size, orientation, and interconnectivity of pores that collectively define the porosity within the microporous matrix. This high total porosity promotes faster blood absorption, cell migration, and subsequent neotissue development. The total volume of pores collectively forming the porosity within the microporous matrix can be directly measured using the microinfusion process (MIP) by monitoring changes in mercury volume during the MIP process. Thus, the pore volume parameter of a composite scaffold represents the total cumulative porosity per unit weight of the composite scaffold, for example, in cm³. 3 / g. Figure 9 Figure 90 shows the relationship between the cumulative total pore volume, measurable in cubic centimeters per gram, and the pore size, measured in micrometers, for several composite scaffold samples and textile-only support structures. Figure 9 In the samples, the textile support structures, whether alone or filled with a microporous matrix, all included PLLA fibers. All samples were produced according to the methods described herein. In the embodiments, the total pore volume of the disclosed composite scaffold can be between approximately 3.0 cm³. 3 / gram and 9.0cm 3 The volume of the disclosed composite scaffold can be between 3.5 cm³ and 600 g / g.3 / gram and 7.0cm 3 The total pore volume of the disclosed composite scaffold can be between 4.0 cm³ and 100 g / g. 3 / gram and 5.0cm 3 Between / gram.

[0172] Porosity

[0173] Another important characteristic of composite scaffolds is porosity, which is a measure of the percentage of the vacant space volume within the microporous matrix to the measurable volume of the composite scaffold itself. This calculation can be performed using measurements obtained during MIP. During the MIP process, the mass of each sample is known, and the occupied volume of the sample is also known by monitoring the mercury volume. At the lowest pressure applied during MIP, no mercury should fill the scaffold, thus the bulk density of the composite scaffold can be calculated. At the higher pressure applied during MIP, the composite scaffold should be almost completely filled with mercury. Therefore, the scaffold skeleton density can be calculated as follows:

[0174] Porosity = 100 * 1 - (density at low pressure / density at high pressure)

[0175] In this way, the measurable volume of the composite stent is calculated not through geometry, but through relative density. Figure 10 This describes the relationship between the composite scaffold density (grams per cubic centimeter) and the mercury pressure (pounds per square inch, i.e., in vacuum) for several composite scaffold samples and textile-only support structures. Figure 10 .exist Figure 10 In the samples, the textile support structures, whether alone or filled with a microporous matrix, all comprise PLLA fibers. All samples were produced according to the methods described herein. In embodiments, the porosity of the disclosed composite scaffold can be between approximately 75% and 98%. In embodiments, the porosity of the disclosed composite scaffold can be between approximately 80% and 90%. In embodiments, the porosity of the disclosed composite scaffold can be between approximately 80% and 85%.

[0176] Penetration

[0177] Another important characteristic of composite scaffolds is the permeability of the microporous matrix, which promotes faster absorption of fluids, particularly blood, both during and after implantation, accelerating cell migration and subsequent neotissue development. The microporous structure (e.g., collagen) within the textile support structure contributes to a more uniform and well-defined pore structure compared to collagen sponges alone, with a permeability approximately 200% that of the collagen sponge itself. This is at least in part due to the more uniform and well-defined structure of the interconnected pores. Reproducible permeability values ​​can be calculated from mercury indentation porosimetry (MIP) data using the Katz-Thompsone equation listed below:

[0178]

[0179] in:

[0180] k(mD): Air permeability

[0181] Pt(psia): Hg begins to flow pass Pressure in pores

[0182] D c (μm): Corresponds to the diameter (D) of Pt c =180 / Pt)

[0183] D max (μm): Diameter at which hydraulic conductivity is at its maximum

[0184] Hydraulic conductivity: a measure of how easily fluids flow through porous materials.

[0185] Porosity from MIP data (minus the void space inaccessible in the fiber)

[0186] S(D max Size is D max and the fraction of larger connected pore space / in D max Fraction of total porosity of the underfill

[0187] The use of the Katz-Thompson equation described above to calculate permeability is illustrated in the following publication: Goa and Hu, “estimating permeability using median poor-throat radius obtained from Mercury intrusion precocity,” *J. Geophysics. Eng.* (2013). In this way, reproducible permeability values ​​can be calculated from data collected during MIP. In embodiments, the permeability of the disclosed composite stent can be between approximately 1200 millidarcy and 3000 millidarcy. In embodiments, the porosity of the disclosed composite stent can be between approximately 1400 millidarcy and 2600 millidarcy. In embodiments, the porosity of the disclosed composite stent can be between approximately 1600 millidarcy and 2000 millidarcy.

