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.

Public Health Relevance

This competitive renewal builds on our previous funding wherein we developed composite nanofibrous scaffolds to engineer dense connective tissues. In this proposal, we apply our unique multi-polymer scaffolds to orchestrate and advance endogenous meniscus repair. Meniscus injuries are plagued by a poor intrinsic healing capacity and current treatment options often fail, resulting in degeneration of the underlying cartilage. To address this, we design scaffolds to respond to the inflammatory environment to increase scaffold porosity and release agents to enable 3D cell migration and recruit cells to the wound interface. If successful, this approach will represent a novel step towards clinical translation an improved treatment of an increasingly prevalent condition. Moreover, this novel material technology and delivery strategy could be extended to treat other dense connective tissues that do not heal.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
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University of Pennsylvania
Schools of Medicine
United States
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Qu, Feini; Li, Qing; Wang, Xiao et al. (2018) Maturation State and Matrix Microstructure Regulate Interstitial Cell Migration in Dense Connective Tissues. Sci Rep 8:3295
Loebel, Claudia; Burdick, Jason A (2018) Engineering Stem and Stromal Cell Therapies for Musculoskeletal Tissue Repair. Cell Stem Cell 22:325-339
Heo, Su-Jin; Szczesny, Spencer E; Kim, Dong Hwa et al. (2018) Expansion of mesenchymal stem cells on electrospun scaffolds maintains stemness, mechano-responsivity, and differentiation potential. J Orthop Res 36:808-815
Szczesny, Spencer E; Driscoll, Tristan P; Tseng, Hsiao-Yun et al. (2017) Crimped Nanofibrous Biomaterials Mimic Microstructure and Mechanics of Native Tissue and Alter Strain Transfer to Cells. ACS Biomater Sci Eng 3:2869-2876
Bansal, Sonia; Mandalapu, Sai; Aeppli, CĂ©line et al. (2017) Mechanical function near defects in an aligned nanofiber composite is preserved by inclusion of disorganized layers: Insight into meniscus structure and function. Acta Biomater 56:102-109
Cao, Xuan; Ban, Ehsan; Baker, Brendon M et al. (2017) Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices. Proc Natl Acad Sci U S A 114:E4549-E4555
Szczesny, Spencer E; Mauck, Robert L (2017) The Nuclear Option: Evidence Implicating the Cell Nucleus in Mechanotransduction. J Biomech Eng 139:
Qu, Feini; Holloway, Julianne L; Esterhai, John L et al. (2017) Programmed biomolecule delivery to enable and direct cell migration for connective tissue repair. Nat Commun 8:1780
Bansal, Sonia; Keah, Niobra M; Neuwirth, Alexander L et al. (2017) Large Animal Models of Meniscus Repair and Regeneration: A Systematic Review of the State of the Field. Tissue Eng Part C Methods 23:661-672
Cucchiarini, M; McNulty, A L; Mauck, R L et al. (2016) Advances in combining gene therapy with cell and tissue engineering-based approaches to enhance healing of the meniscus. Osteoarthritis Cartilage 24:1330-9

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