In situ forming implant drug delivery for non-addictive post-operative analgesia

PROJECT SUMMARY The opioid crisis in the United States resulted in over 100,000 overdose deaths in 2022. Reducing opioid prescriptions, particularly for acute pain, is crucial for minimizing substance use disorders. However, current alternatives for pain management are insufficient, leaving opioids as the predominant treatment strategy. Currently, the longest-acting analgesia available lasts only 72 hours; however, patients may experience pain for up to 168 hours following oral facial surgery. Therefore, extending analgesia beyond 72 hours is critical for effective postoperative pain relief. The proposed in-situ forming implant (ISFI) offers the potential for local anesthetic release, regional nerve blocks, and acute and chronic pain treatment. We will use a poly(beta-amino ester) (PBAE) microparticle derived from poly(ethylene glycol) diacrylate (PEGDA) and hyaluronate acrylate (HA), incorporated into a poly(lactic-co-glycolic acid) (PLGA) system. This ISFI design will be gel-like prior to complexation, and upon injection into an aqueous solution will form a solid. The PEGDA-HA microparticle will be loaded with bupivacaine, ensuring all of the drug is in the inner layer of the polymer matrix, which is hypothesized to reduce and potentially eliminate burst release, and rather yield a monophasic zero-order release profile to ensure consistent drug release in the therapeutic window. Clinical oversight on this project is provided by Dr. Gupta and materials design is provided by Dr. Givens and Dr. Hilt, who each have expertise in polymeric drug delivery. The team has a history of successful collaboration and mentoring, ensuring effective research execution. The research focuses on materials synthesis, characterization, and evaluation of bupivacaine release profiles at different pH levels. Preliminary data indicate the feasibility of generating crosslinked acrylate systems and ISFIs from these systems. The research objectives in this proposal are to achieve high bupivacaine loading to minimize polymer volumes per injection and sustained release over a 168-hour therapeutic window. We will also develop a biomimetic model to evaluate ISFI formation, degradation, and drug release in the orofacial region. The successful completion of this project will provide novel information on PEGDA-HA systems for drug delivery and the potential for ISFIs as long-term analgesic delivery for post-operative pain management.