[0188] Total surface area / support volume

[0189] Another important characteristic of composite scaffolds is the total surface area / scaffold volume ratio. The surface area of ​​each given sample can be determined via MIP. The scaffold density can be calculated as explained by the reference porosity parameters above. Surface area is expressed in square meters per unit sample weight (m²). 2 Reported in units of g (g), and can be converted to cubic meters by multiplying by the sample mass. Scaffold volume equals sample mass divided by scaffold density. In embodiments, the ratio of the void space surface area to the scaffold volume of the disclosed composite scaffold can be between approximately 5,000 cm³. 2 / cm 3 With 16,000cm 2 / cm 3 In an embodiment, the ratio of the void space surface area to the scaffold volume of the disclosed composite scaffold can be between approximately 7,000 cm². 2 / cm 3 With 14,000cm 2 / cm 3 In an embodiment, the ratio of the void space surface area to the scaffold volume of the disclosed composite scaffold can be between approximately 9,000 cm². 2 / cm 3 With 12,000cm 2 / cm 3 between.

[0190] Pore ​​size

[0191] Another important characteristic of the composite scaffold is the median pore size, measured in micrometers, of the interconnected pores within the porous matrix 15. The pores of the microporous matrix must be large enough to allow cell infiltration, but not so large as to slow cell proliferation and new tissue formation before reabsorption of the microporous matrix after implantation. According to this disclosure, several pores of a given diameter are efficiently measured by tracking the indentation volume at a given pressure during MIP. Thus, both the median pore size and the pore size distribution are reported. Figure 12 Figure 120 is a graph illustrating the relationship between pore size distribution measured in micrometers and logarithmic differential volume measured in cubic centimeters per gram. In one embodiment, the microporous matrix may have multiple interconnected pores with a median pore size between approximately 10 μm and 70 μm. In another embodiment, the microporous matrix may have multiple interconnected pores with a median pore size between approximately 12 μm and 50 μm. In yet another embodiment, the microporous matrix may have multiple interconnected pores with a median pore size between approximately 20 μm and 35 μm.

[0192] Another important characteristic of composite scaffolds is the pore size distribution within the microporous matrix of the composite scaffold, measured in micrometers. The cumulative pore volume can be determined using micro-in-micropipe (MIP). The contribution fraction of a pore of a given size to the pore space can be calculated as the cumulative pore space at that pore size divided by the total pore space. Figure 12 It also demonstrates the pore size distribution within the pore space of the microporous matrix. From Figure 12 It can be seen that the majority of the total void space within the microporous matrix comprises pores with a size parameter greater than 10 μm. In one embodiment, the microporous matrix has a large number of interconnected pores that collectively define the void space, wherein at least approximately 99% of the void space comprises pores with a size of 10 μm or larger. In another embodiment, the microporous matrix has a large number of interconnected pores that collectively define the void space, wherein at least approximately 95% of the void space comprises pores with a size of 10 μm or larger. In yet another embodiment, the microporous matrix has a large number of interconnected pores that collectively define the void space, wherein at least approximately 80% of the void space comprises pores with a size of 10 μm or larger.

[0193] Swelling and absorption

[0194] According to embodiments, the composite scaffold disclosed herein provides measurable high absorbability (e.g., the ability to absorb aqueous media) or wicking properties to facilitate faster and larger-volume absorption of biological fluids and / or cells within the scaffold. Specifically, the absorbability of the composite scaffold can be measured using the following formula:

[0195] Absorption % = (Wet sample mass - Dry sample mass) / Dry sample mass * 100

[0196] In the embodiments, the disclosed composite stent has a measurable dry weight value representing the weight of the stent in a substantially dry state and a measurable dry volume value representing the volume of the stent in a substantially dry state, wherein an increase in the weight of the stent due to fluid absorption of approximately 200% to 600% causes a change in the dry volume value of the stent of approximately 0% to 10%. The percentage change in volume of the composite stent can be measured by the following formula:

[0197] Volume change % = (Wet sample volume - Dry sample volume) / Dry sample volume * 100

