CA2983486A1 - Irrigation resistant compositions for regeneration of hard tissues and methods and kits of using the same - Google Patents

Abstract

An irrigation resistant bone repair composition including a biocompatible or bioactive bone repair material and at least one non-ionic surfactant, other than a non-random poly(oxyalkylene) block copolymer, is described. Also, methods for treating a bone having a bone gap or a bone defect with the composition including a biocompatible or bioactive bone repair material and at least one non-ionic surfactant, other than a non-random poly(oxyalkylene) block copolymer, are also provided. Also, kits including the irrigation resistant bone repair composition including a biocompatible or bioactive bone repair material and at least one non-ionic surfactant, other than a non-random poly(oxyalkylene) block copolymer, are described.

Description

IRRIGATION RESISTANT COMPOSITIONS FOR REGENERATION OF HARD
TISSUES AND METHODS AND KITS OF USING THE SAME
RELATED APPLICATIONS
[0001] The present patent document claims the benefit of the filing date of U.S.
Patent Application Serial No. 14/695,910, filed April 24, 2015, which is incorporated herein by reference in its entirety.
BACKGROUND

[0002] Bone is a composite of collagen, cells, calcium hydroxyapatite crystals, and small quantities of other proteins of organic molecules that has unique proper-ties of high strength, rigidity, and ability to adapt to varying loads. When bone inju-ries occur, it is necessary to fill voids or gaps in the bone as well as to encourage the repair and regeneration of bone tissue. There are many materials used today for the repair and regeneration of bone defects. For example, one material useful to en-courage such repair and regeneration is bioactive glass.

[0003] Bioactive glass was originally developed in 1969 by L. Hench.
Additional-ly, bioactive glasses were developed as bone replacement materials, with studies showing that bioactive glass can induce or aid in osteogenesis (Hench et al., J. Bio-med. Mater. Res. 5:117-141 (1971)). Bioactive glass can form strong and stable bonds with bone (Piotrowski et al., J. Biomed. Mater. Res. 9:47-61(1975)).
Further, bioactive glass is not considered toxic to bone or soft tissue from studies of in vitro and in vivo models (Wilson et al., J. Biomed. Mater. Res. 805-817 (1981)).
Exempla-ry bioactive glasses include 45S5, 4555B1, 58S, and 570C30. The original bioac-tive glass, 45S5, is melt-derived. Sol-gel derived glasses can also be produced and include nanopores that allow for increased surface area and bioactivity.

[0004] There are drawbacks to the use of bioactive glass or other materials in the form of liquids, pastes, and solids to fill voids or gaps in the bone. A
liquid or a paste may not remain at the site of the void or gap in the bone. A solid may be difficult to apply and may not conform well to the void or gap in the bone. Solids may migrate or be displaced from the site through washing or other means.

[0005] These drawbacks may be reduced and/or eliminated by adding materials to a bone repair composition, such that the composition is rendered irrigation and migration resistant.

6 PCT/US2016/028764 BRIEF DESCRIPTION OF THE DRAWINGS
[0006] Figure 1 depicts an exemplary delivery system kit for delivering an irriga-tion resistant bone repair composition.

[0007] Figure 2A-B depicts schematic drawings of an adapter (2A) and a delivery gun (2B) for the irrigation resistant bone repair composition.

[0008] Figure 3 depicts a schematic drawing of a plunger of the delivery system.

[0009] Figure 4A depicts exemplary tips for a delivery system.

[0010] Figure 4B depicts exemplary tips for a delivery system.

[0011] Figure 5A is a photograph of the tubes filled with an irrigation resistant bone repair composition for use with a delivery system.

[0012] Figure 5B depicts a schematic drawing of a tube for use with a delivery system.

[0013] Figure 6A is a photograph of an exemplary delivery system for an irrigation resistant bone repair composition.

[0014] Figure 6B is a photograph of an exemplary delivery system for an irrigation resistant bone repair composition.

[0015] Figure 7 is a photograph of an exemplary delivery system for an irrigation resistant bone repair composition.

[0016] Figure 8 is a photograph of an exemplary delivery system for an irrigation resistant bone repair composition.

[0017] Figure 9 is a photograph of an exemplary delivery system for an irrigation resistant bone repair composition.
SUMMARY

[0018] Certain embodiments relate to an irrigation resistant bone repair composi-tion comprising a biocompatible bone repair material and at least one non-ionic sur-factant, wherein the non-ionic surfactant is not a non-random poly(oxyalkylene) block copolymer. The non-ionic surfactant is selected from the group consisting of fatty al-cohols (e.g., stearyl alcohol), alkoxylated alcohols (e.g., Ecosurf LF 45), alkoxylated alkylphenols (e.g., Triton X-100), alkoxylated fatty amides (e.g., polyethoxylated tal-low amine), alkoxylated fatty esters (e.g., PEG 400 monostearate), alkoxylated fatty ethers (e.g., polyethylene glycol lauryl ether (Brij L23), alkoxylated sorbitan esters (e.g., Span 85 (sorbitan trioleate)), alkoxylated sorbitan esters (e.g., polysorbate 20 and polysorbate 80 also referred to as Tween 20 and Tween 80), fatty acid esters or polyol esters (e.g., glycerol monostearate, PEG coconut triglycerides), polyalkylene glycols (e.g., PEG 400 and PEG 600), alkoxylated organic acids, hydroxyacids or diacids and copolymers therefrom. Preferably, one of the non-ionic surfactants in the composition has a melting point above room temperature, and more preferably above body temperature. The bone repair material can be any number of materials that assist in bone repair and production. Such materials include at least bioactive glass in the form of a particle, fiber or sphere and calcium salts, i.e., DCP, alpha TCP, beta-TCP, hydroxyapatite, calcium sulfates, calcium borates or calcium sili-cates, multiphasic calcium phosphates, calcium sulfates, calcium borates or calcium silicates along with elemental substitutions within these materials or coatings applied to these materials.

[0019] Further embodiments relate to bioactive glass particles including a coating comprising at least one non-ionic surfactant, wherein the non-ionic surfactant is not a non-random poly(oxyalkylene) block copolymer.

[0020] Another embodiment relates to a putty or paste including bioactive glass particles including a coating comprising at least one non-ionic surfactant, wherein the non-ionic surfactant is not a non-random poly(oxyalkylene) block copolymer.

[0021] Yet further embodiments relate to methods for treating a bone having a bone gap and/or a bone defect with the composition comprising a biocompatible bone repair material and at least one non-ionic surfactant, wherein the non-ionic sur-factant is not a non-random poly(oxyalkylene) block copolymer. The non-ionic sur-factant or similar material other than the non-random poly(oxyalkylene) block copol-ymer is selected from the group consisting of fatty alcohols (e.g., stearyl alcohol), alkoxylated alcohols (e.g., Ecosurf LF 45), alkoxylated alkylphenols (e.g., Triton X-100), alkoxylated fatty amides (e.g., polyethoxylated tallow amine), alkoxylated fatty esters (e.g., PEG 400 monostearate), alkoxylated fatty ethers (e.g., polyethylene glycol lauryl ether (Brij L23), alkoxylated sorbitan esters (e.g., Span 85 (sorbitan trio-leate)), alkoxylated sorbitan esters (e.g., polysorbate 20 and polysorbate 80), fatty alcohols, fatty acids, fatty acid esters or polyol esters (e.g., glycerol monostearate, PEG coconut triglycerides), polyalkylene glycols (e.g., PEG 400 and PEG 600), alkoxylated organic acids, hydroxyacids or diacids and copolymers therefrom.
At least one of the surfactants in the composition has a melting or cloud point above room temperature, and more preferably a melting point above body temperature.

[0022] Other embodiments relate to an irrigation resistant bone repair composi-tion comprising a biocompatible bone repair material and a mixture of non-ionic sur-factants, wherein the non-ionic surfactants are not non-random poly(oxyalkylene) block copolymers. The bone repair material can be any number of materials that as-sist in bone repair and production. Such materials include at least bioactive glass, spherical bioactive glass in a bimodal size distribution, and tricalcium phosphate, i.e., silicated tricalcium phosphate.

[0023] Further embodiments relate to bioactive glass particles including a coating comprising two or more non-ionic surfactants, wherein the non-ionic surfactants are not non-random poly(oxyalkylene) block copolymers.

[0024] Yet another embodiment relates to a putty or paste including bioactive glass particles including a coating comprising two or more non-ionic surfactants, wherein the non-ionic surfactants are not non-random poly(oxyalkylene) block copol-ymers.

[0025] Yet further embodiments relate to methods for treating a bone having a bone gap and/or a bone defect with the composition comprising a biocompatible bone repair material and a mixture of non-ionic surfactants, wherein the non-ionic-surfactants are not non-random poly(oxyalkylene) block copolymers.
DETAILED DESCRIPTION

[0026] Irrigation resistant bone repair compositions comprising (i) a biocompatible or bioactive bone repair material and at least one non-ionic surfactant, wherein the non-ionic surfactant is not a non-random poly(oxyalkylene) block copolymer, or (ii) a mixture of non-ionic surfactants, wherein the non-ionic surfactants are not non-random poly(oxyalkylene) block copolymers are provided.

