Patent Application
20050031578
The present invention relates generally to compositions for use in medical procedures and methods of performing medical procedures. In particular, the present invention is directed towards compositions for use in medical procedures and methods of performing medical procedures in which the composition promotes bone growth when the composition is positioned in the vicinity of a bone of a mammal.
Human bone includes a solid mineral phase and an organic matrix which is between 90% and 95% type I collagen. The mineral phase includes, inter alia, calcium and phosphate.
The mechanical properties of bone are related to its specific type of construction and internal architecture. Although bone may be relatively light, it also may have a relatively high tensile strength. This combination of high strength coupled with relatively low weight results from, inter alia, the hollow, tubular shape of bone, the layering of bone tissue, and the internal buttressing within the organic matrix. Bone tissue may supplant membranous or fibrous tissue by a mechanism referred to as “intramembranous ossification.” Bone tissue only grows by appositional growth, e.g., the deposition of a new organic matrix on the surface of the bone by adjacent surface cells. A damaged bone repairs itself through a multiphase process. Initially, bone repair begins with an inflammatory phase, involving extensive tearing of the membrane surrounding the bone (the periosteum), rupturing of blood vessels and extensive hemorrhaging. Typically, this leads to a secondary inflammatory response of white blood cells (e.g., polymorphonuclear leukocytes, macrophages, and mononuclear cells), in an effort to prevent infection. Pluripotential mesenchymal cells from the soft tissue and within the bone marrow give rise to the osteoblast cells that synthesize bone.
Known bone replacement technologies can be divided into three transitional matrix categories. The first category relies on replacing bone with either autogenous, homologous, heterologous, or decalcified bone, followed by remodeling. As referred to herein, the term “remodeling” will be understood to mean the process by which bone is continually built and resorbed within the body. This first category may be problematic, however, because of difficulties inherent in harvesting the replacement bone, as well as the risk of transmitting blood-borne pathogens into the body of the recipient. The second category involves synthetic bone replacement, e.g., replacing bone with a bone-like mineral (e.g., crystalline hydroxyapatite or calcium pyrophosphate), followed by remodeling. Synthetic bone replacement may be problematic, however, because the replacement material may have poor tensile strength and may adhere poorly to the surrounding bone. The third category relies on replacing bone with a composition that maintains its chemical and mechanical properties without change or subsequent remodeling (e.g., titanium, stainless steel, PMMA); nevertheless, this category does not allow for the growth of new bone.
A technical advantage of the present invention is that a composition of the present invention may be positioned in the vicinity of a bone of a mammal, e.g., in the vicinity of a damaged portion of the bone, and the composition promotes bone growth. For example, the composition can be applied to an exterior surface of the bone, dispensed in an opening formed within or through the bone, injected into the bone, positioned between two pieces of bone, or the like, without necessitating exposure of the bone, e.g., by injecting the composition through the skin using a syringe. The composition also may be molded into an implant, a screw, a plate, a prosthetic member, or the like, which may be inserted in or positioned on the bone. The composition initially may be liquid, and then may cure into a solid. For example, the composition may cure into a solid in an oxygen environment and/or a hydrophilic environment. The composition may be used to reconstruct bone, fuse bones (intravertebroinfusions), reduce or eliminate bone fractures or otherwise damaged bones, and/or regenerate missing bone, e.g., generate bone growth that fills a void within a bone. The composition also may be used to make plates, screws, prosthetic joints, or the like, and/or may act as an anchor for a suture inserted in an opening in a bone, preventing the suture from falling out of the opening after insertion. Moreover, the composition may be used as a base of a substrate in order to dilate compressed structures, e.g., vertebral disks, intramedullary nails, and in angioplasty type procedures. The newly generated bone has an internal rigid fixation similar to that of bone already present in the body, such that the generated bone is not readily damaged.
Moreover, an embodiment of the present invention facilitates ready preparation of the compositions of the present invention prior to their use in a medical procedure. According to an exemplary embodiment of the present invention, a kit that is useful in promoting bone growth comprises a first container that further comprises a dispensing means and a first compound, and a second container that further comprises a dispensing means and a second compound. The first compound and the second compound may be readily combined to form a composition of the present invention at a desired time before the performance of a medical procedure by dispensing the first compound and the second compound from their respective containers.
According to an exemplary embodiment of the present invention, a composition comprises: isocyanate; and a polyol that comprises a naturally occurring polyol and a biocompatible, synthetic polyol.
According to another exemplary embodiment of the present invention, a composition comprises a naturally occurring polyol, isocyanate, and water.
According to another exemplary embodiment of the present invention, a composition comprises a biocompatible, synthetic polyol and an isocyanate.
According to another exemplary embodiment of the present invention, a composition comprises a naturally occurring polyol and an isocyanate prepolymer that comprises a biocompatible, synthetic polyol and isocyanate.
According to another exemplary embodiment of the present invention, a composition comprises a crosslinker or chain-extender; and an isocyanate prepolymer that comprises isocyanate and a biocompatible, synthetic polyol.
According to another exemplary embodiment of the present invention, a composition comprises a polyester urethane component and at least one filler material, wherein the composition is adapted to stimulate bone growth when the composition contacts or is positioned in the vicinity of a bone of a mammal.