[0198] According to embodiments, the composite scaffold disclosed herein provides a reduced swelling profile, for example, resisting dimensional changes with increasing absorbent fluid. Specifically, the percentage change in swelling of the composite scaffold can be measured using the following formula:

[0199] Swelling % = (Wet sample mass - Dry sample mass) / (Wet sample mass) * 100

[0200] In an embodiment, the disclosed composite stent has a measurable dry weight value representing the weight of the composite stent in a substantially dry state and a measurable dry length value representing the dimensional parameters of the composite stent in a substantially dry state, wherein an increase in the weight of the composite stent due to fluid absorption of approximately 200% to 600% causes a change in the dry length value of the composite stent of approximately 0% to 3%. The percentage change in the length of the composite stent can be measured by the following formula:

[0201] Length change % = (Wet sample length - Dry sample length) / Dry sample length * 100

[0202] In the embodiments, the disclosed composite stent has a measurable dry weight value representing the weight of the composite stent in a substantially dry state and a measurable cross-sectional profile value representing the dimensional parameters of the composite stent in a substantially dry state, wherein an increase in the weight of the composite stent due to fluid absorption of approximately 200% to 600% causes a change in the cross-sectional profile value of the composite stent of approximately 0% to 10%. The percentage change in the cross-sectional profile value of the composite stent can be measured by the following formula:

[0203] Cross-sectional profile change % = ((wet sample width * wet sample height) - (dry sample width * dry sample height)) / (dry sample width * dry sample height) * 100

[0204] Other relevant formulas are as follows:

[0205] Wet density % = ((sample wet weight / sample wet volume) / (sample dry weight / sample dry volume) * 100

[0206] Thickness change % = (Wet sample height - Dry sample height) / Dry sample height * 100

[0207] Wet weight % = Sample wet weight / Sample dry weight * 100

[0208] % of sample volume filled = (wet mass of sample - dry mass of sample) / (dry volume of sample)

[0209] Throughout the manufacturing process, the composite scaffold devices were weighed to obtain the mass of the individual textile, the mass after coating with PEG400, and the mass after adding collagen solution and subsequently freeze-drying. The mass of the collagen microporous matrix in each device can be calculated as follows:

[0210] quality 胶原 -quality 支架 -quality 纺织品 +PEG 400

[0211] Then the dry weight percentage of collagen relative to the entire composite scaffold device can be calculated:

[0212]

[0213] stent density

[0214] Another important characteristic of the composite scaffold is its density. According to embodiments, for the composite scaffold disclosed herein, a higher density or mass support matrix provides the main structure and bulk structure of the disclosed scaffold compared to a more porous matrix disposed within the support matrix. More specifically, the first support matrix 5 and the second support matrix 15 of the scaffold 10 have different density or mass compositions relative to each other. In one embodiment, the first support structure 5 (e.g., textile) has a measurable mass or density greater than or equal to one times the mass or density of the second support matrix 15 (e.g., sponge), and more preferably, two to five times the mass or density of the second support matrix 15. In embodiments, the maximum scaffold density of the disclosed composite scaffold can be less than 0.5 g / cm³. 3 And specifically, it is between approximately 0.05 g / cm³. 3 With 0.3g / cm 3 between.

[0215] Manufacturing method

[0216] The method for manufacturing the composite scaffold according to this disclosure is as follows. A composite scaffold measuring 5 mm wide, 3 mm high, and 260 mm long, made of three-dimensional PLLA textile filled with a highly porous collagen matrix, is manufactured for ACL repair or enhancement. The method utilizes the described warp knitting technique. Figure 2AThe double-column pattern shown herein is manufactured using a three-dimensional (3D) textile supporting a structure. The resulting structure has six coil wales on both the top and bottom layers. The corresponding top and bottom coil wales are interconnected by a series of woven spacer yarns extending through the gap space in the Z direction (e.g., perpendicular to the XY plane of outer layers 12 and 14) and interconnecting layers 12 and 14. The 3D textile is received as a continuous length of 5 mm wide and 3 mm high and ultrasonically scrubbed (e.g., washed) in a DI and IPA solution to remove particles and yarn spinning finishing agents. Multiple washes are performed, with the solution changed between washes. The temperature of the washing solution can be room temperature or up to 40°C. The 3D textile is then air-dried and cut to a specified length.