[0027] Specifically, certain embodiments relate to a synthetic bone grafting com-position, such as a putty for bone repair that incorporates non-ionic surfactants or other similar materials, other than a non-random poly(oxyalkylene) block copoly-mers, having an osteoconductive, osteostimulative and irrigation resistant properties.
The term "irrigation resistant" in connection with the compositions described herein refers to a property of the composition, where the composition can be heavily irrigat-ed following placement in a surgical site without being washed away or displaced from the surgical site. The composition includes at least one slow dissolving non-ionic surfactant(s), other than a non-random poly(oxyalkylene) block copolymers, which is mixed with a biocompatible or bioactive bone repair material, such as bioac-tive glasses or other osteoconductive salts, glasses or ceramics for use in methods for treating a bone having a bone gap and/or a bone defect.

[0028] The irrigation resistant bone repair composition is biocompatible and or bioactive and comprised of entirely synthetic materials, which fully eliminates any risk of disease transmission that may occur with other products containing animal or human derived materials or components to achieve this property.

[0029] The composition promotes osseointegration when introduced into a bone gap and/or a bone defect.

[0030] The bone repair composition has a unique physical property of being irri-gation resistant. The irrigation resistant characteristics provide a material, which maintains position in the surgical site despite the amount of blood, body fluid or sa-line to which it is exposed. Irrigation resistance is beneficial to simplify the application of the bone graft at the site of defect while preventing migration of the graft material during irrigation and after closure of the surgical site. The irrigation resistance of the bone repair composition is especially beneficial for its intended use in orthopedic and spine processes, as the material will stabilize and maintain placement and structure within the body during placement, irrigation and after closure. Specifically, in certain embodiments where a non-setting putty material is used, the bone repair composi-tion will not be displaced easily during irrigation and closure of the surgical site.

[0031] An irrigation resistant, fully synthetic and bioactive putty, when implanted into the body, will maintain position or placement rather than melt, dissolve or disin-tegrate during irrigation or displace upon closure of the surgical site. This feature permits the implant to hold in place more easily, and create beneficial handling prop-erties. The ability to resist displacement allows the bioactive agent to remain at the site of implantation to stimulate bone growth for an extended period of time.
The bi-oactive glass, as the preferred bioactive agent, stimulates the genes necessary to differentiate precursor cells into osteoblasts and the subsequent proliferation of these cells within the surgical site while undergoing an ionic exchange with the sur-rounding body fluid to form microcrystalline hydroxyapatite analogous to natural bone mineral. The combination of these properties in one composition is essential for bone regeneration and hard tissue repair.

[0032] The composition may be a liquid at room temperature. Alternatively, the composition may have the consistency of a solid, gel, putty, paste or any other non-liquid substance at room temperature. The composition may also have the form of a liquid, solid, gel, putty, paste or any other non-liquid substance at room temperature.
Additionally the composition may undergo a phase change when warmed from room temperature to body temperature.

[0033] In some embodiments, the composition is thermoreversible changing sub-stantially from a liquid at 5 C and into a solid at 37 C. This effect can arise from the type and relative amount of non-ionic surfactants in the composition, which in turn determines the viscosity of the composition at room temperature and at body tem-perature. For example, as the temperature rises, the composition becomes substan-tially more viscous liquid or waxy solid to allow the bone repair material, for example, bioactive glass, to more readily remain at the defect site.

[0034] The bone repair composition provides for acceleration in the rate and an enhancement in the quality of newly-formed bone. Improved bone healing may oc-cur in those who may be compromised, such as diabetics, smokers, the obese, the elderly, those who have osteoporosis, those who use steroids, and those who have infections or other diseases that reduce the rate of healing. The rapid hardening of the bone repair composition at the site of the bone defect can serve to localize the bone repair material, such as bioactive glass, at the site.

[0035] The bone repair composition may be provided to a site of a bone defect by means of a syringe or other injection device. In certain embodiments, the bone re-pair composition may be sufficiently liquid so as to be injectable, yet can harden suitably at the bone defect site at body temperature. For instance, if the bone repair composition is a liquid at room temperature, it may become a thick gel at body tem-perature; in other words, the bone repair composition cures upon application to a bone defect at body temperature.

[0036] In certain embodiments, the bone repair composition has the advantages of low viscosity, runny liquid composition with regard to the ease of application to a bone defect site. Further advantages of the composition include more solid paste-like composition characteristics and that it remains positioned at the defect after be-ing applied. The solidification of the composition at body temperature overcomes the disadvantageous property of other liquid compositions that do not exhibit irrigation resistant behavior. At the same time, because the composition is not a solid at room temperature, there is greater ease of applying the composition, such as by means of a syringe. The composition need not be laboriously painted onto a bone defect or applied onto a bone defect by means of pressure.

[0037] Other delivery modes can be used for more viscous bone repair composi-tions. These modes include manually placing the gel or paste directly into a bone defect or extruding the gel or paste using a syringe, delivery gun or other means.

[0038] In certain embodiments, if the bone repair composition is a gel at room temperature, it may become a paste at body temperature.

[0039] In certain other embodiments, if the bone repair composition is a thick gel or paste at room temperature, it may become putty or a solid at body temperature.

[0040] As noted above, the relative amount of a non-ionic surfactant (other than a non-random poly(oxyalkylene) block copolymers), in the composition will determine the viscosity at room temperature and at body temperature.

[0041] In certain embodiments, the irrigation resistant composition includes a bio-compatible or bioactive bone repair material, and at least one non-ionic surfactant, with the proviso that the non-ionic surfactant is not a non-random poly(oxyalkylene) block copolymer.

[0042] The non-ionic surfactant or similar material other than the non-random poly(oxyalkylene) block copolymer is selected from the group consisting of fatty ac-ids (e.g. stearic acid), fatty alcohols (e.g., stearyl alcohol), alkoxylated alcohols (e.g., Ecosurf LF 45), alkoxylated alkylphenols (e.g., Triton X-100), alkoxylated fatty am-ides (e.g., polyethoxylated tallow amine), alkoxylated fatty esters (e.g., PEG

monostearate), alkoxylated fatty ethers (e.g., polyethylene glycol lauryl ether (Brij L23), polyglycerin fatty acid esters, alkoxylated sorbitan esters (e.g., Span 85 (sorbi-tan trioleate)), alkoxylated sorbitan esters (e.g., Polysorbate 20 and Polysorbate 80 also referred to as Tween 20 and Tween 80), fatty acid esters or polyol esters (e.g., glycerol monostearate, PEG coconut triglycerides), polyalkylene glycols (e.g., PEG
400 and PEG 600), alkoxylated organic acids, hydroxyacids or diacids and copoly-mers therefrom. Specific examples of non-ionic surfactants, other than the non-random poly(oxyalkylene) block copolymers, include sorbitan tristearate, polysorbate 20, polysorbate 80, polyoxyethylene 7 coconut, glycerides, poly(ethylene glycol) 400 monostearate (PEG 400 monostearate), PEG 2000 monomethylether, and PEG 400 distearate.

[0043] Further examples of the non-ionic surfactants suitable for use with the irri-gation resistant compositions include polyglycery1-2 isostearate, polyglycery1-di isostearate, polyglycery1-4 isostearate, polyglycery1-6 isostearate, poly(ethylene glycol) 8 stearate (MYRJ S8), polyglyceryl-10 isostearate, polyglyceryl-10 diisos-tearate, poly(ethylene glycol) 25 propylene glycol stearate (MYRJ S25), poly(ethylene glycol) 400 distearate (PEG 400 distearate), polyglycery1-4 laurate, polyglycery1-6 laurate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglycer-y1-2 oleate, polyglycery1-4 oleate, polyglycery1-6 oleate, polyglyceryl-10 oleate, poly-glyceryl-10 stearate, and polyglyceryl-10 distearate.

[0044] Yet further examples of the non-ionic surfactants include polyoxyethylene 7 coconut glyceride (coconut glyceride), polyethylene glycol 2000 monomethyl ether (MME), glyceryl monostearate (monostearin), PEG dimethyl ether (dimethyl polyeth-ylene glycol), PEG 200 adipate (poly(ethylene glycol) 200 adipate, PEG 6000 dis-tearate, sorbitan monostearate, cetyl alcohol, ethylene glycol monostearate, propyl-ene glycol stearate, polyoxyethylene stearyl ether (Brij 2), polyoxyethylene stearyl fatty ether (Brij 10), docosaethylene glycol mono octadecyl ether (Brij 20), polyeth-ylene stearyl ether (Brij 100),polyglycerin fatty acid ester (polyglycery1-2 isostearate, polyglycery1-2 di isostearate, polyglycery1-4 isostearate, polyglycery1-6 isostearate, polyglyceryl-10 isostearate, polyglyceryl-10 diisostearate, polyglycery1-4 laurate, p01-yglycery1-6 laurate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglycery1-2 oleate, polyglycery1-4 oleate, polyglycery1-6 oleate, polyglyceryl-10 oleate, polyglyc-ery1-10 stearate, polyglyceryl-10 distearate).

[0045] In certain embodiments, one of the surfactants in the composition has a melting point or cloud point above room temperature, and more preferably above a melting point above body temperature.

[0046] In certain other embodiments, at least two non-ionic surfactants, other than a non-random poly(oxyalkylene) block copolymers, may be included; alterna-tively, at least three or more non-ionic surfactants, other than a non-random poly(oxyalkylene) block copolymers, may be included.

[0047] In some embodiments, the weight ratio of at least one non-ionic surfactant, other than poly(oxyalkylene) block copolymer is 1%-99% relative to the weight of the bone repair composition. This weight ratio may be from 1-10%, 10-20%, 20-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90-99%. Alter-natively, this weight ratio may be about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 A, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 A, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71 A, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 A, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. The material may have the consistency of a solid, gel, putty, paste or any other non-liquid substance at room temperature.

