WO2009100280A2 - 3-dimensional silk hydroxyapatite compositions - Google Patents
3-dimensional silk hydroxyapatite compositions Download PDFInfo
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- WO2009100280A2 WO2009100280A2 PCT/US2009/033309 US2009033309W WO2009100280A2 WO 2009100280 A2 WO2009100280 A2 WO 2009100280A2 US 2009033309 W US2009033309 W US 2009033309W WO 2009100280 A2 WO2009100280 A2 WO 2009100280A2
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- silk
- hydroxyapatite
- bone
- hydroxyapatite particles
- polymer
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- 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
- A61F2/28—Bones
- A61F2/2846—Support means for bone substitute or for bone graft implants, e.g. membranes or plates for covering bone defects
-
- 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
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic 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
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61F2/28—Bones
- A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
-
- 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
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00179—Ceramics or ceramic-like structures
- A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
-
- 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
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- 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
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/64—Animal cells
-
- 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
Definitions
- the present invention relates to a mixture of silk fibroin and hydroxyapatite.
- the invention further relates to the repair and replacement of bone and teeth.
- a major goal of tissue repair and regeneration is to develop a biological alternative in vitro for producing an implantable structure that serves as a support and speeds regenerative growth in vivo within a defect area.
- biodegradable polymers such as poly (glycolic acid), poly (L-lactic acid)(PLLA) and their copolymers poly(L-lactic-co-glycolic acid) (PLGA) have been used as scaffold materials in studies of tissue formation.
- Advantages of these polymers include their biocompatibility and degradability.
- PLGA can induce inflammation due to the acid degradation products that result during hydrolysis (Sofia et al. Journal of Biomedical Materials Research 2001, 54, 139-148).
- BMSCs bone marrow stem cells
- BMSCs bone marrow stem cells
- Some calcium phosphate scaffolds show limited ability to degrade (Ohgushi et al. 1992. In CRC Handbook of Bioactive Ceramics. T. Yamamuro, L.L. Hench, and J. Wilson, editors. Boca Raton, FL: CRC Press. 235-238), or degradation is too rapid (Petite et al. 2000. Nat. Biotechnol. 18:959-963.) Difficulties in matching mechanical properties to support desired function also remain an issue (Harris et al. J. Biomed. Mater. Res. 42:396-402).
- BMSCs can differentiate along chondrogenic lineage and form three-dimensional cartilage-like tissue on biomaterial substrates, such as poly(lactic-co-glycolic acid) or poly-L-lactic acid (Caterson et al. 2001. J. Biomed. Mater. Res. 57:394-403; Martin et al. 2001. J. Biomed. Mater. Res. 55:229-235).
- biomaterial substrates such as poly(lactic-co-glycolic acid) or poly-L-lactic acid
- Described herein are methods and compositions comprising a mixture of silk polymer and hydroxyapatite.
- the methods described herein can be used to prepare a mixture of silk polymer and hydroxyapatite and further provide mixtures that can be molded into a desired shape.
- the methods and compositions described herein permit the formation of implantable structures, which can be implanted, for example, to facilitate bone healing or tooth structure or support.
- an article of manufacture comprising a mixture of silk polymer and hydroxyapatite particles, wherein silk is formed into an insoluble state about hydroxyapatite particles.
- an article of manufacture can be formed by mixing the silk polymer and hydroxyapatite particles prior to the formation of the silk insoluble state.
- silk polymer and hydroxyapatite particles are mixed together to form a substantially homogenous admixture.
- a mixture of silk polymer and hydroxyapatite particles can be solidified in a vessel of desired shape/size, such that the resulting article substantially retains the shape of a vessel in which it was formed.
- a mixture of silk polymer and hydroxyapatite particles can vary in composition at the discretion of one skilled in the art, such that the article comprises 0.1% to 90% hydroxyapatite by weight (and all compositions within the range of 0.1% to 90% hydroxyapatite).
- an article produced with a mixture of silk polymer and hydroxyapatite further comprises a bioactive agent.
- the article can further comprise raw silk fiber.
- an implantable structure comprising a mixture of silk polymer and hydroxyapatite particles, wherein the silk polymer substantially surrounds the hydroxyapatite particles.