According to an embodiment of the present invention, a method of making a composition comprises the steps of forming a first compound by mixing a naturally occurring polyol with a biocompatible, synthetic polyol; and mixing the first compound with isocyanate.
According to an embodiment of the present invention, a method of making a composition comprises the steps of forming a first compound by mixing a naturally occurring polyol with a biocompatible, synthetic polyol; mixing the first compound with isocyanate; and permitting the first compound and the isocyanate to react to form a polyester urethane.
According to another embodiment of the present invention, a method of making a composition comprises mixing a naturally occurring polyol with isocyanate, and permitting water to be present in the composition.
According to another embodiment of the present invention, a method of making a composition comprises mixing a naturally occurring polyol with isocyanate, permitting the naturally occurring polyol and the isocyanate to react to form a polyester urethane, and permitting water to be present in the composition.
According to another embodiment of the present invention, a method of making a composition comprises the step of mixing a biocompatible, synthetic polyol with an isocyanate.
According to another embodiment of the present invention, a method of making a composition comprises the steps of mixing a biocompatible, synthetic polyol with an isocyanate; and permitting the biocompatible, synthetic polyol and the isocyanate to react to form a polyester urethane.
According to yet another embodiment of the present invention, a method of making a composition comprises the steps of forming an isocyanate prepolymer by mixing a biocompatible, synthetic polyol with isocyanate; and mixing the isocyanate prepolymer with a naturally occurring polyol.
According to yet another embodiment of the present invention, a method of making a composition comprises the steps of forming an isocyanate prepolymer by mixing a biocompatible, synthetic polyol with isocyanate; mixing the isocyanate prepolymer with a naturally occurring polyol; and permitting the isocyanate prepolymer and the naturally occurring polyol to react to form a polyester urethane.
According to still yet another embodiment of the present invention, a method of making a composition comprises the step of forming an isocyanate prepolymer by mixing a biocompatible, synthetic polyol with isocyanate; and mixing the isocyanate prepolymer with a crosslinker or chain-extender.
According to still yet another embodiment of the present invention, a method of making a composition comprises the step of forming an isocyanate prepolymer by mixing a biocompatible, synthetic polyol with isocyanate; mixing the isocyanate prepolymer with a crosslinker or chain-extender; and permitting the isocyanate prepolymer and the crosslinker or chain-extender to react to form a polyester urethane.
According to an embodiment of the present invention, a method of performing a medical procedure comprises at least one step selected from the group consisting of: applying a particular composition to at least one portion of a bone of a mammal, positioning the particular composition in the vicinity of the bone, dispensing the particular composition into an opening formed within or through at least one portion of the bone, and positioning the particular composition between a first bone portion of the mammal and a second bone portion of the mammal for fusing the first bone portion to the second bone portion, wherein the particular composition stimulates bone growth and is a product of a process that comprises the steps of: forming a first compound by mixing a naturally occurring polyol with a biocompatible, synthetic polyol; mixing the first compound with isocyanate; and permitting the first compound and the isocyanate to react to form a polyester urethane.
According to an embodiment of the present invention, a method of performing a medical procedure comprises at least one step selected from the group consisting of: applying a particular composition to at least one portion of a bone of a mammal, positioning the particular composition in the vicinity of the bone, dispensing the particular composition into an opening formed within or through at least one portion of the bone, and positioning the particular composition between a first bone portion of the mammal and a second bone portion of the mammal for fusing the first bone portion to the second bone portion, wherein the particular composition stimulates bone growth and is a product of a process that comprises the steps of: mixing a naturally occurring polyol with isocyanate; permitting the naturally occurring polyol and the isocyanate to react to form a polyester urethane; and permitting water to be present in the composition.
According to an embodiment of the present invention, a method of performing a medical procedure comprises at least one step selected from the group consisting of: applying a particular composition to at least one portion of a bone of a mammal, positioning the particular composition in the vicinity of the bone, dispensing the particular composition into an opening formed within or through at least one portion of the bone, and positioning the particular composition between a first bone portion of the mammal and a second bone portion of the mammal for fusing the first bone portion to the second bone portion, wherein the particular composition stimulates bone growth and is a product of a process that comprises the steps of mixing a biocompatible, synthetic polyol with an isocyanate; and permitting the biocompatible, synthetic polyol and the isocyanate to react to form a polyester urethane.
According to an embodiment of the present invention, a method of performing a medical procedure comprises at least one step selected from the group consisting of: applying a particular composition to at least one portion of a bone of a mammal, positioning the particular composition in the vicinity of the bone, dispensing the particular composition into an opening formed within or through at least one portion of the bone, and positioning the particular composition between a first bone portion of the mammal and a second bone portion of the mammal for fusing the first bone portion to the second bone portion, wherein the particular composition stimulates bone growth and is a product of a process that comprises the steps of: forming an isocyanate prepolymer by mixing a biocompatible, synthetic polyol with isocyanate; mixing the isocyanate prepolymer with a naturally occurring polyol; and permitting the isocyanate prepolymer and the naturally occurring polyol to react to form a polyester urethane.
