Total knee replacement arthroplasty (TKA) is a $3.3 billion U.S. market with annual number of surgeries projected at 3.48 million by 2030 with transitioning shares from in-hospital to ambulatory surgical centers. The procedure can cause significant, immediate and prolonged post-operative pain that undermines rehabilitation and adversely affect outcomes. Pain following TKA is currently managed by a multi-modal strategy of oral pain management and short-term loco-regional therapies. These include local anesthetic blocks of peripheral nerves via single shot injection or continuous infusion ambulatory pain pump, requiring anesthesiologist administration using ultrasound guidance. As an alternative to nerve blocks, surgeon administered local infiltration of bupivacaine or cocktails of other local anesthetics has increased in popularity, but variability in operator administration has given rise to variability in pain control. To facilitate compliance with physical therapy and preempt breakthrough pain, when local anesthetics wear off, opioids are commonly prescribed. However, prevention of opioid dependency and addiction has become an urgent public health emergency. The TKAine system may solve these challenges by providing sustained post-operative analgesia for a 14- day duration with bupivacaine HCl monohydrate as the active pharmaceutical ingredient. Bupivacaine (BUP), a sodium channel blocker, is the active, non-opioid, pharmaceutical ingredient in US-approved MARCAINE and EXPAREL. Each TKAine system implant consists of a compressed film comprising bupivacaine, a biocompatible water-soluble agent, and PLGA bioresorbable polymeric matrix. The implant is fabricated with a drug-containing core layer sandwiched between non-drug-containing bioresorbable polymer layers. This proprietary construction enables a high density loading of drug wherein the drug represents nearly two-thirds the total weight. The TKAine system, which consists of multiple sterile drug delivery implants equaling a 14-day dose of up to 2 grams of BUP, is implanted at the conclusion of TKA utilizing a simple, reliable, straightforward, sterile technique by the orthopedic surgeon. The biodegradable polymer then fully erodes in < 12 weeks leaving no foreign body present. This Phase I will determine dosing levels to achieve a targeted efficacy concentration for 14 days. A major technical challenge is to determine tissue concentration level that corresponds to therapeutic benefit. More specifically, first we will complete a survey of expert pain management clinicians to compile data on optimal dosing levels of BUP (delivered as MARCAINE, EXPAREL, other analgesic cocktails, and/or OnQ* Pump) to achieve 12 to 72 hours of therapeutic benefit for current treatments. Response matrix summary analytics will then provide a dosing strategy for an in vivo sheep study. Sheep will be injected with those targeted doses and tissue samples analyzed at different time intervals to determine the resultin...