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WO2025042830A1 - Formulation de mastic de greffe osseuse à base de facteur de croissance dérivé des plaquettes - Google Patents

Formulation de mastic de greffe osseuse à base de facteur de croissance dérivé des plaquettes Download PDF

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Publication number
WO2025042830A1
WO2025042830A1 PCT/US2024/042915 US2024042915W WO2025042830A1 WO 2025042830 A1 WO2025042830 A1 WO 2025042830A1 US 2024042915 W US2024042915 W US 2024042915W WO 2025042830 A1 WO2025042830 A1 WO 2025042830A1
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WO
WIPO (PCT)
Prior art keywords
implant material
pdgf
collagen
biocompatible matrix
weight percent
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PCT/US2024/042915
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English (en)
Inventor
Bedilu ALLO
Peter DI BENEDETTO
Julie A. BONOMO
Christopher J. Damien
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Biomimetic Therapeutics LLC
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Biomimetic Therapeutics LLC
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Publication of WO2025042830A1 publication Critical patent/WO2025042830A1/fr
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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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
    • A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, e.g. apatite
    • 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
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • 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
    • A61L2430/38—Materials or treatment for tissue regeneration for reconstruction of the spine, vertebrae or intervertebral discs

Definitions

  • Bone fusion is a common form of orthopedic surgery used to treat musculoskeletal problems associated with various joints of patients, particularly the spine or ankle. Bone fusion involves the artificial induction of joint ossification between two bones. Approximately 100,000 lumbar spine fusion surgeries are performed annually in the U.S. in patients with lower back pain due to degenerative disc disease, deformity, unstable spine trauma, or spondylolisthesis. Spine fusion failure rates currently are as high as 30%. The use of various orthopedic devices such as pedicle screws, plates and osteobiologics has led to an improvement in fusion rates, but failed spinal surgeries still remain a serious problem.
  • VBs adjacent vertebral bodies
  • the diseased disc tissue is removed, the endplates of the adjacent vertebral bodies are debrided, and rigid fixation in the form of a cage to stabilize the two levels is implanted between the VBs.
  • Healing progresses with the formation of new bone between the VBs throughout the cage hardware.
  • a bone graft of is used to ensure bony fusion across the cage gap and to stabilize the spine for the patient, alleviating pain and often returning the patient to some level of activity.
  • an osteoconductive and osteoinductive graft is used to enhance the bone healing response.
  • Both interbody and posterolateral spine fusions use a biological osteoinductive agent to generate the bone required for the spinal fusion.
  • the current standard of care is to harvest bone from the iliac crest or other bony site to obtain an osteoinductive graft material.
  • the patient must also undergo a procedure to harvest the graft, usually from the iliac crest, in addition to the spine fusion surgery itself.
  • Harvesting bone graft from the iliac crest is associated with post-operative pain that can persist in up to 25% of patients.
  • Other disadvantages associated with this treatment method are an increased risk of infection, availability and quality of bone autograft material, and the patient inconvenience that is caused due to donor site morbidity. Accordingly, there is a need for improved bone graft compositions that are useful in various bone fusion procedures. Furthermore, there is a need for a graft compositions that have good handling characteristics and can be easily shaped and provided at a site of bone fusion, such as a site of ankle arthrodesis or spine fusion.
  • compositions that can remain at a site of bone fusion, or other orthopedic bone repair site, thereby reducing movement of the graft material into the tissue outside the fusion site so that the graft and any osteoconductive or osteoinductive agents remain localized at the fusion site.
  • grafting compositions should provide a suitable PDGF release profile in order to initiate the healing cascade at the site of fusion.
  • the present disclosure addresses these needs.
  • SUMMARY One aspect of the present disclosure provides an implant material comprising a growth factor, an acid, and a biocompatible matrix, the biocompatible matrix comprising a porous calcium phosphate, a fibrillar collagen, and an aqueous liquid.
  • the biocompatible matrix comprises about 70 to about 95% by weight of the porous calcium phosphate and about 5 to about 30% by weight of the fibrillar collagen wherein the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 2:1.
  • mL/g volume to mass ratio
  • the growth factor is selected from a bone morphogenic protein, platelet-derived growth factor (PDGF), fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF- ⁇ ) and any combination thereof.
  • the growth factor is PDGF.
  • the aqueous liquid and the biocompatible matrix are present in the implant material in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 1.5:1, and in more particular embodiments, the aqueous liquid and the biocompatible matrix are present in the implant material in a volume to mass ratio (mL/g) of about 0.5:1 about 0.75:1, or about 1:1.
  • the porous calcium phosphate is present in the biocompatible matrix in an amount ranging from about 70 weight percent to about 90 weight percent, about 80 weight percent to about 90 weight percent, about 85 weight percent to about 90 weight percent, about 80 weight percent to about 85 weight percent.
  • the porous calcium phosphate is present in the biocompatible matrix in an amount of about 90 weight percent, about 85 weight percent, or about 80 weight percent.
  • the porous calcium phosphate is selected from the group consisting of tricalcium phosphate, hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, octacalcium phosphate, brushite, and mixtures thereof.
  • the porous calcium phosphate is ⁇ -tricalcium phosphate.
  • the calcium phosphate comprises particles having a size ranging from about 100 to about 1000 ⁇ m, preferably about 100 to about 500 ⁇ m, and more preferably from about 100 to about 300 ⁇ m.
  • the fibrillar collagen is present in the biocompatible matrix in an amount ranging from about 10 weight percent to about 25 weight percent, about 10 weight percent to about 20 weight percent, about 10 weight percent to about 15 weight percent, or about 5 weight percent to about 10 weight percent. In other more particular embodiments, the fibrillar collagen is present in the biocompatible matrix in an amount of about 10 weight percent, about 15 weight percent, or about 20 weight percent.
  • the fibrillar collagen comprises bovine collagen, preferably type I bovine collagen.
  • the fibrillar collagen comprises dermis collagen, while in other embodiments, the fibrillar collagen comprises tendon collagen.
  • the biocompatible matrix further comprises about 0.1 to about 10 weight % of soluble collagen about 0.1 to about 5 weight % of soluble collagen, about 0.1 to about 2 weight % of soluble collagen, or about 1 to about 10 weight % of soluble collagen.
  • the soluble collagen comprises bovine collagen, preferably type I bovine collagen.
  • the soluble collagen comprises bovine dermis collagen, while in other embodiments, the soluble collagen comprises tendon collagen.
  • the PDGF is present in the aqueous liquid at a concentration ranging from about 0.1 mg/ml to about 5.0 mg/ml, preferably about 0.1 mg/ml to about 1.0 mg/ml, more preferably, about 0.2 mg/ml to about 0.4 mg/ml, and most preferably about 0.3 mg/ml.
