Validating a new, translatable biomaterial for healing critical bone defects

项目总结/摘要 大面积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， 每年影响超过150万美国人，经常导致感染和其他临床疾病。 并发症、再次手术、功能结果差，最终，常常是肢体丧失。目前的黄金- 标准的治疗是大的金属板固定，其易于感染并保留在患者体内， 生活因此，迫切需要解决人类医学中的这一挑战。研究人员一直致力 几十年来，人们一直在研究组织工程解决方案，使用由磷酸三钙（TCP）制成的支架， 优异的生物活性（骨诱导、骨传导和骨整合），可调的降解速率， 有前途的药物输送能力。然而，尽管具有优异的骨再生特性， 不足以支撑显著的载荷，特别是在关键缺陷中。一个可行的解决方案，以愈合关键 骨缺损需要快速、自然的骨生长、血管发育和机械完整性来支撑负荷， 新的骨头生长。在骨中发现的许多微量元素，如Zn、Mg、Sr、Si和Mn， 被添加到TCP支架（a.k.a.“掺杂”）以改善机械性能和生物活性，并促进 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，但尚未得到证实。 探讨了不幸的是，当一个人考虑所有的组合时，需要一个棘手的研究组合 以及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。这几乎无限的变体集合导致了一个假设， 经过数百万年的试验和错误，天然骨骼可能已经含有理想的矿物质成分。 这项建议不是试图重新设计骨骼的矿物质成分，而是试图制造和充分利用骨骼。 表征由天然来源的骨粉组成的骨再生支架，并测试这些 支架在试验绵羊体内研究。我们依靠大自然母亲来提供一个可能的解决方案。新奇 我们正在测试一种新的仿生生物材料。到目前为止，还没有研究测试过天然来源的 骨再生支架中的骨矿物质。我们的方法依赖于一种天然来源的材料， 因此，与较低的监管负担相关的，应该更容易转化为人类医学。我们 我希望将这项工作扩展到开发类似的方法，使用天然来源的人类骨矿物质进行治疗 人类的严重缺陷。如果成功，该项目可以使更高的孔隙率结构加速生物活性 和血管化，这两者都将对严重缺损骨愈合产生显著影响。我们的长期 我们的目标是能够去除所有金属固定，只留下内源性骨，因为我们期望我们的天然来源 生物材料可以被天然骨替代，因为我们未来的工作加速了骨生长。

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.