Multifunctional Block Copolymer Scaffolds for Bone Repair

目前合成支架材料无法引导成骨细胞增殖、分化成成骨细胞并产生足够数量的骨组织，这限制了合成支架在骨科、牙科和颅面手术等关键领域骨移植应用的发展。我们的长期目标是创造生物启发的组织工程结构，促进骨的形成和修复。作为实现这一目标的第一步，本应用程序的目标是通过利用嵌段共聚物的相分离和自组装特性来设计具有可控结构的新型支架，并评估这些支架促进成骨细胞分化和骨形成的能力。我们的中心假设是，通过在超分子水平上整合“活的”聚合和自组装来精确控制聚合物块设计，将导致具有增强功能的多孔支架。这一假设是基于我们最近对聚合物自组装和指导细胞功能的仿生表面的研究。这项工作的基本原理是，这些新工程基质将增强成骨细胞活性和骨修复，以克服现有合成支架的局限性。基于我们在有机合成、高分子化学、细胞-材料相互作用和组织工程方面的专业知识，我们的多学科团队已经做好了充分的准备来开展拟议的研究。在目标1中，将开发新的合成策略，以实现功能化嵌段共聚物在分子尺度和中观尺度上的自组装特性，以设计支架。在目标2中，结合多种功能的第二代支架包括

The inability of current synthetic scaffold materials to direct osteogenic cells to proliferate, differentiate into osteoblasts, and produce sufficient quantities of bone tissue limits the development of synthetic scaffolds for bone grafting applications in crucial areas such as orthopaedic, dental, and craniofacial procedures. Our longterm goal is to create bio-inspired tissue-engineered constructs that promote bone formation and repair. As a first step toward this goal, the objective of this application is to engineer novel scaffolds with controlled architectures that present biomimetic ligands by exploiting phase separation and self-assembly properties of block copolymers and to evaluate the ability of these scaffolds to promote osteoblastic differentiation and bone formation. Our central hypothesis is that precise control of polymer block design through integration of “living” polymerizations and self-assembly at the supramolecular levels will lead to porous scaffolds with enhanced functionality. This hypothesis is based on our recent studies of polymer self-assembly and biomimetic surfaces that direct cell function. The rationale for this work is that these newly engineered matrices will enhance osteoblast activities and bone repair to overcome existing limitations associated with current synthetic scaffolds. Our multidisciplinary team is well prepared to undertake the proposed research based on our expertise in organic synthesis, polymer chemistry, cell-materials interactions, and tissue engineering. In Aim 1, novel synthetic strategies towards functionalized block copolymers coupled with self assembly properties of these copolymers at the molecular-scale and meso-scale will be exploited in order to engineer scaffolds. In Aim 2, the second generation of scaffolds incorporating multiple functionalities including fibronectin-mimetic ligands to promote enhanced osteoblast cell adhesion and differentiation as well as proteinresistant poly(ethylene glycol) coatings will be fabricated. Osteogenic cell adhesion, proliferation, and differentiation will be evaluated. In Aim 3, we will evaluate the ability of these engineered scaffolds to promote in vivo osteoblastic differentiation and bone formation in an ectopic site. This work is expected to yield the following outcomes. We will: (i) identify block copolymers and controlled foaming approaches that yield families of mesoporous (50-500 μm pores) scaffolds of varying architectures (pore size, interconnectivity, and strut size, shape and separation); (ii) establish surface engineering strategies to render these materials protein adsorption-resistant while presenting controlled cell adhesive ligands; and (iii) demonstrate that these novel materials exhibit superior osteoblast cell adhesion and differentiation and promote in vivo bone formation compared to unmodified and conventional polymeric supports. Collectively, these studies will validate the proposed novel concepts towards high strength biomimetic scaffolds. Optimization of the mechanical properties of the newly developed scaffolds will be part of a future application submission.