Achilles tendinopathy is a debilitating condition affecting the entire spectrum of society and a condition that increases the risk of tendon rupture. Effective therapies remain elusive, as anti-inflammatory drugs and surgical interventions show poor long-term outcomes. Eccentric loading of the Achilles muscle-tendon unit is an effective physical therapy for treatment of symptomatic human tendinopathy. Post-injury analgesia is often achieved with non-steroidal anti-inflammatory drugs such as ibuprofen; however, there is increasing evidence that NSAID usage may interfere with the healing process. The deposition of aggrecan/hyaluronan (HA)-rich matrix within the tendon body and surrounding peritenon impede tendon healing and result in compromised biomechanical properties. Herein, we present work investigating chemical, biological, and mechanical loading approaches to treating Achilles tendinopathy in a murine model. Our previously established TGF-ß1-induced murine model of Achilles tendinopathy was used to investigate the cellular mechanism by which ibuprofen (chemical) therapy might lead to a worsening of tendon pathology, potentially by interfering with the native inflammation phase of tendon healing. We conclude that the use of ibuprofen for pain relief during inflammatory phases of tendinopathy has detrimental effects on the turnover of a pro-inflammatory HA matrix produced ain response to soft-tissue injury, thus preventing the switch to cellular responses associated with functional matrix remodeling and eventual healing. We examined the therapeutic potential of a recombinant human hyaluronidase, rHuPH20 (biologic, FDA approved for reducing HA accumulation in tumors) in a novel Achilles tendinopathy and retrocalcaneal bursitis injury model. The potential of rHuPH20 to effectively clear the pro-inflammatory, HA-rich matrix within the retrocalcaneal bursa (RCB) and tendon strongly supports the future refinement of injectable glycosidase preparations as potential treatments to protect or regenerate tendon tissue by reducing inflammation and scarring in the presence of bursitis or other inducers of damage such as mechanical overuse. Finally, we developed a novel mouse model of hind limb muscle loading (mechanical) designed to achieve a tissue-targeted therapeutic exercise. When applied to a murine Achilles tendinopathy model, muscle loading led to a significant improvement in Achilles tendon biomechanical outcome measures, with a decrease in cross-sectional area and an increase in material properties, compared to untreated animals. Our model facilitates the future investigation of mechanisms whereby rehabilitative muscle loading promotes healing of Achilles tendon injuries. Overall, these findings enhance our understanding of the mechanisms of injury and treatment in Achilles tendinopathy injuries. / Doctor of Philosophy / Achilles tendinopathy is a chronic, overuse condition affecting the entire spectrum of society and a condition that increases the risk of tendon rupture. Therapies are limited, as anti-inflammatory drugs and surgical interventions show poor long-term outcomes. Drugs such as ibuprofen are commonly prescribed at the onset of injury to treat pain. Eccentric loading of the Achilles muscle-tendon unit is an effective physical therapy for treatment of human tendinopathy; however, the reasons driving the healing are not well understood. Characteristics of the disease include pain, increased tendon size, and disorganization of tendon fiber structure. Here, we present work investigating chemical, biological, and mechanical loading approaches to treating Achilles tendinopathy in a mouse model. Our mouse model of Achilles tendinopathy was used to investigate how ibuprofen (chemical) therapy might lead to a worsening of tendon by potentially interfering with the inflammation phase of tendon healing. We conclude that the use of ibuprofen for pain relief during inflammatory phases of tendinopathy has negative effects on the turnover of matrix produced in response to injury, affecting the transition to the next phase in the tendon healing response. We examined the potential of a recombinant human hyaluronidase, rHuPH20 (biologic, FDA approved for reducing HA accumulation in tumors) in a novel Achilles tendinopathy and retrocalcaneal bursitis injury model. The potential of rHuPH20 to effectively clear the proinflammatory, HA-rich matrix within the retrocalcaneal bursa (RCB) and tendon strongly supports the future refinement of injectable treatments as a potential to protect or regenerate tendon tissue by reducing inflammation and scarring in the presence of bursitis or other inducers of damage such as mechanical overuse. Finally, we developed a mouse model of hind limb muscle loading (mechanical) based on physical therapy exercises. This model led to an improvement in biomechanical measures compared to untreated animals. The model allows for investigation of the underlying mechanisms in which physical therapy promotes healing of Achilles tendon injuries. Overall, these findings enhance our understanding of the mechanisms of injury and treatment in Achilles tendinopathy injuries.