Dynamic Fibrous Scaffolds for Repairing Dense Connective Tissues

描述（由申请人提供）：肌肉骨骼系统的纤维组织受到其内在愈合能力差的困扰。在之前的资助周期中，我们开发了一种新型复合静电纺丝支架的技术，并使用这些支架来开发具有天然组织特性和组织结构的基于细胞的组织工程结构。在这种竞争性更新中，我们将重点转移到使用这些使能技术来增强内源性组织修复。我们的重点是膝关节半月板，这是一种纤维组织，对适当的负荷转移至关重要，目前的修复策略无法恢复其功能。这种更新的总体目标是使用这些支架

DESCRIPTION (provided by applicant): Fibrous tissues of the musculoskeletal system are plagued by their poor intrinsic healing capacity. In the previous funding cycle, we developed enabling technologies towards the production of a novel class of composite electrospun scaffolds, and used these scaffolds to develop cell-based tissue engineered constructs with native-like tissue properties and organization. In this competitive renewal, we shift our focus to using these enabling technologies to enhance endogenous tissue repair. Our focus is on the knee meniscus, a fibrous tissue critical for proper load transfer and for which current repair strategies do not restore function. The overall objective of this renewal is to use these scaffolds to deliver multiple agents over different temporal scales to specifically address the inherent limitations to endogenous meniscus repair. These limitations in the adult include synovial inflammation, low endogenous cellularity, and hindered cell mobility to the wound interface. This proposal will employ composite scaffolds (developed during the first funding cycle) that provide a stable fiber fraction (polycaprolactone (PCL), to provide an instructional pattern and mechanical stability), a sacrificial fiber fraction (polyethylene oxide (PEO), to define initial scaffold porosity), and an MMP-cleavable hyaluronic acid (HA) fiber fraction (that degrades in response to elevated proteolytic activity in synovial fluid of patients with meniscus damage). Degradation of the HA fiber fraction will both enhance cellular infiltration (by increasing scaffol porosity) and at the same time reduce degradation of nascent repair tissue (via competitive inhibition of synovial MMPs). These composite scaffolds will also address limited cellular mobility through the dense surrounding ECM by rapidly and locally decreasing nuclear stiffness (via the delivery of agents that reduce heterochromatin content and/or Lamin A/C processing) in endogenous meniscus cells. Finally, these scaffolds will selectively recruit endogenous meniscus cells towards the wound interface, to accelerate and sustain the repair process, via the delivery of stromal derived factor-1� (SDF-1�), a potent cytokine that increases meniscal cell migration. The synergistic interactions of these different repair adjuvants will be validated through in vitro scaffold and meniscal explant studies, and then tested in our large animal (ovine) meniscus defect model. If successful, these studies and technologies will set the stage for clinical translation and treatment of human meniscal injury by overcoming the inherent limitations to endogenous meniscus repair.