医用外科级α-半水硫酸钙的研制及其相关研究
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摘要
临床植骨材料的大量需求推动了人工骨的研究和发展。在众多的无机植骨材料中,α-半水硫酸钙以其可降解性、优良的生物相容性及骨传导性得到了广大临床医生认可。和自体骨复合作为增容剂修复大块骨缺损、促进脊柱融合,与抗生素复合治疗感染性骨不连,作为各种活性因子的控缓释载体是目前研究的热点问题。其广阔应用前景引起了人们的注意,但对其研究还刚刚开始。目前,此种材料我国完全依赖进口,价格昂贵,限制了其在临床的应用。对硫酸钙植骨材料的研究,我国还停留在煅烧硫酸钙阶段。对如何制备出象Osteoset~(?)这样优良人工骨的有效方法还未进行系统研究。而外科级α-半水硫酸钙原料的制备是我们对其展开研究的前提,与此材料的应用和发展至关重要。因此2004年9月我们与沈阳建筑大学材料工程学院合作,展开了医用外科级α-半水硫酸钙的研制及相关研究,为推进α-半水硫酸钙人工骨材料的国产化及深入探索奠定基础。
目的
筛选制备医用外科级α半水硫酸钙的合理处方,并对其理化性质、生物安全性进行评价。
材料与方法
(1)筛选制备α-半水硫酸钙的合理处方:测定制备材料抗压缩强度、标准稠度及孔隙率,运用多因素多水平析因设计法,筛选合理制备条件。(2)理化性质:对优选方案制备的α-半水硫酸钙进行体外降解特点、PH值及Ca~(2+)浓度、固化强度、固化温度、晶体结构、表面特征等方面进行研究,探讨临床应用的可行性。(3)体外生物相容性评价:据ISO10993-5及GB/T 16886-1进行红细胞溶血实验、细胞毒性实验、细胞黏附和生长形态观察、热原实验、皮内注射实验、肌肉内植入实验。(4)骨内植入实验:将α-半水硫酸钙和Osteoset~(?)片分别植入兔股骨髁骨缺损内,进行大体观察、普通X线、骨密度测定、组织学观察、免疫荧光标记及生物力学测试,研究两种人工骨骨肉降
AbstractThe demand of bone grafts for bone defects promotes the development of synthetic bone materials. Among many inorganic bone substitutes, a-calcium sulfate hemihydrate was appreciated by many investigaters on account of its degradation with nearer new bone ingrowth speed, excellent biocompatibility, bone conduction. How to combinie a-calcium sulfate hemihydrate with autogenous bone for restoration of big bone defect, to combine it with antibiotics for bone infections, and to carry all kinds of biological agents had been concerned recently. But it beginned not for a long time. But all surgical grade calcium sulfate materials were imported completely overseas and their prices were very high presently. So in 2004,9, we started to collaborate with Materials and Engineering Institute of Shenyang Architecture College, preparing for Surgical grade a-calcium sulfate hemihydrate.PurposeTo find out a proper formula for the Surgical grade a-hemihydrate calcium sulfate and investigate its physico-chemical property and biocompatibility.Materials and methods(1)Preparation methods: Using method of multi-factor and multi-level factorial design, we evaluated the compressive strength, ratio of gypsum to water and interval porosity, to find out an ideal formula of a- hemihydrate calcium sulfate. (2)Physico-chemical property: Study in-vitro resorption, PH, Ca~(2+), compressive strength, temperature, X-ray disffraction and surface characteristic of CCaS. (3)In-vitro biocompatibility: According to ISO 10993-5 and GB/T 16886-1 standards, we performed haemolysis tests, cytotoxicity test by MTT methods, cell adherence to materials, pyrogenic tests, allergic tests, and implants into muscle. (4)Osteogenous experiments: We implanted CCaS cylinders and Osteoset~(?) pellets into bone defect in the distal femur of rabbits. Using general observations, X-ray, bone density measurements, histological observation, immunofluorescence labeling and mechanical experiments, we investigated in-vivo degradation property of two kinds of synthetic bone and the effects of them on bone ingrowths of bone defects.
