Biomimetic Scaffolds to Promote Stem Cell Differentiation for Cartilage Engineeri

描述：骨关节炎（OA）是一种使人衰弱的疾病，根据关节炎基金会，影响超过2700万美国人。该疾病的特征在于关节软骨细胞外基质（ECM）分子的分解，包括II型胶原蛋白、聚集蛋白聚糖和透明质酸（HA）。随着ECM降解，出现包括疼痛和关节僵硬增加在内的症状。一旦发生胶原损失，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组合以防止基质降解并促进原代牛软骨细胞的软骨ECM合成的协同效应。然而，在人类中，我们的软骨细胞供应有限，并且原代关节软骨细胞的收获可导致供体部位发病。成体间充质干细胞（MSC）是一种有前途的细胞来源，因为它们可以无损伤地收获，具有高增殖能力，并且可以在适当的环境条件下分化为软骨细胞。然而，利用MSC的一个主要挑战是，接种MSC的移植物产生的基质不如接种分化软骨细胞的移植物那么多。因此，建立有效分化和随后基质生产的条件至关重要。我们的长期目标是在组织工程软骨中使用MSC来替代骨关节炎损伤的软骨。为了实现这一目标，我们的目标是创造一个环境，抵抗OA软骨降解的破坏性循环，模仿天然软骨结构，并促进MSC的软骨分化。为了解决这些问题，我们制定了以下具体目标。目的1：评价比对、聚集蛋白聚糖模拟物浓度和BMP肽浓度对干细胞分化的影响。目的2：研究协同相互作用对软骨分化的影响。该应用的结果将阐明影响干细胞分化的局部微环境的特性，从而增强基质产生和机械特性。因此，这些研究将作为未来NIH R01应用的初步数据，该应用将在体内缺损模型中评价这些构建体。识别导致软骨移植物改善的基于材料的线索对于开发涉及成人ste细胞的安全有效的临床疗法至关重要。

DESCRIPTION: 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 applicaton 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 application 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 ste cells.