  • the PDGF comprises PDGF-AA, PDGF-BB, PDGF- AB, PDGF-CC, PDGF-DD, or a mixture or a derivative thereof, preferably PDGF-BB.
  • the PDGF-BB comprises at least 65% intact PDGF-BB.
  • the PDGF-BB is recombinant human (rh)PDGF-BB.
  • the aqueous liquid comprises the growth factor in a buffer, preferably sodium acetate.
  • the putty retains its in vitro structural integrity at 37 oC.
  • at least 20% of the PDGF is released after about 30 minutes in vitro.
  • at least 40% of the PDGF is released after about 1 hour in vitro.
  • at least 50% of the PDGF is released after about 1 hour in vitro.
  • at least 60% of the PDGF is released after about 1 hour in vitro.
  • the acid is selected from acetic acid, citric acid, lactic acid, malic acid, succinic acid, formic acid, tartaric acid, and any combination thereof.
  • the acid is acetic acid.
  • the acid is an aqueous acid.
  • the acid has a concentration in a range of about 10 to about 50 mM in the aqueous liquid. - 4 - FoleyHoagUS12457270.1 SCD-01525
  • biocompatible matrix comprises the acid.
  • the implant material has a pH of about 6.5 or less, preferably about 3 to about 6.5, and more preferably about 3 to about 6, and even more preferably about 3 to about 5.5.
  • Another aspect of the invention provides a method for bone fusion in a subject in need thereof comprising administering the above-described composition to a desired site of bone fusion in the subject.
  • the present disclosure further provides a method for fracture repair in a subject in need thereof comprising administering the above-described composition to a desired site of fracture repair in the subject.
  • FIG.1 Preparation of putty formulation by manual mixing technique.
  • FIG.2 “Paste like” consistency of the AI formulation compared to the Moldable “putty like” consistency of the present formulation.
  • FIG.3 Putty formulation A1 was dispensed from a syringe with a wide-bore opening. The putty formulation was back filled in to a 10 mL syringe and extruded through open bore (without a needle).
  • FIG.4A Structural integrity of various putty formulations at 37 oC (body temperature).
  • FIG.4B A comparison of the structural integrity of the putty formulation and AI at37 oC (body temperature).
  • FIG.5 rhPDGF-BB Release kinetics from 80:20 ⁇ -TCP/collagen putty matrix.
  • FIG.6 The irrigation resistance of the putty formulation when exposed to a saline solution.
  • FIG.7 A putty formulation A4 with 90:10 ⁇ -TCP/collagen and volume:mass ratio (rhPDGF-BB solution: ⁇ -TCP/collagen matrix) of 0.75:1 was applied inside and around a PEEK cage (slides 1-3). Slide 4 displays the AI in a PEEK cage.
  • FIG.8 The implant composition in shredded form is easier to mix and provides with homogeneous distribution of rhPDGF-BB.
  • FIG.9 is a table describing the contents of samples 1 to 5.
  • FIG.10 is a graph showing the PDGF elution results from samples 1 to 5, where sample 5 is Augment Injectable.
  • FIG.11 is a table showing the isoelectric points of various growths factors.
  • FIG.12 is a graph summarizing the ages of diabetes prone BB Wistar rats at the time of fracture.
  • FIG.13 is a graph summarizing the amount of matrix applied to the fracture site.
  • FIG.14 is a graph showing the blood glucose levels from each rat.
  • FIG.15 is a graph showing the blood glucose levels by group.
  • FIG.16 is a graph showing the starting weight of rats.at the time of fracture.
  • FIG.17 is a graph showing the percent weight change of rats over the course of the study.
  • FIG.18 is a graph showing the time from onset of diabetes to the fracture surgery.
  • FIG.19 is a graph showing healing femur X-ray scores.
  • FIG.20 is a graph showing ⁇ CT longitudinal section scores.
  • FIG.21 are images showing ⁇ CT longitudinal section through the medial lateral plane for group A at 4 weeks and 8 weeks.
  • FIG.22 are images showing ⁇ CT longitudinal section through the medial lateral plane for group B at 4 weeks and 8 weeks.
  • FIG.23 are images showing ⁇ CT longitudinal section through the medial lateral plane for group C at 4 weeks and 8 weeks.
  • FIG.24 shows graphs of ⁇ CT of callus bone by group and time points.
  • FIG.25 shows graphs of ⁇ CT of callus bone by group only.
  • FIG.26 shows histological images from fracture calluses of Group A at 4 and 8 weeks.
  • FIG.27 shows histological images from fracture calluses of Group B at 4 and 8 weeks.
  • FIG.28 shows histological images from fracture calluses of Group C at 4 and 8 - 6 - FoleyHoagUS12457270.1 SCD-01525 weeks.
  • FIG.29 is a graph depicting the histomorphometric analysis of callus cartilage by group and time.
  • FIG.30 is a graph depicting the histomorphometric analysis of callus cartilage by group only.
  • DETAILED DESCRIPTION AugmentTM Injectable consists of 2 components, Beta-tricalcium phosphate ( ⁇ - TCP)/ Bovine type I soluble collagen matrix and rhPDGF-BB (0.3 mg/ml solution of rhPDGF-BB in 20 mM sodium acetate solution, pH 6.0).
  • AI is formulated for use by mixing the matrix and rhPDGF-BB solution in a volume to mass ratio of 3:1 (3 mL of rhPDGF-BB solution mixed with 1 gram of the matrix), as per the instructions for use (IFU) using the syringe provided as a part of the AI kit.
  • the AI forms a paste-like formulation that is be applied to a site of fusion through a 14G cannula or blunt needle.
  • the composition of the present disclosures pertains to an improved implant composition comprising where the collagen component is a mixture of non-fibrillar (soluble) and fibrillar (non-soluble collagen).
  • the present composition comprises a ⁇ -TCP/ Bovine type I Collagen matrix (fibrillar and a small proportion of non-fibrillar collagen), which when mixed with rhPDGF-BB solution manually or using a mixing instrument, results in an implant composition.
  • the implant composition advantageously retains its shape after mixing and for a period of time after placement at a site of bone healing (e.g., when exposed to a tissue environment at 37 °C).
  • the putty formulation is also moldable. Accordingly, the putty formulations provide excellent handling and manipulation characteristics during surgical procedures.
  • “promoting” or “facilitating” spinal fusion refers to a clinical intervention designed to desirably affect clinical progression of a spinal fusion procedure. Desirable effects of the clinical intervention include but are not limited to, for example, one or more of: increase in degree of bone density and/or acceleration of bone formation (e.g.
