Multi‐Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing

Abstract

Bone injuries such as fractures are one major cause of morbidities worldwide. A considerable number of fractures suffer from delayed healing, and the unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids with substantial adverse effects. Herein, we tested the hypothesis that the purine molecule, adenosine, can simultaneously alleviate pain and promote healing in a mouse model of tibial fracture by targeting distinctive adenosine receptor subtypes in different cell populations. To achieve this, a biomaterial‐assisted delivery of adenosine is utilized to localize and prolong its therapeutic effect at the injury site. The results demonstrate that local delivery of adenosine inhibited the nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigated pain as demonstrated by weight bearing and open field movement tests. Concurrently, local delivery of adenosine at the fracture site promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) resulting in improved bone healing as shown by histological analyses and microCT imaging. This study demonstrates the dual role of adenosine and its material‐assisted local delivery as a feasible therapeutic approach to treat bone trauma and associated pain.

Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing

“…However, anti-NGF therapy has also been labeled as having a multitude of adverse effects, making it a suboptimal candidate for widespread therapy. Interestingly, one recent finding has shown that exogenous delivery of adenosine can mitigate the nociceptive effects of NGF and reduce pain while simultaneously improving healing outcomes in mice [ 94 ]. In addition to NGF, caspase-6 has been identified as a potential prime regulator of fracture pain, and its inhibition in mice has also shown reduced pain behaviors following fracture [ 95 ].…”