Patent Grant
8657952
The invention relates to bone graft substitute compositions.
Compositions containing calcium sulfate can be used as filler for voids or defects defined by bone. In some embodiments, the compositions can promote bone growth.
The invention relates to bone graft substitute compositions. In one aspect, the invention features a composition including calcium sulfate, such as calcium sulfate hemihydrate, a binder, an accelerant, and a mixing solution.
In another aspect, the invention features a method including providing a mixture having calcium sulfate, such as calcium sulfate hemihydrate, a binder, and an accelerant, and contacting the mixture with a mixing solution.
Embodiments of the invention may include one or more of the following features. The calcium sulfate includes calcium sulfate hemihydrate. The binder includes stearic acid, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose (HPC), and/or hyaluronic acid. The accelerant includes calcium sulfate dihydrate, and/or an ionic salt such as potassium sulfate or sodium sulfate. The mixing solution includes a saline solution.
Embodiments may have one or more of the following advantages. The composition is capable of setting or hardening in a relatively short time. In embodiments, the composition can harden to about 4 MPa in about 5-10 minutes. The composition is capable of setting or hardening in vivo. The composition can be injected through a needle, e.g., an 11-13 gauge needle up to about 10 cm long.
Other features and advantages of the invention will be apparent from the description of the preferred embodiments thereof and from the claims.
A bone graft substitute composition includes calcium sulfate, such as calcium sulfate hemihydrate (CaSO4·½ H2O), a binder, such as stearic acid, a material that accelerates hardening of the composition (“an accelerant”), and a mixing solution. In some embodiments, the calcium sulfate, the binder, and the accelerant are provided as a mixture of powders to which the mixing solution is added to form the composition. The composition can be delivered to a target site by injecting the composition through a needle. The composition can harden in vivo, e.g., such that the hardened composition is capable of supporting orthopedic hardware.
The calcium sulfate is preferably calcium sulfate hemihydrate, CaSO4·½ H2O. Without wishing to be bound by theory, it is believed that during use, e.g., after mixing the powder mixture with the mixing solution, the calcium sulfate hemihydrate is converted, e.g., changes crystalline form, into calcium sulfate dihydrate (CaSO4·½ H2O), which hardens the composition. Calcium sulfate dihydrate is capable of being sorbed by the body. In some embodiments, the mixture of powders includes greater than about 90 weight percent of calcium sulfate, e.g., calcium sulfate hemihydrate. The mixture may include greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 weight percent of calcium sulfate hemihydrate; and/or less than 100, 99, 98, 97, 96, 95, 94, 93, 92, or 91 weight percent of calcium sulfate hemihydrate. Methods of making a calcium sulfate hemihydrate is described in U.S. Pat. Nos. 5,614,206; 5,807,567; and 6,030,636, all hereby incorporated by reference in their entirety.
Without wishing to be bound by theory, it is believed that the binder provides the composition with a consistency that helps the composition to flow, e.g., to be injectable. It is believed that, for example, stearic acid may also make the composition relatively hydrophobic, for example, which may lubricate the inner wall of a syringe and enhance flow of the composition. In some embodiments, the mixture of powders includes between about 1 and 2, e.g., about 1.5-2.0, weight percent of the binder. The mixture may include greater than 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 weight percent of the binder; and/or less than 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, or 1.1 weight percent of the binder. Examples of binders include stearic acid, hydroxypropylmethylcellulose (HPMC), hydroxymethylcellulose (HPC), and hyaluronic acid. Mixtures of two or more binders may be used.