  • the term “effective amount” refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. An effective amount can be provided in one or more administrations. Reference to “about” a value or parameter herein also includes (and describes) embodiments that are directed to that value or parameter per se.
  • PDGF homodimer is a reference to one or multiple PDGF homodimers, and includes equivalents thereof known to those skilled in the art, and so forth. It is understood that all aspects and embodiments of the invention described herein may include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. It is to be understood that methods or compositions “consisting essentially of” the recited elements include only the specified steps or materials and those that do not materially affect the basic and novel characteristics of those methods and compositions.
  • fibrillar collagen means a collagen of a type which can normally form collagen fibrils.
  • the fibrillar collagens are collagen types I-III, V, and XI.
  • the collagen monomers that make up the fibrillar collagens contain "telopeptide” regions at the amino (N) and carboxy (C) terminal ends of the monomers which are non-helical in the collagen trimer. These collagens self-assemble into fibrils with the C-terminal end of the helical domain and the C propeptide of one collagen triple helix overlapping with the N telopeptide and the N-terminal end of the triple helical domain of an adjacent collagen molecule.
  • the monomers that make up the fibrillar collagens are made as preproproteins, including an N-terminal secretion signal sequence and N and C-terminal propeptide domains.
  • the signal sequence is normally cleaved by signal peptidase, as with most secreted proteins, and the propeptides are removed by specific proteolytic processing enzymes after association, folding and secretion of trimeric procollagen.
  • fibrillar collagen encompasses both native ( i.e., naturally occurring) and variant fibrillar collagens (i.e., fibrillar collagens with - 8 - FoleyHoagUS12457270.1 SCD-01525 one or more alterations in the sequence of one or more of the fibrillar collagen monomers).
  • Fibrillar collagen refers to triple helical fibrillar collagen.” “Fibrillar collagen” also may be referred to herein as “insoluble collagen or polymeric collagen.” “Soluble collagen” refers to individual tropocollagen molecules that are soluble in acidic aqueous environments. Tropocollagen may be considered the monomeric unit of fibrillary collagen fibers. “Volume to mass ratio” as used herein refers to ratio of the volume of PDGF in milliliters (mL) to the mass of biocompatible matrix in grams (g).
  • the volume to mass ratio can range from about 0.5:1 to about 1.5:1, about 0.75:1 to about 1:1, about 0.5:1, about 0.75:1, or about 1:1.
  • Exemplary embodiments may comprise, for example, about 0.1 mL of PDGF solution and about 1 g of biocompatible matrix, about 0.75 mL of PDGF and about 1 g of biocompatible matrix, or about 0.5 mL of PDGF solution and about 0.5 g of biocompatible matrix.
  • the implant composition of the present disclosure includes a putty that is moldable, e.g. capable of being molded into a desired shape. In some embodiments, the putty is shape- retaining, e.g., tending to remain in the shape in which it is molded.
  • the implant composition of the present disclosure also includes a putty that is malleable, i.e. capable of being permanently converted from a first shape to a second shape.
  • the implant composition of the present disclosure also includes a putty that is cohesive, i.e. able to remain as a singular, connected mass upon stretching.
  • Implant Materials comprising a growth factor, an acid, and a biocompatible matrix, the biocompatible matrix comprising a porous calcium phosphate, a fibrillar collagen, and an aqueous liquid.
  • the biocompatible matrix comprises about 70 to about 95% by weight of the porous calcium phosphate and about 5 to about 30% by weight of the fibrillar collagen wherein the aqueous liquid and the biocompatible matrix are present in the composition - 9 - FoleyHoagUS12457270.1 SCD-01525 in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 2:1.
  • the present disclosure provides an implant composition consisting essentially of a growth factor, an acid, and a biocompatible matrix, the biocompatible matrix comprising a porous calcium phosphate, a fibrillar collagen, and an aqueous liquid.
  • the biocompatible matrix comprises about 70 to about 95% by weight of the porous calcium phosphate and about 5 to about 30% by weight of the fibrillar collagen wherein the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 2:1.
  • the present disclosure provides an implant composition consisting of a growth factor, an acid, and a biocompatible matrix, the biocompatible matrix comprising a porous calcium phosphate, a fibrillar collagen, and an aqueous liquid.
  • the biocompatible matrix comprises about 70 to about 95% by weight of the porous calcium phosphate and about 5 to about 30% by weight of the fibrillar collagen wherein the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 2:1.
  • the growth factor is selected from a bone morphogenic protein, platelet-derived growth factor (PDGF), fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF- ⁇ ) and any combination thereof.
  • the growth is PDGF, such as PDGF-BB, and more particularly, rhPDGF-BB.
  • the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 1.5:1. In some preferred embodiments, the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) of about 0.5:1. In other preferred embodiments, the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) of about 0.75:1. Most preferably, the aqueous liquid and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) of about 1:1.
  • mL/g volume to mass ratio
  • the porous calcium phosphate is present in the biocompatible - 10 - FoleyHoagUS12457270.1 SCD-01525 matrix in an amount ranging from about 70 weight percent to about 90 weight percent, about 80 weight percent to about 90 weight percent, about 85 weight percent to about 90 weight percent, about 80 weight percent to about 85 weight percent. In more particular embodiments, the porous calcium phosphate is present in the biocompatible matrix in an amount of about 90 weight percent, about 85 weight percent, or about 80 weight percent.
  • the porous calcium phosphate is selected from the group consisting of tricalcium phosphate, hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, octacalcium phosphate, brushite, monetite and mixtures thereof.
  • the porous calcium phosphate is ⁇ -tricalcium phosphate.
  • the calcium phosphate comprises particles having a size ranging from about 100 to about 1000 ⁇ m.
  • the calcium phosphate comprises particles having a size ranging from about 100 to about 500 ⁇ m. In particularly preferred embodiments, the calcium phosphate comprises particles having a size ranging from about 100 to about 300 ⁇ m.
  • the fibrillar collagen is present in the biocompatible matrix in an amount ranging from about 10 weight percent to about 40 weight percent. In other embodiments, the collagen is present in the biocompatible matrix in an amount ranging from about 10 weight percent to about 20 weight percent. In some embodiments, the fibrillar collagen is present in the biocompatible matrix in an amount ranging from about 10 weight percent to about 25 weight percent, about 10 weight percent to about 20 weight percent, about 10 weight percent to about 15 weight percent, or about 5 weight percent to about 10 weight percent.
  • the fibrillar collagen is present in the biocompatible matrix in an amount of about 10 weight percent, about 15 weight percent, or about 20 weight percent.
  • the fibrillar collagen comprises bovine collagen, preferably type I bovine collagen.