According to an embodiment of the present invention, a method of performing a medical procedure comprises at least one step selected from the group consisting of: applying a particular composition to at least one portion of a bone of a mammal, positioning the particular composition in the vicinity of the bone, dispensing the particular composition into an opening formed within or through at least one portion of the bone, and positioning the particular composition between a first bone portion of the mammal and a second bone portion of the mammal for fusing the first bone portion to the second bone portion, wherein the particular composition stimulates bone growth and is a product of a process that comprises the steps of: forming an isocyanate prepolymer by mixing isocyanate with a biocompatible, synthetic polyol; mixing the isocyanate prepolymer with a chain-extender or crosslinker; and permitting the chain-extender or crosslinker and the isocyanate prepolymer to react to form a polyester urethane.
According to another embodiment of the present invention, a method of performing a medical procedure comprises the steps of: forming a mold; dispensing a liquid, particular composition into the mold, wherein the particular composition solidifies within the mold; removing the solidified, particular composition from the mold; and positioning the solidified, particular composition on a bone of a mammal or within an opening formed through or in the bone; wherein the positioned, particular composition stimulates bone growth; and the particular composition is a product of a process that comprises the steps of: forming a first compound by mixing a naturally occurring polyol with a biocompatible, synthetic polyol; and mixing the first compound with isocyanate.
According to another embodiment of the present invention, a method of performing a medical procedure comprises the steps of: forming a mold; dispensing a liquid, particular composition into the mold, wherein the particular composition solidifies within the mold; removing the solidified, particular composition from the mold; and positioning the solidified, particular composition on a bone of a mammal or within an opening formed through or in the bone; wherein the positioned, particular composition stimulates bone growth; and the particular composition is a product of a process that comprises the steps of: mixing a naturally occurring polyol with isocyanate; and permitting water to be present in the composition.
According to another embodiment of the present invention, a method of performing a medical procedure comprises the steps of: forming a mold; dispensing a liquid, particular composition into the mold, wherein the particular composition solidifies within the mold; removing the solidified, particular composition from the mold; and positioning the solidified, particular composition on a bone of a mammal or within an opening formed through or in the bone; wherein the positioned, particular composition stimulates bone growth; and the particular composition is a product of a process that comprises the step of mixing a biocompatible, synthetic polyol with an isocyanate.
According to another embodiment of the present invention, a method of performing a medical procedure comprises the steps of: forming a mold; dispensing a liquid, particular composition into the mold, wherein the particular composition solidifies within the mold; removing the solidified, particular composition from the mold; and positioning the solidified, particular composition on a bone of a mammal or within an opening formed through or in the bone; wherein the positioned, particular composition stimulates bone growth; and the particular composition is a product of a process that comprises the steps of: forming an isocyanate prepolymer by mixing a biocompatible, synthetic polyol with isocyanate; and mixing the isocyanate prepolymer with a naturally occurring polyol.
According to another embodiment of the present invention, a method of performing a medical procedure comprises the steps of: forming a mold; dispensing a liquid, particular composition into the mold, wherein the particular composition solidifies within the mold; removing the solidified, particular composition from the mold; and positioning the solidified, particular composition on a bone of a mammal or within an opening formed through or in the bone; wherein the positioned, particular composition stimulates bone growth; and the particular composition is a product of a process that comprises the steps of: forming an isocyanate prepolymer by mixing isocyanate with a biocompatible, synthetic polyol; and mixing the isocyanate prepolymer with a chain-extender or crosslinker.
Other objects, features, and advantages will be apparent to persons of ordinary skill in the art in view of the following detailed description of the invention and the accompanying drawings.
For a more complete understanding of the present invention, needs satisfied thereby, and objects, features, and advantages thereof, reference now is made to the following descriptions taken in connection with the accompanying drawings.
While the present invention is susceptible to various modifications and alternative forms, specific exemplary embodiments thereof have been shown in the drawings and are herein described. It should be understood, however, that the description herein of specific embodiments is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
Exemplary embodiments of the present invention and their advantages may be understood by referring to
According to an exemplary embodiment of the present invention, a composition of the present invention, such as a composition for use in a medical procedure, generally comprises an isocyanate and a polyol and/or a polyamine. Optionally, the compositions of the present invention also may comprise at least one filler material, at least one catalyst, and other additives (e.g., surfactants, proteins, etc.).
Another example of a composition of the present invention is a composition that comprises a biocompatible polyester urethane component. Generally, the compositions of the present invention that comprise a biocompatible polyester urethane component are those that have been prepared by combining an isocyanate with one or more polyols and/or polyamines, along with optional additives, and permitting them to react to form a composition that comprises a biocompatible polyester urethane component. The biocompatible polyester urethane component may be present in certain exemplary embodiments of the compositions of the present invention in an amount in the range of from about 40% to about 90% by weight. In certain exemplary embodiments of the compositions of the present invention, the biocompatible polyester urethane component is present in the composition in an amount in the range of from about 50% to about 70% by weight. Optionally, the compositions comprising a biocompatible polyester urethane component further may comprise other additives (e.g., at least one filler material, at least one catalyst, surfactants, proteins, etc.), as will be described.
