WO2021077042A1 - Échafaudages à base de fibres pour la migration et la régénération de cellules de tendon - Google Patents

Échafaudages à base de fibres pour la migration et la régénération de cellules de tendon Download PDF

Info

Publication number
WO2021077042A1
WO2021077042A1 PCT/US2020/056187 US2020056187W WO2021077042A1 WO 2021077042 A1 WO2021077042 A1 WO 2021077042A1 US 2020056187 W US2020056187 W US 2020056187W WO 2021077042 A1 WO2021077042 A1 WO 2021077042A1
Authority
WO
WIPO (PCT)
Prior art keywords
mesh
tendon
scaffold
nanofibers
rolled
Prior art date
Application number
PCT/US2020/056187
Other languages
English (en)
Inventor
Helen H. Lu
Romare M. ANTROBUS
Hannah R. CHILDS
Original Assignee
The Trustees Of Columbia University In The City Of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Trustees Of Columbia University In The City Of New York filed Critical The Trustees Of Columbia University In The City Of New York
Publication of WO2021077042A1 publication Critical patent/WO2021077042A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1146—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of tendons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00526—Methods of manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0063—Implantable repair or support meshes, e.g. hernia meshes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/08—Muscles; Tendons; Ligaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A61F2002/0086—Special surfaces of prostheses, e.g. for improving ingrowth for preferentially controlling or promoting the growth of specific types of cells or tissues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/10—Materials or treatment for tissue regeneration for reconstruction of tendons or ligaments