[0048] In some embodiments, the weight ratio of the mixture of at least two non-ionic surfactant, other than a non-random poly(oxyalkylene) block copolymers, is 1%-99% relative to the weight of the bone repair composition. This weight ratio may be from 1-10%, 10-20%, 20-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90-99%. Alternatively, this weight ratio may be about 1 A, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 A, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. The ma-terial may have the consistency of a solid, gel, putty, paste or any other non-liquid substance at room temperature.

[0049] In some embodiments, where the bone repair composition comprises two non-ionic surfactants, the weight ratio of a first non-ionic surfactant to the weight ratio of a second non-ionic surfactant is in the range of from about 1%-99% to about 99%-1%. Specifically, the weight ratio of a first non-ionic surfactant to the weight ratio of a second non-ionic surfactant is about 1 A to 99%; alternatively, the weight ratio of a first non-ionic surfactant to the weight ratio of a second non-ionic surfactant is about

50% to 50%; and alternatively, the weight ratio of a first non-ionic surfactant to the weight ratio of a second non-ionic surfactant is about 99% to 1%. The compositions may vary in molecular weight and be blended in ratios of 10:1 to 1:10.
[0050] The compositions may further comprise ions and other compounds that may be dissolved in water. For example, the addition of salts, such as PBS, can en-hance solidification and setting properties of non-ionic surfactants. Divalent salts may be particularly useful to improve the rheological properties of compositions con-taining non-ionic surfactant mixtures and bioactive glass materials as well as those of compositions containing non-ionic surfactants and other solid bone repair materi-als.

[0051] In certain embodiments, the composition may further include at least one additive, including but not limited to solvents, linear, straight chain and branched ali-phatic hydrocarbons, sugars, polysaccharides, and hydroxyl or alkoxy terminal poly-alkylene oxides along with low molecular weight biodegradable polymers (MW</=10,000).

[0052] Specific examples of additives include sodium hyaluronate, regenerez, polypropylene glycol 3000 (poly 3000), seasame oil, candelilla wax, carnauba wax, sorbitol (D-Glucitol), polycaprolactone, polycaprolactone diol, coconut oil, propylene glycol, polycaprolactone triol, polycaprolactone 10000 mw, mineral oil high viscosity, mineral oil low viscosity, polyethylene glycol 400 (PEG-8), butylene glycol, and hexylene glycol.

[0053] The biocompatible or bioactive bone repair material may be osteoinduc-tive, osteoconductive, or a material that is both osteoinductive and osteoconductive.
The bone repair material may be xenogeneic, allogeneic, autogeneic, and/or allo-plastic.

[0054] The bone repair material can be any number of materials that assist in bone repair and production. Such materials include at least bioactive glass in the form of a particle, sphere, fiber, mesh, sheet or a combination of these forms, i.e. fi-bers within a sphere, and calcium salts, i.e., DCP, alpha TCP, beta-TCP, hydroxyap-atite, calcium sulfates, calcium borates or calcium silicates, multiphasic calcium phosphates, calcium sulfates, calcium borates or calcium silicates along with ele-mental substitutions within these materials or coatings applied to these materials. In certain embodiments, the biocompatible or bioactive bone repair material may also be any combination of various therapeutic materials. The various types of bioactive glass that may be used as bone repair material were previously described In U.S.
Pub. No. US 2014/0079789, entire content of which is incorporated herein by refer-ence.

[0055] In certain embodiments, the composition may be prepared as a composite with a biocompatible or bioactive agent, such as a bioactive glass ceramic which contains silica or boron. The ceramic releases calcium and silicate or calcium and boron ions, which facilitate the differentiation and proliferation of osteoblasts (defined as osteostimulation), which in turn increases the rate of regeneration of hard tissue.

[0056] In addition, the bioactive glass component undergoes an ion exchange with the surrounding body fluid to form hydroxyapatite analogous to bone mineral.
More specifically, dissolution of the bioactive glass ceramics releases the calcium and silicate or calcium and boron ions, which stimulate the genes responsible of the differentiation and proliferation of osteoblast cells within the bony defect upon im-plantation. It is believed that this genetic response is activated through the introduc-tion of the genetic cascade responsible for the osteoblast proliferation and subse-quently promotes the increased rate of regeneration of hard tissue.

[0057] In certain embodiments, the bone repair material is bioactive glass.
Bioac-tive glass may be melt-derived or sol-gel derived. Depending on their composition, bioactive glasses may bind to soft tissues, hard tissues, or both soft and hard tis-sues. The composition of the bioactive glass may be adjusted to modulate the de-gree of bioactivity. Furthermore, borate may be added to bioactive glass to control the rate of degradation.

[0058] In some embodiments, the bioactive glass contains silica and/or boron as well as other ions such as sodium and calcium.

[0059] Certain embodiments relate to an irrigation resistant bone repair composi-tion that includes a biocompatible or bioactive bone repair material suspended in a mixture of at least two non-ionic surfactant, other than a non-random poly(oxyalkylene) block copolymer.

[0060] Certain further embodiments relate to an irrigation resistant bone repair composition that further includes at least one element selected from the group con-sisting of Li, Na, K, Mg, Sr, Ti, Zr, Fe, Co, Cu, Zn, Al, Ga, P, N, S, F, Cl, Ag, Au, Ce and I. For example, small amounts of iodine, fluorine or silver can provide antimi-crobial properties, while small amount of copper can promote angiogenesis (i.e., aid in the formation of blood vessels).

[0061] The preferred embodiment includes non-ionic surfactants, other than a non-random poly(oxyalkylene) block copolymers, as carriers for melt and sol-gel de-rived bioactive glasses. The composites range from 1 to 99% of a mixture of non-ionic surfactants, other than a non-random poly(oxyalkylene) block copolymers, which is conversely 1-99% bioactive glass.

[0062] The bioactive glass may be in a form of particles, spheres, fibers, mesh, sheets or a combination of these forms i.a fibers within a sphere.

[0063] The compositions may vary in molecular weight and may be blended in ratios of 10:1 up to 1:10. Compositions of the glass may comprise from 0-90%
silica or 0-90% boric acid with a plurality of other elements including Li, Na, K, Mg, Sr, Ti, Zr, Fe, Co, Cu, Zn, Al, Ga, P, N, S, F, Cl, Ag, Au, Ce and I. The embodiments take the consistency of a gel, putty, or waxy solid at room temperature.

[0064] In certain embodiments, bioactive glass is in the form of a particle. The composition, porosity and particle sizes of the bioactive glass may vary. In certain preferred embodiments, the particles of the glass may range in size from 0.01 pm to 5mm. In certain embodiments, the bioactive glass comprises 0-80% < 100 pm, 0-80% <500 pm, 0-80% 500-1000 pm, 0-80% 1000-2000 pm, 0-80% 2000-5000 pm, 0-90% 90-710 pm, and 0-90% 32-125 pm bioactive glass. In certain embodiments, the particles may be porous crystalline. In other embodiments, the particles may be porous non-crystalline particles.

[0065] Specifically, the bioactive glass material may have silica, sodium, calcium, strontium, phosphorous, and boron present, as well as combinations thereof. In some embodiments, sodium, boron, strontium, and calcium may each be present in the compositions in an amount of about 1% to about 99%, based on the weight of the bioactive glass. In further embodiments, sodium, boron, strontium and calcium may each be present in the composition in about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In certain embodiments, silica, sodium, boron, and calcium may each be present in the com-position in about 5 to about 10%, about 10 to about 15%, about 15 to about 20%, about 20 to about 25%, about 25 to about 30%, about 30 to about 35%, about 35 to about 40%, about 40 to about 45%, about 45 to about 50%, about 50 to about 55%, about 55 to about 60%, about 60 to about 65%, about 65 to about 70%, about 70 to about 75%, about 75 to about 80%, about 80 to about 85%, about 85 to about 90%, about 90 to about 95%, or about 95 to about 99%. Some embodiments may contain substantially one or two of sodium, calcium, strontium, and boron with only traces of the other(s). The term "about" as it relates to the amount of calcium phosphate pre-sent in the composition means 41-0.5%. Thus, about 5% means 5 1-0.5%.

[0066] The bioactive glass materials may further comprise one or more of a sili-cate, borosilicate, borate, strontium, or calcium, including Sr0, CaO, P205, Si02, and B203. In certain embodiments, bioactive glass includes about 15-45% CaO, about 30-70% Si02, about 0-25% Na20, about 0-17% P205, about 0-10% MgO and about 0-5% CaF2.

[0067] An exemplary bioactive glass is 45S5, which includes 46.1 mol %
Si02, 26.9 mol % CaO, 24.4 mol % Na20 and 2.5 mol % P205,

[0068] An exemplary borate bioactive glass is 45S5B1, in which the Si02 of bioactive glass is replaced by B203.

[0069] Other exemplary bioactive glasses include 58S, which includes 60 mol %
Si02, 36 mol % CaO and 4 mol % P205, and S70C30, which includes 70 mol % Si02 and 30 mol % CaO.

[0070] In any of these or other bioactive glass materials of the invention, Sr0 may be substituted for CaO.

[0071] The following composition provided in Table 1 below, having a weight % of each element in oxide form in the range indicated, will provide one of several bioac-tive glass compositions that may be used to form a bioactive glass material:

[0072] Table 1:
Si02 0-86 CaO 4-35 Na20 0-35 CaF2 0-25 Md0 0-5 CaF 0-35

[0073] In case of the bioactive glass being in the form of a three-dimensional compressible body of loose glass-based fibers, the fibers comprise one or more glass-formers selected from the group consisting of P205, Si02, and B203. Some of the fibers have a diameter between about 100 nm and about 10,000 nm, and a length:width aspect ratio of at least about 10. The pH of the bioactive glass can be adjusted as-needed.

