Biomimetic Scaffolds to Promote Stem Cell Differentiation for Cartilage Engineeri

摘要 骨关节炎(OA)是一种使人衰弱的疾病，根据关节炎基金会的说法，这种疾病影响超过 2700万美国人。该病的特征是关节软骨细胞外的破坏。 基质(ECM)分子，包括II型胶原、聚集素和透明质酸(HA)。作为ECM 退化，症状出现，包括疼痛和关节僵硬增加。一旦胶原蛋白丢失 一旦发生，相信没有辅助的软骨再生的机会就丧失了。考虑到这一点， 我们之前描述了将聚集素的功能模拟物与ALIGNED结合的协同效应 原代牛软骨抑制基质降解和促进软骨细胞外基质合成 软骨细胞！“#。然而，在人类中，我们的软骨细胞供应是有限的，而 原发关节软骨细胞可导致供区病变。成体间充质干细胞 骨髓间充质干细胞(MSCs)是一种很有前途的细胞来源，因为它们可以在不损伤的情况下获得，具有很高的 增殖能力强，在适当环境下可分化为软骨细胞 条件。然而，利用MSCs的一个主要挑战是，种植MSCs的移植物不能 产生与种植分化软骨细胞的移植物一样多的基质！$%&#因此，至关重要的是 为有效分化和随后的基质生产创造条件。 我们的长期目标是将骨髓间充质干细胞用于组织工程软骨中，以取代因 骨性关节炎。为了实现这一目标，我们的目标是创造一个抵制 骨性关节炎软骨降解的破坏性循环，模仿天然软骨结构，以及 促进MSCs向软骨细胞分化。为了解决这些问题，我们开发了 遵循特定的目标。目的1：评估对齐、aggrecan模拟浓度和 BMP多肽浓度对干细胞分化的影响。目标2：研究协同效应 软骨分化过程中的相互作用。 这项研究的结果将阐明影响茎干的局部微环境的性质。 细胞分化，从而增强基质的产生和机械性能。这些研究 因此将作为未来NIH R01提案的初步数据，该提案将在 体内缺陷模型。改善软骨移植的基于材料的线索的鉴定 对于开发安全有效的使用成人干细胞的临床疗法是必不可少的。

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.