Bone Regeneration Via Silk Biomaterials

描述（由申请人提供）：由损伤、疾病或先天性畸形引起的临界尺寸骨缺损仍然是骨科医学中的一个具有挑战性的问题。由于天然骨组织再生速率慢、第二部位发病率、机械稳定性差以及缺乏与周围组织的整合（取决于所采用的临床修复模式），目前恢复此类骨缺损的完全功能的选择有限。需要新的选择来加速新骨形成的速率和程度，以及与周围组织的整合，以克服当前的局限性。在这种竞争性的更新应用中，一种新型的丝蛋白基质将被生物工程化以优化这些目标，从而实现大的缺损骨再生。拟议的研究建立在当前资助的结果基础上，该资助证明了丝素蛋白3D多孔基质用于体外和体内骨再生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蛋白质基质中联合递送BMP-2和VEGF来加速骨形成和整合的速度和程度，并结合生物工程肽粘合剂以促进与相邻母骨的相互作用。这些增强的，可降解的， 将在大鼠临界尺寸股骨缺损模型中研究用生长因子和粘附能力官能化的生物相容性3D多孔丝基质，以优化其设计。优化后，在研究的最终目的中，将在临界尺寸山羊股骨缺损模型中评估植入物。我们的目标是用这些新的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、矿物质分布均匀性和小型和大型动物临界尺寸缺损修复的机械完整性。为了实现这些目标，已经组建了一个跨学科的研究人员团队，以应对生物材料基质设计，干细胞生物学，生物力学，成像和兽医学方面的专业知识的挑战。

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.