Bone Regeneration Via Silk Biomaterials

描述(申请人提供)：由损伤、疾病或先天性畸形引起的临界大小的骨缺损，在骨科医学中仍然是一个具有挑战性的问题。由于自然骨组织再生速度慢，继发部位发病率高，机械稳定性差，缺乏与周围组织的整合，这取决于临床修复的方式，因此目前恢复此类骨缺损完全功能的选择有限。需要新的选择来加速新骨形成的速度和程度，以及与周围组织的整合，以克服目前的限制。在这一竞争性更新应用中，一种新型的丝蛋白基质将被生物工程优化，以实现大缺损骨的再生。拟议的研究建立在目前拨款结果的基础上，该结果证明了丝素蛋白3D多孔基质在体外和体内骨再生方面的独特和有用的属性。在拟议的研究中，我们的目标是通过在3D蛋白质基质中联合输送BMP-2和VEGF来加快骨形成和跨缺损区的骨形成和整合的速度和程度，并加入生物工程多肽粘合剂以促进与邻近母体骨的相互作用。这些增强的、可降解的和 具有生长因子和黏附能力的生物相容3D多孔丝基质将在大鼠临界大小的股骨缺损模型中进行研究，以优化其设计。在优化之后，在这项研究的最终目标中，将在临界大小的山羊股骨缺损模型中对植入物进行评估。我们的目标是以这些新的3D多孔蛋白质基质的优化设计来结束这项研究，以便进行人体临床试验。这三个目标的结果评估将基于矿物质密度、矿物质分布的均质性以及修复小动物和大动物临界大小缺陷的机械完整性。为了实现这些目标，已经组建了一个跨学科的研究团队，利用生物材料基质设计、干细胞生物学、生物力学、成像和兽医方面的专业知识来应对挑战。

DESCRIPTION (provided by applicant): Critical sized bone defects caused by injury, disease or congenital malformations, remain a challenging problem in orthopedic medicine. Current options to restore full function to such bone defects are limited due to slow rates of regeneration of native bone tissue, second site morbidity, poor mechanical stability and lack of integration with surrounding tissues depending on the mode of clinical repair utilized. New options to accelerate the rate and extent of new bone formation, as well as integration to surrounding tissues are needed to overcome current limitations. In this competitive renewal application, a novel silk protein matrix will be bioengineered to optimize these goals to achieve large defect bone regeneration. The proposed studies build off of the results from the current grant that demonstrated the unique and useful attributes of a silk fibroin protein 3D porous matrix for in vitro and in vivo bone regeneration. In the proposed research, our goal is to accelerate the rate and extent of bone formation and integration across the defect through the combined delivery of BMP-2 and VEGF in the 3D protein matrices, and to incorporate bioengineered peptide adhesives to promote interactions with adjacent parent bone. These enhanced, degradable and biocompatible 3D porous silk matrices functionalized with growth factors and adhesion capabilities will be studied in a rat critical sized femur defect model to optimize their design. Subsequent to optimization, in the final aim of the study, the implants will be assessed in a critical-size goat femur defect model. Our goal is to conclude the study with an optimized design for these new 3D porous protein matrices in order to pursue human clinical trials. Outcome assessments for the three aims will be based on mineral density, homogeneity of mineral distribution and mechanical integrity of the repairs in the small and then large animal critical sized defects. To achieve the goals, an interdisciplinary team of investigators has been assembled to address the challenges with expertise in biomaterial matrix design, stem cell biology, biomechanics, imaging and veterinary medicine.