Implantable, Degradable Drug Delivery Devices for Non-Opioid Post-Surgical Pain Management - One out of every nine Americans has surgery each year and 30-80% experience uncontrolled postoperative pain. There is a clear need to 1) localize treatment to simplify delivery and avoid systemic toxicity, 2) achieve long duration release to span the duration of postoperative pain without the need for opioids, and 3) deliver adequate pain control customized to the patient and the location of pain. This R18 HEAL research offers the opportunity to transform postoperative pain control using a new device: a biomaterial film to deliver local anesthetics after surgery. Our device is flexible, can be cut for precise dosing, is sutured in place during surgery, and degrades when no longer needed. It can be placed intraoperatively in multiple locations to target nerve locations and, unlike liquid formulations, it will not migrate. Our device can be used by adults, but includes design features that allow it to be “right-sized” for infants and children. The surfaces of the biocompatible, biodegradable protein films have a dense lawn of brush polymers that are linked via a tethering molecule to the anesthetic ropivacaine. The films feature two modes to control drug release by modifying 1) diffusion through the brush polymer layer and 2) the susceptibility of the tethers to hydrolysis, the combination of which are hypothesized to permit controlled continuous release of ropivacaine at the desired site. Aim 1 will synthesize protein films conjugated with brush polymers that are hydrophilic, hydrophobic, or intermediate in nature that are linked to ropivacaine by a tether of varying composition and will measure the release of ropivacaine in different in vitro environments that mimic the human body. This aim will also characterize the release of ropivacaine from the polymer brushes with different brush spatial arrangements. Aim 2 will assess the safety and efficacy of the film. First, it will be evaluated with in vitro cell viability and in vivo by histological evaluation for local tissue inflammation and film degradation. Plasma concentrations of drug released from implanted films will be quantified in a catheterized rat model, and pharmacokinetic modeling will be used to establish a local in vivo drug release curve as well as to correlate in vitro and in vivo release. Finally, the efficacy of the film to block nerves in vivo and to reduce pain in vivo in mice after surgery will be evaluated along with the local tissue response to the implanted biomaterial. Aim 3 will address the unique requirements of the HEAL RFA, with customer discovery, market research, and manufacturing partnership and FDA meetings as needed to prepare for first-in-human trials. This novel brush polymer technique, never before used for drug delivery, offers the unprecedented opportunity to solve the critical limitations of local anesthetics and provide “right-size”, continuous, opioid-free postoperative pain control to patients.