  • the fibrillar collagen comprises dermis collagen, while in other embodiments, the fibrillar collagen comprises tendon collagen.
  • the biocompatible matrix further comprises about 0.1 to about - 11 - FoleyHoagUS12457270.1 SCD-01525 10 weight % of soluble collagen about 0.1 to about 5 weight % of soluble collagen, about 0.1 to about 2 weight % of soluble collagen, or about 1 to about 10 weight % of soluble collagen.
  • the soluble collagen comprises bovine collagen, preferably type I bovine collagen. In some embodiments, the soluble collagen comprises bovine dermis collagen, while in other embodiments, the soluble collagen comprises tendon collagen.
  • the biocompatible matrix comprises about 80 to about 90% by weight of the porous calcium phosphate (preferably beta tricalcium phosphate), about 5 to about 15 by weight of the fibrillar collagen, and about 1 to about 10 % by weight of the soluble collagen. In some embodiments, the PDGF is present in the at a concentration ranging from about 0.1 mg/ml to about 5.0 mg/ml.
  • the PDGF is present in the aqueous liquid at a concentration ranging from about 0.1 mg/ml to about 1.0 mg/ml, and even more preferably, the PDGF is present in the aqueous liquid at a concentration from about 0.2 mg/ml to about 0.4 mg/ml. Most preferably, the PDGF is present in the aqueous liquid volume at a concentration of about 0.3 mg/ml.
  • the PDGF comprises PDGF-AA, PDGF-BB, PDGF-AB, PDGF- CC, PDGF-DD, or a mixture or a derivative thereof.
  • the PDGF comprises PDGF-BB.
  • the PDGF-BB comprises at least 65% intact PDGF-BB. Most preferably, the PDGF-BB is recombinant human (rh)PDGF-BB. In some embodiments, the PDGF is provided in a buffer, preferably sodium acetate. In some embodiments, the acid is selected from acetic acid, citric acid, lactic acid, malic acid, succinic acid, formic acid, tartaric acid, and any combination thereof. In certain preferred embodiments, the acid is acetic acid. In some embodiments, the implant material has a pH of less than 6.5. In other embodiments, the implant material has a pH of less than 6. In other embodiments, the implant material has a pH of less than 5.5.
  • the total liquid volume has a pH of less than 5.
  • the implant material has a pH of about 3 to about 6.5, about 3 to about 6, or about 3 to about 5.5.
  • the pH of the implant material is determined, in some embodiments, by - 12 - FoleyHoagUS12457270.1 SCD-01525 Method 1: 1. Weigh 1g of putty matrix. 2. Add 1mL of appropriate pH-modifying solution to tubes with 1g of putty matrix. Note: For the final product where the acid incorporated within the matrix, 1 mL of 20mM sodium acetate buffer can be added as the hydration solution to formulate the putty. 3. Homogenize and incubate 2-5min at RT. 4.
  • Method 2 1. Weigh 1g of putty matrix. 2. Add 1mL of appropriate pH-modifying solution to tubes with 1g of AP matrix. Note: For the final product where the acid incorporated within the matrix, 1 mL of 20mM sodium acetate buffer can be added as the hydration solution to formulate the putty. 3. Homogenize and incubate 2-5min at RT. 4.
  • the implant material is a putty that retains its structural integrity at 37 oC.
  • at least 20% of the PDGF is released after about 30 minutes in vitro. More preferably, at least 40% of the PDGF is released after about 1 hour in vitro, at least 50% of the PDGF is released after about 1 hour in vitro, or at least 60% of the PDGF is released after about 1 hour in vitro. In further preferred embodiments, at least 70% of the PDGF is released after 4 hours in vitro.
  • the present disclosure provides a method for fusing bone in a subject comprising administering the implant material to a desired site of bone fusion in the subject.
  • the site of bone fusion is in a foot, toe, ankle, knee, hip, spine, rib, sternum, clavicle, joint, shoulder, scapula, elbow, wrist, hand, or finger.
  • the site of bone fusion is a joint.
  • the site of bone fusion the spine.
  • the bone fusion is a spine fusion.
  • the bone fusion is an ankle fusion.
  • the bone fusion is a hindfoot fusion.
  • the method further comprises placing an intravertebral spacer between vertebral bodies.
  • the composition is disposed in the vertebral spacer prior to placing the vertebral spacer between the vertebral bodies.
  • the spine fusion procedure is an interbody fusion procedure.
  • the spine fusion procedure is a lumbar fusion procedure.
  • the present disclosure also provides a method for fracture repair in a subject comprising administering the composition to a desired site of fracture repair in the subject.
  • the site of fracture repair is an arm or a leg.
  • the composition is used in conjunction with a cage or intervertebral spacer.
  • the composition may be deposited inside the lumen of the cage either prior to implantation of the cage between debrided vertebral bodies or after the cage has been placed between the vertebral bodies during a spine fusion surgical procedure.
  • Interbody fusion places a bone graft (e.g. a composition of the invention) between the vertebrae in the area usually occupied by an intervertebral disc. In preparation for the spinal fusion, the disc may be removed entirely.
  • a device may be placed between the vertebrae to maintain spine alignment and disc height.
  • the intervertebral device may be, for example, a spacer.
  • the intervertebral device may be made from, for example, plastic or titanium.
  • the fusion then occurs between the endplates of the vertebrae.
  • Types of interbody fusion include: - 14 - FoleyHoagUS12457270.1 SCD-01525 anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), and transforaminal lumbar interbody fusion (TLIF).
  • the fusion is augmented by a process called fixation, meaning the placement of metallic screws (pedicle screws often made from titanium), rods or plates, spacers, or cages to stabilize the vertebrae to facilitate bone fusion.
  • fixation meaning the placement of metallic screws (pedicle screws often made from titanium), rods or plates, spacers, or cages to stabilize the vertebrae to facilitate bone fusion.
  • external bracing orthotics
  • the aqueous liquid comprises a solution comprising PDGF, and the solution is disposed or incorporated into the biocompatible matrix, for example by manual or mechanical mixing in order to form the desired consistency.
  • the PDGF is present in the solution in a concentration ranging from about 0.01 mg/ml to about 10 mg/ml, from about 0.05 mg/ml to about 5 mg/ml, or from about 0.1 mg/ml to about 1.0 mg/ml.