[0074] The bioactive glass particles, fibers, spheres, meshes or sheets may fur-ther comprise any one or more of adhesives, grafted bone tissue, in vitro-generated bone tissue, collagen, calcium phosphate, stabilizers, antibiotics, antibacterial agents, antimicrobials, drugs, pigments, X-ray contrast media, fillers, and other ma-terials that facilitate grafting of bioactive glass to bone.

[0075] The silica and/or calcium ions released by the bioactive glass may improve the expression of osteostimulative genes. The silica and/or calcium ions may also increase the amount of and efficacy of proteins associated with such osteostimula-tive genes. In several embodiments, the bone repair material is osteostimulative and can bring about critical ion concentrations for the repair and regeneration of hard tis-sue without the necessity of any therapeutic materials or agents.

[0076] In some embodiments, the bone repair material is 45S5 bioactive glass.
The 45S5 bioactive glass may vary in size from 1 micrometer to 5 millimeters.
The bioactive glass may be about 1-5 micrometers, about 5-15 micrometers, about 15-micrometers, about 50-200 micrometers, about 200-1,000 micrometers, about 1-2 millimeters, about 2-3 millimeters, about 3-4 millimeters, or about 4-5 millimeters.

[0077] In some embodiments, the bioactive glass particle has a diameter of be-tween about 0.01 micrometer and about 5,000 micrometers.

[0078] In some embodiments, the bone repair material is a composition compris-ing calcium salt and silica. The silica is in the form of an inorganic silicate that is ad-sorbed onto the surface of the calcium salt. The silica is not incorporated into the structure of the calcium salt. The composition may be bioactive. These and other bone repair materials are described in U.S. Patent Pub. No. US 2013/0330410, the entire content of which is herein incorporated by reference.

[0079] In some embodiments, the bone repair material is a composition compris-ing suspended autograft bone particles and suspended bioactive glass particles.
Similar bone repair materials are described in U.S. Pub. No. 2015/0079146, the en-tire content of which is incorporated by reference.

[0080] The suspended bioactive glass particle may comprise 5i02.
Alternatively, the suspended bioactive glass particle may comprise P205, P03. or PO4. The sus-pended bioactive glass particle may comprise B203 as well. In some embodiments, the suspended bioactive glass particle may comprise 40-60% 5i02, 10-20% CaO, 0-4% P205, and 19-30% Na0. The suspended bioactive glass particle may further comprise a carrier selected from the group consisting of hydroxyapatite and tricalci-um phosphate.

[0081] The bioactive glass particles; fibers, meshes or sheets may be pretreated in a solution comprising one or more of blood, bone marrow aspirate, bone-morphogenetic proteins, platelet-rich plasma, and osteogenic proteins.

[0082] In some embodiments, the bone repair material may be bioactive glass coated with a glycosaminoglycan, in which the glycosaminoglycan is bound to the bioactive glass. This and other bone repair materials are described in U.S.
Patent Pub. No. US 2014/0079789, the entire content of which is incorporated by reference.
The glycosaminoglycan may be bound to the bioactive glass by means of an ionic bond or a covalent bond. The glycosaminoglycan may be heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, or hyaluronic acid.

[0083] In certain other embodiments, the bone repair material may include sur-face immobilized peptides, as previously described in U.S. Pat. Application No.
14/504,956, filed on October 2, 2014, which is incorporated herein in its entirety.

[0084] In some further embodiments, the bone repair material is a bimodal bioac-tive glass composition comprising large bioactive glass particles and small bioactive glass particles. The large bioactive glass particles have a substantially spherical shape and a mean diameter of between about 90 micrometers and about 2,000 mi-crometers. The small bioactive glass particles have a substantially spherical shape and a mean diameter of between about 10 micrometers and about 500 micrometers.

[0085] In some embodiments, the bone repair material is a trimodal bioactive glass composition comprising large bioactive glass particles, medium bioactive glass particles, and small bioactive glass particles. The large bioactive glass particles have a substantially spherical shape and a mean diameter of between about 500 mi-crometers and about 5,000 micrometers. The medium bioactive glass particles have a substantially spherical shape and a mean diameter of between about 90 microme-ters and about 710 micrometers. The small bioactive glass particles have a substan-tially spherical shape and a mean diameter of between about 1 micrometers and about 125 micrometers.

[0086] In any of the above embodiments, small bioactive glass fibers may be added to the bone repair material. The small bioactive glass fibers have a diameter of less than 2 millimeters. The small bioactive glass fibers may be present in up to 40% by weight relative to the total weight of the bioactive glass. In various embodi-ments, the weight ratio of small bioactive glass fibers to total weight of the bioactive glass may be from 0-10%, 0_5%7 5_10%7 5_1,0,/o 7 10-15%, 10-20%, 15-20%, 15-25%, 20-25%, 20-30%, 25-30%, 25-35%, 30-35%, 30-40%, or 35-40%. The weight ratio of small bioactive glass fibers to total weight of the bioactive glass may be about 1%, 2%7 3%7 4%7 5%7 6%7 7%7 8%7 9%7 10%7 11%7 12%7 13%7 14%7 15%7 16%7 17%7 18%7 19%7 20%7 21%7 22%, 23%, 24%7 25%, 26% 727%7 28%7 29%7 30%7 31%7 32%7 33%7 34%7 35%7 36%7 37%7 38%7 3,o,/0 7 or 40%.

[0087] In some embodiments, any subset of the bioactive glass present, such as bioactive glass particles and/or small bioactive glass fibers, may be coated with silane as described in Verne et al. (Verne et al., "Surface functionalization of bioac-tive glasses," J. Biomed. Mater. Res. A., 90(4):981-92 (2009)). The silane or other functional coatings may then allow for binding of proteins onto the bioactive glass, such as BMP-2.

[0088] In some embodiments, any subset of the bioactive glass present, such as bioactive glass particles and/or small bioactive glass fibers, may have additional sili-cate chains present on them. The additional silicate chains may allow the bioactive glass particles and fibers to interact with one another, as well as with groups of the non-ionic surfactants. The effect of these interactions may be to reduce the surface area of the filler, increase resin demand, and to allow for higher filler loadings.

[0089] In some embodiments, any subset of the bioactive glass present, such as bioactive glass particles and/or small bioactive glass fibers, may have added hydrox-yl triethoxysilanes coated onto the glass. Some of these silanes are available from Gelest, Inc. For example, the glass may be coated with hydroxyl(polyethyleneoxy) propyltriethoxysilane. Additionally, the glass may be coated with other organic sub-stituted ethoxy- and methoxy- silanes that are effective to create an interaction be-tween the coated glass and the EO/PO carrier.

[0090] In any of the above embodiments, the irrigation resistant bone repair com-position may be applied by a syringe at ambient temperature. After application to the bone or other site within the body at 37 C, the bone repair composition will harden and have a substantially lower tendency to migrate away from the application site.

[0091] More viscous bone repair compositions may be applied by painting the composition onto a site at or near the bone defect. Alternatively, more viscous bone repair compositions may be extruded onto the site in the form of a bead.

[0092] Certain embodiments relate to a method for treating hard tissues, such as bones using the irrigation resistant bone repair composition.

[0093] Certain other embodiments relate to a method for treating a bone having a bone defect comprising contacting the bone at or near the site of the bone defect with the irrigation resistant bone repair composition of any of the above-described embodiments.

[0094] Any of the above-described materials or methods may be undertaken to treat any number of bone defects. As such, certain further embodiments relate to a method for treating a bone having a bone defect comprising placing an irrigation re-sistant bone repair composition of any one of the above-described embodiments at a site of a bone gap or a bone defect.

[0095] A bone defect may include bony structural disruptions, in which repair is needed or may be a gap in the bone or may arise from lack of adequate bone re-generation. A bone defect may be a void, which is understood to be a three-dimension defect that includes a gap, cavity, hole or other substantial disruption of the structural integrity of the bone or joint. The bone defects may also be fractures.
The bone defects may also arise in the context of oral bone defects. The different types of bone defects are apparent to those of ordinary skill in the art. Gaps may be at least 2.5 cm and are generally in the range of 3-4 cm. This size is large enough so that spontaneous repair is not likely to occur and/or be complete.
Exemplary bone defects include tumor resection, fresh fractures, cranial and facial abnormali-ties, spinal fusions, and loss of bone from the pelvis.

[0096] The various embodiments of the invention may be particularly useful with respect to orthopedic and spine processes because the material will stabilize and hold a better structure as it becomes more solidified when it heats up to body tem-perature.

[0097] Certain further embodiments relate to a method for treating a bone having a bone defect comprising placing an irrigation resistant bone repair composition of any one of the above-described embodiments at a bone gap or a bone defect.

[0098] In some embodiments, any of the above-described materials or methods may be combined with autograft bone chips for placement onto or near a bone de-fect. The materials may be a liquid or a gel at room temperature with the autograft bone chips suspended therein. Upon placement at or near the bone defect, the ma-terial will solidify around the autograft bone chips and serve to prevent the autograft bone chips from migrating away from the surgical sites.