Definitions

  • This disclosure relates to a mesh scaffold configured to support and promote tendon cell migration and regeneration and methods for producing the mesh scaffold configured to support and promote tendon cell migration and regeneration.
  • tendon transections are one of the most common injuries that occur in military personals, both on-duty and off-duty, and in civilians, including a high incidence of hand lacerations and Achilles tendon ruptures. Additionally, tendon transections are a leading cause of medical evacuation (MEDEVAC) and battle attrition in combat operations. They occur in many trauma scenarios, including lacerations,blasts, gunshot wounds, crushes, falls, and in sports. Acute rupture of the Achilles tendon occurs in up to 40 out of 100,000 people per year and are typically sports-related (Lemme et al., 2018).
  • Tendon healing is generally slow (Sharma et al., 2006) and is of limited reparative capacity (Durgam et al., 2017).Adhesion formation prevents sheath gliding and fibrovascular scar formation can occur (Howell et al., 2017). Moreover, a lacerated tendon often presents a large gap between transected tendon ends post-injury (see, e.g., Figure 2), making it difficult to repair.
  • tendon repair is typically delayed by up to four days to over a week, rather than repaired on-site, and repair becomes more difficult with increased time post-injury (Tang et al. 1994). This delay is because of the challenges with current tendon repair,which uses sutures.Specifically, sutures are used to securely attach severed tendon ends together (see, e.g., Figure 3). However, this requires an operating surgeon's skill and instruments and is time consuming. A delay beyond four days is unadvisable due to the risk of tendons slipping out of the sheath and becoming enlarged due to fibrosis.Then it is difficult to reinsert the tendon into the sheath. Importantly, delayed repair prevents the recovery of full function.
  • sutures are the most widely used method for repairing lacerated tendons, they are inherently disadvantageous when used with soft tissue, such as tendons. Stress concentrations caused by sutures and errors made due to inexperience can lead to severe problems such as tearing of the tendon which can cause insufficient healing. Additionally, sutures are for long term repair and if the surgery is rushed or incorrectly performed in any way, the results lead to sub- optimal results.
  • Nitinol sleeves have also been used to reattach severed tendon stumps. These implants use laser cut tines to grip on to separate sides of the lacerated tendon and connect them without using sutures. However, these implants are expensive and time consuming to manufacture as they require high tolerance laser cutting and custom-made jig to heat set the tines in the correct orientation.
  • Tendon regeneration remains a significant clinical challenge, given its inherently low self-healing potential, undesirable scar-dominated repair response, and poor graft-host integration. These challenges are exacerbated by the large number of tendon injuries reported in an aging, yet active, population in the armed services and in the general population.
  • Biological matrices such as collagen-rich dermis and small intestinal submucosa have been marketed as tendon patches to reinforce surgical repair of tendons. While promising results were noted in animal models, the use of biologically-derived grafts for tendon repair is limited due to the gross mismatch in mechanical properties and rapid graft remodeling in the physiologically demanding joint. Thus, there is significant interest in the development of tissue engineered tendon grafts.
  • Nanofibers are an attractive platform for tendon repair and regeneration because their structural and mechanical properties can be readily tailored to match the native collagenous matrix.
  • Electrospinning is an established fiber fabrication method in which a polymer is dissolved in a solvent, and the resulting polymer solution is loaded into a syringe. Electrostatic forces are applied to the tip of the syringe needle, and charged polymeric fibers are ejected from the syringe at a constant rate. Electrospun fibers can be collected and used in a wide variety of applications, including but not limited to tissue engineering applications such as bone, cartilage, tendon, and ligament repair or regeneration. In such applications, a variety of growth factors, ceramic components, and other materials may be incorporated into the electrospinning solution so that resulting fibers contain advantageous material and biochemical properties.
  • Matrices may be fabricated via electrospinning, in which a polymer melt is ejected from an electrically charged syringe, resulting in porous, fibrous structures that can be functionalized for optimal tissue engineering outcomes.
  • This disclosure reflects the results from efforts to advance the state of the art for securely and rapidly re-attaching lacerated tendons in Prolonged Field Care in order to extend the window of primary repair for an injured tendon-muscular unit. Such result may be achieved by incorporating advances from the domains of biomaterial fabrication and tissue regeneration into the practice of reconstructive surgery.
  • a mesh scaffold such as disclosed herein, may be used to secure severed tendon ends while mimicking the native tendon structure.
  • the mesh scaffold preferably comprises a mesh of nanofibers formed of two or more polymers, rolled along a longitudinal axis of the scaffold to mimic native tendon structure.
  • the mesh is preferably a gelatin nanofiber-based mesh.
  • the two or more biomimetic polymers can preferably be polylactide-co-glycolide (PLGA) and polycaprolactone (PCL).
  • the rolled mesh preferably forms a layered structure, with one layer on another. Further, in a cross-sectional view of the rolled mesh, the rolled mesh preferably has a spiral arrangement.
  • the mesh that is rolled is preferably formed of electrospun nanofibers, and the nanofibers preferably include aligned fibers aligned in an alignment direction parallel to the longitudinal axis of the scaffold.
  • the mesh scaffold is preferably formed of a biomimetic material for repairing a gap between transected tendon ends due to an injury. Further, the rolled mesh may be sutured to the transected tendon ends.
  • the mesh scaffold preferably further comprises a non fouling coating to prevent a foreign body response and/or an antibiotic coating.
  • the mesh scaffold preferably further comprises inductive biomolecules and/or one or more growth factors, which promote faster healing of the tendon, applied to, or embedded in, the nanofibers or the mesh of nanofibers.
  • the mesh scaffold preferably forms a 3-dimensional conduit configured for positioning between, and bridging together, transected tendon ends. Further, the mesh scaffold preferably forms a collar configured for surrounding an injured tendon, and/or for positioning between, and bridging together, transected tendon ends. Further, the mesh scaffold can form a graft collar formed of a biomimetic material that permits migration of a tendon cell population from the graft collar to the injured tendon. Further, the graft collar is preferably formed of a biomimetic material that permits depositing of physiologically relevant extracellular matrix.
  • the method for producing a mesh scaffold preferably includes dissolving gelatin and a polymeric blend of PLGA and PCL in a solvent to form a gelatin polymer solution and electrospinning the gelatin polymer solution onto a rotating collecting drum to form a mesh scaffold comprising aligned nanofibers.
