EP2187837A1 - Système de bague de greffe pour induire une formation de fibrocartilage et procédés apparentés - Google Patents

Système de bague de greffe pour induire une formation de fibrocartilage et procédés apparentés

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Publication number
EP2187837A1
EP2187837A1 EP08831799A EP08831799A EP2187837A1 EP 2187837 A1 EP2187837 A1 EP 2187837A1 EP 08831799 A EP08831799 A EP 08831799A EP 08831799 A EP08831799 A EP 08831799A EP 2187837 A1 EP2187837 A1 EP 2187837A1
Authority
EP
European Patent Office
Prior art keywords
graft
graft collar
polymer
poly
tendon
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08831799A
Other languages
German (de)
English (en)
Other versions
EP2187837A4 (fr
Inventor
Helen H. Lu
Jeffrey P. Spalazzi
Moira C. Vyner
Kristen L. Moffat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Columbia University in the City of New York
Original Assignee
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 Columbia University in the City of New York filed Critical Columbia University in the City of New York
Publication of EP2187837A1 publication Critical patent/EP2187837A1/fr
Publication of EP2187837A4 publication Critical patent/EP2187837A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61F2/30—Joints
    • A61F2/30756—Cartilage endoprostheses
    • 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
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61F2/0811—Fixation devices for tendons or ligaments
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus

Definitions

  • the ACL is the most frequently injured ligament of the knee 31 , with over 300,000 ACL injuries reported 22 and more than 100,000 reconstruction procedures performed annually 1 in the United States.
  • Primary ACL reconstruction has traditionally been based on autologous bone-patellar tendon-bone (BPTB) grafts, with a shift in recent years toward the utilization of semitendinosus or hamstring tendon grafts 21 ' " 66; 75 due to the high incidence of donor site morbidity and complications related to the harvest of BPTB grafts.
  • BPTB autologous bone-patellar tendon-bone
  • Allografts are also routinely utilized for ACL reconstruction 25 ' 30 , especially with advancements in allograft processing ⁇ and comprehensive studies demonstrating comparable clinical outcomes between allogeneic and autologous grafts 26 ' " 45; 56; 57; 65 .
  • Allogeneic grafts used include the patellar, Achilles, anterior or posterior tibialis, semitendinosus or gracilis, and quadriceps tendons, with the tibialis and Achilles tendons being the most common 25 ' ' 26; 56; 57; 65; 72 .
  • ACL reconstruction grafts The long term performance of ACL reconstruction grafts is dependent on several factors, including the structural and material properties of the graft, the initial graft tension 6 ' " 7; 16; 17; 24; 64 , the intra-articular position of the graft 37 ' ' 43 , and graft fixation 33 ' ' 59 . Increased emphasis has been placed on graft fixation since post-surgical rehabilitation regimens require the immediate ability to regain the full range of motion, re-establish neuromuscular function, and bear weight 9 ' ' 61 .
  • the BPTB graft has been the gold standard for ACL reconstruction in part due to its ability to integrate with subchondral bone via the bony ends.
  • the autologous hamstring tendon graft and tendon allografts are fixed mechanically within the femoral bone tunnel by passing the tendon around a transfemoral pin, while an interference screw with a washer or staple is used to fix the graft within the tibial bone tunnel.
  • Post-operative tendon-to-bone healing does not result in the complete re-establishment of the normal transition zones of the native ACL-to-bone enthesis 2 ' " 3; 8; 10; 11; 14; 23; 36; 42, - 53, - 6i; 67, - 7i; 83 ⁇ Rather, a non ⁇ anatomic fibrovascular scar tissue forms at the graft and bone junction within the bone tunnel 60"62 . Consequently, the tendon graft-to-bone interface represents the weak link of the reconstructed ACL graft 33 . Therefore, developing biological fixation methods that promote the regeneration of the native interface on soft tissue-based autografts or allografts will be critical for expediting reconstruction graft healing and achieving long term functionality.
  • the ACL inserts into subchondral bone through a fibrocartilage interface, which can be subdivided into non-mineralized and mineralized regions 12 ' ' 46; 52; 55; 63; 76; 77 .
  • the principal function of this complex interface is to minimize stress concentrations and to facilitate load transfer between two distinct tissue types 4 ' ' 44; 49; 70; 79; 80 . While the mechanism governing, the formation of the fibrocartilage interface is not well understood, it has been postulated that fibrocartilage forms due to metaplasia of tendon or ligament 20 . Nawata et al.
  • proteoglycans 74 resist compressive loading via the accumulation of proteoglycans 74 .
