Background and Summary:

1. In the U.S. Armed Forces, there is a high prevalence of knee injuries from the rigors of training, carrying heavy equipment for long periods of time, enemy engagement, and multiple combat deployments, especially in the Special Operations Forces.

2. Anterior cruciate ligament (ACL) tear is the most common knee injury among military personnel (~3.0 cases per 1000 person years); 10 times higher than in the civilian population.

3. Approximately 2,500 to 3,000 primary ACL reconstructions (ACLR) are performed each year by military surgeons in the Army, Navy, and Air Force.

4. After ACL reconstruction surgery, a new study found that over 50% of Service members continue to have activity limitations or are unable to return to active duty.

5. Our proposal addresses this gap in military medicine with a new drug therapy that protects the knee joint from excessive inflammation and fibrosis during and following surgery.

6. The study’s short-term impact will be to promote faster healing, reduced fibrosis, and early “molecular” evidence of post-traumatic osteoarthritis (PTOA). The long-term impact is the earlier return of more Service members to active duty earlier and reduce later-life complications such as PTOA and total knee replacement surgery.

7. The projected time to have clinically relevant outcomes is 4 to 6 years.

Objective and Rationale of the Study: Our objective is to provide a frontline, small-volume adenosine, lidocaine, and Mg2+ (ALM) therapy to reduce local and systemic inflammation and scarring and improve healing time during and following ACLR surgery. The rationale of the study is to blunt the complex cascades of inflammatory, neural, and fibrotic remodeling events that are triggered in the whole knee joint during and following the trauma of surgery.

Hypothesis: ALM intravenous and knee therapy will switch the “hostile” inflammatory environment of the joint to a more “permissive” restorative and healing environment following ACLR surgery in a military-relevant rat model. The therapeutic strategy will suppress secondary injury progression, reduce fibrosis, and minimize early “molecular” PTOA.

Impact of the Research:

Short-Term: The goal of the proposed work is to promote a permissive healing environment for military Service members undergoing ACLR surgery that will improve outcomes by reducing the inflammatory and fibrotic complications of surgery. The short-term impact will be to restore knee function and return injured personnel to active duty earlier. The projected time to translate the therapy into humans with clinically relevant outcomes is 4 to 6 years.

Long-Term: The long-term impact is to reduce later-life complications such as PTOA and the requirement for knee replacement surgery. In the civilian population (including Veterans and their families), the project’s impact is to improve the quality of life of all ACL-injured patients, particularly in the younger sporting population where ACL injuries are on the rise, and to reduce the cost burden to an already stressed U.S. healthcare system. The project is also relevant to those who have suffered a second or third ACL injury or sustained other traumatic orthopedic injuries and polytrauma.