- the implantable structure is formed from a substantially homogeneous mixture of silk polymer and hydroxyapatite particles.
- a mixture of silk polymer and hydroxyapatite particles can be solidified in a vessel of desired shape/size, such that a resulting structure substantially retains the shape of a vessel in which it was formed.
- a structure of silk and hydroxyapatite provides a temporary support that is bioresorbed after implantation, or alternatively, becomes integrated into bone following implantation.
- Another aspect described herein is a method for manufacture of an implantable structure, which comprises mixing a solution of silk polymer with hydroxyapatite particles and inducing the silk polymer to form an insoluble state, such that the silk polymer is formed into an insoluble state around the hydroxyapatite particles.
- kits for the production of implantable structures comprising (a) lyophilized silk polymer or silk polymer and (b) hydroxyapatite particles (c) packaging materials therefore.
- the kit or system further comprises a solvent, e.g., HFIP.
- the system further comprises a vessel for the formation of silk polymer into an insoluble state.
- Also described herein is a method for repairing or strengthening a bone in an individual, the method comprising the steps of: (a) mixing a solution of silk polymer with hydroxyapatite particles to form a paste composition, (b) applying the paste composition to a region of a bone in need of repair or reinforcement in an individual having a bone injury or a defect; and (c) forming the silk polymer in the applied paste composition into an insoluble state; wherein the applied composition comprising silk polymer in an insoluble state provides a scaffold for replacement by bone tissue.
- silk polymer or "silk fibroin” includes silkworm fibroin and insect or spider silk protein (Lucas et al., Adv. Protein Chem 13: 107-242 (1958)).
- fibroin is obtained from a solution containing a dissolved silkworm silk or spider silk.
- silk polymer of silk fibroin has been treated to substantially remove sericin.
- the silkworm silk protein is obtained, for example, from Bombyx mori
- the spider silk is obtained, for example, from Nephila clavipes.
- silk proteins suitable for use in the present invention can be obtained from a solution containing a genetically engineered silk, such as from bacteria, yeast, mammalian cells, transgenic animals or transgenic plants. See, for example, WO 97/08315 and US Patent 5,245,012.
- a genetically engineered silk such as from bacteria, yeast, mammalian cells, transgenic animals or transgenic plants. See, for example, WO 97/08315 and US Patent 5,245,012.
- the term "raw silk” or “raw silk fiber” refers to silk fiber that has not been treated to remove sericin, and thus encompasses, for example, silk fibers taken directly from a cocoon.
- insoluble state when used in reference to a silk polymer refers to the formation of or state of being in a substantially amorphous, primarily ⁇ -sheet conformation.
- the term 'formed into an insoluble state' is not intended to reflect polymerization of silk monomers into a silk polymer. Rather, it is intended to reflect the conversion of soluble silk polymer to a water insoluble state.
- silk polymer is in an 'insoluble state' if it can be pelleted by centrifugation or if it cannot be dissolved by immersion in or rinsing with water at 37 0 C or less.
- the term "about said hydroxyapatite particles” refers to the formation of a substantially homogeneous mixture of silk polymer and hydroxyapatite particles, such that the solidification or formation of the silk into an insoluble state occurs in the same vessel and as substantially one unit.
- the term “about said hydroxyapatite particles” excludes, for example, the secondary deposition of hydroxyapatite particles onto pre-formed insoluble silk polymers.
- substantially homogeneous means that the silk polymer and hydroxyapatite particles are combined together to form e.g., a paste, wherein the silk and hydroxyapatite are interdispersed well as a mixture.
- bioresorbed or “bioresorption” refers to infiltration of endogenous tissue or cells into an implanted structure, which permits integration of the implantable structure and tissues, where one or more components of the implanted structure is replaced by new tissue.
- compositions, methods, and respective component(s) thereof are used to refer to compositions, methods, and respective component(s) thereof, that are essential to the invention, yet open to the inclusion of unspecified elements, whether essential or not.
- the term “consisting essentially of” describes the incorporation of other elements that can be included in the description of the composition, method or respective component thereof and are limited to those that do not materially affect the basic and novel characteristic(s) of the invention. [028]
- the term “consisting of” refers to inventions, compositions, methods, and respective components thereof as described herein, which are intended to be exclusive of any element not deemed an essential element to the component, composition or method.