  • gene expression for aggrecan was absent in the wrap-around region of fetal and neonatal bovine deep flexor tendons, the proteoglycan was strongly expressed in mature animals, suggesting post-natal remodeling of fibrocartilage with physiological loading 54 .
  • anterior translocation of the rabbit flexor digitorum profundus tendon to remove compressive loading led to a decrease in the size of the fibrocartilage region, breakdown of the collagen fiber network, and lower matrix glycosaminoglycan content 41 .
  • this scaffold system combines a degradable graft collar 38 ' ' 69 with nanofiber meshes fabricated from poly(lactic-co-glycolic acid) (PLGA) 35 ' ' 50 . It is anticipated that with the inherent contraction of the nanofiber meshes 48; 84 , this biphasic scaffold system can be used to apply compressive mechanical loading to tendon grafts and induce fibrocartilage formation.
  • PLGA poly(lactic-co-glycolic acid)
  • the mechano-active scaffold complex can be used clinically to apply both biochemical and mechanical stimuli to induce metaplasia of the tendinous matrix, ultimately facilitating the formation of an anatomic fibrocartilage interface on these grafts.
  • This approach offers significant promise as the functional transition between soft tissue and bone would be re-established, with the potential to ensure long-term graft stability and improve clinical outcome through biological fixation.
  • This application provides an apparatus for inducing formation of fibrocartilage, said apparatus comprising a graft collar having a hollow central portion along a longitudinal axis, wherein an outer surface of the graft collar is wrapped with a polymer-fiber mesh configured to apply compression to the graft collar.
  • This application further provides a method for making a device for inducing formation of fibrocartilage comprising forming a graft collar and wrapping the graft collar with a polymer-fiber mesh, to form said device.
  • This application also provides a method for inducing formation of fibrocartilage comprising enclosing a tendon within a hollow central portion of a polymer-fiber mesh- wrapped graft collar configured to apply compression to the tendon.
  • This application further provides an apparatus for inducing formation of fibrocartilage, said apparatus comprising a graft collar having a hollow central portion along a longitudinal axis wherein an outer surface of the graft collar is clamped by a clamp to apply static loading to the graft collar.
  • FIG. 1 Compression of Graft Collar Scaffold with Nanofiber Mesh.
  • FIG. 3 Compression of Tendon Graft with Nanofiber Mesh.
  • Figure 4 Compression of Tendon Graft with Graft Collar Scaffold and Nanofiber Mesh.
  • FIG. 5 Effects of Compression on Collagen Organization. Scaffold-induced compression modulated collagen organization. Collagen organization was affected by scaffold-mediated loading at (A) control, Day 1, (B) loaded, Day 1, (C) control, Day 14, and (D) loaded, Day 14. In addition, fiber diameter was smaller in the compressed group. Disruption of the collagen matrix was evident only in the control group after 14 days (Stain, picrosirius red as viewed under polarized light; original magnification, x20) .
  • Figure 6 Effects of Compression on Tendon Cellularity and Matrix Composition.
  • Figure 7 Effects of Compression on the Expression of Fibrocartilage-Related Markers. Scaffold-induced compression of the tendon graft resulted in significant up-regulation of type II collagen, aggrecan, and TGF- ⁇ 3 after 24 hours ( *p ⁇ 0.05) . All three fibrocartilage interface-related markers increased in the tendon after scaffold-induced compression.
  • FIG. 10 Comparison of Scaffold-Induced Dynamic and Static Compression on a Tendon Graft.
  • A Experimental Design.
  • B Photogrphs of the compressed group and the control group.
  • FIG. 1 Effects of Compression on Tendon Graft Matrix Morphology.
  • A Control Group.
  • B Dynamic Compression Group.
  • C Static Compression Group.
  • FIG. 13 Effects of Compression on Tendon Graft Collagen Fiber Diameter.
  • A Control Group.
  • B Dynamic Compression Group.
  • C Static Compression Group.
  • Figure 15 Effects of Compression on Cell Number. Cell number constant in the loaded group x 10 6 .
  • Figure 16 Effects of Compression on Gene Expression. Gene expression for fibrocartilage markers up-regulated in static compressed group over seven days (Collagen, Aggrecan, TGF-B3) .
  • Figure 18 Effects of Compression on Tendon Matrix- Preliminary In Vivo Study. Little fiber diameter change at day 1 while notable fiber diameter decrease by day 14.
  • Figure 19 Schematic of Graft Collar + Mesh Complex Applied to Graft .
