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Modulation of tendon mechanics by hyaluronic acid

Award Number: R21AR085969
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Modulation of tendon mechanics by hyaluronic acid - PROJECT SUMMARY There is a need to understand how deviations in glycosaminoglycan (GAG) content affect fiber level- mechanics so we can better inform regenerative therapies that aim to restore function to tendinopathic and aged tendons. Various studies investigating the influence of GAGs and proteoglycans (PGs) on tendon mechanics at the fiber and tissue scale have been conducted, usually via knockout of 1 – 2 components or non-specific enzymatic degradation. However, the effects of enzymatic treatments are inconclusive as most studies do not consider hyaluronic acid (HA), a linear GAG made up of repeating disaccharide units. Despite the simplicity, HA is integral in development, homeostasis and repair by regulating swelling pressure, tissue hydration and cell behavior. To test the effect of HA on fiber scale mechanics, we developed a new methodology that leverages laser ablation of collagen fibers within intact tendons. Excitingly, we observed enzymatic depletion of HA in murine extensor carpi radialis longus (ECRL) tendons significantly reduced the amount individual collagen fibers retract after laser ablation. This preliminary data led us to hypothesize strain recovery in type I collagen fibers is facilitated by interfibrillar HA. Specifically, disruption of HA and/or HA-binding partners will decrease strain recovery of type I collagen fibers. We will test the effect of GAG depletion and (re)addition on fiber-level mechanics of both energy storing (plantaris) and positional (ECRL) murine tendons, as well as in a model where GAG content is disrupted (aged mice). We will use the HA-specific Hyal from S. hyalurolyticus to target HA and compare the mechanical response when sulfated GAGs (sGAGs) are removed via chondroitinase ABC (ChABC). To confirm what components of the ECM were removed via enzymatic digestion, we will use proteomics, ELISA (HA) and dimethylmethylene blue (sGAGs) assays. Finally, we will adapt a strategy previously developed for cartilage by our collaborator, Jason Burdick, to reintroduce HA back into tendons. Comparison of the response of these tendons to Hyal and ChABC in Aim 1 will enable us to see if the effect of HA on fiber strain recovery is broadly applicable to all tendons or unique to the ECRL. To see how fiber sliding is affected in a model of native GAG disruption, we will investigate the effect of HA removal on aged tendons. Finally, we will use proteomics and biochemical assays for GAGs to identify how the ECM changes as a function of enzyme treatment and aging. To directly test if HA alone or HA binding partners affect strain recovery, we will reintroduce HA to the digested tendons in Aim 2. Furthermore, we will investigate if the addition of HA to undigested tendons increases strain recovery in control adult and aged tendons, which will inform how current HA-based treatments can affect tissue mechanics. Demonstration that exogenous HA enhances strain recovery in control and aged tendons will pave the way for new treatments that can reduce pathological stiffening and enhance functionality.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $348,339 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/20/2026	NEW	$348,339
														Subtotal = $348,339

Grand Total All Awards = $348,339

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Modulation of tendon mechanics by hyaluronic acid

Award Number: R21AR085969

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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