Human birth tissue products as a regenerative medicine for post-surgical pain through multi-modal action

Post-surgical pain causes significant suffering. Extracts of the human amniotic membrane (AM) may be novel regenerative matrices, but little is known about their use in pain treatment. Locally applying FLO (particulates of AM) in mice acutely attenuated post-surgical pain hypersensitivity and inhibited its transition to a prolonged state after plantar-incision. Mechanistically, this was achieved through direct nociceptive neuronal inhibition via CD44-dependent mechanisms and indirect anti-pain effect by attenuating immune cell recruitment and promoting wound healing. We purified heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM as a major bioactive matrix component for pain relief, as it mirrored FLO-induced analgesia and nociceptive neuronal inhibition. Strikingly, HC-HA/PTX3 triggered acute cytoskeleton rearrangement to inhibit ion channels on nociceptive neurons, presenting a novel cellular mechanism for pain control. Moreover, long-term drug treatment broadly changed neuronal gene expression. Our study demonstrated the potential and mechanisms of a naturally occurring biologic from human birth tissues as non-opioid treatments for post-surgical pain.