3-D BIOMIMETIC SCAFFOLDS FOR BONE TISSUE ENGINEERING

描述(改编自调查者摘要)：重建 骨骼缺陷是一项重大的临床挑战，有100多万人 每年进行的外科手术。骨再生的新策略 是必要的，因为现有技术的局限性。一种新的战略是 为了创造一种将自体细胞种植到多孔材料上的复合移植物， 可降解脚手架。支架支撑细胞，在结构上和 在生物学上，允许它们生长和分泌新的细胞外基质。 最理想的情况是，组织生长与支架降解同时发生。学位 然而，新骨形成的速度依赖于材料，且不可预测。我们 因此，寻求建立可以优化的材料化学参数 骨细胞功能。为了追求这一目标，我们发展了：(1)体外 扩增人骨髓基质细胞的培养方法； (2)可重复制造高孔3D的聚合物加工技术 聚乳酸-羟基乙酸共聚支架，已成功应用于 设计包括骨骼在内的多个组织；(3)材料科学设计 这些策略使我们能够仿生修改内部的 脚手架和脚手架表面的微环境；和(4)临界 免疫功能低下小鼠的颅骨大小缺陷模型 人骨髓间充质干细胞能够在动物模型中形成新骨。《环球报》 拟议研究的假设是，细胞外微环境 提供的支架调节人骨髓间充质干细胞分化的能力 向成骨细胞表型转化，从而控制生物矿化和 再生骨的结构完整性。来自我们和其他公司的结果 实验室支持这一假设，并通过合成一系列 模型仿生材料。首先，我们合成了对环境友好的 或“智能”脚手架，缓冲脚手架上的微环境 退化。第二，我们合成具有表面的支架 自我矿化成生物磷灰石。第三，我们使用功能分级 矿化在空间上受到控制的支架。其基本原理是 这三种仿生策略中的每一种都取决于大自然设计的 骷髅。骨骼系统能够使用最低限度地执行其功能 质量，因为生物学利用了设计方法，其中包括 适应环境提示的能力(即“聪明”)，一种等级制度 由优雅的矿物合成组成的组织，以及一个 通过在成分和成分中具有梯度来优化生理功能 结构。在拟议的研究中，我们的目标是利用这些方面的每一个 3个仿生策略，以努力创造将调节 以受控的方式进行生物反应。

DESCRIPTION (Adapted from the Investigator's Abstract): Reconstruction of skeletal defects represents a major clinical challenge with over 1 million surgical procedures performed each year. New strategies of regenerating bone are needed because of limitations with existing techniques. One new strategy is to create a composite graft in which autologous cells are seeded onto a porous, degradable scaffold. The scaffold supports the cells, structurally and biologically, allowing them to grow and secrete new extracellular matrix. Optimally tissue growth occurs concurrent with scaffold degradation. The degree of new bone formation is, however, material dependent and not predictable. We therefore seek to establish material chemistry parameters that could optimize bone cell function. In pursuit of this goal, we have developed: (1) in vitro culture methods in which human bone marrow stromal cells (BMSCs) are expanded; (2) polymer processing techniques to reproducibly fabricate highly porous 3D poly(lactic-co-glycolic) scaffolds, which have been successfully used to engineer a number of tissues including bone; (3) materials science design strategies which enable us to biomimetically modify both the internal microenvironment of a scaffold and the scaffold surface; and (4) a critical size cranial defect model in an immunocompromised mouse which has shown that the human BMSCs are capable of forming new bone in an animal model. The global hypothesis of the proposed research is that the extracellular microenvironment provided by the scaffold modulates the ability of human BMSCs to differentiate toward an osteoblast phenotype, and therefore controls biomineralization and structural integrity of regenerated bone. Results from our and other laboratories support this hypothesis, which is tested by synthesizing a series of model biomimetic materials. First, we synthesize environmentally responsive or "smart" scaffolds that buffer the microenvironment upon scaffold degradation. Second, we synthesize scaffolds with a surface that self-mineralizes into a biological apatite. Third, we use functionally-graded scaffolds in which mineralization is spatially controlled. The rationale for each of these 3 biomimetic strategies lies in the way nature has designed the skeleton. The skeletal system is able to perform its functions using a minimum amount of mass because biology has utilized design approaches, which include the ability to adapt to environmental cues (i.e. "smartness"), a hierarchical organization consisting of elegant mineral synthesis, and an organization that is optimized for physiological function by having gradients in composition and structure. In the proposed studies, we aim to exploit aspects of each of these 3 biomimetic strategies in an effort to create biomaterials that will modulate biological response in a controlled manner.