  • PDGF may be present in the solution at any concentration within these stated ranges, including the upper limit and lower limit of each range. In other embodiments, PDGF is present in the solution at any one of the following concentrations: about 0.05 mg/ml; about 0.1 mg/ml; about 0.15 mg/ml; about 0.2 mg/ml; about 0.25 mg/ml; about 0.3 mg/ml; about 0.35 mg/ml; about 0.4 mg/ml; about 0.45 mg/ml; about 0.5 mg/ml; about 0.55 mg/ml; about 0.6 mg/ml; about 0.65 mg/ml; about 0.7 mg/ml; about 0.75 mg/ml; about 0.8 mg/ml; about 0.85 mg/ml; about 0.9 mg/ml; about 0.95 mg/ml; or about 1.0 mg/ml.
  • concentrations are simply examples of particular embodiments, and that the concentration of PDGF may be within any of the concentration ranges stated above, including the upper limit and lower limit of each range.
  • concentration of PDGF or other growth factors in some embodiments of the present disclosure can be determined by using an enzyme-linked immunoassay as described in U.S. Pat. Nos.6,221,625, 5,747,273, and 5,290,708, incorporated herein by reference, or any other assay known in the art for determining PDGF concentration.
  • the molar concentration of PDGF is determined based on the molecular weight (MW) - 15 - FoleyHoagUS12457270.1 SCD-01525 of PDGF dimer (e.g., PDGF-BB; MW about 25 kDa).
  • PDGF may comprise PDGF homodimers and/or heterodimers, including PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, PDGF-DD, and mixtures and derivatives thereof.
  • PDGF comprises PDGF-BB.
  • PDGF comprises a recombinant human (rh) PDGF, such as rhPDGF-BB.
  • PDGF in some embodiments, can be obtained from natural sources. In other embodiments, PDGF can be produced by recombinant DNA techniques. In other embodiments, PDGF or fragments thereof may be produced using peptide synthesis techniques known to one of ordinary skill in the art, such as solid phase peptide synthesis.
  • PDGF can be derived from biological fluids.
  • Biological fluids can comprise any treated or untreated fluid associated with living organisms including blood.
  • Biological fluids in another embodiment, can also comprise blood components including platelet concentrate (PC), apheresed platelets, platelet-rich plasma (PRP), plasma, serum, fresh frozen plasma (FFP), and buffy coat (BC).
  • PC platelet concentrate
  • PRP platelet-rich plasma
  • FFP fresh frozen plasma
  • BC buffy coat
  • rhPDGF-B comprises the following fragments: amino acid sequences 1- - 16 - FoleyHoagUS12457270.1 SCD-01525 31, 1-32, 33-108, 33-109, 1-108 and/or 1-109 of the entire B chain.
  • the complete amino acid sequence (1-109) of the B chain of PDGF is provided in FIG.15 of U.S. Pat. No.5,516,896, the disclosure of which is hereby incorporated by reference in its entirety.
  • the rhPDGF-BB compositions of the present invention may comprise a combination of intact rhPDGF-B (1-109) and fragments thereof.
  • Other fragments of PDGF may be employed such as those disclosed in U.S. Pat. No.5,516,896.
  • Substantially purified PDGF comprises compositions having about 5% to about 95% by weight PDGF prior to incorporation into solutions of the present invention.
  • substantially purified PDGF comprises compositions having about 65% to about 95% by weight PDGF prior to incorporation into solutions of the present invention.
  • substantially purified PDGF comprises compositions having about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, or about 90% to about 95%, by weight PDGF, prior to incorporation into solutions of the present invention.
  • PDGF can be partially purified.
  • Partially purified PDGF comprises compositions having PDGF in the context of platelet rich plasma (PRP), fresh frozen plasma (FFP), or any other blood product that requires collection and separation to produce PDGF.
  • PRP platelet rich plasma
  • FFP fresh frozen plasma
  • Embodiments of the present invention contemplate that any of the PDGF isoforms provided herein, including homodimers and heterodimers, can be purified or partially purified.
  • Compositions of the present invention containing PDGF mixtures may contain PDGF isoforms or PDGF fragments in partially purified proportions.
  • Partially - 17 - FoleyHoagUS12457270.1 SCD-01525 purified and purified PDGF in some embodiments, can be prepared as described in U.S.
  • solutions comprising PDGF can be controlled by the buffers and pH modifiers recited herein.
  • Various proteins demonstrate different pH ranges in which they are stable. Protein stabilities are primarily reflected by isoelectric points and charges on the proteins.
  • the pH range can affect the conformational structure of a protein and the susceptibility of a protein to proteolytic degradation, hydrolysis, oxidation, and other processes that can result in modification to the structure and/or biological activity of the protein.
  • solutions comprising PDGF can further comprise additional components, such as other biologically active agents.
  • solutions comprising PDGF can further comprise cell culture media, other stabilizing proteins such as albumin, antibacterial agents, protease inhibitors [e.g., ethylenediaminetetraacetic acid - 18 - FoleyHoagUS12457270.1 SCD-01525 (EDTA), ethylene glycol-bis(beta-aminoethylether)-N, N,N′,N′-tetraacetic acid (EGTA), aprotinin, .epsilon.-aminocaproic acid (EACA), etc.] and/or other growth factors such as fibroblast growth factors (FGFs), epidermal growth factors (EGFs), transforming growth factors (TGFs), keratinocyte growth factors (KGFs), insulin-like growth factors (IGFs), bone morphogenetic proteins (BMPs), or other PDGFs including compositions of PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and/or
  • the implant material comprises a biocompatible matrix.
  • the biocompatible matrix comprises a porous calcium phosphate and fibrillar collagen.
  • the calcium phosphate provides a framework or scaffold for new bone and tissue growth to occur.
  • a calcium phosphate can be used to permanently or temporarily replace bone. Following implantation, the calcium phosphate can be retained by the body or it can be resorbed by the body and replaced with bone.
  • Exemplary calcium phosphates include, e.g., a calcium phosphate (e.g., tricalcium phosphate, such as ⁇ -tricalcium phosphate ( ⁇ -TCP), hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, and octacalcium phosphate), calcium sulfate, and allograft (e.g., a calcium phosphate (e.g., tricalcium phosphate, such as ⁇ -tricalcium phosphate ( ⁇ -TCP), hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, and oct
  • the calcium phosphate comprises ⁇ -TCP.
  • the composition comprises a plurality of calcium phosphates.
  • Calcium phosphates suitable for use have a calcium to phosphorus atomic ratio ranging from 0.5 to 2.0.
  • biocompatible matrices may include calcium phosphate particles with or without or bone allograft such as demineralized freeze dried bone allograft (DFDBA) or particulate demineralized bone matrix (DBM).
  • biocompatible matrices may include bone allograft such as DFDBA or DBM.
  • the biocompatible matrix is bioresorbable.
  • a biocompatible matrix comprises an allograft such as DFDBA or particulate DBM.
