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Evaluation of licofelone as an adjunct anti-inflammatory therapy to biologic scaffolds in the treatment of volumetric muscle loss

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Abstract

Biologic scaffolds (BS) are the most widely studied therapeutics for the treatment of volumetric muscle loss (VML) owing to their purported effects on cell proliferation, chemotaxis, migration, and differentiation. Despite these claims, variability in reports on the nature of the immune response to their implantation suggests that BS-associated inflammation may be limiting their regenerative efficacy. To address this shortcoming, this study sought to evaluate licofelone (ML3000), a dual 5-LOX/COX inhibitor, as an anti-inflammatory adjunct therapy to a BS in the treatment of VML. Utilizing a well-established rat VML model, a micronized BS was used to treat the VML injury, with or without administration of licofelone. Functional, molecular, and histological outcomes were assessed at both 7- and 28-day post-injury time points. While the BS + licofelone group exhibited decreased transcription of pro-inflammatory markers (Tnf, Ccl5, Nos2) relative to the BS only control group, no differences in expression profile of a panel of inflammatory-related soluble factors were observed between groups. A modest reduction in type I collagen was observed in the licofelone-treated group, but no meaningful differences in histologic presentation of repaired tissue were observed between groups. Furthermore, no differences in end organ functional capacity were observed between groups. Moving forward, efforts related to modulating the wound healing environment of VML should focus on polypharmaceutical strategies that target multiple aspects of the early pathophysiology of VML so as to provide an environment that is sufficiently permissive for local regenerative therapies to promote restoration of myofiber number.

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Funding

Funding for this study was provided by the National Institutes of Health (Award # 5R03EB018889-02).

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Authors and Affiliations

  1. DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD, USA

    Stephen M. Goldman, Naveena Basa Janakiram, Michael S. Valerio & Christopher L. Dearth

  2. Department of Surgery, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Bethesda, MD, USA

    Stephen M. Goldman, Naveena Basa Janakiram, Michael S. Valerio & Christopher L. Dearth

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  1. Stephen M. Goldman
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  2. Naveena Basa Janakiram
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  3. Michael S. Valerio
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  4. Christopher L. Dearth
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Correspondence to Christopher L. Dearth.

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All animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and all experiments were approved by the Institutional Animal Care Committee of the Uniformed Services University.

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Goldman, S.M., Janakiram, N.B., Valerio, M.S. et al. Evaluation of licofelone as an adjunct anti-inflammatory therapy to biologic scaffolds in the treatment of volumetric muscle loss. Cell Tissue Res 385, 149–159 (2021). https://doi.org/10.1007/s00441-021-03449-0

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