Results(1) Preparation methods: Citrated hemi-hydrate calcium sulfate (CCaS), which was made using vapor-heat methods, complicateted salt solutions, high temperature and pressure for 6 hours, had more ratio of gypsum to water, less internal porosity and higher compressive strength. (2) Physio-chemical property: CCaS had uniform crystalline structure, high compressive strength, and a relatively slow resorption speed compared with Osteosef pellets. It could make environments of higher calcium around synthetic bone, but does not change local PH. It could in situ harden and produce less heats. 20 minutes after setting, compressive strength of CCaS can exceed that of cancellous bone. (3) Biocompatibility: The rate of haemolysis was 0.34 percent. Materials had no toxicity to mesenchymal cell proliferaions. Mesenchymal cells could adherece to and proliferate on the surface of materials. The body temperature had no significant changes in pyrogenic test. No erythema, papule and nodule happened in the test of intradermal injection. 6 weeks after implanted into muscles, it was absorbed completely. Throughout its absorbtion, fiber cyst around synthetic bone formed. Inflammatory response and foreign body response was not observed in surrounding tissues. Therefore, CCaS corresponded to the demands of medical biomaterials.(4) Osteogenous experiments: CCaS and Osteoset? restored bone defects completely. Inflammatory and foreign body response were not observed. There were no difference in bone density, compressive strength, osteogenous quantification between two synthetic bones. But degradation speed of CCaS was slightly slower than that of Osteoser9.Conclusion1. An ideal formula for a-hemihydrate calcium sulfate has been achieved. We call it CCaS.2. CCaS is very appropriate for restoration of non-structured confined bone defect, and carrier of antibiotics and biological factor.3. Proved by in-vitro and in-vivo tests that CCaS has a good biocompatibility.4. Proved by osteogenous study that both CCaS and Osteoset9 are ideal synthetic bones. However resorption speed of CCaS is less slowly than Osteoset*.
目的
筛选制备医用外科级α半水硫酸钙的合理处方,并对其理化性质、生物安全性进行评价。
材料与方法
(1)筛选制备α-半水硫酸钙的合理处方:测定制备材料抗压缩强度、标准稠度及孔隙率,运用多因素多水平析因设计法,筛选合理制备条件。(2)理化性质:对优选方案制备的α-半水硫酸钙进行体外降解特点、PH值及Ca~(2+)浓度、固化强度、固化温度、晶体结构、表面特征等方面进行研究,探讨临床应用的可行性。(3)体外生物相容性评价:据ISO10993-5及GB/T 16886-1进行红细胞溶血实验、细胞毒性实验、细胞黏附和生长形态观察、热原实验、皮内注射实验、肌肉内植入实验。(4)骨内植入实验:将α-半水硫酸钙和Osteoset~(?)片分别植入兔股骨髁骨缺损内,进行大体观察、普通X线、骨密度测定、组织学观察、免疫荧光标记及生物力学测试,研究两种人工骨骨肉降
AbstractThe demand of bone grafts for bone defects promotes the development of synthetic bone materials. Among many inorganic bone substitutes, a-calcium sulfate hemihydrate was appreciated by many investigaters on account of its degradation with nearer new bone ingrowth speed, excellent biocompatibility, bone conduction. How to combinie a-calcium sulfate hemihydrate with autogenous bone for restoration of big bone defect, to combine it with antibiotics for bone infections, and to carry all kinds of biological agents had been concerned recently. But it beginned not for a long time. But all surgical grade calcium sulfate materials were imported completely overseas and their prices were very high presently. So in 2004,9, we started to collaborate with Materials and Engineering Institute of Shenyang Architecture College, preparing for Surgical grade a-calcium sulfate hemihydrate.PurposeTo find out a proper formula for the Surgical grade a-hemihydrate calcium sulfate and investigate its physico-chemical property and biocompatibility.Materials and methods(1)Preparation methods: Using method of multi-factor and multi-level factorial design, we evaluated the compressive strength, ratio of gypsum to water and interval porosity, to find out an ideal formula of a- hemihydrate calcium sulfate. (2)Physico-chemical property: Study in-vitro resorption, PH, Ca~(2+), compressive strength, temperature, X-ray disffraction and surface characteristic of CCaS. (3)In-vitro biocompatibility: According to ISO 10993-5 and GB/T 16886-1 standards, we performed haemolysis tests, cytotoxicity test by MTT methods, cell adherence to materials, pyrogenic tests, allergic tests, and implants into muscle. (4)Osteogenous experiments: We implanted CCaS cylinders and Osteoset~(?) pellets into bone defect in the distal femur of rabbits. Using general observations, X-ray, bone density measurements, histological observation, immunofluorescence labeling and mechanical experiments, we investigated in-vivo degradation property of two kinds of synthetic bone and the effects of them on bone ingrowths of bone defects.