  • Non-limiting examples of suitable calcium phosphates suitable comprise amorphous calcium phosphate, monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), ⁇ -tricalcium phosphate, ⁇ -TCP, hydroxyapatite (OHAp), poorly crystalline hydroxapatite, tetracalcium phosphate (TTCP), heptacalcium decaphosphate, calcium metaphosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, carbonated calcium phosphate, or any mixture thereof.
  • MCPM monocalcium phosphate monohydrate
  • MCPA monocalcium phosphate anhydrous
  • DCPD dicalcium phosphate dihydrate
  • DCPA dicalcium phosphate anhydrous
  • OCP octacalcium phosphate
  • OPA oct
  • the calcium phosphate has a porous composition.
  • Porosity is a desirable characteristic as it facilitates cell migration and infiltration into the implant material so that the infiltrating cells can secrete extracellular bone matrix.
  • Porosity also provides access for vascularization.
  • Porosity also provides a high surface area for enhanced resorption and release of active substances, as well as increased cell-matrix interaction.
  • the composition can be provided in a shape suitable for implantation (e.g., a sphere, a cylinder, or a block) or it can be sized and shaped prior to use.
  • the bone substituting agent is a calcium phosphate (e.g., ( ⁇ -TCP).
  • Porous calcium phosphates can comprise pores having diameters ranging from about 1 ⁇ m to about 1 mm.
  • porous calcium phosphates comprises macropores having diameters ranging from about 100 ⁇ m to about 1 mm.
  • porous calcium phosphates comprises mesopores having diameters ranging from about 10 ⁇ m to about 100 ⁇ m.
  • porous calcium phosphates comprises micropores having diameters less than about 10 ⁇ m.
  • Embodiments of the present invention contemplate Porous calcium phosphates comprising macropores, mesopores, and micropores or any combination thereof.
  • the bone scaffolding material comprises interconnected pores.
  • the porous calcium phosphates comprise non- interconnected pores. In some embodiments, the porous calcium phosphates comprise interconnected and non-interconnected pores.
  • the porous calcium phosphates in some embodiments, has a porosity greater than about 25% or greater than about 40%. In another embodiment, porosity is greater than about - 20 - FoleyHoagUS12457270.1 SCD-01525 50%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 80%, or greater than about 85%. In a further embodiment, porosity greater than about 90%. In some embodiments, the porous calcium phosphate comprises a porosity that facilitates cell migration into the scaffolding material.
  • the porous calcium phosphates comprise a plurality of particles. Particles of the porous calcium phosphates, in some embodiments, can individually demonstrate any of the pore diameters and porosities provided herein. In other embodiments, particles of the porous calcium phosphates can form an association to produce a matrix having any of the pore diameters or porosities provided herein. Porous calcium phosphate particles may be mm, ⁇ m or submicron (nm) in size. Porous calcium phosphate particles, in some embodiments, have an average diameter ranging from about 1 ⁇ m to about 5 mm.
  • particles have an average diameter ranging from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, or from about 250 ⁇ m to about 750 ⁇ m. In another embodiment, the particles have an average diameter ranging from about 100 ⁇ m to about 300 ⁇ m. In a further embodiment, the particles have an average diameter ranging from about 75 ⁇ m to about 300 ⁇ m. In additional embodiments, porous calcium phosphate particles have an average diameter less than about 25 ⁇ m, less than about 1 ⁇ m and, in some cases, less than about 1 mm. In some embodiments, porous calcium phosphate particles have an average diameter ranging from about 100 ⁇ m to about 5 mm or from about 100 ⁇ m to about 3 mm.
  • porous calcium phosphate particles have an average diameter ranging from about 250 ⁇ m to about 2 mm, from about 250 ⁇ m to about 1 mm, from about 200 ⁇ m to about 3 mm. Particles may also be in the range of about 1 nm to about 1000 nm, less than about 500 nm or less than about 250 nm. Porous calcium phosphate particles, in some embodiments, have a diameter ranging from about 1 ⁇ m to about 5 mm. In other embodiments, particles have a diameter ranging from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, or from about 250 ⁇ m to about 750 ⁇ m.
  • Porous calcium phosphate particles in another embodiment, have a diameter ranging from about 100 ⁇ m to about 300 ⁇ m. In a further embodiment, the particles have a diameter ranging from about 75 ⁇ m to about 300 ⁇ m. In additional embodiments, porous calcium phosphate particles have a diameter less than about 25 ⁇ m, less than about 1 ⁇ m and, - 21 - FoleyHoagUS12457270.1 SCD-01525 in some cases, less than about 1 mm. In some embodiments, porous calcium phosphate particles have a diameter ranging from about 100 ⁇ m to about 5 mm or from about 100 ⁇ m to about 3 mm.
  • porous calcium phosphate particles have a diameter ranging from about 250 ⁇ m to about 2 mm, from about 250 ⁇ m to about 1 mm, from about 200 ⁇ m to about 3 mm. Particles may also be in the range of about 1 nm to about 1000 nm, less than about 500 nm or less than about 250 nm.
  • porous calcium phosphate materials are moldable, extrudable, and/or injectable. Moldable, extrudable, and/or injectable porous calcium phosphates can facilitate efficient placement of compositions of the present disclosure in and around target sites in bone and between bones at sites of desired bone fusion during spine fusion procedures.
  • moldable porous calcium phosphates can be applied to sites of bone fusion with a spatula or equivalent device.
  • porous calcium phosphates are flowable.
  • Porous calcium phosphates in some embodiments, can be applied to sites of bone fusion through a syringe with a needle or cannula.
  • porous calcium phosphates harden in vivo.
  • porous calcium phosphates are bioresorbable. In some embodiments, at least 30%, 40%, 50%, 60%, 70%, 75% or 90% resorbed within one year subsequent to in vivo implantation.
  • the material can be resorbed at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75% or 90% within 1, 3, 6, 9, 12, or 18 months of in vivo implantation.
  • Bioresorbability will be dependent on: (1) the nature of the matrix material (i.e., its chemical make-up, physical structure and size); (2) the location within the body in which the matrix is placed; (3) the amount of matrix material that is used; (4) the metabolic state of the patient (diabetic/non-diabetic, osteoporotic, smoker, old age, steroid use, etc.); (5) the extent and/or type of injury treated; and (6) the use of other materials in addition to the matrix such as other bone anabolic, catabolic and anti-catabolic factors.
  • the biocompatible matrix includes a fibrillar collagen, for example about 10 to about 40 percent by weight of fibrillar collagen.
  • the biocompatible further comprises non-fibrillar (soluble) collagen) in an amount up to about 10% by weight.