  • aligned fibers shall mean groups of fibers which are oriented along the same directional axis. Examples of aligned fibers include, but are not limited to, groups of parallel fibers .
  • allogenic in regards to a biopolymer mesh, shall mean a biopolymer mesh derived from a material originating from the same species as the subject receiving the biopolymer mesh.
  • 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. Generally, materials that are bioactive develop an adherent interface with tissues that resist substantial mechanical forces.
  • 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 any material derived from a biological source. Examples of a biopolymer mesh include, but are limited to, collagen, chitosan, silk and alginate.
  • BFGF basic fibroblast growth factor
  • BMP bone morphogenic protein
  • BMSC bone marrow-derived stem cells
  • chondrocyte shall mean a differentiated cell responsible for secretion of extracellular matrix of cartilage.
  • clamp shall mean a device which statically compresses the soft tissue graft.
  • the clamp can be made of metal, ceramic, polymers, composites thereof, or other material that can compress a soft tissue graft.
  • the material can be porous, permeable, or degradable .
  • 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.
  • glass transition temperature is the temperature at which, upon cooling, a noncrystalline ceramic or polymer transforms from a supercooled liquid into a rigid glass.
  • the noncrystalline ceramic or polymer may be of multiple form and composition, and may be formed as microspheres.
  • the polymer chains from adjacent microspheres typically entangle, effectively forming a bond between the microspheres upon cooling. As the polymer is heated above its glass transition temperature, long range polymer chain motion begins.
  • graft shall mean a device or material 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.
  • 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. As indicated by the results of the experiment described in this disclosure, the tissues can survive despite the presence of compression.
  • hydrogel shall mean any colloid in which the particles are in the external or dispersion phase and water is in the internal or dispersed phase.
  • a chondrocyte-embedded agarose hydrogel may be used in some instances.
  • the hydrogel may be formed from hyaluronic acid, chitosan, alginate, collagen, glycosaminoglycan and polyethylene glycol (degradable and non-degradable) , which can be modified to be light- sensitive. It should be appreciated, however, that other biomimetic hydrogels may be used instead.
  • lyophilized in regards to a graft collar, shall mean a graft collar that has been rapidly frozen and dehydrated.
  • osteoblast shall mean a bone-forming cell that is derived from mesenchymal osteoprognitor cells and forms an osseous matrix in which it becomes enclosed as an osteocyte. The term is also used broadly to encompass osteoblast-like, and related, cells, such as osteocytes and osteoclasts.
  • osteointegrative shall mean ability to chemically bond to bone.
  • PDGF blood pressure regulator
  • polymer shall mean 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.
  • particle reinforcer shall mean a composite with a higher strength than the original material .
  • porosity shall mean the ratio of the volume of interstices of a material to a volume of a mass of the material.
  • sintering shall mean densification of a particulate polymer compact involving a removal of pores between particles (which may be accompanied by equivalent shrinkage) combined with coalescence and strong bonding between adjacent particles.
  • the particles may include particles of varying size and composition, or a combination of sizes and compositions.
  • soft tissue graft shall mean a graft which is not synthetic, and can include autologous grafts, syngeneic grafts, allogeneic grafts, and xenogeneic graft.
  • synthetic shall mean that the material is not of a human or animal origin.
  • TGF shall mean transforming growth factor .
  • VEGF vascular endothelial growth factor
  • xenogenic in regards to a biopolymer mesh, shall mean a biopolymer mesh derived from a material originating from a species other than that of the subject receiving the biopolymer mesh.
  • This application describes an apparatus for inducing formation of fibrocartilage, comprising a graft collar having a hollow central portion along a longitudinal axis, wherein an outer surface of the graft collar is wrapped with a polymer-fiber mesh, to apply compression to the graft collar.
  • This application further describes a method for making said apparatus and a method for inducing formation of fibrocartilage .
  • the graft collar has a cylindrical body.
  • the graft collar includes a sliced cut parallel to a longitudinal axis of the cylindrical body. This embodiment would permit encasing a soft tissue graft, such as a tendon, on all sides.
  • the outer surface of the graft collar is wrapped in its entirety.
  • the polymer-fiber mesh comprises nanofibers .
  • the nanofibers are aligned.
  • the nanofibers are aligned perpendicular to the longitudinal axis of the graft collar.
  • the nanofibers are unaligned.
  • the graft collar includes at least one of the following substances: anti-infectives, antibiotics, bisphosphonate, hormones, analgesics, antiinflammatory agents, growth factors, angiogenic factors, chemotherapeutic agents, anti-rejection agents, and RGD peptides.
