Treatment to Promote Achilles Tendon Healing

Veterans who experience Achilles tendon (AT) injuries, including tendinopathy (due to overuse) or a tendon tear during active military duty face lifelong risk of physical disability, pain, psychosocial distress, and predisposition to reinjury. This is because tendons lack the ability to regenerate and instead heal as fibrotic scar tissue. Tendon injuries occur with daily, repetitive, and arduous physical training coupled with carrying heavy equipment during military training and service. Tendinopathy that occurs with overuse is associated with microtears, aberrant extracellular matrix (ECM), decreased mechanical properties, and reduced function, and often progress into larger tears. Tears heal as scar tissue with aberrant ECM and mechanical properties that lead to dysfunction and predisposition for reinjury. Unfortunately, current treatments for tendon injuries focus primarily on pain relief rather than improving tendon tissue quality. This creates a vicious cycle in which a patient returns to function upon pain relief, but then re-injures the tendon because the treatment failed to also strengthen the tissue. Others report that after healing from injury, adult tendons possess inferior mechanical properties driven by abnormally low density of lysyl oxidase-mediated collagen crosslinks (LOX-xlinks). Our lab innovatively focuses on developing adult tendon therapeutics based on mechanisms of natural tendon formation in the embryo. We discovered that LOX-xlinking is a critical regulator of AT mechanical properties during tendon development. We also discovered that promoting LOX-xlinking using recombinant LOX (rLOX) can improve tendon mechanical properties during tissue formation without cytotoxicity or over-stiffening. Building on our compelling data, our objective is to enhance functional outcomes (gait, pain) by leveraging the naturally occurring process of LOX-xlinking to improve mechanical properties and collagen organization of healing tendons, without toxicity, and without overstiffening. To achieve this, we will pursue two Aims. Aim 1 will use an established [mouse] Achilles tendon transection model to test how rLOX treatment during healing enhances return to function by improving mechanical properties and collagen alignment. [Fully] transected AT will be treated with rLOX during earlier or later remodeling phases of healing, and then gait, pain behavior, and tissue properties will be quantitatively assessed for females and males. We hypothesize that rLOX treatment will improve animal function relative to vehicle-treated injured controls by increasing AT mechanical properties and collagen organization, with greater functional improvements when treated during the early remodeling phase of healing. Aim 2 will use an established [mouse] Achilles tendinopathy model to test how rLOX treatment improves functional outcomes and tissue properties relative to controls. AT will be injected with collagenase to induce tendinopathy, and then treated with rLOX during early or late stages of tendinopathy. Gait, pain behavior, and tissue properties will be quantitatively assessed for females and males. We hypothesize that rLOX treatment will improve animal function by improving AT mechanical properties relative to vehicle-treated injured controls, with greater functional improvements when treated during early tendinopathy. Aims 1 and 2 will also examine cell phenotype stability, cell behaviors, inflammatory status, and potential for AT overstiffening and off-target crosslinking with rLOX treatments. Successful outcomes will demonstrate the potential for a minimally invasive, injectable rLOX treatment that improves functional outcomes by improving mechanical properties and collagen alignment of healing tendons, without adverse cell behaviors, overstiffening, or off-target crosslinking. The proposed research is a necessary first step toward developing a clinically translatable solution for AT ruptures and tendinopathy that harnesses nature’s Project Number: 1I01RX005328-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Catherine Kuo | Institution: BALTIMORE VA MEDICAL CENTER, BALTIMORE, MD | Activity Code: I01 | Study Section: Musculoskeletal Health & Function[RRD2] View on NIH RePORTER: https://reporter.nih.gov/project-details/11113645