- Figure 1 shows an example of silk cocoons before and after sericin extraction.
- Figure 2 shows a dialysis technique for a silk preparation method described herein.
- the left hand side of the figure shows the silk solution in a dialysis cassette, and the right hand side of the figure shows the dialysis of the cassettes in a hypotonic solution.
- Figure 3 shows a representative example of the freeze dried silk following lyophilization.
- Figure 4 shows an example of a vessel filled with silk solution and subsequent bathing of the silk solution in methanol to drive off the HFIP and allow the silk to solidify or form an insoluble state.
- Figure 5 shows a schematic depiction of one embodiment used herein to produce silk polymers and a photograph depicting exemplary silk blocks made using that method.
- Figure 6 shows an exemplary 30% hydroxyapatite-silk mixture and the packing of the mixture into an exemplary vessel.
- Figure 7 shows photographs of some embodiments of silk polymer structures with various shapes and sizes.
- Figure 8 depicts an exemplary method for producing silk fibers comprising the steps of (a) winding silk around a bracket, (b) sericin extraction, (c) slicing silk, and (d) drying silk.
- Figure 9 shows an exemplary silk polymer block formed in the presence of non- dissolved silk fibers in a cylindrical vessel.
- Figure 10 is a graph that shows the compressive modulus of several exemplary non- mineralized and mineralized silk samples.
- Table 1 shows the compressive modulus values of non-mineralized silk polymer, mineralized silk biopolymer and commercially available dental composite resin restorative material.
- Table 2 shows the shear bond strength of composite and mineralized silk polymer bonded to dentin.
- Silk is a well described natural fiber produced by the silkworm, Bombyx mori, which has been used traditionally in the form of threads in textiles for thousands of years.
- This silk contains a fibrous protein termed fibroin (both heavy and light chains) that form the thread core, and glue-like proteins termed sericin that surround the fibroin fibers to cement them together.
- the fibroin is a highly insoluble protein containing up to 90% of the amino acids glycine, alanine and serine leading to ⁇ -pleated sheet formation in the fibers (Asakura, et al., Encyclopedia of Agricultural Science, Arntzen, C. J., Ritter, E. M. Eds.; Academic Press: New York, NY, 1994; Vol. 4, pp 1-11).
- Silk provides an important set of material options for biomaterials and tissue engineering because of the impressive mechanical properties, biocompatibility and biodegradability (Altman, G. H., et al., Biomaterials 2003, 24, 401-416; Cappello, J., et al., J. Control. Release 1998, 53, 105-117; Foo, C. W. P., et al., Adv. Drug Deliver. Rev. 2002, 54, 1131-1143; Dinerman, A. A., et al., J. Control. Release 2002, 82, 277-287; Megeed, Z., et al., Adv. Drug Deliver. Rev.
- silk polymer is formed into an insoluble state about hydroxyapatite particles.
- the structures find use as implants to support bone or tooth repair, or for example to deliver one or more bioactive agents to a site of implantation. Methods, materials, and considerations for the practice of the invention described herein are described in the following.
- the silk fibroin solution to be concentrated can be prepared by any method known to one skilled in the art.
- Organic solvents can also change the properties of fibroin material. For example, the immersion of silk fibroin films in organic solvents such as methanol causes dehydration of the hydrated or swollen structure, leading to crystallization and thus, loss of solubility in water. Further, with respect to tissue engineering scaffolds, the use of organic solvents can render the silk material to be less degradable.
- Minerals for use in the methods described herein can include any biocompatible mineral that one desires to use.
- a preferred mineral is hydroxyapatite, which has well-known characteristics with respect to its compatibility with bone.
- Hydroxyapatite particles of varying size can be used to synthesize an implantable structure, and are available in nanocrystal, powder, granules and blocks from commercial sources such as Berkeley Advanced Biomaterials (Berkeley, CA).
- the size of hydroxyapatite particles can vary widely depending on the material properties desired following silk insolubilization.
- the particles of hydroxyapatite can be, for example, nanoparticles or alternatively, can be very large, for example, 500 ⁇ m and up to millimeter sizes.
