Impact of Perlecan Mimics on Cartilage Pericellular Matrix Biomechanics

骨性关节炎是由关节软骨退化引起的，是一种影响美国相当一部分人口的疾病，随着个人年龄的增长，发病率不断增加。细胞周围基质是一种围绕软骨细胞(软骨细胞)的结构，已被证明将有关软骨机械载荷的信息传递给细胞。如果蛋白多糖，一种大分子，在细胞周围基质中降解，这可能会导致早发性骨关节炎。然而，这些大分子在关节软骨的力学性能和反应中的确切作用尚不清楚。该项目将使用一种模拟重要的蛋白多糖分子Perlecan行为的分子，来确定它对软骨细胞、细胞周围基质和细胞外基质的机械行为和反应的影响。通过增加这一领域的知识，将开辟软骨退变和潜在治疗方法的新研究方向，以最大限度地减少骨关节炎的影响。研究团队将让本科生和未被充分代表的学生参与研究，并参加支持费城K12社区的STEM夏令营。该项目围绕三个目标组织。首先，将证实Perlecan模拟物在正常人和骨关节炎患者关节软骨中的扩散动力学和分布。其次，无论是否存在Perlecan模拟物，都将使用原子力显微镜来测定正常和骨关节炎关节软骨中软骨细胞、细胞周围基质和细胞外基质的原位纳米力学行为。最后，将确定Perlecan模拟物与自然产生的细胞周围和细胞外基质生物分子的分子相互作用。提高对Perlecan在关节软骨反应中的作用的了解，可能会导致有能力工程细胞周围基质或细胞外基质来支持组织再生，并作为细胞组织工程的增强。这项研究中开发的关节软骨技术将适用于其他肌肉骨骼组织以及其他因退化和老化而受损的软组织，如皮肤或尿路。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Osteoarthritis, which results from the degradation of the articular cartilage, is a condition that affects a significant portion of the population in the US, with increasing occurrence as individuals age. The pericellular matrix, a structure that surrounds cartilage cells (chondrocytes), has been shown to transmit information about mechanical loading in cartilage to the cells. If proteoglycans, a type of macromolecule, in the pericellular matrix degrade, this can lead to early onset osteoarthritis. However, the precise role of these macromolecules in the mechanical properties and response of articular cartilage is unknown. This project will use a molecule that mimics the behavior of an important proteoglycan molecule, perlecan, to determine its effect on the mechanical behavior and response of chondrocytes, the pericellular matrix, and the extracellular matrix. By increasing knowledge in this area, new directions of investigation will be opened up regarding cartilage degeneration and potential therapies to minimize the impact of osteoarthritis. The research team will involve undergraduates and underrepresented students in the research as well as participate in STEM summer camps that support the Philadelphia K12 community.This project is organized around three objectives. First, the diffusion kinetics and distribution of perlecan mimics will be confirmed in normal and osteoarthritic human articular cartilage. Second, the in situ nanomechanical behavior of the chondrocyte, pericellular matrix, and extracellular matrix will be determined using Atomic Force Microscopy for both normal and osteoarthritic articular cartilage, both in the presence and absence of the perlecan mimics. Finally, the molecular interactions of the perlecan mimics with naturally occurring pericellular and extracellular matrix biomolecules will be determined. An improved understanding of the role of perlecan in articular cartilage response could lead to the ability to engineer the pericellular matrix or extracellular matrix to support tissue regeneration and as an augmentation to cellular tissue engineering. The techniques developed in this study for articular cartilage will be appropriate for other musculoskeletal tissues as well as other soft tissues that are compromised through degeneration and aging, such as the skin or urethra.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.