When placed within the body of a mammal according to the methods of the present invention, the compositions of the present invention that comprise a biocompatible polyester urethane component may provide significant advantages over conventional biological materials. For example, other conventional biological materials (e.g., those comprising polylactic acid) may degrade over a particular period of time, irrespective of whether new bone has formed in the vicinity of the material. Such degradations may limit the stability of surrounding structures within the body of the mammal. In contrast to these conventional biological materials, the compositions of the present invention are degraded through a cyclic AMP regulated lipase hydrolysis reaction process that generally maintains a 1-to-1 conversion (e.g., the compositions of the present invention generally are replaced or converted to bone while maintaining regional structural stability). Additionally, conventional biological materials with osteoconductive properties often have an open cellular matrix to support osteoclasts and osteoblasts in growth. While certain exemplary embodiments of the compositions of the present invention may be considered to have a closed cellular matrix, the compositions of the present invention support osteoclasts in growth through local degradations that create micro-open-cellular matrices. Such micro-open-cellular matrices support osteoclast and osteoblast activity, e.g., the osteoclast metabolic activities create an open-cell matrix.
The compositions of the present invention that comprise a biocompatible polyester urethane component generally reside in a moldable state at room temperature for a desired time. Certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component may reside in a moldable state at room temperature for up to about 20 minutes after their formulation; certain other exemplary embodiments may reside in a moldable state at room temperature for a longer or shorter period of time. Absent supplemental heating or cooling, the compositions of the present invention that comprise a biocompatible polyester urethane component generally may solidify at room temperature at a time in the range of from about 20 minutes to about 30 minutes after their formulation. Where an operator desires to solidify the compositions of the present invention, the time required for solidification may be extended by cooling the composition, or may be reduced by heating the composition. Within about 48 hours after their formulation, certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component may attain a final, cured state; certain other exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component may attain a final, cured state at an earlier time. Certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component may have an average porosity in the range of from about 5 to about 500 microns; certain other exemplary embodiments may have an average porosity that is less, or that is greater. Certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component may have an average porosity in the range of from about 5 to about 100 microns. Certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component are resistant to thermal degradation up to temperatures of about 300 F. Certain exemplary embodiments may be capable of withstanding traditional autoclave sterilization cycles. For example, certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component repeatedly may be sterilized in an autoclave without substantially affecting their mechanical properties. Certain exemplary embodiments of the compositions of the present invention that comprise a biocompatible polyester urethane component demonstrate a compressive strength of at least about 50 MPa, a tensile strength of at least about 40 MPa, and/or a Young's Modulus of Elasticity of at least about 1,500 MPa. Certain other exemplary embodiments may demonstrate greater or lesser compressive strength, tensile strength, and/or Young's Modulus.
The compositions of the present invention are biocompatible, and are adapted to stimulate bone growth when positioned in contact with, or in the vicinity of, a bone of a mammal. Certain exemplary embodiments of the compositions of the present invention may be adhesive and cohesive, and certain exemplary embodiments may be bacterial static and bactericidal. Certain exemplary embodiments of the compositions of the present invention also may be osteoinductive or osteoconductive. Certain exemplary embodiments of the compositions of the present invention may be suitable for use as a USP Class VI medical adhesive.
The Isocyanate Component
A broad variety of isocyanates may be suitable for use in the compositions and methods of the present invention. In certain exemplary embodiments of the present invention, the isocyanate may be, e.g., an aromatic isocyanate, an aliphatic isocyanate, a cycloaliphatic isocyanate, or the like. An example of a suitable aromatic isocyanate is diphenylmethane isocyanate, also known as “MDI.” Commercially available examples of diphenylmethane isocyanate include, but are not limited to, mixtures of 2,4-diphenylmethane isocyanate and 4,4-diphenylmethane isocyanate isomers, such as those that are commercially available from Dow Chemical Company under the tradename ISONATE 50 OP, and those that are commercially available from Huntsman under the tradename RUBINATE 9433; these mixtures of 2,4- and 4,4-diphenylmethane isocyanate isomers generally will be liquids at room temperatures. Diphenylmethane isocyanate is also commercially available, inter alia, in its pure 4,4-diphenylmethane isocyanate form from Bayer AG under the tradename MONDUR M, and from Huntsman Corporation under the tradename RUBINATE 44; these compounds generally will be solids at room temperature. Other examples of suitable aromatic isocyanates include, but are not limited to, polymeric isocyanates, such as those that are commercially available from Dow Chemical Company under the tradenames ISONATE 143L, ISONATE PAPI 901, ISONATE PAPI 27, and the like. Examples of suitable cycloaliphatic isocyanates include, but are not limited to, isophorone diisocyanate and dicyclohexylmethane diisocyanate. Isophorone diisocyanate is commercially available from Bayer Corporation under the trade name DESMODUR I. Dicyclohexyl methane diisocyanate is commercially available from Bayer Corporation under the trade name DESMODUR W. An example of a suitable aliphatic isocyanate is 1,6 hexylmethylene diisocyanate.
In certain exemplary embodiments of the present invention, the isocyanate may be chosen so that the compositions of the present invention that comprise the isocyanate will be liquids at room temperature and will have desired flexural properties. For example, an exemplary embodiment of a composition of the present invention that was prepared from an isocyanate prepolymer that comprised ISONATE PAPI 901 demonstrated flexural strength of 64.9 MPa at 5.5% strain (no yield), while another exemplary embodiment of a composition of the present invention that was prepared from an isocyanate prepolymer that comprised ISONATE 500P exhibited flexural strength of 57.4 MPa at 7.0% strain (yield). Furthermore, the quantity of isocyanate that may be included in the compositions of the present invention will also depend on factors including, inter alia, the desired flexural properties of the composition. In certain exemplary embodiments of the present invention where the composition comprises a isocyanate prepolymer that comprises an isocyanate, the isocyanate is generally present in the isocyanate prepolymer in an amount in the range of from about 30% to about 80% by weight of the isocyanate prepolymer. In certain exemplary embodiments, the isocyanate may be present in the isocyanate prepolymer in an amount in the range of from about 30% to about 70% by weight of the isocyanate prepolymer. One of ordinary skill in the art, with the benefit of this disclosure, will be able to identify a suitable amount of isocyanate to include in the compositions of the present invention for a particular application.