- the size of particle used will alter the properties of the article of manufacture, such as compressive modulus, shear bond strength and porosity. Methods for use of a variety of hydroxyapatite particle sizes are contemplated herein.
- the silk polymer is isolated and treated as described herein above.
- Silk polymer and hydroxyapatite particles are mixed into a substantially homogenous mixture, e.g., a paste, and the silk polymer is formed into an insoluble state in the presence of, and preferably surrounding, the hydroxyapatite particles.
- the formation of a homogeneous mixture does not encompass dissolution of the hydroxyapatite particles, but rather the particles are inter-mixed with the dissolved silk to produce a paste-like substance.
- the insoluble structure produced can be used as an implantable structure.
- the amount of hydroxyapatite particles can vary from 0.1% hydroxyapatite by weight to 90% hydroxyapatite by weight.
- the hydroxyapatite particles are at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, up to and including at least 90% by weight, or any percentage of hydroxyapatite within this range.
- the hydroxyapatite particles can be within the range of 0.1% to 90%, 0.1% to 80%, 0.1% to 70%, 0.1% to 60%, 0.1% to 50%, 0.1% to 40%, 0.1% to 30%, 0.1% to 20%, 0.1% to 10%, 0.1% to 5%, 0.1 % to 1%, 90% to 80%, 90% to 70%, 90% to 60%, 90% to 50%, 90% to 40%, 90% to 30%, 90% to 20%, 90% to 10%, 90% to 5%, 90% to 2%, 90% to 1%, 90% to 0.1%, 10% to 50%, 15% to 45%, 20% to 40%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 10% to 30%, 15% to 30%, or 20% to 30%.
- regenerated silk fibroin is soluble in water and requires immersion in an alcohol or other suitable agent to obtain an insoluble, amorphous composition comprising primarily silk polymer as a ⁇ -sheet structure (Sofia et al. Journal of Biomedical Materials Research 2001, 54, 139-148). Therefore, prior to submersion into aqueous solutions the silk structures are first soaked in a ⁇ -sheet structure inducing agent, such as alcohol to induce the phase transition to ⁇ -sheet structure.
- a ⁇ -sheet structure inducing agent such as alcohol to induce the phase transition to ⁇ -sheet structure.
- the type of a ⁇ -sheet structure inducing agent can be selected to generate structures with different properties.
- the silk polymer described herein can be formed into an insoluble state in any vessel, provided that the silk can be removed from the vessel.
- a vessel is any container that the silk mixture can be poured or packed into, which comprises a cavity having the shape of the desired structure following formation of the silk into an insoluble state.
- the silk-hydroxyapatite structure substantially retains the shape of the vessel cavity.
- a vessel can be larger in volume than the volume of the desired structure, since, for example the formation of silk into an insoluble state can be accompanied by a shrinking of a silk-hydroxyapatite mixture.
- vessels around which the silk mixture can be formed into an insoluble state are also contemplated herein, such that solidified silk retains the shape of the outer surface of a vessel.
- a vessel can be composed of, for example, plastic, glass, ceramic or metal. In some embodiments it may be beneficial to utilize a vessel that is flexible to allow silk polymer removal without structural damage to the article produced. Vessels used in the methods described herein can vary widely at the discretion of one skilled in the art. In addition, the choice of vessel can easily be modified to fit a specific need.
- implantable structure as described herein can alternatively, or in addition, be milled from a block or other structure to produce the final implantable structure.
- formation in a vessel of the desired shape can be used, or a given shape can be milled or carved by one of skill in the art to produce the desired shape.
- an "implantable structure” is generally any structure that upon implantation does not generate an immune response in the host organism.
- an implantable structure should not for example, be or contain an irritant, or contain LPS etc.
- an implantable structure should permit or not prohibit cell infiltration, blood vessel growth or other properties that would inhibit bioresorption or integration of the structure into tissue.
- the structure is not simply a solid 3-dimensional form but comprises or develops some porosity such that cells, etc., can gain access during the resorption process (that is, unless the lack of bioresorption is desired).