Results(1) Preparation methods: Citrated hemi-hydrate calcium sulfate (CCaS), which was made using vapor-heat methods, complicateted salt solutions, high temperature and pressure for 6 hours, had more ratio of gypsum to water, less internal porosity and higher compressive strength. (2) Physio-chemical property: CCaS had uniform crystalline structure, high compressive strength, and a relatively slow resorption speed compared with Osteosef pellets. It could make environments of higher calcium around synthetic bone, but does not change local PH. It could in situ harden and produce less heats. 20 minutes after setting, compressive strength of CCaS can exceed that of cancellous bone. (3) Biocompatibility: The rate of haemolysis was 0.34 percent. Materials had no toxicity to mesenchymal cell proliferaions. Mesenchymal cells could adherece to and proliferate on the surface of materials. The body temperature had no significant changes in pyrogenic test. No erythema, papule and nodule happened in the test of intradermal injection. 6 weeks after implanted into muscles, it was absorbed completely. Throughout its absorbtion, fiber cyst around synthetic bone formed. Inflammatory response and foreign body response was not observed in surrounding tissues. Therefore, CCaS corresponded to the demands of medical biomaterials.(4) Osteogenous experiments: CCaS and Osteoset? restored bone defects completely. Inflammatory and foreign body response were not observed. There were no difference in bone density, compressive strength, osteogenous quantification between two synthetic bones. But degradation speed of CCaS was slightly slower than that of Osteoser9.Conclusion1. An ideal formula for a-hemihydrate calcium sulfate has been achieved. We call it CCaS.2. CCaS is very appropriate for restoration of non-structured confined bone defect, and carrier of antibiotics and biological factor.3. Proved by in-vitro and in-vivo tests that CCaS has a good biocompatibility.4. Proved by osteogenous study that both CCaS and Osteoset9 are ideal synthetic bones. However resorption speed of CCaS is less slowly than Osteoset*.
引文
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12.注册号 国药管械(进)字 2002 第3461400号(更)[医疗器械产品]美国osteoset人工骨.
13.注册号 国食药监械(进)字2004第3460504号[医疗器械产品]英国医用硫酸钙stimulan.
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17.宋元进,李明,朱晓东,等.Osteoset植骨材料加自体骨移植在脊柱侧凸中的应用.生物骨科材料与临床研究.2005;2(1):21-24.
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2.田丰,成国祥,刘长军,等.骨组织损伤修复生物医用材料的研究进展.医疗卫生装备.2005;(02).
3.罗磊,李声伟,邓楠,等.致密多晶羟基磷灰石微粒人工骨—煅石膏复合材料的定量组织学研究.中国口腔种植学杂志.1996;1(2):83-85-92-114.
4.韩健生.羟基磷灰石微粒-煅石膏复合物临床应用.甘肃中医学院学报.2000;17(2):40-42.
5.胡清潭,苏国礼,张一楚.石膏填补骨缺损.中华外科杂志.1961;(9):654.
6.李柱田,徐莘香.石膏充填骨缺损的研究.中华外科杂志.1961;(9):657.
7.李声伟,骆雷,邓楠,等.致密多晶羟基磷灰石微粒人工骨-煅石膏复合材料(HA-PP)细胞相容性研究.临床口腔医学杂志.1994;10(1):3-5.
8. Dreesmann H. Ueber knochenplombierung. Bietr kin chir. 1892;(9): 804-810.
9. Peltier LF. The use of plaster of paris to fill large defects in bone. Am J Surg. 1959;97(3): 311-315.
10. Peltier LF. The use of plaster of paris to fill defects in bone. Clin orthop. 1961;21: 1-29.
11.肖群,高峰,刘厚玉.添加剂改善普通模型石膏及人造石性能的实验研究.口腔医学纵横杂志.1998;14(1):35-37.
12.注册号 国药管械(进)字 2002 第3461400号(更)[医疗器械产品]美国osteoset人工骨.
13.注册号 国食药监械(进)字2004第3460504号[医疗器械产品]英国医用硫酸钙stimulan.
14. Orthogen Corporation. SurgiPlaster.
15.范存义,汤林祥,吴文革,等.负载妥布霉素的硫酸钙治疗慢性骨髓炎及合并骨缺损的疗效评价.中华创伤骨科杂志.2005;7(10):954-956.
16.何斌,王云华,黎逢峰,等.OsteoSet-骨移植替代物在修复骨缺损中的应用.生物骨科材料与临床研究.2005;2(3):9-10.
17.宋元进,李明,朱晓东,等.Osteoset植骨材料加自体骨移植在脊柱侧凸中的应用.生物骨科材料与临床研究.2005;2(1):21-24.
18.王新伟,赵定麟,陈德玉,等.可调式中空人工椎体治疗脊柱严重粉碎性骨折(附9例报告).骨与关节损伤杂志.2002;17(3):181-183.
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