Mussel-inspired Injectable Microbubbles Delivery System for Drug Ultrasound Contrast and Long-lasting Analgesic Effect in Peripheral Nerve Block

Abstract

Abstract Background Ultrasound-guided peripheral nerve block is difficult to accurately identify the diffusion location of injected local anesthetics. Moreover, current available local anesthetics are limited in duration, which is inadequate for the treatment of prolonged pain. We designed a drug delivery system by using adhesive polylactic-co-glycolic acid (PLGA) microbubbles loaded with ropivacaine to accurately identify and deliver the local anesthetics to the desired targeted site for prolonged analgesic time in rat pain models. Methods The adhesive PLGA-ropivacaine microbubbles (APRMs) were fabricated by coating polydopamine on the PLGA microbubbles with ropivacaine embedded in the shell. Ropivacaine release and ultrasonographic experiments of APRMs were conducted in vitro. Then, incision surgery and SNI-induced neuropathic pain were conducted for adult male rats to verify the ropivacaine release of APRMs in vivo. Ultrasound imaging was performed to confirm the ultrasonic visualization of APRMs. The in vivo fluorescence imaging experiment was conducted for the adhesion property of APRMs. Finally, systemic toxicity and tissue reaction were histologically evaluated. Results In vivo, these microbubbles were able to accurately identify and release local anesthetics to targeted sites for prolonged analgesia. Results showed that APRMs not only presented a continuous release of ropivacaine for at least 16 days, but also exhibited strong dispersed echo spots in agarose gel. In animal model studies, APRMs alleviated mechanical allodynia and thermal hyperalgesia in neuropathic and postoperative pain, which lasted at least 7 days. More importantly, the APRMs performed a lower agent spread area and longer analgesic time than PRMs and ropivacaine groups in thermal analgesic test. Additionally, histological systemic toxicity and tissue reactions evaluated that APRMs did not display any detectable systemic toxicity or adverse tissue reactions. Conclusions APRMs served as an excellent nerve blocker in this delivery system to achieve accurate, sustainable, and safe analgesic efficacy for pain management.