[0099] In some embodiments, any of the above-described materials or methods may be combined with particles containing allogeneic or xenogeneic bone mineral for placement onto or near a bone defect. The materials may be a liquid or a gel at room temperature with the particles suspended therein. Upon placement at a surgi-cal site, which is at or near the bone defect, the material will solidify around the parti-cles and serve to prevent the particles from migrating away from the surgical site.

[00100] In various embodiments of the invention, the bone repair material is not a natural bone material or a synthetic bone material.

[00101] Further embodiments relate to kits that include an irrigation resistant bone repair composition including a biocompatible or bioactive bone repair material, and at least one surfactant other than the non-random poly(oxyalkylene) block co-polymer. The non-ionic surfactant or similar material, other than the non-random poly(oxyalkylene) block copolymer, is selected from the group consisting of fatty ac-ids (e.g. stearic acid), fatty alcohols (e.g., stearyl alcohol), alkoxylated alcohols (e.g., Ecosurf LF 45), alkoxylated alkylphenols (e.g., Triton X-100), alkoxylated fatty am-ides (e.g., polyethoxylated tallow amine), alkoxylated fatty esters (e.g., PEG

Monostearate), alkoxylated fatty ethers (e.g., polyethylene glycol lauryl ether (Brij L23), polyglycerin fatty acid esters, alkoxylated sorbitan esters (e.g., Span 85 (sorbi-tan trioleate)), alkoxylated sorbitan esters (e.g., Polysorbate 20 and Polysorbate 80 also referred to as Tween 20 and Tween 80), fatty acid esters or polyol esters (e.g., glycerol monostearate, PEG coconut triglycerides), polyalkylene glycols (e.g., PEG
400 and PEG 600), alkoxylated organic acids, hydroxyacids or diacids and copoly-mers therefrom. Specific examples of non-ionic surfactants, other than the non-random poly(oxyalkylene) block copolymers, include sorbitan tristearate, polysorbate 20, polysorbate 80, polyoxyethylene 7 coconut, glycerides, poly(ethylene glycol) 400 monostearate (PEG 400 monostearate), PEG 2000 monomethylether, and PEG 400 distearate. Further examples of the non-ionic surfactants suitable for use with the ir-rigation resistant compositions include polyglycery1-2 isostearate, polyglycery1-2 di isostearate, polyglycery1-4 isostearate, polyglycery1-6 isostearate, poly(ethylene glycol) 8 stearate (MYRJ S8), polyglyceryl-10 isostearate, polyglyceryl-10 diisos-tearate, poly(ethylene glycol) 25 propylene glycol stearate (MYRJ S25), poly(ethylene glycol) 400 distearate (PEG 400 distearate), polyglycery1-4 laurate, polyglycery1-6 laurate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglycer-y1-2 oleate, polyglycery1-4 oleate, polyglycery1-6 oleate, polyglyceryl-10 oleate, poly-glyceryl-10 stearate, and polyglyceryl-10 distearate. Yet further examples of the non-ionic surfactants include, polyoxyethylene 7 coconut glyceride (coconut glyceride), polyethylene glycol 2000 monomethyl ether (MME), glyceryl monostearate (monos-tearin), PEG dimethyl ether (dimethyl polyethylene glycol), PEG 200 adipate (poly(ethylene glycol) 200 adipate, PEG 6000 distearate, sorbitan monostearate, ce-tyl alcohol, ethylene glycol monostearate, propylene glycol stearate, polyoxyethylene stearyl ether (Brij 2), polyoxyethylene stearyl fatty ether (Brij 10), docosaethylene glycol mono octadecyl ether (Brij 20), polyethylene stearyl ether (Brij 100),polyglycerin fatty acid ester (polyglycery1-2 isostearate, polyglycery1-2 diisos-tearate, polyglycery1-4 isostearate, polyglycery1-6 isostearate, polyglyceryl-10 isos-tearate, polyglyceryl-10 diisostearate, polyglycery1-4 laurate, polyglycery1-6 laurate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglycery1-2 oleate, polyglyceryl-4 oleate, polyglycery1-6 oleate, polyglyceryl-10 oleate, polyglyceryl-10 stearate, poly-glyceryl-10 distearate).

[00102] Further embodiments relate to kits that include an irrigation resistant bone repair composition including a biocompatible or bioactive bone repair material, and a mixture of at least two non-ionic surfactants or similar materials.

[00103] Exemplary kits for use with bone resistant compositions were previous-ly described in U.S. Pub. No. US 2015/030684, which is incorporated herein in its entirety.

[00104] The kits may further include a dispensing gun, syringe, clam shell, or other suitable delivery device and accompanying accessories. Specifically, referring to Figures 1 and 2A-B, the exemplary dispensing gun 100, adapter 110, plunger (see also Figure 3), tube(s) 130 (see also Figures 5A and 5B), caps 140, and assort-ed dispensing tips (optional; Figure 4A and Figure 4B) that may be included with the kits are shown. The irrigation resistant bone repair composition may be deposited into the tube(s) 130 as part of the kit (Figure 5A). An exemplary kit for delivery of other materials, such as Bioactive Synthetic Bone Graft Putty is currently being sold by NOVABONE (NOVABONE Bioactive Synthetic Bone Graft Putty MIS Cartridge Delivery System, NovaBone Products, LLC, Alachua, FL).

[00105] Referring to Figures 2A-B, the dispensing gun 100 may include a cover 150, a latch 160, a lever 170 and a handle 180 (Figure 2B). The adapter 110 (shown also in Figure 2A) may be inserted into the dispensing gun at an opening 111.
A
plunger (not shown) may be inserted through the front of the gun and pushed through the opening in the back 190 of the gun.

[00106] Figure 3 depicts an exemplary plunger 120 including gradient markings 200 facing up.

[00107] Figures 4A-B depict exemplary tips for use with the dispensing gun.
The tips may be straight (Figure 4A) or at an angle (Figure 4B).

[00108] Figure 5A is a picture of tubes filled with the irrigation resistant bone re-pair composition; Figure 5B is a graphical illustration of an exemplary tube for use with the kit and specifically with the delivery gun described above. The tubes have a substantially constant inner diameter along their entire length such that the outlets have substantially the same inner diameters as the rest of the tubes.

[00109] Optionally, a "Y" connector, luer syringe and a tube connector may be included to facilitate the simultaneous delivery of biologics and to maintain position during shipping (as shown in Figure 9).

[00110] The components of a kit may be packaged and sold as a kit. The com-ponents of a kit may snap fit into a (inner) tray of a packaging and a retainer may be placed over the components of the kit to maintain position of the components during shipping. The inner tray may hold up to four tubes that can be prefilled with the irri-gation resistant bone repair composition and capped on each end. The inner tray may also contain cavities for the placement of assorted tips, a "Y" connector, tube connector, a syringe and aspiration needle.

[00111] The inner tray may be sealed with a lid and placed into an outer tray also sealed with a lid. The sealed trays are radiation sterilized for use in medical applica-tions. The sealed trays may then be placed in a box.

[00112] Immediately prior to use, the kit may be placed in an operating room and the outer tray is opened. The inner tray is removed by a sterile technician and placed into the sterile field.

[00113] In the sterile field the inner tray is opened and the dispensing gun is as-sembled by inserting the finger grip of the plunger 120 (with the gradient markings 200 facing up and teeth facing down) through the opening in the front of the gun 100 and pushing the plunger through the back of the gun until the piston end of the plunger is seated completely within the gun (see Figures 6A, 7 and 8). The adapter 110 is then inserted into the front of the gun 100. Next a prefilled tube is removed from the inner tray. One cap is removed from the prefilled tube. The tube is thread-ed into the adapter and the other cap is removed from the tube (Figure 6B).
Option-ally a tip can be placed on the end of the tube to direct the flow of the graft material.

[00114] The tip of the instrument may be placed into the surgical site.
Upon pressing the trigger of the gun, the plunger is ratcheted forward to express the bone grafting material into the surgical site. The dispensing gun consists of, a handle, in which a block is moved forward through pressing the trigger which engages the teeth of the plunger moving the piston forward displacing the material from the tube. The trigger is manually disengaged by pushing the lever at the back of the dispensing gun upward allowing the plunger to be pulled back to a starting position. The first tube can be removed from the adapter and additional tubes can be threaded in place as needed.

[00115] Another embodiment involves altering the adapter for the attachment of two tubes and the plunger modified from a single piston to one have two pistons moving simultaneously with each compression of the trigger. Subsequently, the plungers dispense the material from the two tubes through a static mixer to facilitate the addition of a biological or drug material into the non-setting bone grafting material during injection into the surgical site. Any of the above-described aspects and em-bodiments of the invention may be in injectable form. Injection may occur by means of a syringe, for example. The compositions are particularly useful when injected in a gel or liquid form into a bone gap or bone defect. The injected gel or liquid would then solidify at body temperature when placed on or near the bone gap or the bone defect.

[00116] Example 1

[00117] The purpose of the study was to establish a standard for evaluating the handling of irrigation resistant matrix (IRM) samples when immersed in water.

[00118] Materials used in the study were IRM samples as noted in Tables 2-28, deionized water, and crystallization dish. Equipment used included hotplate and an-alytical balance.

[00119] To preparing for the test deionized water was dispensed into the crystal-lization dish so that a 5 ¨ 7.5 g IRM sample was completely immersed. The crystalli-zation dish was then set on the hot plate and heated to 37 C

[00120] Next to run the immersed compression test, each IRM sample (5 ¨ 7.5 g) was molded into a sphere. With the crystallization dish still on the hotplate, each sample was pressed flat against the bottom of the dish. The sample was then picked up out of the water bath, remolded into a sphere, and the process was repeated. The steps were repeated until the sample could no longer be picked up or no longer molded into a sphere.

