Determining the Efficacy of a Novel Apatite-Based Antimicrobial Bone Scaffold for Craniofacial Surgical Applications

项目摘要/摘要 创伤性肌肉骨骼损伤通常涉及大量的骨骼和软组织断裂，随后 感染可能发展为一种常见的并发症。这导致了多个外科清创手术， 进一步增加缺陷的大小。需要外科清创以达到清洁伤口所需的 骨重建成功。因此，解决临界大小的骨缺损--如果没有 用骨移植材料替换丢失的骨--通常被推迟到伤口达到动态平衡。是这样的 延误可能会导致继发性并发症和终身残疾。自体或自体移植的骨是“黄金” 在所有移植材料中“标准”，但可用的骨部位数量有限。这就产生了不足 移植物材料，以填补临界大小的缺陷，这种收获需要二次手术部位。脱细胞和 无菌身体骨或同种异体骨在细菌污染的伤口环境中通常失败。 如果目前这些材料的局限性，工程化骨替代物可能会为这一困境提供解决方案 可以解决，包括它们无法与机械强度、孔隙率和生物活性相匹配 自体移植。理想情况下，这种工程化骨支架材料还应该具有抗菌性能。在……里面 过去，支架表面都涂有抗菌/广谱抗生素，但释放速度很快 或者这些涂层的“爆裂效应”只能提供短期的保护，而抗生素水平突然升高可能会 对愈合所需的局部细胞有毒性。另一种选择是用固有材料定制骨支架 抗菌表面特性。骨基质结晶羟基磷灰石(HA)以其生物相容性而闻名， 成骨性能和生物吸收能力，但缺乏机械强度和可控的再吸收 属性。为了改善HA的力学性能，我们使用了离子化学取代和 温度的变化，以合成各种类型的磷灰石。我们的初步数据显示，氟 取代磷灰石(氟磷灰石(FA))，当在11500℃以上烧结时，产生更高的机械强度， 包括体内模型中的压缩强度和增加的骨沉积。我们还表明， 在已知的情况下，抗菌金属在磷灰石晶体中被共沉积和固定 FA的合成，磷灰石的某些组合在不产生细胞的情况下显示出更好的抗菌性能 细胞毒性。这项建议旨在测试一种这样的磷灰石，锌掺杂氟磷灰石(锌-FA)。基于我们的 初步数据推测，最佳摩尔分数的锌取代多孔氟磷灰石 支架将具有在无菌和感染部位再生骨组织的潜力。这 假设将通过三个具体目标进行检验。特殊目标1旨在制造和测试这两种产品 不同摩尔分数锌取代FA的力学性能和体外抗菌性能 和3将测试优化的摩尔百分比锌取代FA在体内生成骨组织的效果 受污染的口袋和临界大小的口袋。

PROJECT ABSTRACT / SUMMARY Traumatic musculoskeletal injuries commonly involve massive bone and soft tissue disruptions, with subsequent infection possibly developing as a frequent complication. This leads to multiple surgical debridements, which further increases the size of the defect. Surgical debridement is needed to achieve a clean wound required for successful bony reconstruction. Thus, addressing critical-size bone defects— which cannot be healed without replacing the lost bone with bone graft materials—is often delayed until wound homeostasis is obtained. Such delay may lead to secondary complications and life-long disability. Self-sourced or autograft bone is the “gold standard” among all graft materials, but the amount of bone sites available is limited. This produces insufficient graft material to fill critical-size defects, and such harvest requires secondary surgical sites. Decellularized and sterilized cadaveric or allograft bone commonly fails in bacterially contaminated wound environments. Engineered bone substitutes may provide a solution to this dilemma if the current limitations of these materials can be addressed, including their inability to match the mechanical strength, porosity, and bioactivity of autografts. Ideally, such engineered bone scaffolding materials should also possess antimicrobial properties. In the past, scaffold surfaces have been coated with antimicrobial/broad-spectrum antibiotics, but the rapid release or “burst effect” of these coatings only provides short-term protection, and sudden high antibiotic levels can be toxic to the local cells needed for healing. One other option could be to tailor bone scaffolds with intrinsic antimicrobial surface properties. The bone matrix crystalline hydroxyapatite (HA) is known for its biocompatibility, osteogenic properties, and bio-absorbability but lacks mechanical strength and controllable resorption properties. To improve the mechanical properties of HA, we have used both ionic chemical substitution and variation in temperatures to synthesize various apatite types. Our preliminary data revealed that fluoride substituted apatite (fluorapatite (FA)), when sintered above 11500C, produced improved mechanical strengths, including compression strengths and increased bone deposition in an in vivo model. We have also shown that when known antimicrobial metals are co-deposited and immobilized within the apatite crystals during the synthesis of FA, some combination of apatites exhibited improved antimicrobial properties without producing cell cytotoxicity. This proposal is designed to test one such apatite, zinc-doped fluorapatite (Zn-FA). Based on our preliminary data, it was hypothesized that an optimized molar percent zinc substituted porous fluorapatite scaffolds would have the potential to regenerate bone tissue within both sterile and infected sites. This hypothesis will be tested using three Specific Aims. Specific Aim 1 is designed to fabricate and test both mechanical and antimicrobial in vitro properties of various molar percent Zn substituted FA, Specific Aims 2 and 3 will test the efficacy of an optimized molar percent zinc substituted FA to generate bone tissues in contaminated and critical-size pockets, respectively.