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J Knee Surg
DOI: 10.1055/a-2712-4402
Original Article

The Negative Impact of High Molecular Weight Hyaluronan on Anterior Cruciate Ligament Wound Repair

Authors

  • James Rogot 

    1   Biomedical Engineering, Columbia University, New York, United States

  • Lance A. Murphy

    2   Biomedical Engineering, Columbia University, New York, United States (Ringgold ID: RIN5798)

  • Claire Pinnie

    2   Biomedical Engineering, Columbia University, New York, United States (Ringgold ID: RIN5798)

  • Matthew J. Pellicore

    2   Biomedical Engineering, Columbia University, New York, United States (Ringgold ID: RIN5798)

  • Howard J. Nicholson III

    2   Biomedical Engineering, Columbia University, New York, United States (Ringgold ID: RIN5798)

  • James L. Cook

    3   Orthopaedic Surgery, University of Missouri Hospital, Columbia, United States

  • Clark T. Hung

    1   Biomedical Engineering, Columbia University, New York, United States

Supported by: Congressionally Directed Medical Research Programs PR191398
Supported by: Clinical Center 3R01AR068133-03S1
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Surgical reconstruction of the anterior cruciate ligament (ACL) has historically been the only method by which knee stability is restored following ACL rupture. Following ACL rupture the torn ends of the ligament are exposed to the synovial environment, containing hyaluronan (HA), which has been implicated in poor migratory function of ACL fibroblasts (ACLF). We hypothesize that the HA in synovial fluid attenuates the wound healing response of the ACL by inhibition of new focal adhesions between ACLF and the surrounding environment. Juvenile bovine ACLF were isolated and cultured in the presence of endogenous and exogenous high molecular weight HA (HMWHA) to monitor in vitro wound closure. Concurrently, cells were assayed for focal adhesion formation and adhesion strength. Next, human ACLF were cast into tissue engineered constructs to assess their ability to contract within a 3D matrix after treatment with HA. A cellular viability assay was used to determine cytotoxicity of HMWHA. Co-culture of synoviocytes with ACLF wounds demonstrated that HMWHA was the primary cause for attenuated wound healing. When exogenous HMWHA was cultured with ACLF, a dose-dependent negative correlation (r = -0.65, p < 0.001) in cell migration was observed. A significant decrease in number and strength of focal adhesions was found to mirror the dose-dependent pattern. Collagen gel contraction was inhibited in the presence of HMWHA. Direct exposure of ACLF to HMWHA was shown to inhibit ACLF wound healing and contraction. As cytotoxicity remained unchanged, this decreased healing capacity is attributed to reduced focal adhesion formation and weakened adhesion strength of ACLF in the presence of HMWHA. This study identifies HMWHA exclusion as a potential therapeutic strategy and provides insight into the mechanism by which traditional primary repair of the ACL as well as graft reconstructions may fail.



Publication History

Received: 09 May 2025

Accepted: 26 September 2025

Accepted Manuscript online:
30 September 2025

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