[0217] An alternative method for preparing 3-D textiles prior to coating with a hydrophilic solution involves wrapping a continuous length of textile without overlap around a frame (also known as a tenter frame or sewing frame) under moderate tension. The wrapped frame is then immersed in a solution of distilled water and isopropanol and washed with ultrasound or in a vibrating bath for agitation. Multiple washes can be used, changing the solution between washes. The temperature of the washing solution can be room temperature or up to 40°C. The 3D textile is then air-dried on a rack under tension. The textile is then cut to length on the rack while under tension to produce uniform length. By utilizing the sewing frame, washing under tension, and drying under tension, the textile is heat-set, reducing wrinkles, keeping the top and bottom surfaces of the textile relative to each other, and taut in the weave structure, thus resulting in a lower elongation of the final textile under load.

[0218] The 3D textile, after being scrubbed and cut to a certain length, is then immersed in a solution of polyethylene glycol (PEG) and ethanol to increase hydrophilicity. The concentration of PEG in the ethanol is specifically controlled to produce a controlled weight percentage of PEG on the 3D textile. The 3D textile is then air-dried. An alternative method for preparing 3D textiles before coating with a hydrophilic solution involves immersing the 3D textile in a PEG and ethanol solution after scrubbing but before cutting to a certain length. Another alternative method involves immersing the 3D textile wrapped around a frame in a PEG and ethanol solution after scrubbing but before cutting. In the steps mentioned above, multiple combinations of each alternative can be used to achieve the same result.

[0219] Next, a 0.6 wt% collagen solution was prepared using a low molar concentration of acetic acid, and powdered type 1 bovine collagen was blended and vacuum-treated to remove trapped air bubbles. Different low molar concentration acids, such as hydrochloric acid, can be used to prepare the collagen solution. Alternatively, alternative methods can be used to remove trapped air bubbles, for example, by rotating the solution in a centrifuge.

[0220] Collagen solutions of varying weight percentages can be used. Increasing the weight percentage of collagen will increase the amount of collagen in the matrix. Decreasing the weight percentage of collagen will decrease the amount of collagen in the matrix. When used in conjunction with the freeze-drying process described herein, these variations will affect the final collagen matrix density, structural properties, and porosity.

[0221] Figure 5B The stainless steel mold 57 shown is used to guide the collagen solution into the 3D textile and to produce a collagen sponge matrix structure through the next freeze-drying step. The cavity of the mold is filled with a small amount of collagen solution. A segment of the 3D textile is then placed into the mold with the 3D textile surface parallel to the bottom of the cavity, and clamps are used at each end to secure the 3D textile and prevent movement. These clamps add benefit in the subsequent freeze-drying step by creating a flat area without a porous collagen matrix at each end for product handling and stitching attachment.

[0222] Next, additional collagen solution is filled into the cavity containing the textile, thus completely immersing the textile in the collagen solution. The mold containing the textile and collagen solution is then vacuum-treated to remove any remaining air within the 3D textile, ensuring complete filling with the solution. The mold containing the textile and collagen solution is placed in a shelf freeze dryer, and the temperature is lowered to -55°C over a period of approximately 2 hours. The textile filled with the dried, highly porous, and low-density collagen matrix is ​​removed from the mold cavity and placed on a wire rack in a sealed chamber. A formaldehyde and ethanol solution is poured into a tray, which is placed under the shelf of the product, and the chamber door is sealed. Vapor from the solution crosslinks the collagen within the textile. After approximately 2 hours, the tray is removed, and the product is moved to an aeration chamber where clean, dry air is pumped through and exits the chamber, effectively terminating the crosslinking process. After a period of heating and vacuum, a highly porous, low-density collagen matrix is ​​formed within the 3D textile.

[0223] The following describes the fabrication of a 23mm wide, 3mm high, and 30mm long composite scaffold made of a three-dimensional PLLA textile filled with a highly porous collagen matrix for rotator cuff repair or enhancement. The following describes the fabrication of a 5mm wide, 3mm high, and 260mm long composite scaffold made of a three-dimensional PLLA textile filled with a highly porous collagen matrix for ACL repair or enhancement. According to the described warp knitting technique, using… Figure 2A The double-column pattern shown in the image is manufactured using a three-dimensional (3D) textile structure supporting the structure. The resulting structure has approximately 25 coil wales on both the top and bottom layers. The corresponding top and bottom coil wales are interconnected by a series of woven spacer yarns that extend in the Z direction through the gap space and interconnect the layers.