Without wishing to be bound by theory, the accelerant is believed to enhance, e.g., accelerate, the conversion of calcium sulfate hemihydrate to calcium sulfate dihydrate. In particular, it is believed that particles of the accelerant act as crystallization nucleation sites for the conversion of calcium sulfate hemihydrate to calcium sulfate dihydrate. Examples of accelerants include calcium sulfate dihydrate, potassium sulfate, or sodium sulfate. Other examples include ionic salts. A preferred accelerant is calcium sulfate dihydrate crystals (available from U.S. Gypsum) coated with sucrose (available from VWR Scientific Products). A process of stabilizing the dihydrate crystals by coating with sucrose is described in U.S. Pat. No. 3,573,947, hereby incorporated by reference in its entirety. In some embodiments, the mixture of powders includes between about 0.1 and 0.5 weight percent of the accelerant. The mixture may include greater than 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, or 0.45 weight percent of the accelerant; and/or less than 0.50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, or 0.15 weight percent of the accelerant. Mixtures of two or more accelerants can be used.
The mixing solution is generally selected to provide the composition with a desired consistency and hardening time. Examples of a mixing solution include water, e.g., sterile water, solutions containing inorganic salts, or cationic surface-active agents including sodium chloride, saline, e.g., phosphate buffered saline, potassium chloride, sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium acetate, and sodium acetate. A specific example of a mixing solution is 0.9% NaCl saline solution (available from Baxter). In some embodiments, for a 25 g mixture of powders, preferably about 8-10 cc of mixing solution is added to the mixture to form a composition. Mixtures of two or more mixing solutions can be used.
The mixing solution can further include, for example, bone marrow aspirate, platelet concentrate, blood, pharmaceutical additives in solution, or combinations of these materials. Examples of additives are medicaments or pesticides. Examples of medicaments are antibiotics, chemotherapeutic agents, growth factors, and analgesics. Examples of antibiotics are tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycocides such as tobramycin and gentamicin. Examples of chemotherapeutic agents are cis-platinum, ifosfamide, methotrexate, and doxorubicin hydrochloride (Adriamycin®). Examples of growth factors are transforming growth factor beta (TGF-Beta), bone morphogenic protein (BMP), basic fiberblast growth factor, platelet-derived growth factor, and other polypeptide growth factors. Examples of analgesics are anesthetics such as lidocaine hydrochloride (Xylocaine®), bipivacaine hydrochloride (Marcaine®), and non-steroidal anti-inflammatory drugs such as ketorolac tromethamine (Toradol®). Certain mixing solutions can affect, e.g., delay, the hardening properties of the composition.
The composition can be formed by providing the mixture of powders (e.g., calcium sulfate hemihydrate, stearic acid, and calcium sulfate dihydrate) and contacting, e.g., mixing, the mixture with a mixing solution (e.g., NaCl saline) to form the composition. The composition may be a conforming material having a paste-like consistency, e.g., like Plaster of Paris. The material can be injected into a target site, for example, to fill into cracks or voids. In some embodiments, the material can be injected through an 11 to 13-gauge needle up to, for example, 10 cm long. The material is capable of setting to a hardness comparable to or greater than bone within about 5-10 minutes, e.g., greater than 5, 6, 7, 8, or 9 minutes, and/or less than 10, 9, 8, 7, or 6 minutes. The material can have a Vicat set time of about 5-10 minutes, e.g., 5-6 minutes. The material is capable of hardening to about >4 MPa.
The hardened composition can be used for intra-operative support of hardware, such as orthopedic hardware, e.g., bone plates, distal radius hardware, and hardware used for tibial plateau fractures.
In some embodiments, the composition further includes a bioactive agent. Examples of bioactive agents include demineralized bone matrix, growth factors, hyaluronic acid, bone morphogenic proteins, bone autograft, and bone marrow, etc. The composition may include sodium bicarbonate. For example, the composition may include 0.1-2% sodium bicarbonate by weight to provide a porous structure in the resultant composition.
Alternatively or in addition, the bone graft substitute composition may include one or more additives such as an antiviral agent, an antimicrobial agent, an antibiotic agent, an amino acid, a peptide, a vitamin, an inorganic element, a protein synthesis co-factor, a hormone, an endocrine tissue, a synthesizer, an enzyme, a polymer cell scaffolding agent with parenchymal cells, an angiogenic drug, demineralized bone powder, a collagen lattice, an antigenic agent, a cytoskeletal agent, mesenchymal stem cells, a bone digester, an antitumor agent, a cellular attractant, fibronectin, a growth hormone, a cellular attachment agent, an immunosuppressant, a nucleic acid, a surface active agent, calcium phosphate materials, such as hydroxyapatite or tricalcium phosphate, a penetration enhancer, a bone allograft, cancellous bone chips (an osteoconductive substrate), and chunks, shards, and/or pellets of calcium sulfate.