[00121] The pass/fail criteria included: each sample that was pressed and picked up more than once passed the testing; each sample that was only pressed and picked up once failed the testing. The term "immersed compression" refers to the property of stiffness or the ability of the material to be manipulated under warm water while the material is still intact.

[00122] The grading used included: 0 and 1 unsatisfactory; 2-4 acceptable;
and >
4 outstanding.

[00123] The results are shown in Tables 2-28.

[00124] Table 2 BG
% Total BG 1- BG 32pm- MYRJ Sodium Polyglycerol 90pm-Immersed BG mass 2mm 125pm S25 Hyaluronate sebacate 710pm Compression ok 67 30.15 26.80 10.05 13.2 0.3 19.8 0 Kg-01-08-B-1 67 50 15.075 13.4 5.025 6.6 0.15 9.9 0

[00125] Table 3 PEG PEG
All BG Poly- Glyceryl Sodium % Total bio-BG 90pm- 32pm_ 400 400 di-propylene Mono- Hyalu-Immersed BG mass 710pm monos- stea-Compres-glass 125pm glycol stearate ronate tearate rate sion ok 73 0.00 56.00 13.00 5.7 14.5 5.7 5.7 0.3 Kg-01-18-A 73 47.6 0 28 6.5 7.25 2.85 0 2.85 0.15 0 Kg-01-18-B 73 47.6 0 28 6.5 2.85 8.25 0 1.85 0.15 0 Kg-01-18-C 73 47.6 0 28 6.5 2.85 7.25 0 2.85 0.15 0 Kg-01-18-D 73 47.6 0 28 6.5 0 7.25 2.85 2.85 0.15 0 Kg-01-18-E 73 47.6 0 28 6.5 0 7.75 3.35 1.85 0.15 0

[00126] Table 4 BG BG PEG PEG
% Total 400 Poly- Glyceryl Sodium Immersed 90pm- 32pm- 400 propylene Mono-BG mass dis- Hyaluronate Compression 710pm 125pm MONO
tearate glycol stearate ok 73 56.00 13.00 5.7 14.5 5.7 5.7 0.3 Kg-01-19-Al 73 95.2 56 13 14.5 5.7 0 5.7 0.3 6 Kg-01-19-A2 73 95.2 56 13 14.5 0 5.7 5.7 0.3 4 Kg-01-19-E1 73 95.2 56 13 0 15.5 6.7 3.7 0.3 3 Kg-01-19-E2 73 95.2 56 13 0 15.5 6.7 3.7 0.3 4

[00127] Table 5 PEG
BG PEG polypro- Cande- Sodium % Total 90pm- BG 32pm-400 400 Immersed pylene Ulla Sorbitol Hyalu-BG mass 125pm dis-Compres-710pm MONO glycol Wax ronate tearate sion ok 73 59.00 13.65 14.5 15.2 6.0 6.0 .0 0.3 PEG
BG PEG polypro- Cande- Sodium % Total BG 32pm- 400 Immersed 90pm- 400 dis- pylene Ulla Sorbitol Hyalu-BG mass 125pm Compres-710pm MONO tearate glycol Wax ronate sion Kg-01-22-A 73 49.425 29.5 6.825 7.25 0 2.85 2.85 0 0.15 4 Kg-01-22-B 73 49.425 29.5 6.825 0 7.75 3.35 1.85 0 0.15 6 Kg-01-22-C 73 49.425 29.5 6.825 7.25 0 2.85 0 2.85 0.15 0 Kg-01-22-D 73 49.425 29.5 6.825 0 7.75 3.35 0 1.85 0.15 0

[00128] Table 6 PEG
BG PEG 400 poly-poly- Immersed 90pm- BG 400 distea poly- pro-capro- Sodium Com-pylene % Total 710p 32pm- MON tea- capro- Cande- 1 col lactone Hyalu- pression BG mass m 125pm 0 rate lactone !ilia Wax g Y diol ronate Kg-01-23-A 73 98.85 59 13.65 14.5 0 0 5.7 5.7 0 0.3 Kg-01-23-C-1 73 49.425 29.5 6.825 7.25 0 0 0 2.85 2.85 0.15 4 Kg-01-23-C-2 73 49.425 29.5 6.825 0 7.75 0 0 3.35 1.85 0.15 4 Kg-01-23-C-3 73 49.425 29.5 6.825 7.25 0 0 0 2.85 2.85 0.15 5 Kg-01-23-D-1 73 49.425 29.5 6.825 7.25 0 2.85 0 2.85 0 0.15 Kg-01-23-D-2 73 49.425 29.5 6.825 0 7.75 1.85 0 3.35 0 0.15

[00129] Table 7 BG
32p BG m- PEG Glyceryl Poly- Sodium Immersed % Total 90pm- 125p 400 Candelilla Mono-Sesame caprolac- Hyalu- Compres-BG mass 710pm m MONO Wax stearate Oil tone diol ronate sion Kg-01-25-S-2 73 49.9 29.5 7 7.25 0 3 3 0 0.15 4 Kg-01-25-S-4 73 49.9 29.5 7 7.25 3 0 3 0 0.15 4 Kg-01-25-S-5 73 49.9 29.5 7 7.25 0 0 3 3 0.15 2

[00130] Table 8 BG Im-90pm- BG Glyceryl poly-Sodium mersed % Total 710p 32pm- PEG 400 Candelilla Monos-Coconut caprolac- Hyalu- Com-BG mass m 125pm MONO Wax tearate Oil tone diol ronate pression 3-D2 73 49.9 29.5 7 7.25 0 3 3 0 0.15 3-D4 73 49.9 29.5 7 7.25 3 0 3 0 0.15 RK-02- 73 49.9 29.5 7 7.25 0 0 3 3 0.15

[00131] Table 9 BG BG Im-90pm- 32pm- Glyceryl polycapro- Sodium mersed % Total 710p 125p PEG 400 Candelilla Monos-Propylene lactone Hyalu- Com-BG mass m m MONO Wax tearate Glycol diol ronate pression 3-E2 73 49.9 29.5 7 7.25 o 3 3 o 0.15 2 3-E4 73 49.9 29.5 7 7.25 3 o 3 o 0.15 3 3-E5 73 49.9 29.5 7 7.25 o o 3 3 0.15 2

[00132] Table10 Im-Bio-mers Total Bio- glass PEG Glycer-Sodi- ed sam- glass 32pm- 400 Poly- poly- yl Ses-um Com % pie 90pm- 125p MON capro- caprolac- polycaprolac- Monos- ame Hyalu- pres-BG mass 710pm m 0 lactone tone diol tone diol tearate Oil ronate sion 10k mw Diol Triol Kg-01-27-Al 73 49.9 29.5 7 7.25 0 3 3 o 0 0.15 2 Kg-01-27-A2 73 49.9 29.5 7 o o 3 10.25 o 0 0.15 2 Kg-01-27-A3 73 49.9 29.5 7 o o 5 8.25 o 0 0.15 2 Kg-01-27-B1 73 49.9 29.5 7 7.25 3 o 3 o 0 0.15 0 Kg-01-27-B2 73 49.9 29.5 7 o 3 o 10.25 o 0 0.15 0 Kg-01-27-B3 73 49.9 29.5 7 o 5 o 8.25 o 0 0.15 0

[00133] Table 11 BG PEG Poly Immersed % Total 90pm- BG 32pm- 400 propylene Glyceryl Sodium Com-BG mass 710pm 125pm MONO glycol Monostearate Hyaluronate pression Kg-01-28-A 73 47.6 28 6.5 7.25 2.85 2.85 0.15 5

[00134] Table 12 BG BG PEG Glyceryl poly-Sodium Immersed % Total 90pm- 32pm- 400 Candelilla Mono- capro-Hyalu- Com-BG mass 710pm 125pm MONO Wax stearate lactone ronate pression triol diol 4-F2 73 49.9 29.5 7 7.25 o 3 3 0 0.15 4 4-F4 73 49.9 29.5 7 7.25 3 o 3 0 0.15 3 4-F5 73 49.9 29.5 7 7.25 o o 3 3 0.15 3

[00135] Table 13 BG BG Poly pro-% Total 90pm- 32pm- Bioglass PEG 400 pylene Glyceryl Sodium Immersed BG mass 710pm 125pm 2-5mm Monostearate glycol Monostearate Hyaluronate Compression Kg-01-29-A 66 47.6 7.75 23.81 7.25 2.85 2.85 0.15 o

[00136] Table 14 BG Poly BG 32p Mineral ethylene Glycer-90pm- m- Mineral Oil Oil Low glycol yl Sodium Immersed % Total 710p 125p PEG 400 High Viscosi- DiMethyl PEG Monos- Hyalu- Com-BG mass m m MONO Viscosity ty Ether -8 tearate ronate pression Kg-01-30-E 73 49.9 29.5 7 7.25 3 o o o 3 0.15 4 Kg-01-30-F 73 49.9 29.5 7 7.25 o 3 o o 3 0.15 3 Kg-01-30-G 73 49.9 29.5 7 7.25 o o 3 o 3 0.15 2 Kg-01-30-H 73 49.9 29.5 7 7.25 o o o 3 3 0.15 2

