Enhanced Osteoinduction and Angioinduction via Polymer/CaO2 Bone Tissue Engineeri

描述（由申请人提供）：骨组织工程支架通常需要使用骨诱导生长因子（例如骨形态发生蛋白，bmp）使其具有临床可行性。虽然前景看好，但生长因子也有明显的缺点，包括溶解度有限、不稳定、免疫原性和成本高。此外，bmp负载的支架已被证明在支架表面诱导大部分骨形成，而细胞渗透到支架主体的能力有限。为了缓解这一问题，一些研究人员将bmp和血管诱导生长因子（如VEGF）结合使用，以促进整个支架的骨发育。虽然含有两种生长因子的结构已经显示出希望，但使用生长因子的缺点仍然存在。由于这些限制，需要开发新的骨再生治疗策略。来自PI小组的初步数据提供了证据，证明过氧化氢和氢氧化钙可以诱导脂肪来源的干细胞分别产生自身的VEGF和BMP- 2。过氧化钙是一种经fda批准的食品添加剂，它以一种渐进和可控的方式解离成过氧化氢和钙离子。它是高度稳定和廉价的，使其成为临床可行的替代使用生长因子。本研究计划的目的是1)评估过氧化钙在兔间充质干细胞中的血管诱导和骨诱导潜能，2)将这些效应与外源性生长因子VEGF和BMP-2的递送进行比较，以及3)制造复合聚（乳酸-共糖内酯）/过氧化钙烧结微球支架并评估其促进骨再生的能力。支架的生物学性能将通过兔尺骨临界尺寸缺陷模型来确定。我们假设过氧化钙的生物活性将显著改善骨组织再生体内负载的生长因子聚（乳酸-羟基乙酸酯）支架。

DESCRIPTION (provided by applicant): Bone tissue engineering scaffolds often require the use of osteoinductive growth factors (e.g. bone morphogenetic proteins, BMPs) to make them clinically viable. While promising, growth factors have significant drawbacks including their limited solubility, instability, immunogenicity, and high cost. Also, BMP-loaded scaffolds have been shown to induce most bone formation on the surface of the scaffold with limited cellular penetration into the bulk of the scaffold. To alleviate this problem, some researchers have delivered both BMPs and angioinductive growth factors (e.g. VEGF) to facilitate bone development throughout the scaffold. While constructs containing both types of growth factors have shown promise, the disadvantages of using growth factors still exist. Due to these limitations, there exists a need to develop novel strategies for bone regeneration therapies. Preliminary data from the PI's group provides evidence that hydrogen peroxide and calcium hydroxide can induce adipose-derived stem cells to produce their own VEGF and BMP- 2, respectively. Calcium peroxide, a FDA-approved food additive, dissociates into hydrogen peroxide and calcium ions in a gradual and controlled fashion. It is highly stable and inexpensive making it a clinically viable alternative to using growth factors. The objectives of th present research proposal are 1) to evaluate the angioinductive and osteoinductive potential of calcium peroxide in rabbit mesenchymal stem cells, 2) to compare these effects to the exogenous delivery of the growth factors VEGF and BMP-2, and 3) to create composite poly(lactide-co-glyoclide) / calcium peroxide sintered microsphere scaffolds and assess their capacity to facilitate bone regeneration. The biological performance of the scaffolds will be determined using a rabbit ulnar critical size defect model. We hypothesize the bioactivity of calcium peroxide will significantly improve bone tissue regeneration in vivo over growth factor loaded poly(lactide-co-glycolide) scaffolds. PUBLIC HEALTH RELEVANCE: The Laurencin laboratory has focused on developing tissue engineering strategies for the regeneration of orthopaedic tissues such as bone, cartilage, and ligament. To achieve these goals, we collaborate with experts from a wide range of scientific fields including clinicians, cell and molecular biologists, and engineers from the University of Connecticut and around the world. The innovation of the current proposal is the development of controlled release composite scaffolds that can induce angiogenesis and osteogenesis without the need for exogenous growth factors.