  • the method preferably includes rolling the mesh scaffold around a rod, the nanofibers of the rolled mesh including fibers aligned in an alignment direction parallel to the longitudinal axis of the scaffold and form a multi layer scaffold structure mimicking native tendon structure.
  • the solvent is preferably 2,2,2,-trifluoroethanol.
  • the method preferably comprises crosslinking each side of the mesh scaffold with glutaraldehyde.Further, the method preferably comprises soaking the mesh scaffold in media.
  • the concentration of the polymeric blend is preferably at least 32% weight by volume of the solvent.
  • the ratio of PLGA to PCL of the polymeric blend is preferably 5:1 weight by weight %.
  • Such inventive mesh scaffolds can be employed in meshes, implantable devices, grafts and other tissue engineering tools, etc.
  • Figure 1 shows a graphical representation of an apparatus employing electrospinning for generating a mesh of fibers, for tissue engineering.
  • Figure 2 shows a gap between transected tendon ends due to laceration of the tendon (Dashboard M., 2012).
  • Figure 3 shows a graphical representation of suture repair of a lacerated tendon (Jarrett P., 2016).
  • Figure 4 shows a graphical representation of hierarchical structure of a tendon (Spang C., 2015).
  • Figure 5 shows a graphical representation of a nanofiber-based mesh scaffold.
  • Figure 6 shows an SEM (scanning electron microscopy) image of a nanofiber mesh that can be employed as a biomimetic scaffold for tendon regeneration.
  • Figure 7 shows an SEM image providing an end view of a rolled mesh that may operate as a Tendon-Scaffold Junction.
  • Figure 8 shows a notional representation of a spiral arrangement, such as may be similar to a cross-sectional view of a rolled mesh.
  • Figure 9 shows a transected patellar tendon displaying injury surface (S).
  • Figure 10 shows a schematic diagram of an experimental set-up for cell migration study.
  • Figure 11 shows a notional representation of tendon cell migration from an injured tendon to a nanofiber mesh.
  • Figure 12 shows SEM images of cell migration and morphology.
  • Figure 13B shows that cells migrated onto the mesh over time and viability was maintained over 14 days of culture.
  • Figure 16 shows that tendon cells migrated out and remained viable on nanofibers up to 28 days similar to tissue culture plastic.
  • Figure 17A shows a notional representation of a mesh of fibers in which a non-fouling coating 171, and/or an antibiotic coating 172, has been applied to the mesh, to prevent a foreign body response.
  • Figure 17B shows a notional representation of a mesh to which inductive biomolecules 173 and/or one or more growth factors 174, have been applied, to promote faster healing of the tendon.
  • the white dots representative of the inductive biomolecules 173 or one or more growth factors 174 are not to scale.
  • Figure 18 shows a flow chart for a method for producing a mesh scaffold, according to an embodiment.
  • active agent shall mean a component incorporated into the fibrous, polymeric mesh scaffolds, which when released over time, supports alignment, proliferation and matrix deposition of a selected cell.
  • growth factors such as transforming growth factor-beta 3(TGF-3), growth/differentiation factor-5 (gdf-5), bone morphogenetic protein (BMP) 1 through 14, fibroblast growth factor (FGF) and basic fibroblast growth factor (bGF).
  • TGF-3 transforming growth factor-beta 3
  • gdf-5 growth/differentiation factor-5
  • BMP bone morphogenetic protein
  • FGF fibroblast growth factor
  • bGF basic fibroblast growth factor
  • active agent it is also meant to include an active pharmaceutical ingredient such as, but not limited to, an anti-inflammatory, an antibiotic or a pain medicament added to the fibrous, polymeric mesh scaffolds to enhance treatment and/or healing of the subject upon implantation.
  • aligned fibers shall mean groups of fibers which are oriented generally in an alignment direction along the same directional axis. Examples of aligned fibers include, but are not limited to, groups of parallel fibers.
  • bioactive shall include a quality of a material such that the material has an osteointegrative potential, or in other words the ability to bond with bone.
  • materials that are bioactive develop an adherent interface with tissues that resist substantial mechanical forces.
  • a “biocompatible” material is a synthetic or natural material used to replace part of a living system or to function in intimate contact with living tissue. Biocompatible materials are intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the body. The biocompatible material can perform with an appropriate host response in a specific application and does not have toxic or injurious effects on biological systems.Nonlimiting examples of biocompatible materials include a biocompatible ceramic, a biocompatible polymer or a biocompatible hydrogel.
  • biocompatible matrices shall mean three-dimensional structures fabricated from biocompatible material.
  • the biocompatible material can be biologically-derived or synthetic.
  • biodegradable means that the material, once implanted into a host, will begin to degrade.
  • biomimetic shall mean a resemblance of a synthesized material to a substance that occurs naturally in a human body and which is not rejected by (e.g., does not cause an adverse reaction in) the human body.
  • biopolymer mesh shall mean a mesh including any material derived from a biological source.
  • examples of a biopolymer mesh include, but are not limited to, collagen, chitosan, silk and alginate.
  • damaged soft tissue shall mean damage of muscles, ligaments and tendons throughout the body. Damaged soft tissue can include injuries such as a sprain, strain, a one-off blow resulting in a contusion or overuse of a particular part of the body.
  • electrostatic forces shall mean a force (attractive or repulsive) that exist between electrically charged particle or objects where the attractive or repulsive forces between particles that are caused by their electric charges. In electrospinning, the electric charge is applied to the needle attached to the syringe.
  • fibroblast shall mean a cell of connective tissue, mesodermally derived, that secretes proteins and molecular collagen including fibrillar procollagen, fibronectin and collagenase, from which an extracellular fibrillar matrix of connective tissue may be formed.
  • matrices are composed of man-made material, such as synthetic polymer, or a polymer-ceramic composite, but it does not preclude further treatment with material of biological or natural origin, such as seeding with appropriate cell types, (e.g., seeding with osteoblasts, osteoblast like cells, and/or stem cells), or treating with a medicament, (e.g., anti-infectives, antibiotics, bisphosphonate, hormones, analgesics, anti-inflammatory agents, growth factors, angiogenic factors, chemotherapeutic agents, anti-rejection agents, and RGD peptides).
  • a medicament e.g., anti-infectives, antibiotics, bisphosphonate, hormones, analgesics, anti-inflammatory agents, growth factors, angiogenic factors, chemotherapeutic agents, anti-rejection agents, and RGD peptides.
  • gelatin shall mean a substance that is typically a glutinous mixture of peptides and proteins derived from collagen taken from animal parts, from seaweed extracts, from plant extracts, etc.
  • graft shall mean the device to be implanted during medical grafting, which is a surgical procedure to transplant tissue without a blood supply, including but not limited to soft tissue graft, synthetic grafts, and the like.
  • the graft can be an allograft or an autograft.
