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Despite development of protocols to differentiate human pluripotent stem cells (hPSCs), those used to produce sensory neurons remain difficult to replicate and result in heterogenous populations. There is a growing clinical burden of chronic pain conditions, highlighting the need for relevant human cellular models. This study presents a hybrid differentiation method to produce nociceptive sensory neurons from hPSCs. Lines harboring an inducible construct were patterned toward precursors with small molecules followed by overexpression. Neurons expressed key markers, including and , with single-cell RNA sequencing, revealing populations of nociceptors expressing and channels. Physiological profiling with multi-electrode arrays revealed that neurons responded to noxious stimuli, including capsaicin. Finally, we modeled pain-like states to identify genes and pathways involved in pain transduction. This study presents an optimized method to efficiently produce nociceptive sensory neurons and provides a tool to aid development of chronic pain research.

The use of high definition transcranial direct current stimulation (HD-tDCS) has shown analgesic effects in some chronic pain patients, but limited anti-nociceptive effects in healthy asymptomatic subjects. This double-blinded sham-controlled study assessed the effects of HD-tDCS applied on three consecutive days on central pain mechanisms in healthy participants with (N=40) and without (N=40) prolonged experimental pain induced by intramuscular injection of nerve growth factor into the right hand on Day1. Participants were randomly assigned to Sham-tDCS (N=20 with pain, N=20 without) or Active-tDCS (N=20 with pain, N=20 without) targeting simultaneously the primary motor cortex and dorsolateral prefrontal cortex for 20 min with 2mA stimulation intensity. Central pain mechanisms were assessed by cuff-algometry on the legs measuring pressure pain sensitivity, temporal summation of pain (TSP) and conditioned pain modulation (CPM), at baseline and after HD-tDCS on Day2 and Day3. Based on subject's assessment of received HD-tDCS (sham or active) they were effectively blinded. Compared with Sham-tDCS, Active-tDCS did not significantly reduce the average NGF-induced pain intensity. Tonic pain-induced temporal summation at Day2 and Day3 was significantly lower in the NGF-pain group under Active-tDCS compared to the pain group with Sham-tDCS (P≤0.05). No significant differences were found in the cuff pressure pain detection/tolerance thresholds or CPM effect across the 3 days of HD-tDCS in any of the four groups. HD-tDCS reduced the facilitation of TSP caused by tonic pain suggesting that efficacy of HD-tDCS might depend on the presence of sensitized central pain mechanisms.

The main objective of this study is to examine chronic pain and limping in relation to lower extremity and pelvic fracture location in addition to fracture combinations if multiple fractures are present on the same leg that have not been previously reported. We hypothesize that fracture pattern and location of lower extremity and pelvis fractures of multiple injured patients influence their long-term pain outcome.