Chondrogenic composite grafts for the repair of cartilage defects

描述（由申请方提供）：与关节软骨（AC）相关的创伤性损伤和年龄相关退行性疾病可导致患者严重发病，并导致骨关节炎的发生。疾病控制和预防中心估计，到2030年，近6700万（25%）的美国成年人将患有临床诊断的关节炎，使其成为美国残疾的主要原因。由于无血管的性质和有限的生长和自我修复的潜力，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。无限期地或直到患者达到适合全关节置换的年龄，修复或再生受损AC组织的社会和经济影响是巨大的。本项目的目标是设计合成AC组织移植物，其具有软骨样压缩行为、梯度生化微环境、人骨髓基质细胞（hMSC）的分层分布以及增强的表面结合亲和力，用于重建全层关节软骨缺损。制定了三个具体目标。在目的1中，我们将测试的假设，硫酸软骨素模拟（CS-M）的纤维网可以制造保留和释放外源性软骨和成骨生长因子，诱导软骨和成骨分化的hMSC在培养中，分别。在目标2中，我们将检验以下假设：预先接种hMSC细胞的成软骨和成骨CS-M纤维网片可以层状包封在光交联水凝胶中，以产生具有软骨样压缩行为、分层带状细胞分布和跨复合移植物厚度的成软骨-成骨梯度生化微环境的复合AC移植物。在目标3中，我们将测试AC移植物表面可以用小分子羟基磷灰石（HA）结合配体共价官能化以增强移植物与软骨下骨组织的结合的假设。拟议项目的成功执行将有助于开发一种新的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组织的策略。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。疾病控制和预防中心估计，到2030年，近6700万（25%）的美国成年人将患有临床诊断的关节炎，使其成为美国残疾的主要原因。由于无血管性和有限的生长和自我修复潜力，关节软骨组织损伤的修复特别具有挑战性。组织工程化软骨构建体在严重病变（例如终末期骨关节炎）软骨组织的临床治疗或置换中具有很大的前景。可行的合成软骨结构的成功开发具有显著的社会和经济意义，并有助于改善普通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.