Novel Bone Graft Material With Osteoinductive and Hemostatic Function

描述（申请人提供）：骨是人体植入量仅次于血液的材料之一。骨移植和牙科植入物的市场目前超过48亿美元，预计未来将迅速增长。自体骨移植传统上被使用，但是有限的供应、供体部位的风险和成本导致了对骨移植替代品的需求。脱矿化骨基质（DBM）作为一种骨诱导移植材料，已成为自体骨移植的有效替代材料。但如果没有载体，DBM很难处理，其颗粒可能从骨缺损处被血液分散，从而削弱了其临床疗效。具有延展性、止血性和可快速吸收性的载体可显著改善DBM的处理和临床疗效。美国南加州大学研究人员发明的氧化亚烯共聚物（Ostene）具有这些特性。它最近被FDA批准为骨蜡的合成替代品；它可以很好地粘附在潮湿的表面，并通过机械闭塞来阻止骨出血。Ostene是一种生物相容性水溶性聚合物的组合，在植入后2-3天内完全溶解。它是非含水性和非炎性的；它不会增加感染的风险或抑制成骨。这一特性的结合使得骨基质成为向任何骨缺损输送DBM的理想载体。本项目的目的是开发一种新型的DBM-Ostene骨移植物，该移植物具有骨诱导性和止血性，骨传导性和易于操作。聚合物的非水成分将作为DBM的天然防腐剂，只有在植入后才能激活它。载体可以阻止血液从骨缺损处流出，形成更浓缩的DBM支架，促进骨诱导和更好的骨融合；快速吸收可以使DBM快速激活，在不增加风险的情况下更早开始愈合。该申请描述了导致新化合物临床前配方的研究，体外验证，稳定性，骨诱导性测试，释放动力学研究，以及体内功能评估和生物相容性研究。该研究将在第二阶段进行更高层次的动物研究，以测试特定功能应用的最佳复合材料，如脊柱融合和胸骨修复。最终DBM产品的成功开发将缩短目前的骨移植手术，改善骨移植的处理，促进更强的骨融合，并在不增加风险的情况下实现早期愈合和术后恢复。公共卫生相关性：骨组织用于填补创伤、肿瘤切除、重建和先天性或年龄相关问题的修复，是体内仅次于血液的植入最多的材料之一。自体骨移植-患者自己的骨-一直是骨移植的首选，但其有限的供应和采集和植入所需的多个程序，再加上风险和高成本，导致对功能性骨移植替代品的需求不断增长；目前已有几种替代材料，但这些材料存在成骨性不足、操作困难、缺乏骨止血和副作用等问题。我们建议将脱矿化骨基质（DBM）——一种最接近患者自身组织的人类骨源异体移植物——与一种新的惰性、可延展性和可快速吸收的骨止血材料结合起来作为载体，以创造一种易于操作、高度骨诱导和多功能的骨移植物替代品，并增加止血功能，这将有助于缩短目前的骨科手术，加强骨融合，并显著促进早期愈合和术后恢复，而不增加风险。

DESCRIPTION (provided by applicant): Bone is one of the most implanted materials in the body, second only to blood. The market for bone grafting and dental implants is currently over $4.8 billion and is expected to grow rapidly in the future. Autograft has traditionally been used, but limited supply, donor-site risks, and cost created a demand for bone graft substitutes. As an osteoinductive bone graft material, demineralized bone matrix (DBM) has emerged as an effective alternative to autograft. But without a carrier, DBM is difficult to handle and its particles may be dispersed by blood from the bone defect, which weakens its clinical effectiveness. A malleable, hemostatic, and rapidly resorbable carrier may significantly improve DBM's handling and clinical effectiveness. Alkylene oxide copolymer (Ostene) invented by USC researchers has all these characteristics. It was recently cleared by the FDA as a synthetic alternative to bone wax; it sticks well to wet surfaces and stops bone bleeding by mechanical occlusion. Ostene is a combination of biocompatible water-soluble polymers which dissolves completely within 2-3 days of implantation. It is non-aqueous and non-inflammatory; it does not increase the risk of infection or inhibit osteogenesis. This combination of properties makes Ostene an ideal carrier for delivery of DBM to any bone defect. The objective of this project is to develop a novel DBM-Ostene bone graft that is both osteoinductive and hemostatic, osteoconductive and easy to handle. The polymer's non-aqueous composition would act as a natural preservative for DBM, activating it only after implantation. The carrier would prevent blood flow from the bone defect and create a more concentrated DBM scaffold for osteoinductivity and better bone fusion; rapid resorption would allow quick activation of DBM and earlier onset of healing without adding risk. This application describes the research leading to new compound's pre-clinical formulation, in vitro validation, stability, osteoinductivity testing, and kinetics of release study, as well as in vivo functional evaluation and biocompatibility studies. The research will be followed by higher order animal studies in phase II to test the optimal composite for specific functional applications, such as spinal fusion and sternal bone repair. Successful development of the final DBM product will shorten the current bone graft procedure, improve the bone graft's handling, promote stronger bone fusion, and enable earlier healing and post-operative recovery without adding risk. PUBLIC HEALTH RELEVANCE: Bone tissue, used to fill defects caused by trauma, tumor resection, reconstruction, and repair of congenital or age-related problems, is one of the most implanted materials in the body, second only to blood. Autograft - patient's own bone -- has been the bone graft of choice, but its limited supply and multiple procedures required for harvesting and implantation combined with risk and high cost created a growing demand for functional bone graft substitutes; several alternatives have become available, but the materials have problems ranging from insufficient osteinductivity and difficult handling to lack of bone hemostasis and side effects. We propose to combine Demineralized Bone Matrix (DBM) - a human bone-derived allograft most closely resembling the patient's own tissue - with a newly available inert, malleable, and rapidly resorbable bone hemostasis material as a carrier to create an easy to handle, highly osteoinductive, and versatile bone graft substitute with added hemostatic function which will help shorten the current orthopedic procedure, strengthen bone fusion, and promote significantly earlier onset of healing and postoperative recovery without increased risk.