- an implantable structure does not raise or provoke an immune response (e.g., inflammation or the raising of antibodies against a component of an implant), in some cases it can be beneficial for the structure to induce an immune-response (e.g., generation of antibodies against a specific antigen) or to prevent integration into tissue.
- an immune response e.g., inflammation or the raising of antibodies against a component of an implant
- an immune-response e.g., generation of antibodies against a specific antigen
- an implantable structure can be applied to a wide variety of uses, however it is preferred that an implantable structure, as described herein, is implanted for the repair or support of bone or tooth structures.
- Implantable silk structures can be used e.g., to give temporary support for teeth, for broken bones, for fragile/weak bones, or to speed healing of bone fractures, breaks, loss of calcification, etc.
- Structures or articles of manufacture described herein can also be used to deliver a bioactive agent, either as a primary use or secondary to repair or support of a tissue. Bioactive agents useful in such embodiments are described herein below.
- the length of the tissue regenerative growth period will depend on the particular tissue being implanted with a silk structure.
- the growth period can be continued until the new tissue has attained desired properties, e.g., until the regenerating tissue has reached a particular thickness, size, strength, composition of proteinaceous components, and/or a particular cell density. Methods for assessing these parameters are known to those skilled in the art.
- the implantable structure should reabsorb at a rate that does not exceed the growth period of the tissue. Thus, the structure should remain substantially intact until sufficient infiltration of surrounding tissue occurs (as detected by methods known in the art) and the implantable structure is no longer necessary for tissue strength or structure (e.g., bone density).
- tissue strength or structure e.g., bone density
- Such agents can provide prophylactic or therapeutic benefit either in situ, e.g., through promotion of desired biological processes, or, e.g., by leaching out of the structure after implantation.
- additives such as pharmaceutical/therapeutic agents, or biologically active agents, are incorporated into a silk-hydroxyapatite mixture.
- growth factors, pharmaceuticals, or biological components can be incorporated into the mixture during formation of the implantable structure.
- bioactive agents which can be administered via the invention include, without limitation: anti-infectives such as antibiotics and antiviral agents; chemotherapeutic agents (i.e. anticancer agents); anti- rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones such as steroids; growth factors (bone morphogenic proteins (i.e. BMP's 1-7), bone morphogenic-like proteins (i.e. GFD-5, GFD-7 and GFD-8), epidermal growth factor (EGF), fibroblast growth factor (i.e.
- FGF 1-9) platelet derived growth factor (PDGF), insulin like growth factor (IGF-I and IGF-II), transforming growth factors (i.e. TGF- ⁇ -III), vascular endothelial growth factor (VEGF)); anti-angiogenic proteins such as endostatin, and other naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.
- PDGF platelet derived growth factor
- IGF-I and IGF-II insulin like growth factor
- TGF- ⁇ -III transforming growth factors
- VEGF vascular endothelial growth factor
- anti-angiogenic proteins such as endostatin, and other naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.
- the mixtures described herein can be used to deliver any type of molecular compound, such as pharmacological materials, vitamins, sedatives, steroids, hypnotics, antibiotics, chemotherapeutic agents, prostaglandins, and radiopharmaceuticals.
- the silk hydroxyapatite structures described herein are suitable for delivery of the above materials and others including but not limited to proteins, peptides, nucleotides, carbohydrates, simple sugars, cells, genes, anti-thrombotics, anti-metabolics, growth factor inhibitor, growth promoters, anticoagulants, antimitotics, fibrinolytics, anti-inflammatory steroids, and monoclonal antibodies.
- the articles of manufacture themselves can be thought of, in some aspects, as a carrier for delivery of a bioactive agent
- the bioactive agents/therapeutics/pharmaceuticals of the article of manufacture described herein can be formulated by mixing with a pharmaceutically acceptable carrier. Any pharmaceutical carrier can be used that does not dissolve or otherwise interfere with the solidified silk/hydroxyapatite structure.
- the bioactive or therapeutic agents can be added to the silk- hydroxyapatite mixtures as a liquid, a finely divided solid, or any other appropriate physical form.
- a bioactive agent can be added to a pre-formed silk-hydroxyapatite structure as described herein by immersing the structure in a solution comprising the bioactive agent. That is, the agent need not necessarily be present when the silk-hydroxyapatite structure is formed.