The Polyol/Polyamine Component
The compositions of the present invention further may comprise a polyol and/or a polyamine. A broad variety of polyols may be suitable for use in the compositions and methods of the present invention, including, but not limited to, naturally occurring polyols and biocompatible, synthetic polyols, and mixtures thereof. The polyols used in the present invention generally comprise at least one ester group. In certain exemplary embodiments, a polyol used in the present invention may comprise in the range of from about 2 to 3 ester groups. In certain exemplary embodiments, a polyol used in the present invention may comprise in the range of from about 5 to 10 ester groups.
As referred to herein, the term “naturally occurring polyols” will be understood to include, inter alia, naturally occurring polyols as well as polyols that are derived from various vegetable oils. Generally, the naturally occurring polyols that are suitable for use in the present invention are those that have at least one hydroxyl group. In certain exemplary embodiments, the naturally occurring polyols have two or more hydroxyl groups. Examples of naturally occurring polyols include, but are not limited to, castor oil, safflower oil, lesquerella oil, the polyols that may be obtained by chemical modification of naturally occurring vegetable oils (e.g., castor oil, olive oil, sesame oil, corn oil), naturally occurring oils that have been trans-esterified (e.g., a modified castor oil polyol that has been prepared by the transesterification reaction of natural castor oil with suitable crosslinkers (e.g., glycerol, trimethylolpropane, and the like)), naturally occurring oils that have been hydrogenated, and the like. Another example of a suitable naturally occurring polyol is a difunctional castor-oil-based polyol that is commercially available from CasChem, Inc., under the tradename CASPOL® 5001.
As referred to herein, the term “biocompatible, synthetic polyols” will be understood to include, inter alia, biocompatible synthetic polyols that are derived from crude oil. Examples of suitable biocompatible, synthetic polyols include, but are not limited to, polycaprolactone polyols, polyester polyols, polyadipate polyols (e.g., poly(hexane-adipate) diol, poly(butane-adipate) diol, poly(ethylene/propylene-adipate) diol, poly(hexane/adipate/isophthalate diol)), polyols that have been derived from a synthetic acid (e.g., isophthalic acid, maleic acid), and the like. In certain exemplary embodiments, the biocompatible, synthetic polyol may be biodegradable. An example of a suitable polycaprolactone polyol is a polycaprolactone diol that is commercially available from Dow Chemical under the trade name TONE 32 B8.
In certain exemplary embodiments of the present invention, an isocyanate prepolymer may be reacted with a polyamine to form a polyurethane according to a method of the present invention. In certain exemplary embodiments, the polyamine may be a product of a chemical transformation of a naturally occurring polyol. In certain exemplary embodiments, the polyamine may be a secondary di-amine. The choice of a particular polyol or polyamine for use in accordance with the present invention may depend on factors including, inter alia, the desired flexural properties of the compositions of the present invention that are produced from the particular polyol or polyamine. The use of a relatively short-chain polyol or polyamine will tend to impart less flexibility to the composition of the present invention than will the use of a relatively long-chain polyol or polyamine. One of ordinary skill in the art, with the benefit of this disclosure, will be able to identify a suitable polyol or polyamine for a particular application.
In certain exemplary embodiments of the present invention, the polyol or polyamine is generally present in the isocyanate prepolymer in an amount in the range of from about 10% to about 50% by weight of the isocyanate prepolymer. In certain exemplary embodiments, the polyol or polyamine may be present in the isocyanate prepolymer in an amount in the range of from about 20% to about 35% by weight of the isocyanate prepolymer. One of ordinary skill in the art, with the benefit of this disclosure, will also be able to identify a suitable amount of polyol or polyamine to include in the compositions of the present invention for a particular application.
The Chain-Extender/Crosslinker Component
Examples of suitable crosslinkers include, but are not limited to, trimethylolpropane, glycerine, a trifunctional castor-oil-based polyol that is commercially available from CasChem, Inc., under the tradename CASPO® 1962, a quadrifunctional castor-oil-based polyol that is commercially available from CasChem, Inc., under the tradename CASPOL® 5004, and the like.
Examples of suitable chain-extenders include, but are not limited to, 1,4-butanediol, 1,6-hexanediol, diethylene glycol, and the like.
In certain exemplary embodiments wherein a composition of the present invention comprises a chain-extender or crosslinker, the chain-extender or crosslinker may be present in the composition in an amount in the range of about 50% to about 80% by weight of the isocyanate prepolymer. In certain exemplary embodiments, the chain-extender or crosslinker may be present in the composition in an amount in the range of about 60% to about 70% by weight of the isocyanate prepolymer.