[0224] 3D textiles are received as continuous lengths of textiles 5 mm wide and 3 mm high and ultrasonically scrubbed (e.g., washed) in a DI and IPA solution to remove particles and yarn spinning finishing agents. Multiple washes are performed, with the solution changed between washes. The temperature of the washing solution can be room temperature or up to 40°C. The 3D textiles are then air-dried and cut to length. The scrubbed and cut 3D textiles are then immersed in a solution of PEG and ethanol to increase hydrophilicity. The concentration of PEG in the ethanol is specifically controlled to produce a controlled PEG weight percentage on the 3D textiles. The 3D textiles are then air-dried.

[0225] Next, a 0.6% by weight collagen solution was prepared using acetic acid with a low molar concentration, and powdered type 1 bovine collagen was blended and vacuum-treated to remove trapped air bubbles.

[0226] Figure 5B The stainless steel mold shown is used to guide the collagen solution into the 3D textile and to create a collagen sponge matrix structure through the next freeze-drying step. The cavity of the mold is filled with a small amount of collagen solution. A segment of the 3D textile is then placed into the mold with the 3D textile surface parallel to the bottom of the cavity, and clamps are used at each end to secure the 3D textile and prevent movement. These clamps add benefit in the subsequent freeze-drying step by creating a flat area without a porous collagen matrix at each end for product handling and stitching attachment.

[0227] Next, additional collagen solution is filled into the cavity containing the textile, thus completely immersing the textile in the collagen solution. The mold containing the textile and collagen solution is then vacuum-treated to remove any remaining air within the 3D textile, ensuring complete filling with the solution. The mold containing the textile and collagen solution is placed in a shelf freeze dryer, and the temperature is lowered to -55°C over a 2-hour period. A vacuum is drawn in the freeze dryer chamber, and the shelf temperature is gradually increased to provide energy to the frozen solvent, causing the sublimation process to occur. The sublimated solvent is collected in a separate condenser and completely removed from the condenser. After a period of warming and vacuum treatment, a highly porous, low-density collagen matrix is ​​formed within the 3D textile.

[0228] The mold design allows the entire scaffold to be encapsulated in collagen gel, which can provide the benefit of protecting the body from the textile scaffold components through a more biocompatible collagen gel.

[0229] Medical procedures

[0230] The composite scaffold described in this article can be used in a wide range of medical procedures, including reinforced suture repair, stand-alone repair or reconstruction, or reconstruction using tissue grafts and for fixation purposes. Reinforced repair or reconstruction using the composite scaffold can be applied to the knee, ankle, shoulder, elbow, and hand, as well as non-musculoskeletal soft tissues. The knee can include any of the ACL (anterior cruciate ligament), PCL (posterior cruciate ligament), LCL (lateral collateral ligament), MCL (medial collateral ligament), MPFL (medial patellofemoral ligament), ALL (anterolateral ligament), and posterolateral horn injuries (fibular collateral ligament, popliteal tendon, poplitofibular ligament). The ankle can include any of the ATFL (anterior talofibular ligament) and CFL (calcaneofibular ligament). The shoulder, elbow, and hand can include any of the rotator cuff (supraspinatus, infraspinatus, subscapularis, and teres minor tendons), acromioclavicular ligament, UCL (ulnar collateral ligament), and flexor tendons. Non-musculoskeletal soft tissues can include any of the breast, abdominal wall, and pelvic floor. The composite scaffolds described in this article can be used to fix permanent and reabsorbable materials, including sutures, suture anchors, flathead pins, and suture staples.

