Project Summary Approximately 32M musculoskeletal injuries in the US cost nearly $322B annually (1). The high economic burden is due in part to post-operative scar formation (i.e., adhesions), which is the leading cause of disability following tendon surgery (4, 5). We are developing a sprayable adhesion barrier derived from extracellular matrix (ECM Spray), which serves as a mechanical barrier and elicits a healing response from the patient’s own body to prevent adhesions from forming. Around 1.5M patients suffer flexor tendon injuries each year and as many as 30-40% of these individuals will subsequently have limited range of motion due to adhesions (6). Current options to mitigate adhesions are limited and flawed, and there is an unmet need for a technology which can safely and effectively prevent adhesion formation to maintain normal joint function after tendon injury. ECM Spray is thermally responsive, forming a thin film hydrogel over the tissue where applied and prevents adhesions by acting as a mechanical barrier between adjacent tissues. Application of ECM Spray as the last step of a surgical procedure resulted in >70% reduction on post-operative adhesions in abdominal and pelvic animal models of adhesion formation. A major limitation of currently available orthopedic tendon protectors / adhesion barriers is that they are bulky sheets unable to conform to the region of the repaired flexor tendon and therefore impair tendon movement / gliding. Newer thin sheet products are available, but surgeons describe them as performing like “wet toilet paper” because they disintegrate upon hydration. ECM Spray is applied as a liquid, rather than a sheet, to conform to the repaired flexor tendon and surrounding flexor tendon sheath. Past attempts at developing sprayable adhesion barriers have been unsuccessful, in part because of impaired tissue healing after application. While it remains unknown what impact ECM Spray will have upon tendon healing, we have shown that ECM Spray acts as an inductive scaffold to support constitutive repair of the peritoneum. Based upon these data, the objective of the present study is to determine ECM Spray’s safety, efficacy, and usability in orthopedic surgery following flexor tendon injury. In Aim 1, we will characterize tenocyte cellular response to ECM Spray, which will determine if ECM is biocompatible and supportive of tenocyte and synoviocyte growth. In Aim 2, we will determine if ECM Spray effective for reducing tendon adhesion formation without compromising the biomechanics of healing tendons. In Aim 3, we will demonstrate usability in human anatomy, which is critical to surgeon adoption and commercialization. Results from this safe-by-design approach will lead to key research and development milestones necessary for use of ECM Spray in orthopedic surgery and could ultimately improve the lives of the millions affected each year by adhesion-related morbidity.