Water
Optionally, the compositions of the present invention also may comprise water. The water may be added to the compositions of the present invention in a variety of ways. For example, formulating the compositions of the present invention in an atmosphere that contains moisture may cause water to become incorporated into the compositions. As another example, an operator may add a desired amount of water by injecting it into the compositions of the present invention during their formulation. Because water is known to react with isocyanate to produce carbon dioxide, the presence of water in certain exemplary compositions of the present invention that also comprise an isocyanate may generate a sufficient amount of carbon dioxide to impart a degree of porosity to the compositions of the present invention. In certain exemplary embodiments of the present invention, water is present in the composition in an amount sufficient to provide a desired porosity. In certain exemplary embodiments, water may be present in the compositions of the present invention in an amount in the range of from about 0.1% to about 1% by weight of the composition. One of ordinary skill in the art, with the benefit of this disclosure, will be able to identify an appropriate amount of water to include in the compositions of the present invention for a particular application.
The Optional Filler Material Component
A broad variety of filler materials may be suitable for use in the compositions of the present invention, including, but not limited to, calcium carbonate, bone (e.g., demineralized bone, allograft bone, and/or autogenous bone), calcium phosphate, calcium pyrophosphate, hydroxyapatite, poly methyl methacrylate, glass-ionomer, calcium sulfate, tricalcium phosphate (e.g., beta tricalcium phosphate), or any combination thereof, or the like. In certain exemplary embodiments, the filler material may be chosen so as to impart a desired degree of porosity in the compositions of the present invention. Generally, the greater the adhesion between the filler material and other components in the composition, the lower the composition's porosity; and vice versa. Generally, the filler material will be present in the compositions of the present invention in an amount sufficient to modify the composition's mechanical properties (e.g., Young's Modulus of Elasticity, flexural strength, and the like). In certain exemplary embodiments, the filler material is present in the compositions of the present invention in an amount in the range of from about 0.01% to about 55% by weight. In certain exemplary embodiments, the filler material may be present in the compositions of the present invention in an amount in the range of from about 25% to about 35% by weight. In certain exemplary embodiments, the filler material comprises calcium carbonate. In certain of these embodiments, the filler material comprises calcium carbonate in an amount sufficient to provide free calcium to a body of a mammal and enhance osteoconductivity. In certain exemplary embodiments, the filler material comprises at least about 98% pure calcium carbonate by weight of the filler material. In certain exemplary embodiments, the calcium carbonate is implantable grade calcium carbonate. In certain exemplary embodiments, the calcium carbonate has a particle size distribution that is capable of enhancing resorption of calcium within the body of a mammal. In certain exemplary embodiments, the particle size distribution further enhances bone remodeling. An example of a suitable filler material is poly ether ether ketone (often referred to as “PEEK”). Another example of a suitable filler material is commercially available from Cortek, Inc., of Dedham, Mass., under the trade name “Replace™.”
The Optional Catalyst Component
Optionally, certain exemplary embodiments of the compositions of the present invention further may comprise at least one catalyst. In certain exemplary embodiments of the present invention where a catalyst is used, the catalyst may be used by adding the catalyst to a polyol that may be mixed into the compositions of the present invention. The inclusion of the catalyst in the compositions and methods of the present invention may permit an operator to control, inter alia, certain polymerization reactions that occur during the formulation of the compositions of the present invention (e.g., a polymerization reaction between a polyol and a isocyanate prepolymer that comprises an isocyanate). In certain exemplary embodiments of the present invention, at least one catalyst is present in the compositions of the present invention in an amount sufficient to ensure that such polymerization reactions have proceeded to completion for the compositions of the present invention are placed within the body of a mammal. This may ensure, inter alia, that the isocyanate that may be present within the compositions of the present invention at the time of their placement within the body of a mammal is not free to react while within the body.
A broad variety of catalysts may be used, including, but not limited to, a tertiary amine, and organometallic compounds such as, for example, stannous octoate, and dibutyl tin dilaurate. In certain exemplary embodiments wherein the catalyst is an organometallic catalyst, the presence of the organometallic catalyst in the compositions of the present invention will not adversely impact the radiotransparency or radiopacity of the composition. An example of a suitable tertiary amine is commercially available from Air Products, Inc., under the trade name DABCO 33LV. An example of a suitable source of dibutyl tin dilaurate is commercially available from Air Products, Inc., under the trade name DABCO T12. A tertiary amine may be preferred in, inter alia, certain exemplary embodiments of the present invention wherein a catalyst is to be used during preparation of a composition of the present invention that may be placed within a body of a mammal while in liquid form.
In certain exemplary embodiments of the compositions of the present invention that comprise a catalyst, the catalyst will remain in the composition after its formulation and curing, e.g., as a monomer that is present in the matrix of the cured composition. In certain exemplary embodiments of the present invention where a catalyst is added to a polyol that may be mixed into the compositions of the present invention, the catalyst may be present in the polyol in an amount in the range of from about 0.05% to about 0.5% by weight of the polyol. In certain exemplary embodiments, the catalyst may be present in the polyol in an amount in the range of from about 0.15% to about 0.4% by weight of the polyol. One of ordinary skill in the art, with the benefit of this disclosure, will be able to identify a suitable at least one catalyst, and a suitable amount for inclusion in the compositions of the present invention, for a particular application.