[0231] The physical dimensions and biomechanical properties of the composite scaffolds disclosed herein are optimized for use in a wide range of medical procedures, including reinforced suture repair, stand-alone repair or reconstruction, or reconstruction using tissue grafts and for fixation purposes. Reinforced repair or reconstruction using composite scaffolds can be applied to the knee, ankle, shoulder, elbow, and hand, as well as non-musculoskeletal soft tissues. These physical properties differ significantly from those of commercially available products such as hernia mesh and orthopedic sutures, and are better suited to the aforementioned procedures. For example, orthopedic sutures exist as a three-dimensional solid and are measurable; for all intentions and purposes related to surgery, they are essentially two-dimensional and offer little value for the tissue volume necessary for regenerative reinforcement or mimicking the properties of tendons or ligaments. For surgical meshes and patches made of bioresorbable materials with wide applications and which can be considered scaffolds, the resulting tissue plane formed after complete material reabsorption can be very thin and weak; this is due to a lack of thickness and / or sufficient pore volume for appropriate pore size for inward cell growth within the scaffold. Therefore, there is a clear need for tissue scaffolds that produce sufficiently thick tissue planes that regenerate after polymer degradation, resulting in thicker and stronger tissue planes.

[0232] In an exemplary embodiment, Figure 12 Table 4 below, along with several samples, demonstrates that tendons reinforced by the disclosed composite scaffold are consistently stronger and able to withstand greater forces at similar extensions compared to individual tendons.

[0233] Table 4

[0234]

[0235] Another alternative form of the disclosed composite scaffold utilizes tubular spacers, whether warp-knitted or weft-knitted, which can be used as "shrouds" on autologous grafts, allogeneic grafts, or repaired tendons or ligaments. One method of producing these tubular spacers is to use a flat spacer fabric and then attach opposing edges by sewing, heat sealing, or other means to create a tubular structure, such as... Figure 14 As shown. Alternatively, a custom circular knitting machine can be used to weave tubular spacer fabrics without connecting seams. Another alternative method for manufacturing tubular spacers is to weave the structure using a 3D circular knitting preform method, the method and structure of which are described in Figure 15 It is displayed in the middle.

[0236] An alternative method for manufacturing textile components as structures for containing porous matrices is to 3D print structures using elastic or inelastic materials and then fill the structures with porous matrices.

[0237] Alternatively, both the structure and the matrix can be 3D printed from one or more materials, as separate but combined entities, or as a single entity providing strength, porosity, and compressibility.

[0238] In one embodiment, the scaffold comprises a composite structure having a textile outer covering for providing strength and a 3D-printed internal support structure for providing compression resistance. Such scaffolds can be rectangular or tubular in shape. Braiding can be used as a cost-effective method for producing tubular structures. By braiding on the 3D-printed internal support structure insert, continuous space required for tissue growth inward is provided. Polymer fibers braided longitudinally into the outer braided structure can be provided to further modulate the tensile properties of the scaffold.

[0239] Example

[0240] Example 1—Manufacturing of Textile Frames

[0241] 75 denier 30 filament poly-L-lactic acid (PLLA) yarn was produced for use in manufacturing the support fabric. Warp beams were produced for use in fabric production on a Karl Mayer Double Needle Bar Machine. Fabrics 5 mm wide with 6 loops across the warp and 23 mm wide with 27 loops across the warp were produced, i.e., using a 22 gauge needle bed. Two surface layers were separated in the Z direction by spacer yarns to create a 2 mm thick fabric. The fabric was scrubbed and dried in an ultrasonic bath containing a mixture of deionized water and isopropyl alcohol.

[0242] Example 2—Manufacturing of ACL Enhancement / Repair Devices

[0243] A 0.6% collagen solution (by weight) was prepared using a low molar concentration of acetic acid and powdered type 1 bovine collagen. This solution was then blended and vacuum-treated to remove trapped air bubbles. Figure 5A The cavity of the stainless steel mold shown is filled with a small amount of collagen solution. A textile support (a sample 26 cm long and 5 mm wide) from Example 1 is placed into the mold with the textile surface parallel to the bottom of the cavity, and clamps are used at each end to secure the textile and prevent movement. Additional collagen solution is then filled into the cavity containing the textile, thus completely immersing the textile in the collagen solution. The mold containing the textile and collagen solution is then vacuum-treated to remove any remaining air within the textile so that it is completely filled with the solution.

[0244] The mold was then placed in an SP Scientific Advantage Plus Lyophilizer, and the sample was lyophilized, with the freeze-drying process lowering the freeze-dryer's interior from room temperature to -55°C over a 2-hour period. The textile filled with a dry, highly porous, and low-density collagen matrix was removed from the mold cavity and placed on a wire rack in a sealed chamber. A formaldehyde and ethanol solution was poured into a tray, which was placed under the product rack, and the chamber door was sealed. Vapor from the solution crosslinked the collagen within the textile. After 2 hours, the tray was removed, and the product was moved to an aeration chamber where clean, dry air was pumped through and exited, effectively terminating the crosslinking process. The final apparatus is suitable for ACL enhancement or repair.