  • growth factors include, but are not limited to, TGFs, BMPs, IGFs, VEGFs, BFGFs and PDGFs.
  • TGF is TGF- ⁇ .
  • the BMP is BMP-2.
  • the graft collar includes one or more of the following types of cells: chondrocytes, osteoblasts, osteoblast-like cells and stem cells. In another embodiment, the graft collar includes at least one of the following: osteogenic agents, osteogenic materials, osteoinductive agents, osteoinductive materials, osteoconductive agents, osteoconductive materials and chemical factors.
  • the graft collar can comprise multiple phases.
  • the graft collar comprises first through third phases, wherein the first phase comprises a material which promotes growth and proliferation of fibroblasts, (ii) the second phase adjacent to the first phase comprises a material which promotes growth and proliferation of chondroblasts, and (iii) the third phase adjacent to the second phase comprises a material which promotes the growth and proliferation of osteoblasts.
  • the graft collar can comprise a degradable cell barrier, such as a nanofiber mesh, inserted between the adjacent phases.
  • the graft collar has multiple phases joined by a gradient of properties.
  • the multiple phases of the graft collar are processed through one or more sintering stages.
  • the gradient of properties across the multiple phases of the graft collar includes mechanical properties.
  • the gradient of properties across the multiple phases of the graft collar includes chemical properties.
  • the gradient of properties across the multiple phases of the graft collar includes mineral content.
  • the gradient of properties across the multiple phases of the graft collar includes structural properties.
  • the gradient of properties across the multiple phases of the graft collar includes porosity.
  • the gradient of properties across the multiple phases of the graft collar includes geometry.
  • the polymer-fiber mesh is selected from the group comprising aliphatic polyesters, poly (amino acids), copoly (ether-esters ), polyalkylenes oxalates, polyamides, poly (iminocarbonates) , polyorthoesters, polyoxaesters, polyamidoesters, poly ( ⁇ -caprolactone) s, polyanhydrides, polyarylates, polyphosphazenes, polyhydroxyalkanoates , polysaccharides, and biopolymers, and a blend of two or more of the preceding polymers.
  • the polymer-fiber mesh comprises at least one of the poly (lactic-co-glycolic acid), poly (lactide) and poly (glycolide) .
  • the polymer-fiber mesh is 35% poly (DL-lactide-co-glycolic acid) 85:15, 55% N, N-dimethylformamide, and 10% ethanol .
  • the polymer-fiber mesh comprises particulate reinforcers.
  • the particulate reinforcers comprise nanoparticles .
  • the graft collar is porous. In another embodiment, the graft collar is lyophilized. In another embodiment, the graft collar is biodegradable. In another embodiment, the graft collar is osteointegrative . In one embodiment, the graft collar is permeable, so the tissue can survive despite the presence of compression. As evidence by the cell number and matrix production results described in this application, tissue can survive despite the presence of compression.
  • the graft collar is composed of microspheres.
  • the microspheres comprise poly (DL-lactide-co-glycolic acid).
  • microspheres comprise poly (DL-lactide-co- glycolic acid) and bioactive glass.
  • the apparatus further comprise a device which applies static loading to the graft collar.
  • the device is a clamp.
  • the degree of strain of said graft collar is adjusted based on polymer composition. In another embodiment, the degree of strain of said graft collar is adjusted based on nanofiber composition. In one embodiment, the graft collar comprises (a) a first region comprising a biopolymer mesh and hydrogel and (b) a second region adjoining the first region and comprising polymer microspheres.
  • the first region supports the growth and maintenance of an interfacial zone between tendon and bone
  • the second region supports the growth and maintenance of bone tissue.
  • the hydrogel is photopolymerized, thermoset or chemically cross-linked.
  • the hydrogel is polyethylene glycol.
  • the biopolymer mesh comprises aligned fibers .
  • the first region contains TGF, such as TGF- ⁇ .
  • the first region contains chondrocytes.
  • the chondrocytes can be, but are not limited to, BMSC- derived chondrocytes.
  • the first region contains stem cells.
  • the stem cells can be, but are not limited to, BMSCs.
  • the biopolymer mesh is derived from at least one of collagen, chitosan, silk and alginate. In another embodiment, the biopolymer mesh is allogenic or xenogenic .
  • the second region contains at least one of the following growth factors: BMP, IGF, VEGF, BFGF and PDGF.
  • BMP can be, but is not limited to, BMP-2.
  • the second region includes osteoblasts and/or osteoblast-like cells.
  • the osteoblasts and/or osteoblast like cells can be BMSC-derived.
