Chenshuang Li
| Chenshuang Li |
Chenshuang Li1, Xue Xu2, Yulong Zhang2, Pin Ha3, Benjamin M. Wu4, Andrew Da Lio3, Kang Ting5, Chia Soo3, Zhong Zheng2
1Orthodontics, University of Pennsylvania, School of Dental Medicine; 2School of Dentistry, University of California, Los Angeles; 3Division of Plastic and Reconstructive Surgery, David Geffen School of Medicine, University of California, Los Angeles; 4Division of Regenerative and Reconstructive Sciences, School of Dentistry, University of California; 5Forsyth Research Institute, Harvard University
Introduction
As 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. Existing treatments for tendon healing have not shown a major clinical improvement despite numerous efforts to find a safe and effective treatment.
Methods
Fibromodulin (FMOD) is a 59-kD small leucine-rich proteoglycan (SLRP) that regulates tendon collagen fibrillogenesis during the entire tendon developing period. Hydrogels are hydrophilic polymer networks prepared by physical or chemical cross-linking of synthetic and natural hydrophilic polymers with a unique 3-dimensional structure that can absorb large amounts of water or biological fluids. Its aqueous solubility allows for the modification of hyaluronic acid (HA) into various hydrogel systems with porous and 3D structures as the vehicle for growth factors, morphogens, and stem cells. In this study, the pro-healing effects of FMOD were first confirmed on tenocytes in vitro, and an injectable, FMOD-releasing granular HA hydrogel (FMOD/gHA-hydrogel) was developed for in vivo application. A rat’s Achilles tendon injury model was used to explore the potential benefits of the engineered FMOD/gHA-hydrogel on tendon healing. The animals were evaluated histologically, mechanically, and functionally for a comprehensive assessment.
Results
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 micro-invasive 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.
Conclusion
In summary, a novel effective FMOD/gHA-hydrogel is developed in response to the urgent demand for promoting tendon healing. A single administration of the FMOD/gHA-hydrogel is sufficient and permits a prompt delivery of FMOD followed by a constant dose-maintaining period.