Multifunctional Block Copolymer Scaffolds for Bone Repair

目前的合成支架材料不能引导成骨细胞增殖、分化为成骨细胞并产生足够数量的骨组织，限制了合成支架在骨科、牙科和颅面外科等关键领域的骨移植应用的发展。我们的长期目标是创造受生物启发的组织工程结构，促进骨骼的形成和修复。作为实现这一目标的第一步，本应用的目标是设计具有可控结构的新型支架，通过利用嵌段共聚物的相分离和自组装特性来呈现仿生配体，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“活性”聚合和自组装来精确控制聚合物嵌段设计，将导致具有增强功能的多孔支架。这一假说是基于我们最近对指导细胞功能的聚合物自组装和仿生表面的研究。这项工作的基本原理是，这些新设计的基质将增强成骨细胞的活性和骨修复，以克服现有的与当前合成支架相关的限制。我们的多学科团队基于我们在有机合成、聚合物化学、细胞-材料相互作用和组织工程方面的专业知识，为开展拟议的研究做好了充分的准备。在目标1中，将开发具有分子尺度和介观尺度自组装特性的官能化嵌段共聚物的新的合成策略，以实现支架工程。在目标2中，包含多种功能的第二代支架包括 将制备促进成骨细胞黏附和分化的纤维连接蛋白模拟配体以及抗蛋白聚乙二醇涂层。将评估成骨细胞的黏附、增殖和分化。在目标3中，我们将评估这些工程支架在异位部位促进体内成骨细胞分化和骨形成的能力。这项工作预计将产生以下成果。我们将：(I)确定嵌段共聚物和受控发泡方法，以产生不同结构(孔径、互连性、支柱尺寸、形状和分离)的介孔(50-500μm孔)支架家族；(Ii)建立表面工程策略，使这些材料在抗蛋白质吸附的同时提供受控的细胞黏附配体；以及(Iii)证明这些新型材料与未经修饰的和传统的聚合物载体相比，具有更好的成骨细胞黏附和分化能力，并促进体内骨形成。总的来说，这些研究将验证所提出的高强度仿生支架的新概念。对新开发的脚手架的力学性能进行优化将是未来申请的一部分。

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.