  • An "allograft” is tissue taken from one person for transplantation into another. Allografts can include, most commonly, Achilles and tibialis, patellar and quadricep's tendons.
  • An “autograft” or “autologous graft” is a graft comprising tissue taken from the same subject to receive the graft.
  • Graft can also be allogeneic (e.g., derived from a material originating from the same species as that of the subject receiving the graft) or xenogenic (e.g., derived from a material originating from a species other than that of the subject receiving the graft).
  • the graft can be a soft tissue graft, such as a tendon.
  • the graft can be a graft for a ligament in a subject, including the ACL.
  • the tendon graft can be a bone- patellar tendon-bone (BPTB) graft, a semitendinosus or a hamstring- tendon (HST) graft.
  • BPTB bone- patellar tendon-bone
  • HST hamstring- tendon
  • graft collar shall mean a device embodying a graft and configured like a collar, that is, having a hollow cylindrical body in a longitudinal direction.A graft collar can be permeable, so the tissue can survive.
  • growth factors shall mean proteins that regulate many aspects of cellular function, including survival, proliferation, migration and differentiation.
  • growth factors can include cytokines, therapeutic peptides/proteins to aid in tendon cell repair or regeneration, hormones that bind to specific receptors on the surface of their target cells, PDGF, etc.
  • implantable or “suitable for implantation” means surgically appropriate for insertion into the body of a host, (e.g., biocompatible), or having the design and physical properties set forth in more detail below.
  • matrix shall mean a three-dimensional structure fabricated from biomaterials.
  • the biomaterials can be biologically- derived or synthetic.
  • the mesh means a network of material.
  • the mesh may be woven synthetic fibers, non-woven synthetic fibers, microfibers and nanofibers suitable for implantation into a mammal, (e.g., a human).
  • the woven and non-woven fibers may be made according to well-known techniques.
  • the microfiber or nanofiber mesh may be made according to techniques known in the art and those disclosed in, e.g., PCT International Application No. PCT/US2008/001889, filed February 12, 2008 to Lu et al., which application is incorporated by reference as if recited in full herein. Fibers of the mesh may be aligned or unaligned.
  • muscleculoskeletal cell shall mean a chondrocyte, fibrochondrocyte, fibroblast or osteoblast.
  • nanofiber mesh shall mean a flexible netting of nanofibers, oriented such that at least some of the nanofibers are not parallel to others of the nanofibers.
  • nanofiber scaffold is constructed of “nanofibers.”
  • nanofibers shall mean fibers with diameters not more than about 1000 nanometers (and preferably less than 1000 nanometers).
  • a “nanofiber” is a biodegradable polymer that is electrospun into a fibrous, polymeric mesh scaffold as described in more detail herein below.
  • the nanofibers of the fibrous, polymeric mesh scaffolds are oriented in such a way (i.e., aligned or unaligned) so as to mimic the natural architecture of the soft tissue to be repaired.
  • the nanofibers and the subsequently formed fibrous,polymeric mesh scaffolds are controlled with respect to their physical properties, such as for example, fiber diameter, pore diameter, and porosity so that the mechanical properties of the nanofibers and fibrous, polymeric mesh scaffolds are similar to the native tissue to be repaired, augmented or replaced.
  • the fibrous, polymeric mesh scaffolds are able to mimic the native tendon structure and bridge the gap between lacerated tendon ends.
  • the fibrous, polymeric mesh scaffolds may be engineered to remain in place for as long as the treating physician deems necessary.
  • the fibrous, polymeric mesh scaffolds will be engineered to have biodegraded between 6-18 months after implantation, such as for example 12 months.
  • PDGF blood pressure regulator
  • PGA shall mean polyglycolide or poly(glycolic acid).
  • PLA shall mean poly(lactic acid) or polylactic acid or polylactide.
  • PLGA shall mean poly(lactic-co-glycolic acid).
  • PCL shall mean polycaprolactone
  • polymer means a chemical compound or mixture of compounds formed by polymerization and including repeating structural units. Polymers may be constructed in multiple forms and compositions or combinations of compositions. Polymers may be natural or synthetic. Examples of natural polymers include collagen, cellulose, silk fibroin, keratin, gelatin and polysaccharides such as chitosan and alginate. Examples of synthetic polymers include poly(lactic acid) (PLA), polycaprolactone (PCL), polyurethane (PU), poly(lactic-co- glycolic acid) (PLGA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), and poly(ethylene-co-vinylacetate) (PEVA).
  • PLA poly(lactic acid)
  • PCL polycaprolactone
  • PU polyurethane
  • PLGA poly(lactic-co- glycolic acid)
  • PHBV poly(3-hydroxybutyrate-co-3-hydroxyvalerate)
  • PEVA poly(ethylene-co-vinylacetate)
  • polymer solution shall mean a solution in which a polymer has been dissolved.
  • polymeric blend shall mean a blend of two or more polymers to form a material having physical properties different than each polymer alone.
  • polymeric fibers shall mean a subset of man-made fibers, which are based on a polymer.
  • polymeric matrices shall mean matrices produced from fibrous polymer.
  • soft tissue includes, as the context may dictate, tendon and ligament, as well as the bone to which such structures may be attached.
  • soft tissue refers to tendon- or ligament- bone insertion sites requiring surgical repair, such as for example tendon-to-bone fixation.
  • soft tissue graft shall mean a graft which is not fully synthetic, and can include autologous grafts, syngeneic grafts, allogeneic grafts, and xenogeneic graft.
  • stem cell means any unspecialized cell that has the potential to develop into many different cell types in the body, such as mesenchymal osteoprogenitor cells, osteoblasts, osteocytes, osteoclasts, chondrocytes, and chondrocyte progenitor cells.
  • the cells are from a compatible human donor. More preferably, the cells are from the patient (i.e., autologous cells).
  • synthetic shall mean that the material is not of a human or animal origin.
  • Figure 1 shows an electrospinning apparatus 1 including a syringe 3 configured with a vessel 11 and connected at one end of the vessel 11 to a needle 7 in the form of a cone from which a jet of solution 13 ejects toward the grounded plate 17.
  • a syringe plunger 7 connects to the vessel 11 at the other end of the syringe 3, and applies pressure on the content of the cylindrical vessel, in particular the content in the cylindrical vessel is the polymer solution 5.
  • the polymer solution 5 ejects towards the grounded plate 17 and forms a batch of polymeric fibers 15 on the grounded plate 17.
  • the syringe 3 is configured with a volume of 5 ml
  • the needle 7 connected to cylindrical vessel of the syringe at one end is configured with a 26G needle.
  • the syringe plunger that provides pressure on the content of the cylindrical vessel, ejects the content at a flow rate in the range of 0.4-1.0 ml/hr.
  • the electrospinning apparatus is in an enclosing cabinet, which includes a humidifier that maintains the humidity in the enclosing cabinet in a range of 45% to 55%.
  • Electrospinning short for electrostatic spinning, involves the fabrication of fibers by applying a high electric potential to a polymer solution. The material to be electrospun, is loaded into a syringe or spoon, and a high potential is applied between the solution and a grounded substrate.
