Objective: Achilles Tendonitis is a degenerative condition characterized by inflammation and micro-tears, leading to impaired mobility and long-term functional deficits. Despite current therapies, challenges remain in effectively reducing localized inflammation and promoting tendon regeneration, especially in the early stages of injury. Nicotinamide riboside (NR), a key precursor of NAD+, has shown potential in supporting cellular energy metabolism and tissue repair. However, systemic administration of NR complicates its localized therapeutic effect. To overcome these limitations, we developed a biodegradable, adhesive hydrogel conjugated with NR (ideal-NR) for localized delivery aimed at enhancing NAD+ replenishment at the site of tendon injury, thereby facilitating effective tendon repair.
Methods: The ideal-NR hydrogel was developed and evaluated in a murine model of Achilles Tendonitis. Therapeutic efficacy was assessed using high-resolution spatial transcriptomics to map gene expression changes across tissue sections with single-cell precision, allowing for accurate localization of cellular responses. Additional validation was conducted in vitro to explore specific cellular effects.
Results: NAD+ metabolism was found to be dysregulated in tendonitis patients based on publicly available datasets. Localized delivery of ideal-NR significantly improved tendon motion and strength by enhancing tissue repair, collagen remodeling, and reducing inflammation and oxidative stress. These findings were corroborated by high-resolution spatial transcriptomics, revealing specific spatial gene expression patterns associated with improved tendon healing, and further supported by in vitro studies with human tenocytes and macrophages.
Conclusion: Local NAD+ replenishment via ideal-NR presents a promising therapeutic approach for Achilles Tendonitis, overcoming the limitations of systemic therapies and promoting tendon regeneration through targeted biological mechanisms.