Injectable local anesthetics that would last up to 7 days could have a significant impact on chronic musculoskeletal pain management. However, current formulations have been limited by their relatively short duration of action required repeated administrations. In addition, local anesthetics are often associated with systemic toxicity and local tissue site inflammatory responses. To address these issues, we propose is to develop a novel injectable analgesia delivery system lasting up to 7 days with minimum side effects. Approaches that synergistic drug combinations used in conjunction with biodegradable hydrogel polymer have been shown to prolong neural blockade. We have previously demonstrated that a hydrogel system composed of chitosan, ropivacaine and dexamethasone resulted in controlled anesthetic drug delivery and sustained anesthetic effects in vivo. Although the system is quite promising, the use of dexamethasone has been problematic to musculoskeletal tissue, this it might not be suitable for musculoskeketal pain management. Alpha cobratoxin ( -CTx) is believed to be the new regimen to combat pain with the advantages of long-lasting analgesia activity, non-addictive, minimal side effects, relatively inexpensive, an commercial availability. Our preliminary data indicated that -CTx has less cytotoxic effect to osteoblast and neurons. Here we propose to develop an extended local injectable hydrogel based controlled release system by synergistically combining ropivavaine and -CTx. We hypothesize that an enzymatically cross-linked chitosan hydrogel can locally deliver and sustain the release of ropivacaine and -CTx and that the synergistic effect of ropivacaine and - CTx will help to achieve pain relief for up to 7 days with minimal inflammatory response. We propose to test the hypothesis via two specific aims 1) To develop and characterize a ropivacaine- CTx loaded injectable chitosan hydrogel as a local control delivery system and evaluate the in vitro bioactivity of the formulation using cell culture model. 2) To evaluate the in vivo biological performance of the ropivacaine and CTx -loaded chitosan hydrogel. If successful the proposed study will have a significant impact in the clinical translation of prolonged local pain relief systems for efficient musculoskeletal pain management.

Public Health Relevance

Injectable local anesthetics that would last for many days could have a significant impact on chronic musculoskeletal pain management. The purpose of this application is to develop a novel injectable analgesic delivery device lasting up to 7 days with minimum side effects. By combining the expertise of the researchers in material science, drug delivery, cell molecular biology, and small animal surgery, our studies will result in novel injectable analgesic delivery device that can potentially become a viable alternative to current formulation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Musculoskeletal Tissue Engineering Study Section (MTE)
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Washabaugh, Charles H
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University of Connecticut
Schools of Medicine
United States
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Khanal, Manakamana; Gohil, Shalini V; Kuyinu, Emmanuel et al. (2018) Injectable nanocomposite analgesic delivery system for musculoskeletal pain management. Acta Biomater 74:280-290
Bagshaw, Kyle R; Hanenbaum, Curt L; Carbone, Erica J et al. (2015) Pain management via local anesthetics and responsive hydrogels. Ther Deliv 6:165-76