Background: Traumatic hand injuries in the military are caused by closure of vehicle doors, hatches, and turrets; accidental tool cuts; explosions; and bullets. Complex flexor tendon repair is required to restore function in these and analogous civilian injuries, but complications are common. The incidence of traumatic tendon injury in the United States is roughly 33/100,000, or approximately 100,000 affected individuals per year. Males aged 20 to 29 are most commonly affected. After primary repair, reoperation rates as high as 50% have been reported. This is especially true when the injury involves crushing, blast, head injury, or injury to other tissues in addition to the tendon. The proposed project will refine a bio-lubricant to reduce a frequent complication of flexor tendon repair—scar (adhesion) formation—optimizing functional recovery and return to duty, a fiscal year 2017 Peer Reviewed Orthopaedic Research Program Soft Tissue Trauma Focus Area goal.In cases of complex injury, like those sustained in combat, repaired tendons are immobilized after surgery. Immobilization greatly increases the incidence of complications, especially adhesion formation within the finger tendon sheath. After injury, even small adhesions between the tendons and pulleys can limit the ability of the tendon to move the finger. To improve patient outcomes, our team has developed a bio-lubricant composed of ingredients that have been approved by the U.S. Food and Drug Administration (FDA) for other indications. Our lubricant, a combination of carbodiimide-derivatized hyaluronic acid (cd-HA) and a gelatin called cd-HA gel, can increase the tendon’s gliding ability and reduce the formation of adhesions. Currently, there is no FDA-approved treatment that can be applied to the narrow tendon sheath to reduce adhesion formation and maintain gliding function. The unique properties of the proposed cd-HA gel allow it to strongly adhere to the tendon surface in a thin layer of only a few molecules so that it does not disrupt tendon-pulley movement. Our goal is to have our cd-HA gel and delivery system approved for clinical use, and we propose here to complete work that will support an FDA Investigational Device Exemption application.Objective/Hypothesis: Our objective is to test the safety and effectiveness of a current Good Manufacturing Practices (cGMP)-compliant cd-HA gel and delivery system in a large animal model in vivo. The results of this proposal will allow our team to pursue the first study of this product in human subjects. We hypothesize that the cGMP-grade cd-HA gel will safely decrease adhesion formation and improve digit function following tendon repair associated with post-operative immobilization, compared to the non-lubricated standard of care.Specific Aims: The proposed project has the following three Specific Aims: (1) refine the cd-HA gel manufacturing process and complete development of the delivery device, compliant with cGMP, to meet expected FDA approval requirements; (2) assess the toxicity of cGMP cd-HA gel in cellular and animal models; and (3) determine whether cd-HA gel treatment decreases adhesion formation and improves digit function in a turkey model of immobilized flexor tendon repair.Study Design: As a prelude to in vivo work, we will refine design of the delivery device and produce cGMP cd-HA gel. Using human cadaver fingers and turkey feet, we will optimize use of the delivery device in mock sterile conditions—simulating clinical use—with a focus group of hand surgeons and measure tendon ability to confirm the effectiveness of the cGMP cd-HA gel. In collaboration with a contract research organization, we will assess the toxicity of cGMP cd-HA gel in cellular and animal models using test, control, and analytic methods designed to satisfy FDA standards to initiate clinical studies. Finally, we will conduct in vivo studies using a novel turkey flexor tendon injury model to test tendon ability (work of flexion, gliding resistance, etc.) following repair of experimental tendon lacerations in digits treated with the gel compared to non-gel-treated controls. Digit and tendon size, anatomy, structure, and function in our turkey model are very similar to the human finger.Military Benefit: Hand trauma is a common injury sustained by Service members, occurring in both active combat and as a noncombat-related injury in combat zones, during training, or in sport. In combat trauma scenarios, hand injury repair is often delayed due to prioritizing more life-threatening injury and a lack of access to specialized surgeons. However, delay of surgery and prolonged immobilization of the injured hand or tendon enhance the risk of adhesion formation. The proposed work offers the potential of reduced adhesion formation and may significantly enhance the quality of tendon healing in situations where repair and reconstructive surgery is delayed. By reducing adhesion development and improving digit function, this project will optimize Service members’ rehabilitation outcomes and speed return to duty. Development of this cd-HA gel for clinical use offers the potential for a reduced need for reconstructive surgery and recovery time, as well as improved full-hand function for flexor tendon trauma patients in the military, Veteran, and civilian health care systems.
|Effective start/end date||8/1/18 → 7/31/21|
- Congressionally Directed Medical Research Programs: $750,000.00