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Introduction/Aims: Prior studies have emphasized the role of inflammation in the response to injury and muscle regeneration, but little emphasis has been placed on characterizing the relationship between innate inflammation, pain, and functional impairment. The aim of our study was to determine the contribution of innate immunity to prolonged pain following muscle contusion. Methods: We developed a closed‐impact mouse model of muscle contusion and a macrophage‐targeted near‐infrared fluorescent nanoemulsion. Closed‐impact contusions were delivered to the lower left limb. Pain sensitivity, gait dysfunction, and inflammation were assessed in the days and weeks post‐contusion. Macrophage accumulation was imaged in vivo by injecting i.v. near‐infrared nanoemulsion. Results: Despite hindpaw hypersensitivity persisting for several weeks, disruptions to gait and grip strength typically resolved within 10 days of injury. Using non‐invasive imaging and immunohistochemistry, we show that macrophage density peaks in and around the affected muscle 3 day post‐injury and quickly subsides. However, macrophage density in the ipsilateral sciatic nerve and dorsal root ganglia (DRG) increases more gradually and persists for at least 14 days. Discussion: In this study, we demonstrate pain sensitivity is influenced by the degree of lower muscle contusion, without significant changes to gait and grip strength. This may be due to modulation of pain signaling by macrophage proliferation in the sciatic nerve, upstream from the site of injury. Our work suggests chronic pain developing from muscle contusion is driven by macrophage‐derived neuroinflammation in the peripheral nervous system. [ABSTRACT FROM AUTHOR]

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN., (© 2024. The Author(s).)