  • the second region includes at least one of the following: osteogenic agents, osteogenic materials, osteoinductive agents, osteoinductive materials, osteoconductive agents, osteoconductive materials and chemical factors.
  • the second region contains nanoparticles of calcium phosphate.
  • examples of calcium phosphate include, but are not limited to, tricalcium phosphate, hydroxyapatite or a combination thereof.
  • the second region contains nanoparticles of bioactive glass.
  • the graft collar is biodegradable.
  • the graft collar is osteointegrative .
  • the graft collar comprises (a) a first region comprising a polymer-fiber mesh and hydrogel and (b) a second region adjoining the first region and comprising polymer microspheres.
  • the first region supports the growth and maintenance of an interfacial zone between tendon and bone
  • the second region supports the growth and maintenance of bone tissue
  • the graft collar includes at least one of the following substances: anti-infectives, antibiotics, bisphophonate, hormones, analgesics, antiinflammatory agents, growth factors, angiogenic factors, chemotherapeutic agents, anti-rejections agents, and RGD peptides
  • the hydrogel is photopolymerized, thermoset or chemically cross-linked.
  • the hydrogel is polyethylene glycol.
  • the polymer-fiber mesh comprises aligned fibers.
  • the first region contains TGF.
  • the TGF can be, but is not limited to, TGF- ⁇ .
  • the first region contains chondrocytes.
  • the chondrocytes can be BMSC-derived chondrocytes.
  • the first region contains stem cells.
  • the stem cells can be, but are not limited to, BMSCs.
  • the second region contains at least one of the following growth factors: BMP, IGF, VEGF, BFGF and PDGF.
  • BMP can be, but is not limited to, BMP-2.
  • the second region includes osteoblasts and/or osteoblast-like cells.
  • the osteoblasts and/or osteoblast like cells can be BMSC-derived.
  • the second region includes at least one of the following: osteogenic agents, osteogenic materials, osteoinductive agents, osteoinductive materials, osteoconductive agents, osteoconductive materials and chemical factors.
  • the second region contains nanoparticles of calcium phosphate.
  • examples of calcium phosphate include, but are not limited to, tricalcium phosphate, hydroxyapatite or a combination thereof.
  • the microspheres comprise poly (DL- lactide-co-glycolic acid) . In another embodiment, the microspheres comprise poly (DL- lactide-co-glycolic acid) and bioactive glass.
  • the second region contains nanoparticles of bioactive glass.
  • the graft collar is biodegradable.
  • the graft collar is osteointegrative .
  • This application further discloses a method for making a device for inducing formation of fibrocartilage comprising (a) forming a graft collar and (b) wrapping the graft collar prepared in step (a) with a polymer-fiber mesh, to form said device.
  • said step (a) comprises (al) processing a plurality of microspheres, (a2) laying the microspheres processed in step (a) in a mold and (a3) sintering together the microspheres in the mold above a glass transition temperature.
  • the microspheres further comprise bioactive glass.
  • the polymer-fiber mesh comprises nanofibers .
  • the polymer-fiber mesh is selected from the group comprising aliphatic polyesters, poly (amino acids), copoly (ether-esters) , polyalkylenes oxalates, polyamides, poly (iminocarbonates) , polyorthoesters, polyoxaesters, polyamidoesters, poly ( ⁇ -caprolactone) s, polyanhydrides , polyarylates, polyphosphazenes, polyhydroxyalkanoates, polysaccharides, and biopolymers, and a blend of two or more of the preceding polymers.
  • the polymer-fiber mesh comprises at least one of the poly (lactic-co-glycolic acid), poly (lactide) and poly (glycolide) .
  • the polymer-fiber mesh is 35% poly (DL-lactide-co-glycolic acid) 85:15, 55% N, N-dimethylformamide, and 10% ethanol .
  • the polymer-fiber mesh comprises particulate reinforcers.
  • the particulate reinforcers comprise nanoparticles .
  • the nanofibers wrapped around the graft collar are perpendicular to the longitudinal axis of the graft collar.
  • the method further comprises incubating the polymer-fiber mesh-wrapped graft collar at a suitable temperature, time and humidity to allow sintering of the polymer-fiber mesh to the graft collar.
  • the polymer-fiber-mesh-wrapped graft collar is incubated at or around 37 °C and at or around 5% CO 2 .
  • This application further describes a method for inducing formation of fibrocartilage comprising enclosing a tendon within a polymer-fiber mesh-wrapped graft collar configured to apply compression to the tendon.