  • the electrostatic force applied to the polymer solution overcomes surface tension, distorting the solution droplet into a Taylor cone from which a jet of solution ejects toward the grounded plate or a cylindrical vessel.
  • the jet splays into randomly oriented fibers. These fibers have diameters ranging from nanometer scale to greater than 1 pm and are deposited onto the grounded plate or onto objects inserted into the electric field forming a non-woven batch of polymeric fibers.
  • a distance between the tip of the needle and the grounded plate during the electrospinning of the batch of polymeric fibers is in a range of 10-15 cm.
  • a voltage applied to the needle during the electrospinning of the batch of polymeric fibers is in the range of 8-15 kV.
  • a mesh scaffold includes a mesh of nanofibers formed of a polymeric blend of two or more polymers.
  • the mesh of electrospun nanofibers is rolled along a longitudinal axis of the scaffold to mimic native tendon structure.
  • the mesh is a gelatin nanofiber-based mesh.
  • the polymeric blend includes polylactide-co- glycolide (PLGA) and polycaprolactone (PCL).
  • the mesh scaffold formed of the rolled mesh of nanofibers is biomimetic and supports and promotes guided migration and regeneration of tendon cells.
  • the rolled mesh forms a layered structure, with one layer on another layer.
  • the rolled mesh in a cross-sectional view of the rolled mesh, has a spiral arrangement.
  • the mesh that is rolled is formed of electrospun nanofibers, and the nanofibers include aligned fibers aligned in an alignment direction parallel to the longitudinal axis of the scaffold.
  • the rolled mesh of electrospun nanofibers forms a 3-dimensional conduit configured for positioning between, and bridging together, transected tendon ends.
  • the rolled mesh is sutured to the transected tendon ends.
  • the rolled mesh of electrospun nanofibers forms a collar configured for surrounding an injured tendon, and/or for positioning between, and bridging together, transected tendon ends.
  • the collar is a graft collar formed of a biomimetic material that permits migration of a tendon cell population from the graft collar to the injured tendon.
  • the collar is a graft collar formed of a biomimetic material that permits depositing of physiologically relevant extracellular matrix.
  • the mesh scaffold is formed of a biomimetic material for repairing a gap between transected tendon ends due to an injury.
  • the mesh characteristics can be customized by altering green electrospinning parameters.
  • fiber diameter and morphology can be altered, including the formation of the fibers, by controlling applied voltage and polymer solution surface tension and viscosity.
  • fiber orientation can be controlled by rotating the grounded plate. This high degree of customizability and ability to use many different materials, such as biodegradable polymers and silks, grant this fabrication method a high potential in the development of materials for biomedical application.
  • Management of fiber diameter allows surface area to be controlled, and polymers with different degradation rates can be combined in various ratios to control fiber degradation, both of which are significant in drug delivery applications.
  • controlling the orientation of fiber deposition grants a degree of control over cell attachment and migration.
  • the ability to electrospin fiber meshes onto non-metal objects placed in the electric field enables the fabrication of multiphasic scaffold systems.
  • the mesh scaffold can also include additional components.
  • the mesh can include an active agent that is released from the mesh over time, inductive biomolecules, or one or more growth factors to promote faster healing of the tendon.
  • the mesh scaffold can include selected musculoskeletal cells or stem cells which differentiate into the musculoskeletal cells, or with soft tissue graft to replace or repair damaged soft tissue. Examples of musculoskeletal cells which can be seeded onto the mesh scaffold include chondrocytes, fibro chondrocytes, fibroblasts and osteoblasts.
  • the mesh scaffold comprises inductive biomolecules applied to, or embedded in, the nanofibers or the mesh of nanofibers.
  • the mesh scaffold comprises one or more growth factors, which promote faster healing of the tendon, applied to, or embedded in, the rolled mesh of nanofibers.
  • the mesh scaffold comprises a non-fouling coating to prevent a foreign body response. In another embodiment, the mesh scaffold comprises an antibiotic coating.
  • the polymer used in the mesh scaffold can include polylactide-co- glycolide (PLGA), PLA or PGA.
  • Another example of the polymer in the mesh scaffold can include polycaprolactone (PCL).
  • the polymer in the mesh scaffold can also include a blend of polylactide-co-glycolide (PLGA), PLA and/or PGA and polycaprolactone (PCL).
  • the polymer solution used for electrospinning the mesh can include a concentration of at least 32% (w/v) 5:1 blend of poly(lactide-co-glycolide) (PLGA) and poly(e-caprolactone) (PCL) in a solvent.
  • the mesh scaffold is preferably biodegradable, and can integrate with host bone tissue, and/or exhibits distinct regions with different chemical and mechanical properties which allow it to support the growth of multiple tissue types, and to be bioactive.
  • a method for producing a mesh scaffold.
  • Such method includes a) dissolving gelatin and a polymeric blend of PLGA and PCL in a solvent to form a gelatin polymer solution; b) electrospinning the gelatin polymer solution onto a rotating collecting drum to form a mesh scaffold comprising aligned nanofibers; and c) rolling the mesh scaffold around a rod, the nanofibers of the rolled mesh including fibers aligned in an alignment direction parallel to the longitudinal axis of the scaffold and form a multi-layer scaffold structure mimicking native tendon structure.
  • the solvent is 2,2,2,-trifluoroethanol.
  • the method further comprises crosslinking each side of the mesh scaffold with glutaraldehyde.
  • the method further comprises soaking the mesh scaffold in media.
  • the concentration of the polymeric blend is at least 32% weight by volume of the solvent.
  • the ratio of PLGA to PCL of the polymeric blend is 5:1 weight by weight %.
  • the method may include adding additional components to the mesh scaffold.
  • the additional components may include active agents, one or more growth factors, hydroxyapatite or a calcium phosphate, calcium-deficient apatite (CDA).Such additional components may permit the mesh scaffold to provide a functional interface between multiple tissue types.
  • Such components can further include an active pharmaceutical ingredient such as, but not limited to, an anti-inflammatory, an antibiotic or a pain medicament added to the mesh scaffold to enhance treatment and/or healing of the subject upon implantation of the mesh scaffold.
  • the method may further include seeding the mesh scaffold with selected musculoskeletal cells or stem cells which differentiate into the musculoskeletal cells, or with soft tissue graft to replace or repair damaged soft tissue. Examples of musculoskeletal cells which can be seeded onto the mesh scaffold include chondrocytes, fibro chondrocytes, fibroblasts and osteoblasts.
  • the method further includes applying to, or embedding in, the electrospun nanofibers or the mesh of electrospun nanofibers, an active agent.
  • the active agent may release over time. In this embodiment, release of the active agent over time supports tendon cell migration and regeneration. Examples of the active agent include but are in no way limited to growth factors.