[0245] Example 3—Manufacturing of Rotator Cuff Reinforcement / Repair Device

[0246] Following the method of Example 2, a mold suitable for accommodating 23mm wide fabric was used to impregnate the 50mm × 23mm fabric sheet from Example 1, but... Figure 5B The mold. The final device is suitable for rotator cuff reinforcement or repair.

[0247] Example 4—Manufacturing of Matrix Materials

[0248] A 0.6% collagen solution (by weight) was prepared using a low molar concentration of acetic acid and powdered type 1 bovine collagen. This solution was blended and vacuum-treated to remove trapped air bubbles. The solution was then lyophilized as in Examples 2 and 3.

[0249] Example 5—Evidence of tendon reinforcement

[0250] The deep flexor tendon of pigs was obtained from a local slaughterhouse. The composite scaffold device from Example 1 was folded in half on the tissue and cross-sutured at one end with #2 suture. A tensile testing machine was used to simulate a graft preparation table. The cross-sutured end was secured in the upper jaw of the tensile testing machine. Pretensioning was achieved by loading appropriate forces onto both ends of the composite scaffold and securing the lower jaw. The construct was cycled to an extension of 3.75 mm and then returned to zero. Performance data are shown in Table 3 below, demonstrating the ability of the composite scaffold pretensioning to control the reinforcement provided by the scaffold.

[0251] Table 4

[0252]

[0253] While the size of the composite scaffold described herein can vary depending on the intended application, it is considered that the scaffold can have a length of up to 1000 mm and a width of 3 mm to 1000 mm to accommodate different soft tissue sizes and applications. Furthermore, at the ends of the scaffold, the width can gradually narrow to the suture width.

[0254] This disclosure will be more fully understood through the following description, which should be read in conjunction with the accompanying drawings. In this specification, similar figures refer to similar elements in various embodiments of this disclosure. Those skilled in the art will readily understand that the methods, apparatus, and systems described herein are merely exemplary and can be modified without departing from the spirit and scope of this disclosure. The terms “comprising,” “including,” and / or their respective plural forms are open-ended and include only the listed portions and may include additional portions not listed. The term “and / or” is open-ended and includes one or more of the listed portions and combinations thereof.

[0255] Throughout this specification, numerical values ​​are disclosed in the form of groups or ranges. It is specifically intended that this specification encompass each individual sub-combination of the members of such groups and ranges, as well as any combination of the various endpoints of such groups or ranges. For example, integers in the range 0 to 40 are specifically intended to be disclosed individually as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range 1 to 20 are specifically intended to be disclosed individually as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Real numbers are intended to have similar inclusion properties, containing values ​​with up to at least three decimal places.

[0256] The foregoing description has been presented for illustrative purposes. It is not exhaustive and is not limited to the precise forms or embodiments disclosed. Modifications and adaptations will be apparent to those skilled in the art upon consideration of this specification and the disclosed embodiments.

[0257] As used herein, the indefinite article “a / an” means “one or more / one or more kinds”. Similarly, unless the use of a plural term is explicit in the given context, it does not necessarily indicate a plural number. Unless otherwise explicitly stated, words such as “and” or “or” mean “and / or”. Furthermore, since various modifications and changes will be readily made by studying this disclosure, it is not intended to limit this disclosure to the exact constructions and operations shown and described, and therefore all suitable modifications and equivalents falling within the scope of this disclosure may be adopted.

[0258] While several embodiments of this disclosure have been shown in the accompanying drawings, it is not intended to limit this disclosure to these embodiments, but rather to be as broad as permitted in the art, and this specification should be read in the same manner. Any combination of the above embodiments is also contemplated and falls within the scope of the appended claims. Furthermore, while illustrative embodiments have been described herein, the scope of any and all embodiments includes equivalent elements, modifications, omissions, combinations (e.g., combinations of aspects of various embodiments), adaptations, and / or alterations as understood by those skilled in the art based on this disclosure. Limitations in the claims are to be interpreted broadly based on the language used in the claims and are not limited to the examples described herein. Examples should be interpreted as non-exclusive. Furthermore, the steps of the disclosed method may be modified in any way, including by reordering steps and / or inserting or deleting steps. Therefore, the specification and embodiments are to be considered illustrative only, and the true scope and spirit are indicated by the full scope of the following claims and their equivalents.