  • a method for inducing formation of fibrocartilage comprising enclosing a tendon within a polymer-fiber mesh-wrapped graft collar configured to apply compression to the tendon.
  • Any of the aforementioned graft collar systems can be utilized in this method.
  • This application further describes an apparatus for inducing formation of fibrocartilage, said apparatus comprising a graft collar having a hollow central portion along a longitudinal axis wherein an outer surface of the graft collar is clamped by a clamp to apply static loading to the graft collar.
  • ACL Anterior Cruciate Ligament
  • Patellar tendon grafts were isolated from neonatal bovine tibiofemoral joints (1-7 days old) obtained from a local abattoir (Green Village Packing, Green Village, NJ) . Briefly, the joints were first cleaned in an antimicrobial bath. Under antiseptic conditions, midline longitudinal incisions were made through the subcutaneous fascia to expose the patellar tendon. The paratenon was removed, and the patellar tendon dissected from the underlying fat pad. Sharp incisions were made through the patellar tendon at the patellar and tibial insertions, and the insertions were completely removed from the graft.
  • Aligned nanofiber meshes (Fig. IA, B) were fabricated by electrospinning 13 .
  • a viscous polymer solution consisting of 35% poly (DL-lactic-co-glycolic acid) 85:15 (PLGA, I. V. 0.70 dL/g, Lakeshore Biomaterials, Birmingham, AL), 55% N, N-dimethylformamide (Sigma, St. Louis, MO), and 10% ethanol (Commercial Alcohol, Inc., Toronto, Ontario) was loaded into a syringe fitted with an 18-gauge needle (Becton Dickinson, Franklin Lakes, NJ) .
  • Aligned fibers R 9 were obtained using an aluminum drum with an outer diameter of 10.2 cm rotating with a surface velocity of 20 m/s.
  • Fig. 8 Fiber morphology, diameter and alignment of the as-fabricated mesh samples were analyzed using scanning electron microscopy (SEM) . Briefly, the samples were sputter-coated with gold (LVC-76, Plasma Sciences, Lorton, VA) and subsequently imaged (JSM 5600LV, JEOL, Tokyo, Japan) at an accelerating voltage of 5 kV.
  • a tendon graft collar based on a sintered microsphere scaffold was fabricated following published methods 38 ' ' 69 .
  • the microspheres were formed following the methods of Lu et al. 3 ⁇ , where the polymer was first dissolved in dichloromethane (Acros Organics, Morris Plains, NJ) and then BG particles were added (20 wt%) .
  • the suspension was poured into a 1% solution of polyvinyl alcohol (Sigma, St. Louis, MO) to form the microspheres.
  • the microspheres were subsequently sintered at 7O 0 C for 5 hours in a custom mold to form cylindrical scaffolds with an outer diameter of 0.7 cm and an inner diameter of 0.3 cm. (Fig. 9)
  • Nanofiber Mesh contraction was evaluated using digital image analysis. Briefly, the nanofiber meshes were cut into 10 mm x 10 mm squares and immersed in Dulbecco's Modification of Eagle's Medium (DMEM, Mediatech, Inc., Herndon, VA) supplemented with 10% fetal bovine serum (FBS, Atlanta Biologicals, Norcross, GA) and incubated at 37 0 C and 5% CO2. The meshes were imaged using stereomicroscopy at 0, 2, 24, and 72 hours.
  • DMEM Dulbecco's Modification of Eagle's Medium
  • FBS Atlanta Biologicals, Norcross, GA
  • the potential of utilizing nanofiber mesh contraction to directly apply compression to the tendon graft was evaluated over time. Briefly, the aligned electrospun meshes were cut into 10 cm x 2 cm strips, with fiber alignment oriented along the long axis of the mesh. The patellar tendon graft was bisected along its long axis, and one half of the tendon was wrapped with the nanofiber mesh while the other half served as the unloaded control
  • Fig. 3A The samples were cultured in DMEM supplemented with 1% non-essential amino acids, 1% antibiotics, and 0.1% antifungal (all from Mediatech) and 10% FBS (Atlanta Biologicals) . At days 5 and 14, the effects of compression on tissue morphology and cellularity were characterized by histology 68 .
  • the samples were rinsed with phosphate buffered saline (PBS, Sigma) , fixed with 10% neutral buffered formalin (Fisher Scientic and Sigma) and embedded in paraffin (Fisher Scientific, Pittsburgh, PA). The samples were then cut into 7- ⁇ m thick sections and stained with hematoxylin and eosin (H&E) .
