Fibrous tissues of the musculoskeletal system (e.g., the knee meniscus) are plagued by their poor intrinsic healing capacity. In the previous funding cycles, we developed enabling technologies including multi-fiber scaffolds to introduce various temporal and structural signals towards the repair of meniscal tissue. We used these scaffolds to engineer constructs with properties and organization similar to native tissues (1st cycle) and then developed scaffolds to enhance endogenous tissue repair through the delivery of factors to recruit local cells (2nd cycle). The overall objective of this renewal is to further improve endogenous meniscus repair with engineered scaffolds through the appropriate temporal and spatial orchestration of factor delivery, to first (i) soften nuclei in cells (via a temporary reduction in heterochromatin content) near the injury site and then (ii) recruit and stabilize the phenotype of these cells within the repair scaffolds. We hypothesize that the delivery of these factors will permit recruitment of viable endogenous cells from the meniscus to the scaffolds and that the spatial control of these factors will improve scaffold colonization, even with thick scaffolds. We will employ composite scaffolds (developed during the previous funding cycles) 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 provide early release of factors into the environment), and an engineered hyaluronic acid (HA) fiber fraction (that degrades over weeks and releases factors in a sustained fashion). To address our hypotheses, the first Aim will utilize in vitro microfluidic- platforms to investigate the timing and dosing of nuclear-softening (Trichostatin A), chemotactic (platelet- derived growth factor), and fibro-chondrogenic factors (transforming growth factor-?3) to alter nuclear mechanics, cell recruitment, and promote resumption of the cellular phenotype of cells migrating into fibrous scaffolds from meniscal tissue. In the second Aim, we will control release from either the entire scaffold (as before) or from an internal layer (newly proposed) across a variety of scaffold thicknesses and release rates to promote population of thick scaffolds.
This Aim will be conducted using our recently developed subcutaneous model of meniscus tissue repair. In the third Aim, scaffolds will be implanted into meniscal defects in Yucatan minipigs to evaluate their efficacy in a clinically relevant defect model. If successful, these studies and technologies will advance our understanding of the use of engineered scaffolds for endogenous meniscus repair and provide a step towards clinical translation.

Public Health Relevance

Menisci of the knee cushion our joints during normal loading, but are commonly injured. Unfortunately, healing of the meniscus in adults is limited, and current treatment options do not restore function, resulting in degeneration of the underlying cartilage. To address this, we engineer fibrous scaffolds with tailored release of factors that sequentially promote endogenous cell migration from the surrounding tissue and direct differentiation upon arrival at the wound site, and test these in a large animal model of meniscus repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056624-12
Application #
10092955
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Fei
Project Start
2009-07-14
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
12
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Orthopedics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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
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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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