The bone graft substitute composition can also be used as a carrier, for example, by mixing it with other materials, such as, for example, allografts, antibiotics, growth factors, cancellous bone chips, or synthetically derived or naturally derived chips of minerals such as calcium phosphate or calcium carbonate. This can provide the composition with versatility and flexibility by allowing a user to formulate a mixed composition according to a desired application.
The following example is illustrative and not intended to be limiting.
A 25-gram mixture of powders was formed having 98.08 wt % of CaSO4·½ H2O, 1.77 wt % of stearic acid (triple pressed powder, available from VWR Scientific Products), and 0.15 wt % of CaSO4·2 H2O. About 9 cc of mixing solution (0.9% NaCl saline) was added to the mixture of powders, and mixed together to form a composition having a paste-like consistency.
The composition could be injected through a 6 cm long, 11-gauge needle. After about 7 minutes, the composition hardened, e.g., comparable to the hardness of bone. More specifically, the composition hardened to about 8 MPa (8.17 MPa±0.23, n=3) after about twenty minutes; to about 17 MPa (16.54 MPa±1.05, n=8) after about one hour; and to about 35 MPa (34.94 MPa±4.04, n=5) after about 24 hours.
As described above, the composition can also harden in vivo. Following procedures similar to ASTM-F451, cylindrical samples (6 mm diameter, 12 mm high) of the composition were submerged in bovine calf serum to simulate in vivo conditions. The hardness of the samples was measured at different times. After about seven minutes, the composition hardened to about 1 MPa (1.04 MPa±0.29, n=3). After about twenty minutes, the composition hardened to about 4 MPa (3.82 MPa±0.87, n=3). After about one hour, the composition hardened to about 15 MPa (14.94 MPa±0.82, n=8). After about 24 hours, the composition hardened to about 10 MPa (10.59±0.73, n=8).
The amount of mixing solution added to the mixture of powders can affect the time the composition takes to set, i.e., the set time. Increasing the amount of mixing solution can increase the set time. For example, in embodiments, adding more than 12 cc of saline to the above 25-gram mixture may delay hardening to over 30-40 minutes. Decreasing the amount of mixing solution added to the mixture of powders can reduce the set time, but injecting the composition can be relatively difficult. Other embodiments are within the claims.
This application is a continuation of U.S. patent application Ser. No. 10/402,192, filed on Mar. 28, 2003 now U.S. Pat. No. 7,211,266, which claims priority under 35 U.S.C. §119(e) to U.S. Patent Application Ser. No. 60/368,924, filed on Mar. 29, 2002, the entire contents of which are hereby incorporated by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3573947 | Kinkade et al. | Apr 1971 | A |
| 3947285 | Jones et al. | Mar 1976 | A |
| 4430760 | Smestad | Feb 1984 | A |
| 4526619 | Ohi et al. | Jul 1985 | A |
| 4568536 | Kronenthal et al. | Feb 1986 | A |