  • a single active agent or a combination of active agents may be incorporated into the mesh scaffold.
  • active agent it is also meant to include an active pharmaceutical ingredient such as, but not limited to, an anti-inflammatory, an antibiotic or a pain medicament added to the mesh scaffold to enhance treatment and/or healing of the subject upon implantation.
  • the method includes applying to, or embedding in, the electrospun nanofibers or the mesh of electrospun nanofibers, one or more inductive biomolecules.
  • the method includes applying to, or embedding in, the rolled mesh of electrospun nanofibers, one or more growth factors, which may promote faster healing of the tendon.
  • growth factors may release from the rolled mesh over time once in a subject.
  • the growth factors include, but are in no way limited to, growth factors such as transforming growth factor-beta 3(TGF-3), growth/differentiation factor-5 (gdf-5), bone morphogenetic protein (BMP) 1 through 14, fibroblast growth factor (FGF) and basic fibroblast growth factor (bGF).
  • TGF-3 transforming growth factor-beta 3
  • gdf-5 growth/differentiation factor-5
  • BMP bone morphogenetic protein
  • FGF fibroblast growth factor
  • bGF basic fibroblast growth factor
  • the growth factors in the mesh are in a range of up to 200 pg per electrospinning.
  • nanofiber-based mesh scaffolds of this application can be engineered to remain in place for as long as the treating physician deems necessary.
  • these nanofiber-based mesh scaffolds are engineered to biodegrade between 6-18 months after implantation, such as for example 12 months.
  • polymers which can be selected for the mesh scaffolds include, but are not limited to, biodegradable polymers selected from the group consisting of aliphatic polyesters, poly(amino acids), modified proteins, polydepsipeptides, copoly(ether-esters), polyurethanes, polyalkylenes oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters,poly(£-caprolactone)s,polyanhydrides,polyarylates, polyphosphazenes, polyhydroxyalkanoates, polysaccharides, modified polysaccharides, polycarbonates, polytyrosinecarbonates, polyorthocarbonates, poly(trimethylene carbonate), poly(phosphoester)s, polyglycolide, polylactides, polyhydroxybutyrates, polyhydroxyvalerates, polydioxanones, polyalkylene oxalates, polyalkylene succinate
  • the polymer comprises at least one of polylactide-co- glycolide (PLGA), PLA or PGA.
  • the polymer can include at least one of polycaprolactone (PCL).
  • the polymer can include at least a blend of polylactide- co-glycolide (PLGA), PLA and/or PGA and polycaprolactone (PCL).
  • the polymer is a copolymer, such as for example a poly(D,L-lactide-co-glycolide (PLGA) and/or poly-caprolactone (PCL).
  • a concentration of the polymer is at least 32% (w/v) of 5:1 blend of poly(lactide-co-glycolide) (PLGA) and poly(s- caprolactone) (PCL) in a solvent.
  • Selection of a polymer or polymers used in the mesh scaffold is based upon the length of time needed to remain in place as well as the polymer's degradation characteristics which control release of the active agent or agents from the mesh scaffold.
  • a polymer such as PLGA is bulk-eroding while a polymer such as PCL is surface eroding.By using only a bulk-eroding polymer or only a surface eroding polymer or combining both of these types of polymers into a mesh scaffold, release of the active agent or agents from the mesh scaffold can be controlled and a temporal gradient of release of the active agent or agents supportive of tendon cell migration and regeneration can be created.
  • a tendon cell migration study was performed to investigate the therapeutic potential of a PLGA:PCL nanofibrous mesh for tendon injury in an in-vitro tendon transection model using bovine patellar tendon and sheath explants. The study further assessed which tendon cell population the mesh targets for repair.
  • tendon cells would migrate from injury site onto the nanofiber-based mesh, and deposit tendon extracellular matrix (collagen and proteoglycans).
  • tendon extracellular matrix collagen and proteoglycans.
  • the inventors further hypothesized that more cells would originate from the tendon proper compared to the tendon sheath.
  • Patellar tendons were isolated from fetal bovine knees (aged 3-5 months) acquired from a local abattoir (Green Village, NJ) and transected (19 x 5 x 5 mm) into explants (See Figure 10). Fabrication of mesh scaffolds:
  • the aligned PLGA:PCL blend was 32% w/v of the solvent.
  • Post-fabrication modifications include crosslinking each side of the scaffold with glutaraldehyde vapor for 15 minutes in a vacuum chamber.
  • Crosslinked scaffolds will then be rolled around a rod (formed of, for example, PTFE—polytetrafluoroethylene) so that the electrospun fibers are aligned parallel to the longitudinal axis of the scaffold and sealed along the outside flap with glutaraldehyde.
  • the PLGA:PCL meshes were soaked in DMEM media overnight.
  • GAG glycosaminoglycans
  • DMMB 1,9- dimethylmethylene blue
  • Migrated cells produced both collagen and proteoglycans after 14 days of culture that reflected the typical composition of the native tendon matrix: 65-80% collagen and 1-5% proteoglycans.
  • inventive mesh scaffolds described herein support cell migration and viability, are mechanically competent, bridge large gaps between transected tendon ends in a lacerated tendon, guide tissue formation, and mimic native tendon architecture. These mesh scaffolds facilitate a tendon repair strategy that guides healing and aims to prevent scar and adhesion formation for an improved restoration of function post- injury.
  • the subject matter disclosed herein will bring a paradigm shift in two ways: first, in the treatment of transected tendons in Prolonged Field Care because it prolongs the window for primary care for a highly prevalent problem; and second, in broader orthopedic and reconstructive surgery since it paves the way for suture-free mesh scaffolds that can be used to attach lacerated tendon ends.
  • the aforementioned nanofiber-based mesh scaffolds are configured to minimize scarring and promote tendon regeneration.
  • Such mesh scaffolds can be rolled along a longitudinal axis of the scaffold to mimic native tendon structure and provide a supporting structure through which tendon cells from either end of injury can migrate to join ends of the injury. It has not heretofore been suggested that such mesh scaffolds are so configured as to be suitable to bridge the large gap between transected tendon ends and therefore facilitate functional repair of tendon injuries with large gaps.
  • the scaffold can be used along with sutures to bridge the gap between transected tendon ends.
  • the mesh scaffolds guide cell growth and provide bulk mechanical support.
  • the mesh scaffolds disclosed herein are configured so that even an inexperienced field medic can easily and rapidly re-attach a lacerated tendon without using sutures.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Surgery (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medical Informatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne des échafaudages maillés à base de nanofibres configurés pour supporter et favoriser la migration et la régénération de cellules de tendon et des procédés de production d'échafaudages maillés à base de nanofibres.
PCT/US2020/056187 2019-10-16 2020-10-16 Échafaudages à base de fibres pour la migration et la régénération de cellules de tendon WO2021077042A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201962916120P 2019-10-16 2019-10-16
US62/916,120 2019-10-16
US202062962708P 2020-01-17 2020-01-17
US62/962,708 2020-01-17