  • PBS phosphate buffered saline
  • H&E hematoxylin and eosin
  • Sample fluorescence was measured using a microplate reader (Tecan, Research Triangle Park, NC) , with excitation and emission wavelengths set at 485 and 535 nm, respectively.
  • the total number of cells in the sample was calculated using the conversion factor of 8 pg DNA/cell 40 .
  • GAG content was quantified using a colorimetric 1, 9-dimethylmethylene blue (DMMB) assay. Tissue digest from the cell quantitation assay was combined with DMMB dye, and the concentration of GAG- DMMB complexes was determined using a plate reader at 540 and 595 nm and correlated to a standard prepared with chondroitin-6-sulfate .
  • DMMB colorimetric 1, 9-dimethylmethylene blue
  • fibrocartilage markers such as collagen I, II, aggrecan, and Transforming Growth Factor- Beta 3 (TGF- ⁇ 3) was determined at day 1 using reverse- transcription polymerase chain reaction (RT-PCR) . Briefly, after removing the graft collar and nanofiber mesh, total RNA of the tendon graft was obtained using the Trizol extraction method (Invitrogen, Carlsbad, CA) . The isolated RNA was reverse-transcribed into cDNA using the Superscript III First-Strand Synthesis System (Invitrogen, Carlsbad, CA) and the cDNA product was amplified using recombinant Platinum Taq DNA polymerase (Invitrogen) . GAPDH was used as the housekeeping gene, and expression band intensities were measured (ImageJ) and normalized against GAPDH.
  • RT-PCR reverse- transcription polymerase chain reaction
  • Results are presented in the form of mean ⁇ standard deviation, with n equal to the number of samples analyzed.
  • Two-way analysis of variance (ANOVA) was first performed to assess if differences exist among the means. Fisher's LSD post-hoc test was subsequently performed for all pair- wise comparisons and statistical significance was attained at p ⁇ 0.05.
  • ANOVA analysis of variance
  • Fisher's LSD post-hoc test was subsequently performed for all pair- wise comparisons and statistical significance was attained at p ⁇ 0.05.
  • All statistical analyses were performed using the JMP statistical software package (SAS Institute, Cavy, NC) .
  • the nanofiber mesh exhibited a high degree of alignment with an average fiber diameter of 0.9 ⁇ 0.4 ⁇ m (Fig. IA).
  • Anisotropic mesh contractile behavior was observed in the mesh, with significantly higher contraction found in the direction of nanofiber alignment.
  • the mesh contracted over 57% along the aligned fiber direction (y- axis) by 2 hours, with less than 13% reduction in the x- axis (Fig. IB) .
  • Mesh contraction continued over time, exhibiting over 70% contraction in the y-axis and 20% in the x-axis by 24 hours and stabilizing thereafter, with no significant differences found between the 24- and 72-hour groups .
  • the tendon graft was compressed by a complex of the graft collar scaffold and nanofiber mesh. It was observed that at 24 hours post-compression (Fig. 4B, top), the tendon graft matrix organization was distinct from that of the unloaded control, with increased matrix density and less of the characteristic crimp of the tendon. After 14 days of compression by the scaffold+mesh complex, it was found that the matrix remodeling visible 24 hours following the onset of loading was maintained over time (Fig. 4B, bottom) . In contrast, the control tendon retained its characteristic crimp, with evident disruption of the matrix ultrastructure. Further, compression distinctly changed matrix collagen organization.
  • fibrocartilage markers such as types I and II collagen, aggrecan and TGF- ⁇ 3 were evaluated after compression with the graft collar scaffold and nanofiber mesh. As shown in Fig. 6, after 24 hours of compression, gene expression of type II collagen, aggrecan and TGF- ⁇ 3 were all up-regulated in the loaded group when compared to non-compressed tendons (Fig. I) 1 with significant differences found in aggrecan and TGF- ⁇ 3 expression.
  • the morphology of the control group is maintained from day 1 to day 14. Crimp in the tissue was maintained. In both the dynamic and the static compression group, fiber morphology was compressed after day 1 and continues to compress to day 14. (Fig. 12)
  • the cell number is greater in the static compression group than in the dynamic compression group.
  • the long term goal is to achieve biological fixation by engineering a functional and anatomical fibrocartilage interface on biological and synthetic soft tissue grafts used in orthopaedic repair 39 .
  • the current study focuses on the design and evaluation of a novel graft collar scaffold system capable of applying mechanical loading and inducing fibrocartilage formation on tendon grafts.
  • scaffold-mediated compression of a patellar tendon graft was evaluated over time, focusing on the effects of loading on tendon matrix organization and cell response.
