Validating a new, translatable biomaterial for healing critical bone defects

项目摘要/摘要 大型骨缺损愈合不良仍然是人类骨科医学面临的最大挑战之一， 每年影响150多万美国人，经常导致感染和其他临床 并发症、再手术、功能结果差，最终往往会失去肢体。目前的黄金-- 标准的治疗方法是大型金属板固定，这种钢板容易感染，并留在患者体内 生活。因此，迫切需要解决人类医学中的这一挑战。研究人员一直在努力 几十年来，使用由三钙磷酸盐(TCP)制成的支架的组织工程解决方案，由于其 良好的生物活性(骨诱导、骨传导和骨整合)、可调的降解率和 前景看好的药物输送能力。然而，尽管这些支架具有优异的骨再生性能， 不够坚固，不足以承受重大载荷，特别是在严重缺陷时。治愈危重病人的可行解决方案 缺陷需要快速、自然的骨生长、血管发育和机械完整性来支持负荷，同时 新骨就会长出来。在骨骼中发现的许多微量元素，如锌、镁、锶、硅和锰，都有 已添加到TCP脚手架(也称为“兴奋剂”)，以提高机械性能和生物活性，并加速 新骨形成。许多其他微量元素也可能在骨骼发育中发挥作用，但尚未发挥作用 探索过了。不幸的是，当一个人考虑所有的组合时，需要一个棘手的组合研究 在骨骼中发现的微量元素和每种元素的理想浓度。再多的资金也不足以 评估所有这些组合在骨愈合中的作用。这种几乎无限的变种集合导致了一种假设 经过数百万年的反复试验，天然骨可能已经含有理想的矿物成分。 这项提议并不是试图重新设计骨骼的矿物组成，而是试图制造和充分 表征由天然骨粉组成的骨再生支架并对其进行测试 支架在试验性绵羊体内的研究。我们依靠大自然来提供可能的解决方案。新奇之处 我们的方法是我们正在测试一种新的仿生生物材料。到目前为止，还没有研究证明是自然衍生的 骨再生支架中的骨矿物质。我们的方法依赖于一种自然衍生的材料，它可以 因此，与较低的监管负担相关，应该更容易转化为人类药物。我们 希望将这项工作扩展到开发类似的方法，使用天然提取的人骨矿物进行愈合 人类的严重缺陷。如果成功，这个项目可以使更高孔隙率的结构加速生物活性 和血管化，这两个都会对严重的缺损骨愈合产生重大影响。我们的长期合作 目标是能够移除所有的金属固定，只留下我们期望的自然衍生的内源性骨骼 生物材料可被天然骨替代，因为我们未来的工作将加速骨的生长。

PROJECT SUMMARY/ABSTRACT Poor healing of large bone defects remains one of the biggest challenges in human orthopedic medicine, affecting more than 1.5 million Americans per year and often leading to infections and other clinical complications, reoperations, poor functional outcomes, and ultimately, all too often, limb loss. The current gold- standard treatment is large metal plate fixation, which is prone to infection and remains in the patient’s body for life. Thus, there is a critical need to address this challenge in human medicine. Researchers have been working on tissue engineered solutions for decades, using scaffolds made of tri-calcium-phosphate (TCP) due to their excellent bioactivity (osteoinduction, osteoconduction and osseointegration), tunable degradation rate and promising drug delivery capabilities. However, despite excellent bone regeneration properties, these scaffolds are not strong enough to support significant loads, especially in critical defects. A viable solution to healing critical defects requires fast, natural bone growth, vascular development, and mechanical integrity to support loads while the new bone grows. Numerous trace elements that are found in bone, such as Zn, Mg, Sr, Si and Mn, have been added to TCP scaffolds (a.k.a. “doping”) to improve mechanical properties and bioactivity, and accelerate new bone formation. Many other trace elements may also play a role in bone development but have yet to be explored. Unfortunately, an intractable combination of studies is required when one considers all combinations of trace elements found in bone and ideal concentrations of each. No amount of funding will be enough to evaluate all these combinations in bone healing. This virtually unlimited set of variants leads to a hypothesis that natural bone may already contain the ideal mineral composition, after many millions of years of trial and error. Rather than trying to re-engineer the mineral composition of bone, this proposal seeks to fabricate and fully characterize bone regeneration scaffolds composed of naturally derived bone powder and test these scaffolds in a pilot ovine in vivo study. We lean on mother nature to provide a possible solution. The novelty of our approach is that we’re testing a new biomimetic biomaterial. No study to date has tested naturally derived bone mineral in bone regeneration scaffolds. Our approach depends on a naturally derived material that would be associated with lower regulatory burden, therefore, should be easier to translate to human medicine. We hope to extend this work to develop similar methods using naturally derived human bone mineral for healing human critical defects. If successful, this project could enable higher porosity structures to accelerate bioactivity and vascularization, both of which would have a significant impact on critical defect bone healing. Our long-term goal is to enable removal of all metal fixation, leaving only endogenous bone as we expect our naturally derived biomaterials to be replaceable by native bone as our future work accelerates bone growth.