| 4595713 | St. John | Jun 1986 | A |
| 4596574 | Urist | Jun 1986 | A |
| 4612009 | Drobnik et al. | Sep 1986 | A |
| 4619655 | Hanker et al. | Oct 1986 | A |
| 4650665 | Kronenthal et al. | Mar 1987 | A |
| 4681763 | Nathanson et al. | Jul 1987 | A |
| 4820306 | Gorman et al. | Apr 1989 | A |
| 4880660 | Aasen et al. | Nov 1989 | A |
| 4882149 | Spector | Nov 1989 | A |
| 4892734 | Leonard | Jan 1990 | A |
| 4975526 | Kuberasampath et al. | Dec 1990 | A |
| 4994030 | Glowczewskie, Jr. et al. | Feb 1991 | A |
| 4994264 | Verdon et al. | Feb 1991 | A |
| 5061286 | Lyle | Oct 1991 | A |
| 5073373 | O'Leary et al. | Dec 1991 | A |
| 5147403 | Gitelis | Sep 1992 | A |
| 5162114 | Kuberasampath et al. | Nov 1992 | A |
| 5219897 | Murray | Jun 1993 | A |
| 5236456 | O'Leary et al. | Aug 1993 | A |
| 5236971 | Murray | Aug 1993 | A |
| 5264214 | Rhee et al. | Nov 1993 | A |
| 5284655 | Bogdansky et al. | Feb 1994 | A |
| 5290558 | O'Leary et al. | Mar 1994 | A |
| 5298254 | Prewett et al. | Mar 1994 | A |
| 5306304 | Gendler | Apr 1994 | A |
| 5314476 | Prewett et al. | May 1994 | A |
| 5320844 | Liu | Jun 1994 | A |
| 5336699 | Cooke et al. | Aug 1994 | A |
| 5356629 | Sander et al. | Oct 1994 | A |
| 5366507 | Sottosanti | Nov 1994 | A |
| 5385887 | Yim et al. | Jan 1995 | A |
| 5405390 | O'Leary et al. | Apr 1995 | A |
| 5417975 | Lussi et al. | May 1995 | A |
| 5425769 | Snyders et al. | Jun 1995 | A |
| 5439684 | Prewett et al. | Aug 1995 | A |
| 5462722 | Liu et al. | Oct 1995 | A |
| 5482551 | Morris et al. | Jan 1996 | A |
| 5484601 | O'Leary et al. | Jan 1996 | A |
| 5507813 | Dowd et al. | Apr 1996 | A |
| 5510396 | Prewett et al. | Apr 1996 | A |
| 5512610 | Lin | Apr 1996 | A |
| 5531791 | Wolfinbarger, Jr. | Jul 1996 | A |
| 5569308 | Sottosanti | Oct 1996 | A |
| 5573771 | Geistich et al. | Nov 1996 | A |
| 5578662 | Bennett et al. | Nov 1996 | A |
| 5614206 | Randolph et al. | Mar 1997 | A |
| 5618549 | Patat et al. | Apr 1997 | A |
| 5676146 | Scarborough | Oct 1997 | A |
| 5681873 | Norton et al. | Oct 1997 | A |
| 5697981 | Ison et al. | Dec 1997 | A |
| 5700289 | Breitbart et al. | Dec 1997 | A |
| 5707962 | Chen et al. | Jan 1998 | A |
| 5727945 | Dannenbaum | Mar 1998 | A |
| 5756127 | Grisoni et al. | May 1998 | A |
| 5763416 | Bonadio et al. | Jun 1998 | A |
| 5766618 | Laurencin et al. | Jun 1998 | A |
| 5769897 | Harte | Jun 1998 | A |
| 5788976 | Bradford | Aug 1998 | A |
| 5807567 | Randolph et al. | Sep 1998 | A |
| 5824087 | Aspden et al. | Oct 1998 | A |
| 5830493 | Yokota et al. | Nov 1998 | A |
| 5861445 | Xu et al. | Jan 1999 | A |
| 5899939 | Boyce et al. | May 1999 | A |
| 5910315 | Stevenson et al. | Jun 1999 | A |
| 5948426 | Jefferies | Sep 1999 | A |
| 5948428 | Lee et al. | Sep 1999 | A |
| 5964805 | Stone | Oct 1999 | A |
| 5972368 | McKay | Oct 1999 | A |
| 5981828 | Nelson et al. | Nov 1999 | A |
| 6030635 | Gertzman et al. | Feb 2000 | A |
| 6030636 | Randolph et al. | Feb 2000 | A |
| 6037519 | McKay | Mar 2000 | A |