[00137] Table 15 Poly eth-ylene BG BG PEG
Mineral PEG Sodium Mineral glycol Im-Oil Oil Low DiMe- mersed % Total 90pm- 32pm- 400 Cande- High -8 Hyalu- Com-BG thyl y Com-BG mass 710pm 125pm MONO Dila Wax Viscosity ronate Ether pression Kg-01-30-M 73 49.9 29.5 7 7.25 3 3 o o 0 0.15 3 Kg-01-30-N 73 49.9 29.5 7 7.25 3 o 3 o 0 0.15 2 Kg-01-30-0 73 49.9 29.5 7 7.25 3 o o 3 0 0.15 1 Kg-01-30-P 73 49.9 29.5 7 7.25 3 o o o 3 0.15 3

[00138] Table 16 BG
32 Im-pm Mineral Poly- mersed BG
1 400 High Vis-- PEG Mineral Oil Oil Low Poly eth-capro- Corn-Total 90pm-ylene glycol lac- Sodium pression DiMethyl PEG- tone Hyalu-% 5p mass 710pm MONO Viscosity cosity BG m Ether 8 diol ronate Kg-01-30-Q 73 49.9 29.5 7 7.25 3 0 0 0 3 0.15 1 Kg-01-30-R 73 49.9 29.5 7 7.25 0 3 0 0 3 0.15 1 Kg-01-30-S 73 49.9 29.5 7 7.25 0 0 3 0 3 0.15 1 Kg-01-30-T 73 49.9 29.5 7 7.25 0 0 0 3 3 0.15 3

[00139] Table 17 BG
Poly-Immersed % Total 90p BG PEG
Candelilla Propylene Sodium m- 32pm- 400 caprolactone Compression BG mass Wax Glycol Hyaluronate 710 125pm MONO diol Pm 7-E4 73 99.8 59 14 14.5 6 6 0 0.3 0 7-E5 73 99.8 59 14 14.5 0 6 6 0.3 0

[00140] Table 18 PEG poly-Glyceryl PEG Sodium Total BG BG 400 Candelilla %BG 90pm- 32pm- capro-Immersed Monos- 200 Hyalu-mass MON Wax lactone Com-710pm 125pm0 tearate adipate diol ronate pression Kg-01-31-W 73 49.9 29.5 7 7.25 0 3 3 0 0.15 Kg-01-31-Y 73 49.9 29.5 7 7.25 3 0 3 0 0.15 Kg-01-31-Z 73 49.9 29.5 7 7.25 0 0 3 3 0.15

[00141] Table 19 BG
% Total BG 90pm- 32pm- PEG 400 PEG 400 DI Propylene PCL
Sodium Immersed BG mass 710pm 125p MONO Glycol diol Hyalu-ronate Compression m Kg-01-34-E51 73 49.9 29.5 7 7.25 3 3 0.15 Kg-01-34-E52 73 49.9 29.5 7 2 5.25 3 3 0.15 Kg-01-34-E53 73 49.85 29.5 7 3.6 3.6 3 3 0.15

[00142] Table 20 BG BG
ok Total 90pm- 32 PCL propylene Sodium pm-diol glycol Hyaluronate BG mass Immersed 710pm 125pm Compression Kg-01-35-10 74 49.95 29.5 7 10.3 3 0.15

[00143] Table 21 BG BG Name of % Total Propyleme Variable Immersed BG mass 90pm- 32pm-Glycol Component Variable Compression 710pm 125pm Component Ethylene Glycol ZT-02-19-4 73 49.7 29.5 7 5.1 8.1 Monostearate 0 Propylene Glycol ZT-02-19-5 73 49.7 29.5 7 5.1 8.1 Stearate ZT-02-19-6 73 49.7 29.5 7 5.1 8.1 Brij 2 ZT-02-19-7 73 49.7 29.5 7 5.1 8.1 Brij 10 ZT-02-19-8 73 49.7 29.5 7 5.1 8.1 Brij 20 ZT-02-19-9 73 49.7 29.5 7 5.1 8.1 Brij 100 ZT-02-19-1 73 49.7 29.5 7 5.1 8.1 Distearate Sorbitan ZT-02-19-2 73 49.7 29.5 7 5.1 8.1 Monostearate 0 ZT-02-19-3 73 49.7 29.5 7 5.1 8.1 Cetyl Alcohol 0

[00144] Table 22 BG BG Name of % Total PEG Variable BG mass 90pm- 32pm-A Variable Immersed dipate Component 710pm 125pm Component Compression ZT-02-20-A1 73 49.7 29.5 7 5.1 8.1 Distearate 3 ZT-02-20-A6 73 49.7 29.5 7 5.1 8.1 Brij 2 2 ZT-02-20-A7 73 49.7 29.5 7 5.1 8.1 Brij 10 3 ZT-02-20-A8 73 49.7 29.5 7 5.1 8.1 Brij 20 3 ZT-02-20-A9 73 49.7 29.5 7 5.1 8.1 Brij 100 2 Sorbitan ZT-02-20-A2 73 49.7 29.5 7 5.1 8.1 Monostearate 0 ZT-02-20-A3 73 49.7 29.5 7 5.1 8.1 Cetyl Alcohol 0 ZT-02-20-A4 49.7 29.5 7 5.1 8.1 Ethylene Gly-BG BG Name of % Total 90pm- 32pm- PEG Variable Variable Immersed BG mass Adipate Component 710pm 125pm Component Compression col Monos-73 tearate 0 Propylene Glycol Stea-ZT-02-20-A5 73 49.7 29.5 7 5.1 8.1 rate 0 Calcium Stea-ZT-02-20-A10 73 49.7 29.5 7 5.1 8.1 rate

[00145] Table 23 BG BG Name of % Total Butylene Variable pp Variable Immersed 90m- 32m-BG mass Glycol Component 710pm 125pm Component Compression Ethylene Glycol ZT-02-20-B4 73 50.9 29.5 7 6.3 8.1 Monostearate 3 Propylene Glycol Stea-ZT-02-20-B5 73 51.7 29.5 7 7.1 8.1 rate Propylene ZT-02-20- Glycol Stea-MB5 73 48.8 29.5 7 8.3 4 rate 2 ZT-02-20-B6 73 49.7 29.5 7 5.1 8.1 Brij 2 ZT-02-20-B7 73 49.7 29.5 7 5.1 8.1 Brij 10 ZT-02-20-B8 73 49.7 29.5 7 5.1 8.1 Brij 20 ZT-02-20-B9 73 50.2 29.5 7 5.6 8.1 Brij 100 ZT-02-20-B1 73 49.7 29.5 7 5.1 8.1 Distearate 0 Sorbitan ZT-02-20-B2 73 49.7 29.5 7 5.1 8.1 Monostearate 0 ZT-02-20-B3 73 49.7 29.5 7 5.1 8.1 Cetyl Alcohol 0 ZT-02-20- Calcium B10 73 49.7 29.5 7 5.1 8.1 Stearate 0

[00146] Table 24 BG BG Name of % Total Hexylene Variable 90pm- 32pm- Variable Immersed BG mass Glycol Component 710pm 125pm Component Compression ZT-02-20- Sorbitan H2 73 50.2 29.5 7 5.6 8.1 Monostearate 0 Ethylene ZT-02-20- Glycol H4 73 50.7 29.5 7 6.1 8.1 Monostearate 1 Propylene ZT-02-20- Glycol Stea-H5 73 49.7 29.5 7 5.1 8.1 rate 1 H6 73 49.7 29.5 7 5.1 8.1 Brij 2 1 H7 73 49.7 29.5 7 5.1 8.1 Brij 10 1 BG BG Name of % Total Hexylene Variable BG mass 90pm- 32pm-Glycol Component Variable Immersed 710pm 125pm Component Compression H9 73 49.7 29.5 7 5.1 8.1 Brij 100 1 H1 73 49.7 29.5 7 5.1 8.1 Distearate 0 H3 73 49.7 29.5 7 5.1 8.1 Cetyl Alcohol 0 H8 73 49.7 29.5 7 5.1 8.1 Brij 20 1 ZT-02-20- Calcium H10 73 49.7 29.5 7 5.1 8.1 Stearate 0

[00147] Table 25 BG
BG õ Propylene Ethylene Immersed % Total 90pm- --P Hexylene Cetyl PEG PEG
GI col Glycol Compres-BG mass 710p 12115-p Glycol Alcohol 6E0i0s0 Adipate Steayrate Mt onots- sion m m tearate 23-M1H1 73 49.7 29.5 7 7.2 0 6 0 0 0 1 23-M2H1 73 49.7 29.5 7 9 0 4.2 0 0 0 0 23-M1H3 73 49.7 29.5 7 7.2 6 0 0 0 0 0 23-M2H3 73 49.7 29.5 7 9 4.2 0 0 0 0 0 23-M1A4 73 49.7 29.5 7 0 0 7.2 0 6 0 23-M2A4 73 49.7 29.5 7 0 0 9 0 4.2 0 23-M1A5 73 49.7 29.5 7 0 0 7.2 6 0 0

[00148] Table 26 BG BG
ok Total BG mass 90pm- 32pm- Brij 20 Brij 100 Propylene Immersed 710pm 125pm Glycol Compression ZT-02-24-1 73 49.7 29.5 7 0 6 7.2 2 ZT-02-24-2 73 49.7 29.5 7 8.1 0 5.1 9

[00149] Table 27 BG BG
ok Total Propylene 90pm- 32pm- Brij 20 Brij 100 Immersed BG mass 710pm 125pm Glycol Compression Kg-01-37-1 49.7 29.5 7 4 3 6.2 I

[00150] Table 28 BG BG
ok Total 90pm- 32pm- Propylene Sodium Immersed BG mass 710pm 125pm Brij 20 Glycol Hyaluronate compression Kg-01-37-6 73 49.85 29.5 7 8.1 5.1 0.15 8 Kg-01-37-7 73 49.75 29.5 7 8.1 5.1 0.05 8 Kg-01-37-8 72 50.85 29.5 7 8.1 6.1 0.15 8

[00151] Overall the irrigation data shows that samples can be manipulated in an aqueous environment without migrating, washing away or being displaced from the site.

