Sustained Release of Ropivacaine from Adhesive Injectable Microbubbles with Contrast-Enhanced Ultrasonography in Pain Management: An Animal Model Study

Background: Perioperative pain poses a significant challenge for surgical patients, with regional anesthesia commonly employed for postoperative pain relief. However, the utility of regional anesthesia is limited by the lack of real-time visualization during drug delivery and the rapid diffusion of anesthetics, which result in imprecise targeting and short duration of analgesia. Methods: An innovative ultrasound-guided drug sustained-release capsules were fabricated by bioinspired adhesive polylactic-co-glycolic acid (PLGA) loaded with ropivacaine microbubbles (APRMs). Ropivacaine release and ultrasonographic experiments of APRMs were conducted in vitro. For in vivo evaluation, a total of 127 adult male Sprague–Dawley rats (200– 250 g) were used. 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: APRMs achieved real-time visualization during drug delivery and significantly prolonged antinociceptive effects, maintaining mechanical analgesia for 9 days and thermal analgesia for up to 15 days, whereas free ropivacaine produced only transient effects (mechanical: approximately 24 h; thermal: approximately 4 h). Histological assessments revealed no toxicity or adverse tissue reactions, underscoring the safety of APRMs. Conclusion: APRMs represent a novel and promising strategy for pain management by integrating sustained anesthetic release, bioinspired adhesive properties for prolonged retention, and contrast-enhanced ultrasonography (CEUS) for real-time visualization. While these findings are encouraging, further in vivo validation and extended preclinical studies will be essential to confirm safety and efficacy before considering translation into clinical practice. Keywords: pain management, microbubbles, ropivacaine, polydopamine