The Optional Surfactant Component
Optionally, certain exemplary embodiments of the compositions of the present invention further may comprise at least one surfactant. The inclusion of the at least one surfactant in the compositions and methods of the present invention may, inter alia, impart a desired degree of porosity to the composition, and may permit an operator to control, inter alia, the size and/or the shape of pores within the composition. A broad variety of surfactants may be suitable for inclusion in the compositions of the present invention. Commercially available examples of suitable surfactants include, but are not limited to, DABCO DC 193 and DABCO DC 5241, both of which are commercially available from Air Products, Inc., as well as copolymerizable surfactants with phosphate ester functionality that are available under the tradenames “MAXEMUL 6106” and “MAXEMUL 6112” from Uniqema, and silicone surfactants that are commercially available from Struktol Corporation. One of ordinary skill in the art, with the benefit of this disclosure, will be able to identify an appropriate amount of surfactant to include in the compositions of the present invention for a particular application.
The Optional Radiotransparent/Radiopaque Component
Optionally, the compositions of the present invention also may comprise at least one radiotransparent substance or at least one radiopaque substance. The inclusion of such radiotransparent or radiopaque substances in the compositions of the present invention may be useful, inter alia, when the composition has been placed in contact with, or in the vicinity of, a bone of a mammal, and a physician subsequently seeks to determine the condition or location of the composition or the bone through the use of, inter alia, X-ray photographs. When an exemplary embodiment of the compositions of the present invention includes a radiotransparent substance (e.g., air, nitrogen gas, carbon dioxide, oxygen gas, or the like), the attenuation of the composition in the X-ray decreases. Consequently, a physician more readily may visualize the extent to which the underlying damaged bone has been repaired by the bone growth facilitated by treatment with the compositions of the present invention. Similarly, when an exemplary embodiment of the compositions of the present invention includes a radiopaque substance (e.g., insoluble zirconium oxide, a radioactive tracer, a Barium Sulfate contrast media, a gadolinium contrast media, a water-soluble Iodinated contrast media, an oily Iodinated contrast media, an implantable metal (e.g., a chip, flake, or the like comprising a metal such as titanium, cobalt, or chromium), or the like), the attenuation of the composition in the X-ray increases. Consequently, the physician more readily may visualize the adequacy of the coverage of the compositions of the present invention on the damaged bone. Moreover, the at least one radiotransparent substance and/or the at least one radiopaque substance may be non-reactive substances, such that they may be included within the compositions of the present invention at any time during the process of manufacturing the compositions. Generally, the at least one radiotransparent substance and/or the at least one radiopaque substance may be present in the compositions of the present invention in an amount in the range of from about 5% to about 30% by weight of the composition. In certain exemplary embodiments, the at least one radiotransparent substance and/or the at least one radiopaque substance may be present in the compositions of the present invention in an amount in the range of from about 10% to about 20% by weight of the composition. Examples of commercially available radiopaque substances include “LIPIODOL,” “HYPAQUE,” and “OMNIPAQUE.”
Other Optional Additives
Optionally, the compositions of the present invention further may comprise at least one protein. The at least one protein may be used to control the rate of bone regrowth, e.g., the type of protein may be selected, such that the protein increases or decreases the rate of bone growth relative to when the at least one protein is not present in the composition. For example, when a physician wishes to closely monitor the bone growth produced by treatment with the compositions of the present invention, the physician may opt to include within the composition at least one protein that tends to decrease the rate of bone growth relative to when the at least one protein is not present in the composition. Moreover, the at least one protein may be non-reactive, such that the at least one protein may be included in the compositions of the present invention at any time during the manufacture of the composition. Examples of suitable proteins include, but are not limited to, OPI (commercially available from Stryker Homedica), or any recombinant bone morphogenic protein. Further, at least one steroid-based intracellular messenger may be included in the compositions of the present invention, inter alia, to modulate the rate of bone growth.
Methods of Use
Referring now to
While not willing to be bound by a theory, it is believed that cyclic adenosine monophosphate (cyclic AMP) regulated lipases within the body of a mammal may facilitate the metabolism of the compositions of the present invention after placement of these compositions in contact with, or in the vicinity of, a bone of the mammal. The compositions of the present invention that comprise a polyester urethane and that are placed in contact with, or in the vicinity of, a bone of a mammal generally comprise at least one ester group (e.g., a glyceride group) within their chemical structure. Water that naturally is present within the mammal then may react with the at least one ester group so as to be converted into glycerol, fatty acids, and the conversion of adenosine diphosphate to adenosine triphosphate. While not willing to be bound by theory, it is believed that adenosine triphosphate units within the mammal may support various anabolic activities that may result in the formation of bone.
When a composition of the present invention is placed in contact with, or in the vicinity of, a bone of a mammal, the composition may be a liquid, and may conform to a shape of the bone. The composition may transform into a solid after such placement within the mammal. In another embodiment of the present invention, method 1600 also may comprise the step of increasing or decreasing a temperature of the composition before or after the placement of the composition within the body of the mammal. Increasing the temperature of a composition of the present invention may decrease an amount of time which it takes for the particular composition to transform or cure from a liquid to a solid. Analogously, decreasing the temperature of a composition of the present invention may increase an amount of time which it takes for such transformation or curing of the composition to occur.
