Introduction: Bone regeneration procedures require invasive and painful interventions. Bone fixation for instance involve invasive incision through skin and muscle to expose bone in order to place fixation plates. Pain management in bone regeneration interventions is limited to the use of drugs such as non-steroidal anti-inflammatories, opioids, acetaminophen and local anesthetics. However, these drugs have several limitations; non-steroidal anti-inflammatories delay bone healing and increase the risk of gastrointestinal diseases[1],[2]. Opioids are controlled drugs, and have major side effects such as constipation and addiction[3]. Acetaminophens are usually not effective in moderate or severe bone pain. Local anesthetics are relatively the most effective and have the least side effects, however they are limited by their short duration of action[3].
Due to the issues raised above, a bone regeneration biomaterial that can relief pain and be applied through minimal invasive procedures could bring a paradigm shift to the field of orthopedic and craniofacial interventions. Recently, we have shown that sodium magnesium phosphate nanocrystals (gel) are osteoinductive, thixotropic colloidal suspension and can be injected through high gauge needles (unpublished work) and therefore can be used for minimal invasive interventions. In this study, we investigated how this gel can control the release of local anesthetic (mepivacaine) in-vitro and in-vivo with the ultimate goal of developing an injectable bone regeneration biomaterial with analgesic property.
Materials and Methods: The gel was prepared by dissolving 85 mg of Mg(OH)2 in 2.2 mL of H3PO4 1.5 M and subsequent addition of 3.8 mL of NaOH 1.5 M under vigorous stirring. The resulting colloidal suspension was centrifuged, and the supernatant was discarded. Different concentrations of mepivacaine were dissolved in the gel for drug release by placing them in Pur-L-Lyzer dialysis kit, incubated in 30mL of PBS at 37Co. The PBS was changed and analyzed with UV-Vis spectroscopy at different time points (0-168) hours in order calculate the amount of drug released. The analgesic action of the mepivacaine with gel was assessed in-vivo using the mouse-hindpaw-model. Twelve mice were assigned into four groups (n=3, each); saline, mepivacaine, gel and gel+mepivacaine. Each mouse received a single injection of the assigned treatment (5 μL subcutaneously) into the planter surface of the hindpaw. Sensitivity to thermal stimuli was tested using radiant heat at different time points (15-120 minutes).
Results and Discussions: The gel was able to control the release of mepivacaine for up to 24 hours. Higuchi and Korsmeyer-Peppas models indicated that mepivacaine was release by diffusion. The mepivacaine released by the gel presented no change in its molecular structure as shown by UV-Vis spectra, indicating that the drug was compatible the gel (figure 1).
Radiant heat test showed that the gel loaded with mepivacaine provides analgesia and the analgesic action of mepivacaine was prolonged by the gel (figure 2).
Conclusion: The bone regeneration biomaterial described here can be injected through high gauge needle and provide analgesia. This biomaterial could minimize the invasiveness of bone regeneration procedures, shorten the healing period and mobilization time while eliminating the need for systemic drugs for pain management.
McGill University, Faculty of Dentistry; University of Dammam, College of Dentistry; Saudi Arabian Cultural Bureau
References:
[1] Gerstenfeld, L. C. et al. Differential inhibition of fracture healing by non‐selective and cyclooxygenase‐2 selective non‐steroidal anti‐inflammatory drugs. Journal of orthopaedic research 21, 670-675 (2003).
[2] Aspenberg, P. Avoid cox inhibitors after skeletal surgery! Acta Orthopaedica 73, 489-490 (2002).
[3] Andersen, L. J., Poulsen, T., Krogh, B. & Nielsen, T. Postoperative analgesia in total hip arthroplasty: a randomized double-blinded, placebo-controlled study on peroperative and postoperative ropivacaine, ketorolac, and adrenaline wound infiltration. Acta orthopaedica 78, 187-192 (2007).