PROJECT SUMMARY/ABSTRACT Drug addiction and overdose are a growing problem in the US, accounting for 107,622 overdose deaths in 2021. Over 60% of drug overdose deaths involved misuse of prescription or illicit opioids. 30% of opioid prescriptions are written following oral surgical or dental procedures to control acute post-operative pain. Approximately 10 million wisdom teeth are removed annually. A statistically significant 6.8% absolute risk increase in persistent opioid use and a 5.4% increase in the subsequent diagnosis of opioid abuse follows a single course of opiates following wisdom tooth extraction. Therefore, there is a compelling need to develop non-opioid-based acute pain management strategies for outpatient oral surgical procedures, preferably via local delivery of medication to the target tissue because the medication can provide the desired pain control with lower total dosage and lower incidence of serious side effects. RevBio has developed Tetranite® Adhesive Dental Bone Scaffold (ADBS), a novel adhesive mineral-organic biomaterial that can both fill space as an osteoconductive scaffold and exclude irritants from reaching cut bone surface. This device-led patented combination product can serve as a drug delivery vehicle with designing controls available to vary porosity to provide drug release profiles for any targeted indication. A Phase I investigation into the TN-ADBS drug release kinetics has shown that bupivacaine (Bp) follows predictable and tunable patterns over the time window of interest, and an in vivo pilot study has demonstrated feasibility of the proposed model. Preliminary safety studies have shown that TN-ADBS+Bp was not cytotoxic and that overlying gingival tissues healed uneventfully following the material’s implantation into proposed model extraction sites in canines. The company is confident that an effective Bp dose can be released over the 5-day window when analgesia is most needed to limit post-operative pain following wisdom tooth removal. Prior Phase I funding (1R43DE029369-01) awarded by NIH-HEAL Initiative has been used to: (a) designed a porous cohesive and adhesive formulation that enables time-dependent release of bupivacaine, (b) evaluated the handling properties of the formulation without the inclusion of bupivacaine, (c) determined soft tissue compatibility of the formulation using a canine molar defect, and (d) conducted preliminary efficacy of the formulation without the drug, i.e., rate of bone substitution in a canine model. Additionally, the proposed regulatory pathway was presented to FDA via request for designation (RFD) process. Based on FDA’s feedback, this product will be regulated as a device-led combination product in which OPLS, and bupivacaine are classified as the drug constituents. The following proposed Phase II grant application is to address the following two Specific Aims: (1) conduct human factor assessment and (2) to demonstrate the ability to mitigate pain and bone regenerative properties of BP loaded TN-ADBS in canine model by (i) developing a validation model for the use of Telemetric data collection, (ii) demonstrate pain mitigation efficacy of TN-ADBS and TN-ADBS+Bp in comparison to controls (p<0.05), (iii) demonstrate bone regenerative efficacy of TN-ADBS and TN-ADBS+Bp in comparison to controls (p<0.05), and (iv) demonstrate safety of TN-ADBS and TN-ADBS+Bp on local soft and hard tissue as per ISO 10993-6:2016 (Annex E). The results from this Phase II study, surgeon validated simulated use trails and in vivo animal studies, will translate to assessment of this promising method to humans in Investigational Device Exemption (IDE)-approved studies. This would close one of the major gateways into opioid exposure to vulnerable populations as supported by the NIH Helping to End Addiction Long-term® (HEAL) Initiative. RevBio’s mission is to provide surgeons with a novel bone grafting product to simplify surgery and improve patient outcomes following procedures generating bony defects.

PROJECT NARRATIVE Drug addiction and overdose are major problems in the US. Over 60% of drug overdose deaths involved misuse of prescription or illicit opioids. A major factor in drug addiction rates is post-operative opioid prescription following routine dental surgeries such as wisdom tooth extraction. Finding an alternative to opioid prescription is paramount, most importantly for patients undergoing wisdom tooth extraction as they are predominantly teens and young adults. The proposed study aims at developing a novel regenerative bone scaffold that can administer locally acting pain medication, as an alternative pain mitigation strategy to opioid prescription.