- biologically active agents suitable for use in the methods described herein include, but are not limited to: cell attachment mediators, such as collagen, elastin, fibronectin, vitronectin, laminin, proteoglycans, or peptides containing known integrin binding domains e.g. "RGD” integrin binding sequence, or variations thereof, that are known to affect cellular attachment (Schaffner P & Dard 2003 Cell MoI. Life Sci. Jan; 60(1): 119-32; Hersel U. et al. 2003 Biomaterials Nov; 24(24):4385-415); biologically active ligands; and substances that enhance or exclude particular varieties of cellular or tissue ingrowth.
- cell attachment mediators such as collagen, elastin, fibronectin, vitronectin, laminin, proteoglycans, or peptides containing known integrin binding domains e.g. "RGD" integrin binding sequence, or variations thereof, that are known to affect cellular attachment (Sch
- Such additives are particularly useful in tissue engineering applications where, for example, structures are engineered in vitro to include cells that impart a beneficial characteristic on the structure to be implanted.
- the steps of cellular population of a 3-dimensional silk-hydroxyapatite scaffold matrix preferably are conducted in the presence of growth factors effective to promote proliferation of the cultured cells employed to populate the matrix.
- growth factors effective to promote proliferation will be dependent on the cell type employed.
- a growth factor for use herein may be fibroblast growth factor (FGF), most preferably basic fibroblast growth factor (bFGF) (Human Recombinant bFGF, UPSTATE Biotechnology, Inc.).
- FGF fibroblast growth factor
- bFGF basic fibroblast growth factor
- additive agents that enhance proliferation or differentiation include, but are not limited to, osteoinductive substances, such as bone morphogenic proteins (BMP); cytokines, growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I and II), TGF- ⁇ and the like.
- BMP bone morphogenic proteins
- cytokines growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I and II), TGF- ⁇ and the like.
- EGF epidermal growth factor
- PDGF platelet-derived growth factor
- IGF-I and II insulin-like growth factor
- Implantable structures can be used to deliver therapeutic agents to cells and tissues.
- the ability to incorporate, for example pharmaceutical agents, growth factors and other biological regulators, enzymes or possibly even cells in the structure described herein provides for stabilization of these components for long term release and stability, as well as better control of activity and release.
- bioactive agent reagents, necessary or indicated for assisting the stability or activity of a bioactive agent can also be included in the mixtures used to create mineralized silk structures with bioactive agents as described herein.
- necessary buffers, salts or co-factors can be added as necessary.
- Compressive modulus testing is known to, and can be performed by, one of skill in the art.
- compressive modulus testing can be performed with an Instron® 3366 tester using a 1OkN load cell.
- Instron® 3366 tester using a 1OkN load cell.
- samples are soaked in 0.9% NaCl solution.
- Testing parameters are modified from ASTM Standard ASTM D695: Standard Test Method for Compressive Properties of Rigid Plastics (Volumes 03.01, 444-476 (2006); and 08.01, 78-85 (2006), which are incorporated herein by reference.
- a crosshead extension rate of lmm/min can be used with load, and displacement can be recorded at a sampling rate of 200 samples/min.
- the compressive modulus for the silkworm silk material is calculated using e.g., BlueHill® 1.9 Materials Testing Software using a segment modulus method that applies a least squares fit to the recorded data points between two load boundaries.
- the compressive modulus for composite material is calculated using stress-strain data recorded in a load range of IOON and 300N, as well as a 2500N and 4500N range. These ranges of loads are judged to be within the linear portions of the load deformation curve for each material.
- the shear bond stress test is a measure of the strength at which a silk-hydroxyapatite structure remains bonded to dentin under a certain shear.
- a silk-hydroxyapatite structure is prepared for testing and comparison to a similarly prepared composite of known shear bond strength.
- One method for preparing a silk- hydroxyapatite structure is as follows. In one embodiment, human teeth are extracted and set in acrylic. The teeth are trimmed to expose flat dentin surfaces, and polished wet with 240 grit sandpaper. A cylindrical mineralized silk biopolymer structure is prepared with appropriate dimensions for testing (e.g., ⁇ 6.5mm diameter, ⁇ 4-6mm height).
