Project Summary Total knee arthroplasty (TKA) is one of the most performed orthopedic surgeries to relieve joint pain in patients with end-stage osteoarthritis (OA) or rheumatic arthritis (RA). In the US, over 700,000 TKA procedures are performed annually. To manage TKA pain patients are commonly prescribed opioids, contributing to a spiraling opioid epidemic. The misuse and addiction to opioids is a national public health crisis with an estimated economic burden of $78.5 billion per year. As opioid addiction is now a national health focus, novel non-opioid and non-pharmacological treatments for postoperative pain are a top scientific priority. There is an urgent need for a long-lasting, drug-free means of relieving post-TKA pain–which is the overall goal of this project. Cryoneurolysis is an opioid-sparing, perioperative intervention used to reduce postoperative pain. Current cryoneurolysis methods apply very low-temperature cryoprobes to freeze peripheral nerves, resulting in reversible and long-lasting pain relief. However, due to extremely cold temperatures (–88oC and below) in direct contact with a nerve and surrounding tissues, these methods are not nerve-selective nor easy to administer. They also are not injectable, making the treatments time-consuming and challenging to adopt in clinic. Our initial goal – an easier to use, injectable method of cryoneurolysis to reduce postoperative pain from TKA, significantly reducing or eliminating the use of opioids. We invented a novel injectable and nerve-selective cryoneurolysis method that overcomes the limitations of current options. Neural Ice™ can be injected around sensory peripheral nerves that transmit pain. We have shown in a rat model that injection of our ice-slurry, formulated to bring peri-nerve temperatures to around -5oC, extracts enough thermal energy to reversibly disrupt nerve structure and reduce pain sensation for up to 8 weeks without damage to surrounding tissue. At the end of 2023, we also completed an initial 16- patient feasibility study showing significant pain reduction response with no serious adverse events (See Significance). In response to these findings (pre-clinical and clinical) in October 2023 the FDA granted Brixton Breakthrough Designation. In Phase II, we seek to optimize a clinical use device that produces an injectable, biocompatible, and sterile ice slurry which meets the FDA requirements for an Investigative Device Exemption (IDE) for a pivotal efficacy trial. With our HEAL Phase I grant we generated single-use, terminally sterilized pre-filled syringes that contain on-demand injectable slurry for use at point-of-care facilities. In Phase II we seek to optimize our design for human use (ease, effectiveness, cost, etc.) and test for in-vivo biologic response in rat model. We will also establish manufacturing of human use system & prepare to submit pivotal trial IDE application to the FDA at the end of the funding period. If successful, our study will lead to the development of a novel, long-lasting and non-opioid treatment for patients with post-TKA pain.

Project Narrative Using opioids for severe osteoarthritis (OA) in the knee for pain control can lead to opioid use disorder (OUD). We are developing a platform technology, Coolio™ using Neural Ice™ that has the potential to reduce pain for up to 8 weeks. Our goal, focusing initially on OA in the knee, is to develop an affordable, easy-to-use, effective treatment for pain that directly aligns with NIH’s HEAL Initiative, advancing heath equity in meaningful way.