Dynamic Acellular Materials for Repairing Dense Connective Tissues

Abstract Dense musculoskeletal tissues, such as the meniscus, are plagued by poor healing. Meniscal tears disrupt load transfer in the knee and instigate more widespread degenerative and inflammatory processes. Unfortunately, there are no current treatment options that restore meniscus function and joint homeostasis. To address this, we developed an injectable (shear-thinning) bicontinuous hydrogel that can be delivered in a minimally invasive manner to a meniscal tear to promote rapid colonization by cells. This hydrogel, composed of gelatin and hyaluronic acid (HA), exhibits unique microinterfaces with a high interfacial surface area that allows for rapid cell infiltration from adjacent tissue. Beyond a material that can be delivered to the damaged meniscus and supports subsequent cellularization, meniscus repair strategies must also address the physical and biological impediments to healing. We previously identified nuclear mechanics as a key impediment to meniscus cell migration and transiently reduced nuclear stiffness (using the histone deacetylase inhibitor trichostatin A, TSA) to enable rapid endogenous cell migration. We also found that inflammation present in the joint post-injury reduced meniscus cell migration, and that this could be reversed by applying FDA-approved interleukin antagonists (IL1ra). To deliver these factors, we developed a novel class of mechano-activatable microcapsules (MAMCs) that enable efficient encapsulation and staged release of sensitive biologic factors. In this renewal, we combine these exciting biomaterial (Aim 1) and drug delivery (Aim 2) advances to translate an innovative injectable hydrogel platform that concomitantly releases factors to enable cell migration, quell inflammation, and promote matrix production via controlled delivery in a load bearing joint setting. We test this novel therapy in vivo, in our large animal meniscus injury model (Aim 3) in the setting of established joint disease. Our overall hypothesis is that injectable bicontinuous materials coupled with mechanically activatable delivery of pro- migratory and anabolic agents will improve meniscus repair after injury. The proposed studies build on over 15 years of collaboration by our team of engineers and clinicians on the development of implantable and injectable biomaterials for meniscus injury. If successful, this work will provide a novel therapeutic material designed to treat meniscus tears that are otherwise considered irreparable, restoring joint health to the millions of patients with meniscal injuries.