Absorbable, Self-setting Bone Cement

描述（由申请人提供）：自早期开发聚甲基丙烯酸甲酯骨水泥（PMMA-BC）以来，已经有许多努力开发替代组合物来规避其一些临床缺陷，其中包括：(1)单体细胞毒性；(3)组织-水泥界面处不能形成牢固的结合部；(3)是永久性的，不可吸收的植入物，可能会引起感染。PMMA-BC的主要替代品是自固化磷酸钙骨水泥（CPC），但CPC易碎且极易骨折。认识到PMMA-BC和CPC的缺点，以及最近可吸收的氰基丙烯酸酯组织粘合剂配方的商业化，促使了对拟议计划的追求。其第一阶段的目标是证明开发一种自固化可吸收、生物活性、氰基丙烯酸酯磷酸盐基复合材料作为不可吸收PMMA-BC的首选替代品的可行性。因此，I期计划包括(1)利用该实验室获得的自固化、可吸收、氰基丙烯酸酯磷酸盐基复合材料（SCC-P）的初步结果制备5种候选体系，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)使用磷酸盐和硅酸盐的混合物重复对SCC-P系统的研究，以产生包含磷酸盐和硅酸盐成分的另外三种候选物（SCC-PS），选择最有前途的SCC-PS，并与典型的PMMA-BC进行体外比较评估；(3)使用两种选定的SCC-P和SCC-PS候选物，相对于PMMA-BC对照，确定它们在修复兔典型骨缺损中的体内效果；(4)用经编可吸收网对选定的SCC-P和SCC-PS候选材料进行补强，测定增强复合材料老化前后的体外物理性能；(5)分析体外和体内性能数据，选择候选药物进行II期研究。II期研究的计划将包括：(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），有或没有编织网状增强物，依靠体外物理和机械性能作为胶结/缺陷填充材料，有或没有可吸收的网状增强物；(2)完成开发、扩大规模、灭菌和包装研究；(3)完成所有工艺的验证研究；(4)开发至少3种临床适应症的合适动物模型，并使用选定的动物模型证明ABS-BC的体内疗效；(5)确保营销合作伙伴制定ABS-BC的生产和营销计划。公共卫生相关性：开发可吸收的、自固化的、生物活性的氰基丙烯酸酯基复合材料，包括无机硅酸盐和/或磷酸盐微粒，带或不带可吸收的编织网增强，将为临床社区提供新型生物材料，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颌面骨缺损。

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.