- the silk bonding surfaces are etched with 9.5% hydrofluoric acid and then cemented to dentin surfaces using resin cement (Variolink II, Ivoclar Vivadent) under an appropriate bonding pressure level (e.g., ⁇ 500g+/-100g).
- resin cement Variolink II, Ivoclar Vivadent
- bonded composite-resin cylinders of similar dimensions can be prepared and bonded to dentin for comparison with the silk- hydroxyapatite structures.
- Composite-resin (4 Seasons, Ivoclar Vivadent) can be loaded into a plastic straw, in order to fabricate uniform composite cylinders for bonding ( ⁇ 5.8mm diameter, ⁇ 5mm height).
- the resin composite cylinders are bonded onto dentin surfaces using 5th generation single-component adhesive (Excite, Ivoclar Vivadent) and light-cured for 20s. Bonded specimens can be stored in 37 0 C water for 24 hrs.
- Shear bond strength can be obtained with an Instron 4202 at crosshead speed of 0.5 mm/min. The resulting strength of a silk-hydroxyapatite structure can then be compared to a composite of known strength or the strength of a silk structure lacking hydroxyapatite.
- the structure can applied in a paste form and cured into an insoluble state in vivo.
- This method of administration is especially useful for tailoring the shape and size of the structure directly to the site of injury and is easily illustrated, for example, by bone repair.
- a portion of a bone can effectively be replaced or strengthened by the application of a silk-hydroxyapatite mixture directly to the region of disease or injury (i.e., defect site) and then formation of the mixture into an insoluble state.
- the bone can begin to repair itself and the implanted structure degrades over time to be replaced by the individual's own bone. Thus, there is no need for a further procedure to remove the silk structure.
- the basic steps for in vivo structure formation include forming the silk-hydroxyapatite into an admixture, placing the admixture into a site requiring repair, and then forming the admixture into an insoluble state at the repair site (also referred to herein as "curing").
- the silk solution (in water) containing the hydroxyapatite particles is prepared in a concentration gel or slurry.
- This system can either be injected into a defect site, or molded into a putty-like consistency and placed within the defect.
- the materials will harden during application and over time as the silk undergoes stabilization via beta sheet formation. Formation of the beta sheet occurs due to the shear stress imposed during injection or molding of the putty, due to local dehydration in the wound side, or a combination of these two effects.
- Curing of the silk-hydroxyapatite paste into an insoluble state can also be achieved by preheating the mixture and then cooling prior to placement in the body.
- physiologically neutral accelerants such as glycerol can be used.
- the silk- hydroxyapatite mixture is sonicated prior to placing it within the defect.
- An article of manufacture comprising a mixture of silk polymer and hydroxyapatite particles, wherein the silk is formed into an insoluble state about the hydroxyapatite particles.
- An article of manufacture comprising a mixture of silk polymer and hydroxyapatite particles, wherein the silk is formed into an insoluble state in the presence of the hydroxyapatite particles.
- An implantable structure comprising a mixture of silk polymer and hydroxyapatite particles, wherein the silk polymer substantially surrounds the hydroxyapatite particles.
- a method for manufacture of an implantable structure comprising mixing a solution of silk polymer with hydroxyapatite particles and inducing the silk polymer to form an insoluble state, such that the silk polymer is formed into an insoluble state around the hydroxyapatite particles.
- the implantable structure comprises 0.1 to about 90% hydroxyapatite by weight. 16. The method of paragraph 13, 14, or 15, wherein the implantable structure further comprises a bioactive agent.
- implantable structure further comprises raw silk fiber.
- kits for production of the implantable structures comprising:
- kit of paragraph 21 the kit further comprising HFIP solvent.
- kit of paragraph 21 or 22 the kit further comprising a vessel for formation of silk polymer into an insoluble state.
- a method for repairing or strengthening a bone in an individual comprising the steps of:
- Example 1 One embodiment of the methodology used to make silk/hydroxyapatite articles and implantable structures.
- the silk was then dissolved in a 9.3M LiBr solution at a silk concentration of 20% weight/volume ratio of silk mass/LiBr.