  • Biocompatible matrices may be provided in block form or may be shredded. In preferred embodiments, the matrix is shredded, thus advantageously providing a putty consistency when combined with the aqueous liquid.
  • Matrices containing collagen and calcium phosphate are available from several commercial suppliers, including DSM and CMI.
  • ⁇ -Tricalcium Phosphate In some embodiments, the porous calcium phosphate is ⁇ -TCP.
  • ⁇ -TCP can comprise a porous structure having multidirectional and interconnected pores of varying diameters.
  • ⁇ -TCP comprises a plurality of pockets and non-interconnected pores of various diameters in addition to the interconnected pores.
  • the porous structure of ⁇ -TCP in some embodiments, comprises macropores having diameters ranging from about 100 ⁇ m to about 1 mm, mesopores having diameters ranging from about 10 ⁇ m to about 100 ⁇ m, and micropores having diameters less than about 10 ⁇ m.
  • Macropores and micropores of the ⁇ -TCP can facilitate osteoinduction and osteoconduction while macropores, mesopores and micropores can permit fluid communication and nutrient transport to support bone regrowth throughout the ⁇ -TCP biocompatible matrix.
  • ⁇ -TCP in some embodiments, can have a porosity greater than 25% or greater than about 40%. In other embodiments, ⁇ -TCP can have a porosity greater than 50%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, or greater than about 85%. In a further embodiment, ⁇ -TCP can have a porosity greater than about 90%.
  • ( ⁇ -TCP can have a porosity that facilitates cell migration into the ⁇ -TCP.
  • ⁇ -TCP particles in some embodiments, can individually demonstrate any of the pore diameters and porosities provided herein for ⁇ -TCP.
  • ⁇ -TCP particles of a bone scaffolding material can form an association to produce a matrix having any of the pore diameters or porosities provided herein for the bone scaffolding material. Porosity may facilitate cell migration and infiltration into the matrix for subsequent bone formation.
  • ⁇ -TCP particles in some embodiments, have an average diameter ranging from about 1 ⁇ m to about - 23 - FoleyHoagUS12457270.1 SCD-01525 5 mm.
  • ⁇ -TCP particles have an average diameter ranging from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, from about 250 ⁇ m to about 750 ⁇ m, from about 250 to about 1 mm, from about 250 ⁇ m to about 2 mm, or from about 200 ⁇ m to about 3 mm.
  • ⁇ -TCP particles have an average diameter ranging from about 100 ⁇ m to about 300 ⁇ m.
  • ⁇ -TCP particles have an average diameter ranging from about 75 ⁇ m to about 300 ⁇ m.
  • ⁇ -TCP particles have an average diameter less than about 25 ⁇ m, average diameter less than about 1 ⁇ m, or less than about 1 mm.
  • ⁇ -TCP particles have an average diameter ranging from about 100 ⁇ m to about 5 mm or from about 100 ⁇ m to about 3 mm.
  • a biocompatible matrix comprising ⁇ -TCP particles in some embodiments, can be provided in a shape suitable for implantation (e.g., a sphere, a cylinder, or a block).
  • a ⁇ -TCP bone scaffolding material can be moldable, extrudable, and/or injectable thereby facilitating placement of the matrix in and around target sites of desired bone fusion during spine fusion procedures.
  • Flowable matrices may be applied through syringes, tubes, or spatulas or equivalent devices.
  • Flowable ⁇ -TCP bone scaffolding materials in some embodiments, can be applied to sites of bone fusion through a syringe and needle or cannula.
  • ⁇ -TCP bone scaffolding materials harden in vivo.
  • ⁇ -TCP is bioresorbable.
  • a ⁇ - TCP bone scaffolding material can be at least 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, or 85% resorbed one year subsequent to in vivo implantation.
  • a ⁇ - TCP bone scaffolding material can be greater than about 90% resorbed one year subsequent to in vivo implantation.
  • the fibrillar (non-soluble) collagen comprises Type I collagen comprises any type of collagen, including Type I, Type II, and Type III collagens.
  • a collagen comprises a mixture of collagens, such as a mixture of Type I and - 24 - FoleyHoagUS12457270.1 SCD-01525 Type II collagen.
  • Other types of collagen present in bone or musculoskeletal tissues may be employed. Recombinant, synthetic and naturally occurring forms of collagen may be used in the present invention.
  • the implant material is free from or substantially free from soluble collagen.
  • collagen is substantially all fibrillary collagen.
  • the biocompatible matrix may include up to about 10%, up to about 5%, up to about 2%, up to about 1% or up to 0.5% of soluble collagen. While not being bound by theory, it is believed that the presence of a small amount of soluble collagen advantageously enhances matrix cohesivity and/or acts as blocking agent to prevent non-specific interactions of PDGF with the insoluble collagen component, while the fibrillar collagen helps maintain the putty structural integrity.
  • ⁇ -TCP particles suitable for use with a collagen can comprise any of the ⁇ -TCP particles described herein. In some embodiments, ⁇ -TCP particles suitable for combination with a collagen have an average diameter ranging from about 1 ⁇ m to about 5 mm.
  • ⁇ -TCP particles suitable for combination with a collagen have an average diameter ranging from about 1 ⁇ m to about 1 mm, from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, from about 250 ⁇ m to about 750 ⁇ m, from about 250 ⁇ m to about 1 mm, from about 250 ⁇ m to about 2 mm, from about 200 ⁇ m to about 1 mm, or from about 200 ⁇ m to about 3 mm.
  • ⁇ -TCP particles in other embodiments, have an average diameter ranging from about 100 ⁇ m to about 300 ⁇ m.
  • ⁇ -TCP particles suitable for combination with a collagen have an average diameter ranging from about 75 ⁇ m to about 300 ⁇ m.
  • ⁇ -TCP particles suitable for combination with a collagen have an average diameter less than about 25 ⁇ m and, less than about 1 mm or less than about 1 ⁇ m. In some embodiments, ⁇ -TCP particles suitable for combination with a collagen have an average diameter ranging from about 100 ⁇ m to about 5 mm or from about 100 ⁇ m to about 3 mm. ⁇ -TCP particles, in some embodiments, can be adhered to one another by the collagen so as to produce a biocompatible matrix having a porous structure. In some embodiments, a biocompatible matrix comprising ⁇ -TCP particles and a collagen can comprise pores having diameters ranging from about 1 ⁇ m to about 1 mm.
  • a biocompatible matrix comprising ⁇ -TCP particles and a collagen can comprise macropores having diameters - 25 - FoleyHoagUS12457270.1 SCD-01525 ranging from about 100 ⁇ m to about 1 mm, mesopores having diameters ranging from about 10 ⁇ m to 100 ⁇ m, and micropores having diameters less than about 10 ⁇ m.