  • effects of scaffold-induced dynamic and static compression on a tendon graft were compared.
  • fibrocartilage markers including type II collagen, aggrecan, and Transforming Growth Factor- ⁇ 3 (TGF- ⁇ 3) .
  • TGF- ⁇ 3 Transforming Growth Factor- ⁇ 3
  • fibrocartilage in tendons is largely comprised of types I and II collagen, as well as proteoglycans 5 ' ' 15; 32; qi .
  • compressive loading of fibrocartilaginous regions of tendons has been reported to increase the synthesis cf Transforming Growth Factor- ⁇ l (TGF- ⁇ l) 58 and large proteoglycans, as well as enhancing aggrecan gene expression 15 ' ' 32 .
  • polyester co-polymer utilized in this study has a high D,L-lactide content (85%) and is non-crystalline, thus the above mechanism may explain the high degree of contraction observed.
  • fiber alignment-related scaffold anisotropy may be controlled to modulate mesh contraction, and consequently, the magnitude and direction of compressive loading on the graft may be controlled by customizing the degree of fiber alignment. Future studies will focus on elucidating the mechanism of mesh contraction as well as exploring methods to control this process for mechanical stimulation.
  • the mesh- collar system is intended to be applied clinically as a degradable graft collar, and will be used to initiate and direct regeneration of an anatomical fibrocartilage interface at the insertion of tendon-based ACL reconstruction grafts.
  • the innovative scaffold system described here can also apply physiologic mechanical stimulation crucial for directing cellular function and tissue remodeling.
  • the graft For utilization with viable autografts, it is envisioned that the graft would be inserted through the collars immediately prior to implantation, and compression of the graft and subsequent fibrocartilage formation would occur in vivo. Allografts, which do not contain viable cells necessary for remodeling the tendon matrix, would need to be repopulated with fibroblasts or stem cells delivered either from the scaffold in vitro prior to graft implantation. It has been reported that mesenchymal stem cell (MSC) -seeded type I collagen sponges inserted into excised sheep patellar tendons and loaded using an ex vivo wrap-around system results in an up-regulation of chondrogenic markers such as Sox9 and Fos 2i .
  • MSC mesenchymal stem cell
  • a similar response by a cell-populated tendon allograft is anticipated following scaffold-mediated compressive loading.
  • the mesh-scaffold system is based on degradable poly- ⁇ -hydroxyester polymers, thus it is expected that the mechano-active scaffold will be replaced by newly formed tissue after a functional fibrocartilage interface has been formed on the graft.
  • Glousman,RE Revision anterior cruciate ligament reconstruction: three- to nine-year follow-up. Arthroscopy 21:418-423, 2005.
  • Mnaymneh,W A study of retrieved allografts used to replace anterior cruciate ligaments. Arthroscopy 18:163-170, 2002. 43. Markolf,KL, Hame,S, Hunter, DM, et al: Effects of femoral tunnel placement on knee laxity and forces in an anterior cruciate ligament graft. J.Orthop.Res. 20:1016-1024, 2002.
  • Niyibizi,C, Sagarrigo, VC, Gibson, G, and Kavalkovich, K Identification and immunolocalization of type X collagen at the ligament-bone interface. Biochem.Biophys .Res Commun. 222:584-589, 1996.
  • Rodeo, SA Studies of tendon-to-bone healing: exploring ways to improve graft fixation following anterior cruciate ligament reconstruction. Jornal of Bone and Joint Surgery 2001.
  • Mizuno,K Graft healing in the bone tunnel in anterior cruciate ligament reconstruction. Clin.Orthop. 278-286, 2000. 84. Zong,X, Ran, S, Kim, KS, et al: Structure and
  • Nanofiber Membrane Biomacromolecules . 4:416- 423, 2003.

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Abstract

L'invention porte sur des appareils et des procédés pour induire une formation d'un fibrocartilage. Par exemple, l'invention porte sur un appareil qui comprend une bague de greffe comportant une partie centrale creuse le long d'un axe longitudinal, une surface externe de la bague de greffe étant recouverte par maillage de fibres polymères, ou une surface externe de la bague de greffe étant serrée par un organe de serrage, pour appliquer une charge de compression, ou statique, à la bague de greffe. L'invention porte également sur un procédé de fabrication dudit appareil et d'induction de la formation d'un fibrocartilage.
EP08831799.5A 2007-09-21 2008-09-22 Système de bague de greffe pour induire une formation de fibrocartilage et procédés apparentés Withdrawn EP2187837A4 (fr)

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