Tendinopathy is a common tendon disorder resulting from repetitive motion in the workplace or during athletic activity that can cause severe pain and long-term disability. A hallmark of tendinopathy is disruption of extracellular matrix (ECM), particularly collagen, which leads to loss of tissue mechanical properties and function. Although various classes of ECM proteases have been implicated in tissue degeneration in tendinopathy, their relative amounts and the timing of their expression remains unclear. This lack of knowledge has significantly hampered development of treatments to deliver inhibitory agents for these enzymes to reduce pathology progression and improve healing in tendinopathy. Our long-term goal is to develop improved regenerative medicine strategies to aid repair of tendinopathic tissues. The central hypothesis of this proposal is that long-term regulation of protease activity in tendinopathy using injectable biomaterials supporting sustained delivery of a protease inhibitor will result in greater tendon tissue structure and mechanical properties compared with injection of inhibitor without the carrier. Our overall objective will be accomplished by testing our central hypothesis in the following two specific aims: 1) Investigate proteases and inhibitors related to ECM degradation in vivo in a rat supraspinatus tendon overuse model. 2) Evaluate the effects of sustained release of a protease inhibitor on the development of overuse injury in rat supraspinatus tendons. The proposed work is innovative because it employs a well-controlled, injectable carrier to achieve local, sustained release of protease inhibitors to protect against further tissue degeneration in tendinopathy. Results from these studies are expected to have a significant impact because they will lead to more efficacious regenerative medicine therapies for tendinopathy, as well as other protease- mediated degenerative conditions in a range of tissues throughout the body.
The proposed research is relevant to public health because results from this study are expected to lead to improved regenerative medicine-based therapies for tendon overuse injuries. These studies will also result in greater understanding of the role of proteases in the progression of tissue degeneration in tendon overuse injuries. This is relevant to the NIH's mission as this research provides new methodologies that will lead directly to better treatments of protease-mediated degenerative diseases throughout the body.
|Ogle, Molly E; Krieger, Jack R; Tellier, Liane E et al. (2018) Dual Affinity Heparin-Based Hydrogels Achieve Pro-Regenerative Immunomodulation and Microvascular Remodeling. ACS Biomater Sci Eng 4:1241-1250|
|Tellier, L E; Krieger, J R; Brimeyer, A L et al. (2018) Localized SDF-1? Delivery Increases Pro-Healing Bone Marrow-Derived Cells in the Supraspinatus Muscle Following Severe Rotator Cuff Injury. Regen Eng Transl Med 4:92-103|
|Parks, Akia N; McFaline-Figueroa, Jennifer; Coogan, Anne et al. (2017) Supraspinatus tendon overuse results in degenerative changes to tendon insertion region and adjacent humeral cartilage in a rat model. J Orthop Res 35:1910-1918|
|Rinker, Torri E; Philbrick, Brandon D; Temenoff, Johnna S (2017) Core-shell microparticles for protein sequestration and controlled release of a protein-laden core. Acta Biomater 56:91-101|
|Peng, Yifeng; Tellier, Liane E; Temenoff, Johnna S (2016) Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery. Biomater Sci 4:1371-80|
|Seto, Song P; Parks, Akia N; Qiu, Yongzhi et al. (2015) Cathepsins in Rotator Cuff Tendinopathy: Identification in Human Chronic Tears and Temporal Induction in a Rat Model. Ann Biomed Eng 43:2036-46|