Referring now to
According to an exemplary embodiment of the present invention, a kit that is useful in promoting bone growth comprises a first container that further comprises a dispensing means and a first compound, and a second container that further comprises a dispensing means and a second compound. In certain exemplary embodiments, the first container and the second container each may be a syringe. In certain exemplary embodiments, the first container and the second container may be packaged together in a moisture resistant package, such that the first compound and the second compound may be maintained in the same package, but separated from each other. The first compound and the second compound may be readily combined to form a composition of the present invention at a desired time before the performance of a medical procedure by dispensing the first compound and the second compound from their respective containers. In certain exemplary embodiments, the first compound may comprise a naturally occurring polyol. In certain of such exemplary embodiments, the second compound may comprise an isocyanate prepolymer comprising isocyanate. In certain exemplary embodiments, the first compound may comprise a biocompatible, synthetic polyol. In certain of such exemplary embodiments, the second compound may comprise isocyanate. In certain exemplary embodiments, the first compound may comprise a polyol comprising a naturally occurring polyol and a biocompatible synthetic polyol. In certain of such exemplary embodiments, the second compound may comprise isocyanate.
To facilitate a better understanding of the present invention, the following examples of some exemplary embodiments are given. In no way should such examples be read to limit, or to define, the scope of the invention.
A sample composition of the present invention was prepared by mixing RUBINATE 9433 with CASPOL® 5001 in a 4:1 equivalent ratio to form an isocyanate prepolymer. Calcium carbonate then was added to the isocyanate prepolymer in an amount of 72.4% by weight of the isocyanate prepolymer, and mixed for one minute to form a paste. CASPO® 1962 (containing DABCO 33LV in the amount of 0.20% by weight of the CASPOL® 1962) then was added to the isocyanate prepolymer and calcium carbonate mixture in the amount of 68.65% by weight of the isocyanate prepolymer, and mixed for 2 minutes in a plastic beaker with a spatula. To prepare test samples for hardness testing, a portion of the above mixture was poured into a cylindrical cavity (dimensions 1 in2 by ½ inch) in a Teflon-coated mold, and visually observed for evidence of gelation. Once gelation was detected, the mold was covered with a Teflon-coated plate and placed into a Carver press under slight pressure. Hardness testing was performed according to ASTM 2240.
To prepare test samples for flexural property testing, a portion of the above mixture was poured at its gel time into a cavity of a rectangular aluminum mold (1.5 mm thick) that was coated with a Teflon sheet. Once gelation was detected, the mold was covered with a Teflon-coated plate, placed into a Carver press, and compression molded at about 20,000 psi. The test samples were cut by a saw. Flexural properties were tested according to ASTM D 790 by using an Instron Tester Model 1122 and Merlin software.
The results of the testing are set forth in the table below.
The above example demonstrates, inter alia, that the compositions of the present invention have mechanical properties that may be suitable for bone cements.
Sample Composition No. 2, a sample composition of the present invention, was prepared by mixing ISONATE 50 OP with CASPOL® 5001 in a 4:1 equivalent ratio to form an isocyanate prepolymer. Calcium carbonate then was added to the isocyanate prepolymer in an amount of 72.4% by weight of the isocyanate prepolymer, and mixed for one minute to form a paste. CASPOL® 1962 (containing DABCO 33LV in the amount of 0.35% by weight of the CASPOL® 1962) then was added to the isocyanate prepolymer in the amount of 68.5% by weight of the isocyanate prepolymer, and mixed for 2 minutes in a plastic beaker with a spatula.
To prepare test samples for hardness testing, a portion of the above mixture was poured into a cylindrical cavity (dimensions 1 in2 by {fraction (1/2)} inch) in a Teflon-coated mold, and visually observed for evidence of gelation. Once gelation was detected, the mold was covered with a Teflon-coated plate and placed into a Carver press under slight pressure. Hardness testing was performed according to ASTM 2240.
To prepare test samples for flexural property testing, a portion of the above mixture was poured at its gel time into a cavity of a rectangular aluminum mold (1.5 mm thick) that was coated with a Teflon sheet. Once gelation was detected, the mold was covered with a Teflon-coated plate, placed into a Carver press, and compression molded at about 20,000 psi. The test samples were cut by a saw. Flexural properties were tested according to ASTM D 790 by using an Instron Tester Model 1122 and Merlin software.
The results of the testing are set forth in the table below.
The above example demonstrates, inter alia, that the compositions of the present invention have mechanical properties that may be suitable for bone cements.
While the invention has been described in connection with preferred embodiments, it will be understood by those of ordinary skill in the art that other variations and modifications of the preferred embodiments described above may be made without departing from the scope of the invention. Other embodiments will be apparent to those of ordinary skill in the art from a consideration of the specification or practice of the invention disclosed herein. It is intended that the specification and the described examples are considered as exemplary only, with the true scope and spirit of the invention indicated by the following claims.
The present application is a continuation-in-part application of U.S. patent application Ser. No. 10/395,001, entitled “Methods of Performing Medical Procedures Which Promote Bone Growth, Compositions Which Promote Bone Growth, and Methods of Making Such Compositions,” which was filed on Mar. 24, 2003, and claims priority from U.S. Provisional Patent Application No. 60/366,335, entitled “Three Part Biodegradable Osteoconductive Polymer and Dispensing System,” and filed on Mar. 22, 2002, the disclosures of which are incorporated herein by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60366335 | Mar 2002 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10395001 | Mar 2003 | US |
| Child | 10808188 | Mar 2004 | US |