Publications (1)

Publication Number Publication Date
WO2021077042A1 true WO2021077042A1 (fr) 2021-04-22

Family

ID=75538686

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/056187 WO2021077042A1 (fr) 2019-10-16 2020-10-16 Échafaudages à base de fibres pour la migration et la régénération de cellules de tendon

Country Status (1)

Country Link
WO (1) WO2021077042A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115068687A (zh) * 2022-07-08 2022-09-20 重庆科技学院 梯度纳/微纤维支架及其制备方法与应用
CN115845136A (zh) * 2022-12-15 2023-03-28 南京市第一医院 一种近场直写静电纺丝3d仿生腱骨修复支架及其制备方法
EP4282445A1 (fr) * 2022-05-27 2023-11-29 Lietuvos Sveikatos Mokslu Universitetas Construction anti-inflammatoire tridimensionnelle et procédé de fabrication
EP4282447A1 (fr) * 2022-05-27 2023-11-29 Lietuvos Sveikatos Mokslu Universitetas Construction cellulaire tridimensionnelle bioactive pour la régénération d'anomalies cartilagineuses locales symptomatiques
EP4282446A1 (fr) * 2022-05-27 2023-11-29 Lietuvos Sveikatos Mokslu Universitetas Échafaudage bioactif tridimensionnel pour réparation de cartilage
WO2023239640A1 (fr) * 2022-06-07 2023-12-14 The Penn State Research Foundation Échafaudages tissulaires à base de biopolymères et appareil et procédé pour leur fabrication
WO2024097250A1 (fr) * 2022-10-31 2024-05-10 The Trustees Of Columbia University In The City Of New York Support polymère pour probiotiques

