Chondrogenic composite grafts for the repair of cartilage defects

描述（由申请人提供）：与关节软骨（AC）相关的创伤性损伤和年龄相关的退行性疾病可导致显著的患者发病率并导致骨关节炎的发展。美国疾病控制与预防中心估计，到2030年，近6700万（25%）美国成年人将患有临床诊断的关节炎，使其成为美国致残的主要原因。由于关节软骨的无血管性和有限的生长和自我修复潜力，关节软骨损伤的治疗仍然是骨科医疗保健中最具挑战性的课题之一。修复或再生受伤的AC组织，无论是无限期地或直到患者达到全关节置换术合适的年龄，其社会和经济意义是巨大的。本课题的目标是设计具有软骨样压缩行为、梯度生化微环境、人骨髓基质细胞（hMSC）分层分布、增强与软骨下骨表面结合亲和力的人工合成AC组织移植物，用于全层关节软骨缺损的重建。制定了三个具体目标。在Aim 1中，我们将验证一个假设，即可以制造模拟硫酸软骨素（CS-M）多电解质纤维网，以保留和释放外源性软骨生长因子和成骨生长因子，分别诱导培养的hMSC的软骨和成骨分化。在Aim 2中，我们将验证这样一个假设，即预先植入hMSC细胞的成软骨和成骨CS-M纤维网可以被层状包裹在光交联水凝胶中，以创建具有软骨样压缩行为、分层带状细胞分布和跨越复合移植物厚度的软骨-成骨梯度生化微环境的复合AC移植物。在Aim 3中，我们将验证AC移植物表面可以与小分子羟基磷灰石（HA）结合配体共价功能化的假设，以增强移植物与软骨下骨组织的结合。拟议项目的成功实施将有助于制定一种新的战略，用于临床治疗或替换因慢性疾病、衰老、创伤和先天性畸形而严重受损的AC组织。公共卫生相关性：与关节软骨相关的创伤性损伤和年龄相关的退行性疾病可导致显著的患者发病率并导致骨关节炎的发展。美国疾病控制与预防中心估计，到2030年，近6700万（25%）美国成年人将患有临床诊断的关节炎，使其成为美国致残的主要原因。由于无血管的性质和有限的潜力生长和自我修复，关节软骨组织损伤是特别具有挑战性的修复。组织工程软骨结构在临床治疗或严重病变（如终末期骨关节炎）软骨组织的替代方面具有很大的前景。成功开发可行的合成软骨结构具有重要的社会和经济意义，并有助于改善一般人群的肌肉骨骼健康。

DESCRIPTION (provided by applicant): Traumatic injuries and age-related degenerative diseases associated with articular cartilage (AC) can result in significant patient morbidity and lead to the development of osteoarthritis. The Centers for Disease Control and Prevention estimates that nearly 67 million (25%) of US adults will have clinically-diagnosed arthritis by 2030, making it the nation's leading cause of disability. Because of the avascular nature and limited potential for growth and self-repair, the treatment of articular cartilage damage remains one of the most challenging topics in orthopedic healthcare. The social and economic implications of repairing or regenerating injured AC tissues either indefinitely or until the patient reaches the age at which total joint replacement is appropriate are enormous. The goal of this project is to design synthetic AC tissue grafts possessing cartilage-like compressive behavior, gradient biochemical microenvironment, stratified distribution of human marrow stromal cells (hMSC), and enhanced surface bonding affinity to subchondral bone for the reconstruction of full thickness articular cartilage defects. Three specific aims are developed. In Aim 1, we will test the hypothesis that chondroitin sulfate-mimicking (CS-M) polyelectrolyte fiber meshes can be fabricated to retain and release exogenous chondrogenic and osteogenic growth factors to induce chondrogenic and osteogenic differentiation of hMSC in culture, respectively. In Aim 2, we will test the hypothesis that chondrogenic and osteogenic CS-M fiber meshes pre-seeded with hMSC cells can be laminally encapsulated in photo-crosslinked hydrogel to create composite AC graft with cartilage-like compressive behavior, stratified zonal cellular distribution, and chondrogenic-to-osteogenic gradient biochemical microenvironment across the thickness of the composite graft. In Aim 3, we will test the hypothesis that the surface of the AC graft can be covalently functionalized with small molecule hydroxyapatite (HA)-binding ligands to enhance the graft bonding to subchondral bony tissue. The successful execution of the proposed project will contribute to the development of a novel strategy for the clinical treatment or replacement of AC tissues severely damaged due to chronic diseases, aging, trauma and congenital deformity. PUBLIC HEALTH RELEVANCE: Traumatic injuries and age-related degenerative diseases associated with articular cartilage can result in significant patient morbidity and lead to the development of osteoarthritis. The Centers for Disease Control and Prevention estimates that nearly 67 million (25%) of US adults will have clinically-diagnosed arthritis by 2030, making it the nation's leading cause of disability. Because of the avascular nature and limited potential for growth and self-repair, articular cartilage tissue damages are particularly challenging to repair. Tissue engineered cartilage constructs hold great promise in the clinical treatment or replacement of severely diseased (e.g. end-stage osteoarthritic) cartilage tissues. The successful development of viable synthetic cartilage constructs has significant social and economic implications, and contributes to improving the musculoskeletal health of the general population.