Absorbable, Self-setting Bone Cement

描述(申请人提供)：自从早期开发聚甲基丙烯酸甲酯骨水泥(PMMA-BC)以来，人们一直在努力开发替代组合物来规避其一些临床缺点，包括(1)单体细胞毒性；(3)无法在组织-水泥界面形成坚固的结合；以及(3)作为一种永久的、不可吸收的植入物，可能会导致感染。PMMA-BC的主要替代品之一是自固化磷酸钙骨水泥(CPC)，这种骨水泥非常脆弱，非常容易骨折。认识到PMMA-BC和CPC的缺点，以及最近可吸收氰基丙烯酸酯组织粘合剂配方的商业化，促使人们追求拟议的计划。它的第一阶段目标是证明开发一种可自固化的、可吸收的、生物活性的氰基丙烯酸酯磷酸盐复合材料作为非可吸收PMMA-BC的首选替代品的可行性。因此，第一阶段计划包括：(1)利用本实验室在自固化、可吸收的氰基丙烯酸酯磷酸盐基复合材料(SCC-P)方面获得的初步结果，制备五个候选体系，并根据与典型PMMA-BC的体外比较评估，选择最有希望的SCC-P；(2)重复使用磷酸盐和硅酸盐混合物的SCC-P体系的研究，以产生另外三个包含磷酸盐和硅酸盐成分(SCC-PS)的候选材料，选择最有希望的SCC-PS，并进行与典型PMMA-BC的体外比较评价；(3)使用所选的两种SCC-P和SCC-PS候选材料来确定它们相对于PMMA-BC对照材料在修复典型兔骨缺损中的体内有效性；(4)用经编可吸收网对所选的SCC-P和SCC-PS候选材料进行加固，并测定其老化前后的体外物理性能；以及(5)分析体外和体内性能数据，并选择进行第二阶段研究的候选材料。第二阶段研究的计划将包括：(1)将选定的SCC-P或SCC-SP系统优化为可吸收的、生物活性的、自固化的骨水泥(ABS-BC)，有无针织网状增强，依赖于作为粘结/缺陷填充材料的体外物理和机械性能，使用或不使用可吸收、网状增强；(2)完成开发、放大、灭菌和包装研究；(3)完成所有工艺的验证研究；(4)开发适合至少三种临床适应症的动物模型，并通过选定的动物模型演示ABS-BC的体内疗效；以及(5)寻找营销合作伙伴来制定ABS-BC的制造和营销计划。公共卫生相关性：开发由无机硅酸盐和/或磷酸盐微粒组成的可吸收、自固化、生物活性的氰基丙烯酸酯复合材料，无论是否带有可吸收针织网状物增强，将为临床社区提供新的生物材料，作为不可吸收的聚甲基丙烯酸甲酯骨水泥的首选替代品，并通过引导骨再生修复或替代颅面部骨缺损。

DESCRIPTION (provided by applicant): Since early development of polymethyl methacrylate bone cement (PMMA-BC), there have been many efforts to develop alternative compositions to circumvent some of its clinical shortcomings, which include (1) monomer cytotoxicity; (3) inability to form strong joint at the tissue-cement interface; and (3) being a permanent, non-absorbable implant, which may induce infection. Among the major alternatives to PMMA-BC is the self-setting calcium phosphate bone cement (CPC), which suffers from being fragile and highly susceptible to fracture. Acknowledging PMMA-BC and CPC shortcomings and recent commercialization of absorbable cyanoacrylate tissue adhesive formulations prompted the pursuit of the proposed program. And its Phase I objective is to demonstrate the feasibility of developing a self-setting absorbable, bioactive, cyanoacrylate phosphate-based composite as a preferred alternative to non-absorbable PMMA-BC. Accordingly, Phase I plans entail (1) using initial results acquired in this laboratory on self-setting, absorbable, cyanoacrylate phosphate-based composites (SCC-P) to prepare five candidate systems and selecting the most promising SCC-P as per a comparative in vitro evaluation against a typical PMMA-BC; (2) repeating the study on SCC-P systems using mixtures of a phosphate and a silicate to produce three additional candidates comprising phosphate and silicate components (SCC-PS), selecting the most promising SCC-PS, and conducting a comparative in vitro evaluation against a typical PMMA-BC; (3) using the two selected SCC-P and SCC-PS candidates to determine their in vivo efficacies, relative to a PMMA-BC control, in repairing a typical bone defect in rabbits; (4) reinforcing the selected SCC-P and SCC-PS candidates with warp-knitted absorbable mesh and determining the in vitro physical properties of the reinforced composites before and after aging; and (5) analyzing the in vitro and in vivo performance data and selecting a candidate for Phase II study. Plans for Phase II study will include (1) optimization of the selected SCC-P or SCC-SP system into an absorbable, bioactive, self-setting bone cement (ABS-BC) with and without knitted mesh reinforcement, relying on in vitro physical and mechanical properties as cementing/defect filling materials, with or without absorbable, mesh reinforcements; (2) completion of development, scale-up, sterilization, and packaging studies; (3) completion of the validation studies of all processes; (4) development of a suitable animal model for at least three clinical indications and demonstrating the ABS-BC in vivo efficacy using selected animal models; and (5) securing a marketing partner to develop plans for the manufacturing and marketing of the ABS-BC. PUBLIC HEALTH RELEVANCE: Developing absorbable, self-setting, bioactive cyanoacrylate-based composites comprising inorganic silicate and/or phosphate microparticles with or without reinforcement with an absorbable knitted mesh will provide the clinical community with novel biomaterials for use as preferred alternatives to the non-absorbable polymethyl methacrylate bone cement and in repairing or substituting cranial and maxillofacial bone defects through guided bone regeneration.