Biomimetic Scaffolds to Promote Stem Cell Differentiation for Cartilage Engineeri

总结 骨关节炎（OA）是一种使人衰弱的疾病，根据关节炎基金会， 两千七百万美国人。这种疾病的特点是关节软骨细胞外的破坏 基质（ECM）分子，包括II型胶原蛋白、聚集蛋白聚糖和透明质酸（HA）。随着ECM 当关节功能退化时，出现包括疼痛和关节僵硬增加在内的症状。一旦胶原蛋白流失 当发生这种情况时，据信失去了无辅助软骨再生的机会。考虑到这一点， 我们先前描述了将聚集蛋白聚糖的功能模拟物与对齐的 软骨以防止基质降解并促进原代牛软骨ECM合成 软骨细胞！"#.然而，在人类中，我们的软骨细胞供应有限， 原发性关节软骨细胞可导致供体部位发病。成体间充质干细胞 骨髓间充质干细胞（MSC）是一种有前途的细胞来源，因为它们可以在无损伤的情况下收获，具有高的细胞增殖能力， 增殖能力强，在适当的环境条件下可分化为软骨细胞 条件然而，利用MSC的一个主要挑战是，用MSC接种的移植物不 产生与接种分化软骨细胞的移植物一样多的基质！$%&#。因此， 为有效分化和随后的基质生产建立条件。 我们的长期目标是在组织工程软骨中使用MSC，以替代因软骨损伤而受损的软骨。 骨关节炎为了实现这一目标，我们的目标是创造一个环境， OA引起的软骨退化的破坏性循环，模仿天然软骨结构， 促进MSC的软骨分化。为了解决这些问题，我们制定了 具体目标。目的1：评价比对、聚集蛋白聚糖模拟物浓度和蛋白聚糖浓度的影响。 BMP肽浓度对干细胞分化的影响。目的2：研究协同效应 软骨分化的相互作用。 这一建议的结果将阐明影响茎的局部微环境的特性 细胞分化，导致增强的基质生产和机械性能。这些研究 因此，将作为未来NIH R 01提案的初步数据，该提案将评估这些构建体， 体内缺陷模型。识别导致软骨移植物改善的基于材料的线索 在开发涉及成体干细胞的安全有效的临床疗法中至关重要。

Summary Osteoarthritis (OA) is a debilitating disease that, according to the Arthritis Foundation, affects over 27 million Americans. The disease is characterized by a breakdown of articular cartilage extracellular matrix (ECM) molecules, including collagen type II, aggrecan, and hyaluronic acid (HA). As the ECM degrades, symptoms appear including pain and increasing joint stiffness. Once loss of collagen occurs, it is believed that the opportunity for unaided cartilage regeneration is lost. With this in mind, we previously described synergistic effects of combining a functional mimic of aggrecan with aligned cartilage to prevent matrix degradation and promote cartilage ECM synthesis by primary bovine chondrocytes !"#. However, in humans, we are limited in our supply of chondrocytes, and harvest of primary articular chondrocytes can lead to donor site morbidity. Adult mesenchymal stem cells (MSCs) are a promising cell source because they can be harvested without injury, have a high proliferation capacity, and can differentiate into chondrocytes under appropriate environmental conditions. One major challenge of utilizing MSCs, however, is that grafts seeded with MSCs do not produce as much matrix as grafts seeded with differentiated chondrocytes !$%&#. Thus, it is vital to establish conditions for effective differentiation and subsequent matrix production. Our long-term goal is to use MSCs in tissue-engineered cartilage to replace cartilage damaged by osteoarthritis. To achieve this goal, our objective is to create an environment that resists the destructive cycle of cartilage degradation from OA, mimics the native cartilage structure, and promotes chondrogenic differentiation of MSCs. To address these issues, we have developed the following specific aims. Aim 1: Evaluate the effects of alignment, aggrecan mimic concentration, and BMP peptide concentration on stem cell differentiation. Aim 2: Investigate the effect of synergistic interactions on cartilage differentiation. The results from this proposal will elucidate properties of the local microenvironment that affect stem cell differentiation, resulting in enhanced matrix production and mechanical properties. These studies will thus serve as preliminary data for a future NIH R01 proposal that will evaluate these constructs in an in vivo defect model. Identification of material-based cues that result in improved cartilage grafts is essential in the development of safe and effective clinical therapies involving adult stem cells.