[00152] Throughout this specification various indications have been given as to preferred and alternative embodiments of the invention. However, the foregoing de-tailed description is to be regarded as illustrative rather than limiting and the inven-tion is not limited to any one of the provided embodiments. It should be understood that it is the appended claims, including all equivalents, are intended to define the spirit and scope of this invention.

Claims (38)

1. An irrigation resistant bone repair composition comprising:
a biocompatible or bioactive bone repair material, and at least one non-ionic surfactant, wherein the non-ionic surfactant is not a non-random poly(oxyalkylene) block copolymer.

2. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 1%-99% relative to the weight of the bone repair composition.

3. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 1%-20% relative to the weight of the bone repair composition.

4. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 20%-30% relative to the weight of the bone repair composition.

5. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 30%-40% relative to the weight of the bone repair composition.

6. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 40%-50% relative to the weight of the bone repair composition.

7. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 50%-60% relative to the weight of the bone repair composition.

8. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 60%-70% relative to the weight of the bone repair composition.

9. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 70%-80% relative to the weight of the bone repair composition.

10. The bone repair composition of claim 1, wherein the weight ratio of the at least one non-ionic surfactant is 80%-99% relative to the weight of the bone repair composition.

11. The bone repair composition of claim 1, wherein the composition is os-teoconductive.

12. The bone repair composition of claim 1, wherein the composition is os-teostimulative.

13. The bone repair composition of claim 1, wherein the bone repair mate-rial is a bioactive glass or ceramic.

14. The bone repair composition of claim 13, wherein the bioactive glass is melt-derived bioactive glass or sol-gel derived bioactive glass.

15. The bone repair composition of claim 14, wherein the bioactive glass is in the form of a particle, sphere, fiber, mesh, sheet or a combination of these forms.

16. The bone repair composition of claim 14, wherein the bioactive glass comprises about 15-45% CaO, about 30-70% SiO2, about 0-25% Na2O, about 0-17% P2O5, about 0-10% MgO and about 0-5% CaF2.

17. The bone repair composition of claim 14, wherein the bioactive glass comprises about 45% SiO2, about 24.5% CaO, about 6% P2O5, and about 2.5%
Na2O.

18. The bone repair composition of claim 15, wherein the size of the bioac-tive glass particle is in a range from about 0.01 µm to about 5 mm.

19. The bone repair composition of claim 15, wherein the bioactive glass comprises 0-80% < 100 µm bioactive glass, 0-80% < 500 µm bioactive glass, 0-80%
500-1000 µm bioactive glass, 0-80% 1000-2000 µm bioactive glass, 0-80%

5000 µm bioactive glass, 0-90% 90-710 µm bioactive glass, and 0-90% 32-125 µm bioactive glass.

20. The bone repair composition of claim 15, wherein the bone repair ma-terial is one or more particles of bioactive glass coated with a glycosaminoglycan, wherein the glycosaminoglycan is bound to the bioactive glass.

21. The bone repair composition of claim 20, wherein the glycosaminogly-can is selected from the group consisting of heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid.

22. The bone repair composition of claim 1, further comprising at least one element selected from the group consisting of Li, K, Mg, Sr, Ti, Zr, Fe, Co, Cu, Zn, Al, Ag, Ga, P, N, S, F, CI, Ag, Au, Ce and I.

23. The bone repair composition of claim 14, wherein the bioactive glass is pretreated in a solution comprising one or more of blood, bone marrow, bone marrow concentrate, bone-morphogenetic proteins, platelet-rich plasma, and osteogenic pro-teins.

24. The bone repair composition of claim 23, wherein the proteins are se-lected from the group consisting of WP9QY(W9), OP3-4, RANKL, B2A, P1, P2, P3, P4, P24, P15, TP508, OGP, PTH, NBD, CCGRP, W9, (Asp)8, (Asp)8, and (Asp, Ser, Ser)8, and mixtures thereof.

25. The bone repair composition of claim 1, wherein the composition is in a form of a putty, paste, gel, solid or waxy solid.

26. The bone repair composition of claim 1, wherein the composition, when implanted into a surgical site, maintains position and does not displace upon irriga-tion of the surgical site.

27. The bone repair composition of claim 1, wherein the non-ionic surfac-tant other than the non-random poly(oxyalkylene) block copolymer is selected from the group consisting of fatty alcohols, alkoxylated alcohols, alkoxylated alkylphenols, alkoxylated fatty amides, alkoxylated fatty esters, alkoxylated fatty ethers, alkoxylat-ed sorbitan esters, alkoxylated sorbitan esters, fatty acids, fatty acid esters, poly-glycerin fatty acid esters, polyol esters, polyalkylene glycols, alkoxylated organic ac-ids, hydroxyacids or diacids, and copolymers therefrom, and combinations thereof.

28. The bone repair composition of claim 1, wherein the non-ionic surfac-tant is selected from the group consisting of stearic acid, stearyl alcohol, Ecosurf LF
45, Triton X-100, polyethoxylated tallow amine, poly(ethylene glycol) 400 Monos-tearate (PEG 400 monostearate), polyethylene glycol lauryl ether (Brij L23), Span 85 (sorbitan trioleate), polysorbate 20, polysorbate 80, glycerol monostearate, PEG co-conut triglyceride, PEG 400, PEG 600, sorbitan tristearate, polysorbate 20, poly-sorbate 80, polyoxyethylene 7 coconut, glyceride, PEG 400 monostearate, PEG
2000 monomethylether, and PEG 400 distearate, polyglyceryl-2 isostearate, poly-glyceryl-2 diisostearate, polyglyceryl-4 isostearate, polyglyceryl-6 isostearate, poly(ethylene glycol) 8 stearate (MYRJ S8), polyglyceryl-10 isostearate, polyglyceryl-diisostearate, poly(ethylene glycol) 25 propylene glycol stearate (MYRJ S25), poly(ethylene glycol) 400 distearate (PEG 400 distearate), polyglyceryl-4 laurate, polyglyceryl-6 laurate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglycer-yl-2 oleate, polyglyceryl-4 oleate, polyglyceryl-6 oleate, polyglyceryl-10 oleate, poly-glyceryl-10 stearate, polyglyceryl-10 distearate, polyoxyethylene 7 coconut glyceride (coconut glyceride), polyethylene glycol 2000 monomethyl ether (MME), glyceryl monostearate (monostearin), PEG dimethyl ether (dimethyl polyethylene glycol), PEG 200 adipate (poly(ethylene glycol) 200 adipate, PEG 6000 distearate, sorbitan monostearate, cetyl alcohol, ethylene glycol monostearate, propylene glycol stea-rate, polyoxyethylene stearyl ether (Brij 2), polyoxyethylene stearyl fatty ether (Brij 10), docosaethylene glycol mono octadecyl ether (Brij 20), polyethylene stearyl ether (Brij 100),polyglycerin fatty acid ester (polyglyceryl-2 isostearate, polyglyceryl-2 diisostearate, polyglyceryl-4 isostearate, polyglyceryl-6 isostearate, polyglyceryl-10 isostearate, polyglyceryl-10 diisostearate, polyglyceryl-4 laurate, polyglyceryl-6 laurate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-2 oleate, pol-yglyceryl-4 oleate, polyglyceryl-6 oleate, polyglyceryl-10 oleate, polyglyceryl-10 stea-rate, and polyglyceryl-10 distearate.

29. The bone repair composition of claim 1, further comprising an additive selected from the group consisting of a solvent, a linear aliphatic hydrocarbon, straight chain aliphatic hydrocarbon, branched aliphatic hydrocarbon, sugar, poly-saccharide, and hydroxyl terminal polyalkylene oxide, alkoxy terminal polyalkylene oxide, and a low molecular weight biodegradable polymers (MW<=10,000).

30. The bone repair composition of claim 29, wherein the additive is se-lected from the group consisting of sodium hyaluronate, regenerez, polypropylene glycol 3000 (poly 3000), seasame oil, candelilla wax, carnauba wax, sorbitol (D-Glucitol), polycaprolactone, polycaprolactone diol, coconut oil, propylene glycol, pol-ycaprolactone triol, polycaprolactone 10000 mw, mineral oil high viscosity, mineral oil low viscosity, polyethylene glycol 400, butylene glycol, and hexylene glycol.

31. An irrigation resistant putty or paste including the composition of claim 1 mixed with water, saline, blood, or BMA.

32. The bone repair composition of claim 1, wherein the composition is for treating a bone defect or a bone gap.

33. The bone repair composition claim 1, wherein the composition is for regeneration of hard tissues.

34. A method for treating a bone having a bone gap or a bone defect com-prising contacting the bone at or near the site of the bone defect with the bone repair composition of claim 1.

35. A kit comprising:
at least one tube comprising the bone repair composition of claim 1, a dispensing gun, an adapter, and optionally, at least one dispensing tip.

36. The kit of claim 35, wherein the tube comprising the bone repair com-position is capped.

37. The kit of claim 35, further comprising a syringe.

38. The kit of claim 35, further comprising at least one of "Y" connector, tube connector, and an aspiration needle.