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100047309A1 (en) * 2006-12-06 2010-02-25 Lu Helen H Graft collar and scaffold apparatuses for musculoskeletal tissue engineering and related methods
US20100310623A1 (en) * 2009-06-05 2010-12-09 Laurencin Cato T Synergetic functionalized spiral-in-tubular bone scaffolds
US20110250308A1 (en) * 2010-04-12 2011-10-13 The UAB Foundation Electrospinning apparatus, methods of use, and uncompressed fibrous mesh
US20130149667A1 (en) * 2011-12-13 2013-06-13 The Trustees Of Columbia University In The City Of New York Multiphase tissue complex scaffolds
US20130280318A1 (en) * 2010-07-12 2013-10-24 The Trustees Of Columbia University In The City Of New York Tissue Scaffolds for Controlled Release of Active Agents
US20150190222A1 (en) * 2000-03-24 2015-07-09 Drexel University Ligament and tendon replacement constructs and methods for production and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150190222A1 (en) * 2000-03-24 2015-07-09 Drexel University Ligament and tendon replacement constructs and methods for production and use thereof
US20100047309A1 (en) * 2006-12-06 2010-02-25 Lu Helen H Graft collar and scaffold apparatuses for musculoskeletal tissue engineering and related methods
US20100310623A1 (en) * 2009-06-05 2010-12-09 Laurencin Cato T Synergetic functionalized spiral-in-tubular bone scaffolds
US20110250308A1 (en) * 2010-04-12 2011-10-13 The UAB Foundation Electrospinning apparatus, methods of use, and uncompressed fibrous mesh
US20130280318A1 (en) * 2010-07-12 2013-10-24 The Trustees Of Columbia University In The City Of New York Tissue Scaffolds for Controlled Release of Active Agents
US20130149667A1 (en) * 2011-12-13 2013-06-13 The Trustees Of Columbia University In The City Of New York Multiphase tissue complex scaffolds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4282445A1 (fr) * 2022-05-27 2023-11-29 Lietuvos Sveikatos Mokslu Universitetas Construction anti-inflammatoire tridimensionnelle et procédé de fabrication
EP4282447A1 (fr) * 2022-05-27 2023-11-29 Lietuvos Sveikatos Mokslu Universitetas Construction cellulaire tridimensionnelle bioactive pour la régénération d'anomalies cartilagineuses locales symptomatiques
EP4282446A1 (fr) * 2022-05-27 2023-11-29 Lietuvos Sveikatos Mokslu Universitetas Échafaudage bioactif tridimensionnel pour réparation de cartilage
WO2023239640A1 (fr) * 2022-06-07 2023-12-14 The Penn State Research Foundation Échafaudages tissulaires à base de biopolymères et appareil et procédé pour leur fabrication
CN115068687A (zh) * 2022-07-08 2022-09-20 重庆科技学院 梯度纳/微纤维支架及其制备方法与应用
CN115068687B (zh) * 2022-07-08 2023-12-12 重庆科技学院 梯度纳/微纤维支架及其制备方法与应用
WO2024097250A1 (fr) * 2022-10-31 2024-05-10 The Trustees Of Columbia University In The City Of New York Support polymère pour probiotiques
CN115845136A (zh) * 2022-12-15 2023-03-28 南京市第一医院 一种近场直写静电纺丝3d仿生腱骨修复支架及其制备方法
CN115845136B (zh) * 2022-12-15 2024-01-26 南京市第一医院 一种近场直写静电纺丝3d仿生腱骨修复支架及其制备方法

Similar Documents

Publication Publication Date Title
WO2021077042A1 (fr) Échafaudages à base de fibres pour la migration et la régénération de cellules de tendon
Sahoo et al. Development of hybrid polymer scaffolds for potential applications in ligament and tendon tissue engineering
Liu et al. Tendon tissue engineering using scaffold enhancing strategies
Cheng et al. Promoting osteogenic differentiation in pre-osteoblasts and reducing tibial fracture healing time using functional nanofibers
Koh et al. In vivo study of novel nanofibrous intra-luminal guidance channels to promote nerve regeneration
JP5579904B2 (ja) 不織状の組織支持骨格
Di Martino et al. Electrospun scaffolds for bone tissue engineering
JP5485169B2 (ja) コーティングされた組織工学スカフォールド
US20130274892A1 (en) Electrospun Mineralized Chitosan Nanofibers Crosslinked with Genipin for Bone Tissue Engineering
CN108452382B (zh) 含有骨填补材料的无纺布
Sun et al. A synthetic bridging patch of modified co-electrospun dual nano-scaffolds for massive rotator cuff tear
Zhang et al. “Swiss roll”-like bioactive hybrid scaffolds for promoting bone tissue ingrowth and tendon-bone healing after anterior cruciate ligament reconstruction
US20190151510A1 (en) Trizonal membranes for periosteum regeneration
Maghdouri-White et al. Electrospun silk–collagen scaffolds and BMP-13 for ligament and tendon repair and regeneration
Shiroud Heidari et al. Biofabrication and signaling strategies for tendon/ligament interfacial tissue engineering
Ladd et al. Electrospun nanofibers in tissue engineering
Washington et al. The role of nanomaterials and biological agents on rotator cuff regeneration
Anjana et al. Nanoengineered biomaterials for tendon/ligament regeneration
Nijsure et al. Collagen-based scaffolds for bone tissue engineering applications
Vorrapakdee et al. Modification of human cancellous bone using Thai silk fibroin and gelatin for enhanced osteoconductive potential
Ramakrishna Biodegradable Biphasic Scaffolds using Braiding Technology and Surface Treatments for Regeneration of Tendon-Bone Junction Tissue
Wang et al. Macroporous 3D Scaffold with Self-Fitting Capability for Effectively Repairing Massive Rotator Cuff Tear
Salehi et al. Medical textiles as substrates for tissue engineering
US20220331490A1 (en) Fibrous polymeric scaffolds for soft tissue engineering
Manoukian et al. Tissue-Engineered Medical Products

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20877290

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20877290

Country of ref document: EP

Kind code of ref document: A1