- the silk was allowed to dissolve in a 60°C chamber for 4 hours.
- a syringe was used to transfer 12mL aliquots of the dissolved silk solution into 12mL dialysis cassettes.
- Each dialysis cassette with silk solution was dialyzed against IL of distilled water.
- up to 4 cassettes may be included in one plastic 5L capacity bucket and would require 4L of water, as shown in Figure 2.
- the distilled water was changed after 1 hour, 4 hours and then every 12 hours for the following 2 days to a total of 6 changes.
- the silk solution was collected from a dialysis cassette using a syringe and transferred into a 45mL FalconTM centrifuge tube.
- the silk solution was refrigerated and then centrifuged @ 9,000 RPM for 30 minutes to remove any impurities/debris left over from the original cocoon (see Figure 3).
- the centrifuge was allowed to slow to a gentle stop over a 20 minute period.
- the silk solution was transferred into new tubes, refrigerated and the centrifugation repeated a second time.
- a syringe was used to transfer discrete volumes of the silk solution (following complete dissolution) into capsules for formation of insoluble silk structures.
- the capsules were chosen to seal tightly, but were of arbitrary shape such that the eventual silk blocks took the form of the capsule utilized (see Figure 6).
- Inorganic mineral content was added to the silk solution, after it had been dissolved in HFIP, as a variation of the 17% silk polymer fabrication process. Prototypes of a mineral- loaded silk polymer were fabricated, e.g., to improve the mechanical properties of the material.
- HA Ca 10 (PO 4 ) O (OH) 2 ).
- Mineral loaded silk polymer materials with up to 30% HA were synthesized. Higher proportions can be prepared, if so desired, up to, e.g., 40%, 50%, 60%, 70%, 80%, 90% or more.
- the resulting material had a dough-like consistency, as shown in Figure 8.
- the viscosity of the mineral loaded silk material was higher than that of the pure silk solution, such that it was not feasible to aliquot with the use of a syringe.
- the mineralized silk solution mixture could be poured into cavities of arbitrary geometry and size for the formation of insoluble silk-hydroxyapatite structures.
- the material was packed into items such as plastic pipette tips and cylindrical plastic capsules. It was discovered that a small opening at the distal end of the cavity being packed with material yielded better success allowing it to be filled with fewer voids.
- Another variation of the silk polymer material in addition to added hydroxyapatite is to add non-dissolved silk fibers into the mixture to help structurally reinforce the silk polymer. This can be especially advantageous if, for example, the fibers are aligned parallel to the direction of compressive force being applied.
- the silk fibers were processed through the sericin extraction step and were sliced into sections approximately 3mm in length as shown in Figure 10.
- a prototype of a mineralized silk block with approximately 2% of non-dissolved silk fibers by mass was made and is shown in Figure 11.
- the silk fibers were not oriented in any particular direction, but were inserted into the silk-mineral mixture while it was being packed into the capsule.
Abstract
Description
Claims
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CA2713251A CA2713251A1 (en) | 2008-02-07 | 2009-02-06 | 3-dimensional silk hydroxyapatite compositions |
CN2009801043637A CN101970023A (en) | 2008-02-07 | 2009-02-06 | 3-dimensional silk hydroxyapatite compositions |
EP09707377.9A EP2249886A4 (en) | 2008-02-07 | 2009-02-06 | 3-dimensional silk hydroxyapatite compositions |
JP2010546025A JP2011511668A (en) | 2008-02-07 | 2009-02-06 | Three-dimensional silk hydroxyapatite composition |
US12/866,256 US9504575B2 (en) | 2008-02-07 | 2009-02-06 | 3-dimensional silk hydroxyapatite compositions |
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Also Published As
Publication number | Publication date |
---|---|
US20110046686A1 (en) | 2011-02-24 |
EP2249886A2 (en) | 2010-11-17 |
WO2009100280A3 (en) | 2009-10-08 |
US9504575B2 (en) | 2016-11-29 |
JP2011511668A (en) | 2011-04-14 |
EP2249886A4 (en) | 2013-05-22 |
JP2015205208A (en) | 2015-11-19 |
CN101970023A (en) | 2011-02-09 |
CA2713251A1 (en) | 2009-08-13 |
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