  • a biocompatible matrix comprising ⁇ -TCP particles collagen can have a porosity greater than about 25% or greater than 40%.
  • the biocompatible matrix can have a porosity greater than about 50%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 80%, or greater than about 85%.
  • the biocompatible matrix can have a porosity greater than about 90%. Porosity facilitates cell migration and infiltration into the matrix for subsequent bone formation.
  • a biocompatible matrix comprising ⁇ -TCP particles in some embodiments, can comprise collagen in an amount ranging from about 10 weight percent to about 20 weight percent. In a further embodiment, a collagen can be present in an amount of about 20 weight percent of the biocompatible matrix. In a further embodiment, a collagen can be present in an amount of about 15 weight percent of the biocompatible matrix. In a further embodiment, a collagen can be present in an amount of about 10 weight percent of the biocompatible matrix.
  • a biocompatible matrix comprising ⁇ -TCP particles and a collagen can be moldable.
  • the biocompatible matrix can be in the form of a putty.
  • a paste or putty can advantageously be molded into the desired implant shape or can be molded to the contours of the implantation site.
  • a biocompatible matrix comprising ⁇ -TCP particles and a collagen in some embodiments, can be provided in a predetermined shape such as a block, sphere, or cylinder.
  • a biocompatible matrix comprising ⁇ -TCP particles and a collagen can be resorbable.
  • a biocompatible matrix comprising ⁇ -TCP particles and a collagen can be at least 30%, 40%, 50%, 60%, 70%, 75%, or 90% resorbed one year subsequent to in vivo implantation.
  • this matrix can be resorbed at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75% or 90% within 1, 3, 6, 9, 12, or 18 months subsequent to in vivo implantation.
  • the biocompatible matrix advantageously includes a pH modifier. While not being bound theory, it is believed that growth factors, such as PDGF, may interact with fibrillary collagen such that its release rate after implantation is inhibited and/or slowed down. A “burst” release of PDGF is desired at the site of implantation in order to initiate the healing cascade. Accordingly, the present invention includes a pH modifier in order to lower the pH of the implant material.
  • the lower pH may reduce the interaction of the growth factor with the fibrillar collagen, thereby improving its release.
  • Suitable pH modifiers include acids, such as acetic acid, citric acid, lactic acid, malic acid, succinic acid, formic acid, tartaric acid, or any combination thereof.
  • the acid is acetic acid.
  • the acid may be added to a fibrillar collagen/calcium phosphate matrix before, during, or after inclusion of the PDGF solution.
  • an acid solution is added to the collagen/calcium phosphate material before the addition of a PDGF solution.
  • a biocompatible matrix may be treated with aqueous acid and lyophylized, thus providing a dry matrix for use in the implant material.
  • a control article was similarly prepared with the 0.5 g matrix and 1.0 mL 20 mM of sodium acetate, pH 6.0.
  • a 10 mL syringe equipped with an 18 gauge needle was used to draw 1.0 mL of the PDGF solution from a vial and into the barrel of the syringe.
  • Example 2 Integrity of Putty Formulation Exemplary putty formulation of the present disclosure having a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 1.5:1, dos not dissolve and retains its structural integrity when incubated at 37 °C (body temperature).
  • Example 4 Structural Integrity in Aqueous Environment
  • the putty formulation of the present disclosure wherein the solution and the biocompatible matrix are present in the composition in a volume to mass ratio (mL/g) ranging from about 0.5:1 to about 1.5:1, retains its shape when irrigated with a saline solution and does not wash away (FIG.6). However, the AI formulation washes away when irrigated using a saline solution.
  • Example 5 Fusion Cage It was demonstrated that the putty formulation of the present disclosure can be packed inside and around a PEEK spine cage (FIG.7).
  • the reformulated rhPDGF-BB solution (0.3mg/mL) should be sufficient to treat multiple - 33 - FoleyHoagUS12457270.1 SCD-01525 fractures. While dispensing the rhPDGF-BB solution, gradually move the solution containing syringe out of the needle hub of the syringe containing the matrix, so that the rhPDGF-BB solution that is dispensed hydrates as much matrix as possible. After dispensing all of the rhPDGF-BB solution, remove the empty syringe and replace the cap back on the needle hub of the syringe containing the hydrated Control Matrix and then allow the mixture to be incubated for 2 min. 5.
  • X-rays were scored based on apparent bony bridging of the callus at the left and at the right periphery of the callus and at the left and right femur cortical fracture site.
  • CT Imaging and Analysis Following euthanization, femurs were resected, fixed in formalin, and then stored in 70% ethanol. Stainless steel rods were removed and then the resected femurs underwent ⁇ CT imaging using a Bruker Skyscan 1275 using the following scan parameters: 71kV, 133 ⁇ A, 24 ⁇ m resolution, 0.4o rotation step, with 4X frame averaging.
  • a longitudinal section through the medial-lateral plane was obtained from each specimen and scored for healing using the 0-4-point scoring system described above.
  • the reconstructed 3D volume of each specimen was also analyzed to determine callus volume (TV), callus bone volume (BV), and normalized callus bone volume (BV/TV).
  • Histology & Histomorphometry Following ⁇ CT scanning, the femurs were embedded in polymethylmethacrylate.
  • a longitudinal section through the medial-lateral plane was obtained using diamond wafering saw blades, polished, and applied to a plexiglass slide using methacrylate glue.
  • the femurs were examined by medial-lateral and dorsal-ventral X- rays which were scored for apparent bony bridging. Scores were summed between the two X- rays views and are shown in Figure 19. Between group comparisons were performed using Kruskal-Walis tests. No significant difference was detected.
  • ⁇ CT Imaging and Analysis All fractured femurs were scanned by ⁇ CT. Select images (longitudinal section through the medial-lateral plane) are shown in Figures 21-23. Additional images, including - 39 - FoleyHoagUS12457270.1 SCD-01525 3D rendering for 1 specimen in each cohort can be found in the supplemental files.
  • Percent callus bone area significantly increased from 24% at 4 weeks to 50% at 8 weeks (p 0.02) for the Group A specimens. However, no difference in callus percent bone was detected from 4 to 8 weeks in either the Group B (mean 41%) or C specimens (mean 34%).

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Abstract

La présente invention fournit des matériaux d'implant contenant un facteur de croissance dérivé des plaquettes et une matrice biocompatible utiles pour la réparation osseuse, y compris les procédures de fusion osseuse et la réparation des fractures.
PCT/US2024/042915 2023-08-18 2024-08-19 Formulation de mastic de greffe osseuse à base de facteur de croissance dérivé des plaquettes Pending WO2025042830A1 (fr)

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