| 6051247 | Hench et al. | Apr 2000 | A |
| 6056970 | Greenawalt et al. | May 2000 | A |
| 6071530 | Polson et al. | Jun 2000 | A |
| 6083522 | Chu et al. | Jul 2000 | A |
| 6118043 | Nies et al. | Sep 2000 | A |
| 6171388 | Jobbins | Jan 2001 | B1 |
| 6224635 | Ricci et al. | May 2001 | B1 |
| 6478825 | Winterbottom et al. | Nov 2002 | B1 |
| 6652887 | Richelsoph et al. | Nov 2003 | B1 |
| 6998128 | Haggard et al. | Feb 2006 | B2 |
| 7291179 | Miller et al. | Nov 2007 | B2 |
| 7371408 | Petersen et al. | May 2008 | B1 |
| 7371409 | Petersen et al. | May 2008 | B2 |
| 7371410 | Petersen et al. | May 2008 | B2 |
| 7972630 | Lidgren | Jul 2011 | B2 |
| 20020016636 | Ricci et al. | Feb 2002 | A1 |
| 20020071827 | Petersen et al. | Jun 2002 | A1 |
| 20030096718 | Sugimoto et al. | May 2003 | A1 |
| 20030143258 | Knaack et al. | Jul 2003 | A1 |
| Number | Date | Country |
|---|---|---|
| 196 20 117 | Jul 1997 | DE |
| 2 093 348 | Sep 1982 | GB |
| WO 8904646 | Jun 1989 | WO |
| WO 9639203 | Dec 1996 | WO |
| WO 9840113 | Sep 1998 | WO |
| WO 9915150 | Apr 1999 | WO |
| WO 0074690 | Dec 2000 | WO |
| WO 0205750 | Jan 2002 | WO |
| WO 03024316 | Mar 2003 | WO |
| WO 03030956 | Apr 2003 | WO |
| WO 03045455 | Jun 2003 | WO |
| Entry |
|---|
| Adkisson et al., “Rapid Quantitative bioassay of Osteoinduction”, Journal of Orthopaedic Research, 18:503-511, 2000. |
| “Advances in Biomaterials for Bone Regeneration”, Orthopedics, vol. 26, No. 5/Supplement, May 2003. |
| Betz, M.D., Randall R. “Limitations of Autograft and Allograft: New Synthetic Solutions”, Orthopedics, vol. 25, No. 5, Supplement May 2002. |
| Biomaterials Tutorial, www.btec.cmu.edu/tutorial/biomaterials/biomaterials.htm, Undated. |
| “Bone Graft Substitutes Safe, Effective”, AMA Science News Media Briefings, Dec. 6, 2001. |
| Greenwald et al., “Bone-Graft Substitutes: Facts, Fictions, and Applications”, The Journal of Bone & Joint Surgery, JBJS Org., vol. 83-A, Supplement 2, Part 2, 2001. |
| Grimandi et al., “In vitro evaluation of a New Injectable Calcium Phosphate Material”, J. Biomed. Mater Res., 1998, pp. 660-666, vol. 39, John Wiley & Sons, Inc. |
| Hanker et al., “Setting of Composite Hydroxylaptie/Plaster Implants with Blood for Bone Reconstruction”, Proceedings of the 44th Annual Meeting of the Electron Microscopy Society of America, 1986. |
| Kelly, Ph.D., Evelyn B., “New Frontiers in Bone Grafting”, Orthopaedic Technology Review, vol. 2, No. 9, Oct. 2000. |
| Turner et al.., “Radiographic and Histologic Assessment of Calcium o Sulfate in Experimental Animal Models and Clinical Use as a Resorbable Bone-Graft Substitute, a Bone-Graft Expander, and a Method for Local Antibiotic Delivery”, The Journal of Bone and Joint Surgery, Incorporated, vol. 83-A, Supp. 2, Part 1, 2001. |
| Number | Date | Country | |
|---|---|---|---|
| 20070186819 A1 | Aug 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60368924 | Mar 2002 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10402192 | Mar 2003 | US |
| Child | 11739416 | US |