[0259] While several embodiments of this disclosure have been shown in the accompanying drawings, it is not intended to limit the disclosure to these embodiments, but rather to be as broad as permitted in the art, and this specification should be read in the same manner. Any combination of the above embodiments is also contemplated and falls within the scope of the appended claims. Therefore, the above description should not be construed as restrictive, but merely as examples of particular embodiments. Other modifications within the scope and spirit of the appended claims will be envisioned by those skilled in the art.

Claims

1. A composite scaffold comprising: a three-dimensional support structure having a length dimension defined by first and second end portions thereof and by first and second outer layers separated by an interior space, a plurality of spacer elements extending through the interior space and connecting the first and second outer layers; and a microporous matrix comprising one of collagen and a hydrogel, the microporous matrix disposed in the interior space and having a multiplicity of interconnected pores collectively defining a void space between the first and second end portions of the support structure.

2. The composite scaffold of claim 1, wherein at least 60% of the void space comprises pores having a size dimension of at least 10 pm or greater.

3. The composite stent of claim 1, wherein the volume of the void space is between 3.0 cm 3 / gram and 9.0 cm 3 / gram.

4. The composite stent of claim 1, wherein the composite stent has a surface area between 0.3 m 2 / gram and 1.5 m 2 / gram.

5. The composite scaffold of any of the preceding claims 1-4, wherein the ultimate stress of the composite scaffold is between 2.5 MPa and 30 MPa.

6. The composite scaffold of any of the preceding claims 1-4, wherein the yield stress of the composite scaffold is between 2.5 MPa and 30 MPa.

7. The composite scaffold of any of the preceding claims 1-4, wherein the modulus of the composite scaffold is between 2.5 MPa and 70 MPa, wherein modulus is calculated using the cross-sectional area of material comprising the composite scaffold and the void space.

8. The composite scaffold of any of the preceding claims 1-4, wherein the modulus of the composite scaffold is between 150 MPa and 600 MPa, wherein modulus is calculated using the cross-sectional area of material comprising only the composite scaffold.

9. The composite scaffold of claim 1, wherein the microporous matrix comprises a foam, or a textured fiber, or a combination thereof, disposed within the scaffold by any of braiding, lyophilization, particulate leaching, open-cell extrusion, solvent casting, solid-state foaming, and crosslinking.

10. The composite scaffold of claim 1, wherein the microporous matrix comprises a sponge, or a textured yarn, or a combination thereof, disposed within the scaffold by any of braiding, lyophilization, particulate leaching, open-cell extrusion, solvent casting, solid-state foaming, and crosslinking.

11. The composite scaffold of any of claims 1-4, 9, and 10, wherein the support structure comprises monofilament yarns or multifilament yarns or a combination thereof braided into a three-dimensional structure.

12. The composite scaffold of any of claims 1-4, 9, and 10, wherein the support structure comprises textured yarns braided into a three-dimensional structure.

13. The composite scaffold of any of claims 1-4, 9, and 10, wherein the support structure comprises any combination of synthetic bioabsorbable polymers, natural polymers, and / or additives.

14. The composite scaffold of claim 1, wherein the void space volume is between 75% and 98% of the measurable volume of the composite scaffold.

15. The composite scaffold of claim 1, wherein a tortuosity of the plurality of interconnected pores is between 1 pm / pm and 50 pm / pm, wherein the tortuosity defines a ratio of an actual flow path length to a straight-line distance between a first end and a second end of the microporous matrix.

16. The composite scaffold of claim 1, wherein the microporous matrix comprises a plurality of interconnected pores having a median pore size between 10 pm and 100 pm.

17. The composite stent of claim 1, wherein the void space surface area to measurable volume ratio is between 5,000 cm 2 / cm 3 and 16,000 cm 2 / cm 3 or wherein a density of the composite scaffold is between 0.05 g / cc and 0.75 g / cc, wherein the density is defined as a mass of the composite scaffold per unit volume.

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