Enabling adenosine signaling to promote aged fracture healing

Despite its regenerative capacity, the healing potential of bone tissue declines with aging. With the increase in global aging population, bone fractures pose a tremendous burden to the healthcare system. Therapeutic interventions that circumvent age-associated impairments and promote bone tissue regeneration are attractive options for geriatric fracture repair. We and others have demonstrated the role of extracellular adenosine in bone homeostasis and regeneration. Herein, we examined the changes in extracellular adenosine with aging and the potential of local delivery of adenosine to promote fracture healing using aged mice as a model system. Extracellular adenosine level was significantly lower in aged bone tissue compared to those from young mice. Concomitantly, the ecto-5'-nucleotidase CD73 expression was also found to be lower in the aged bone tissue. Local delivery of adenosine using injectable, in situ curing microgel delivery units yielded a pro-regenerative environment and promoted fracture healing in aged mice. This study offers new insights into age-related physiological changes in adenosine levels and demonstrates the therapeutic potential of adenosine supplementation to circumvent the compromised healing of geriatric fractures. Overall design: Calluses from mice treated with either 1) adenosine-containing microgel or 2) empty microgel were harvested seven days after treatment and analyzed using scRNA-seq