Microgel-Assisted Delivery of Adenosine to Accelerate Fracture Healing.

Extracellular adenosine plays a key role in promoting bone tissue formation. Local delivery of adenosine could be an effective therapeutic strategy to harness the beneficial effect of extracellular adenosine on bone tissue formation following injury. Herein, we describe the development of an injectable in situ curing scaffold containing microgel-based adenosine delivery units. The two-component scaffold includes adenosine-loaded microgels and functionalized hyaluronic acid (HA) molecules. The microgels were generated upon copolymerization of 3-acrylamidophenylboronic acid (3-APBA)- and 2-aminoethylmethacrylamide (2-AEMA)-conjugated HA (HA-AEMA) in an emulsion suspension. The PBA functional groups were used to load the adenosine molecules. Mixing of the microgels with the HA polymers containing clickable groups, dibenzocyclooctyne (DBCO) and azide (HA-DBCO and HA-Azide), resulted in a 3D scaffold embedded with adenosine delivery units. Application of the in situ curing scaffolds containing adenosine-loaded microgels following tibial fracture injury showed improved bone tissue healing in a mouse model as demonstrated by the reduced callus size, higher bone volume, and increased tissue mineral density compared to those treated with the scaffold without adenosine. Overall, our results suggest that local delivery of adenosine could potentially be an effective strategy to promote bone tissue repair.

pH-Sensitive nanocarrier assisted delivery of adenosine to treat osteoporotic bone loss.

Bone tissue undergoes continuous remodeling via osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An imbalance in this process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche. This acidic environment could serve as a potential trigger for the delivery of therapeutic agents into the osteoporotic bone tissue. To this end, we developed a pH-responsive nanocarrier-based drug delivery system that binds to the bone tissue and delivers an osteoanabolic molecule, adenosine. Adenosine is incorporated into a hyaluronic acid (HA)-based nanocarrier through a pH-sensitive ketal group. The HA-nanocarrier is further functionalized with alendronate moieties to improve binding to the bone tissues. Systemic administration of the nanocarrier containing adenosine attenuated bone loss in ovariectomized mice and showed comparable bone qualities to that of healthy mice. Delivery of osteoanabolic small molecules that can contribute to bone formation and inhibit excessive osteoclast activity by leveraging the tissue-specific milieu could serve as viable therapeutics for osteoporosis.