Project Summary Total knee arthroplasty (TKA) is one of the most commonly performed orthopedic surgeries to relieve joint pain in patients with end-stage osteoarthritis or rheumatic arthritis. In the United States, over 700,000 TKA procedures are performed each year. Most patients experience significant pain after TKA. To manage this 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 has become a national emergency, novel non-opioid and non-pharmacological treatments for postoperative pain have become 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 the use of extremely cold temperatures (–60oC 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. We aim to develop a novel, injectable method of cryoneurolysis to reduce postoperative pain from TKA, significantly reducing or eliminating the use of opioids. We invented and developed a novel injectable and nerve-selective method of cryoneurolysis that overcomes the limitations of currently available treatments. Our proprietary technology employs a formulated, biocompatible ice-slurry consisting of small ice particles suspended in solution that can be injected around sensory peripheral nerves that transmit pain. We have shown in a rat model that injection of our formulated ice- slurry extracts enough heat to reversibly disrupt nerve structure and reduce pain sensation for up to 8 weeks without damage to surrounding tissue. The advantages of this innovative technology stem from the use of an ice-slurry mixture containing injectable ice particles, which upon melting extracts large amounts of tissue heat. The temperature attained with the formulated ice-slurry is cold enough to cause cryoneurolysis but is not damaging to surrounding tissues. We propose to develop a commercial prototype device that can produce proprietary on-demand, injectable, biocompatible, and sterile ice-slurry “coolant” at the point-of-care. Proposed Phase I will establish the technical merit, feasibility and performance of this device. We will establish that the design for custom- made syringes can generate injectable ice-slurry and will test performance in reproducibly extracting heat. Next, we will test both the feasibility of consistent injection through a standard clinical needle and in-vivo tissue cooling using the rat sciatic nerve model. The results of these studies will lay groundwork for the development of a novel, long-lasting and non-opioid treatment for patients with post-TKA pain. If successful, this new pain management therapy will deliver on the important and urgent goal of reducing opioid use.

Project Narrative The use of opioids after knee replacement surgery to control pain is a major contributor to the opioid epidemic. We developed a cooling solution technology that, with one injection, reduces pain for up to 8 weeks. Our goal is to develop a device that makes the injectable solution at point-of-care to allow clinicians to treat postoperative knee pain. A non-opioid, long-lasting therapy that reduces post-surgery pain will significantly stem opioid use.