A novel injectable fibromodulin‐releasing granular hydrogel for tendon healing and functional recovery

Abstract

A crucial component of the musculoskeletal system, the tendon is one of the most commonly injured tissues in the body. In severe cases, the ruptured tendon leads to permanent dysfunction. Although many efforts have been devoted to seeking a safe and efficient treatment for enhancing tendon healing, currently existing treatments have not yet achieved a major clinical improvement. Here, an injectable granular hyaluronic acid (gHA)‐hydrogel is engineered to deliver fibromodulin (FMOD)—a bioactive extracellular matrix (ECM) that enhances tenocyte mobility and optimizes the surrounding ECM assembly for tendon healing. The FMOD‐releasing granular HA (FMOD/gHA)‐hydrogel exhibits unique characteristics that are desired for both patients and health providers, such as permitting a microinvasive application and displaying a burst‐to‐sustained two‐phase release of FMOD, which leads to a prompt FMOD delivery followed by a constant dose‐maintaining period. Importantly, the generated FMOD‐releasing granular HA hydrogel significantly augmented tendon‐healing in a fully‐ruptured rat's Achilles tendon model histologically, mechanically, and functionally. Particularly, the breaking strength of the wounded tendon and the gait performance of treated rats returns to the same normal level as the healthy controls. In summary, a novel effective FMOD/gHA‐hydrogel is developed in response to the urgent demand for promoting tendon healing.

Understanding Tendon Fibroblast Biology and Heterogeneity

“…In terms of injectable treatments, hydrogels are widely used because they are biodegradable and resemble the physical properties of biological tissue, such that they do not interfere but still deliver the drug of interest. Examples of hydrogels used include hyaluronic acid and bioactive glass/sodium alginate, and delivery agents include fibromodulin and Mg 2+ with curcumin [74][75][76].…”

Hydrogels in the Treatment of Degenerative Tendinopathy

“…An example of this is a sustained-release hydrogel-based Rhynchophylline delivery system used to repair injured tendons [22] . Xu et al [81] developed an injectable fibromodulin-releasing hydrogel for tendon healing that significantly improved the histological results of tendon wound healing and led to the recovery of mechanical properties. Various cell delivery methods, such as hydrogel-based cell delivery, which delivers dermal fibroblasts into the tendon, can enhance and stimulate this process compared to adipose-derived stem cells [82] .…”

Fibromodulin, a Multifunctional Matricellular Modulator

“…Particularly, as an indispensable component of the tendon stem/progenitor cell (TSPC) niche that locates between the long parallel chains of collagen fibrils, FMOD regulates TSPC self-renewal and tenogenic differentiation, as well as protects TSPCs from BMP-induced calcium accumulation and ectopic tendon ossification (Bi et al 2007). Moreover, our recent studies demonstrate that FMOD effectively enhances the recruitment of tenocytes (the predominant cell population in tendons and the major contributor to its repair) by stimulating the expression of matrix metalloproteinases (MMPs), as well as upregulates lysyl oxidase (LOX) expression to augment collagen cross-linking for tensile strength establishment (Xu, Zhang, et al 2022), to aid tendon healing. To pave the path for FMOD’s clinic application, a hyaluronic acid–based granular hydrogel has been engineered to sustainably deliver FMOD in wounded tendons with a minimally invasive procedure.…”