Hydrogel Delivery of Suramin Decreases Muscle Fibrosis after Injury

Abstract

A primary challenge to muscle repair and regeneration following injury is the infiltration of fibrous tissue, which can negatively impact the recovery of normal muscle function. A number of molecules have been implicated in the development of tissue fibrosis after muscle injury, but foremost among these appears to be transforming growth factor-, (TGF-β). Suramin is a small molecule known to antagonize TGF-β, activity. PURPOSE: To determine the effects of local suramin delivery on muscle repair after injury. METHODS: A model of deep penetrant injury, fibula osteotomy with associated damage to lateral compartment muscles (fibularis longus and brevis), was used in mice under isoflurane anesthesia. Following fibula fracture and laceration of the surrounding muscles, mice received an injection of approximately 30 ul of hyaluronan hydrogel injected directly into the injury site. Hydrogels were loaded with 0, 2.5, or 5.0 mg/kg suramin (8 mice per treatment group) prior to addition of the PEGDA cross-linker. Mice were euthanized 15 days following the surgical procedure. Bone repair was assessed using microCT and histological evaluation of the fracture callus. Muscle healing was assessed using Masson trichrome staining of the injury site, and image analysis used to quantify the degree of fibrosis and muscle regeneration. RESULTS: Body weights did not change significantly over the two-week period in any treatment group. MicroCT data revealed no differences in fracture callus bone volume or density in any treatment group, but trichrome staining of the injury site revealed a dose-dependent decrease in tissue fibrosis with suramin treatment. Specifically, fibrotic staining was reduced approximately 10% in the low-dose (2.5 mg/kg) group and by 20% (P<.05) in the high-dose group (5.0 mg/kg) compared to control (0 mg/kg) hydrogels. CONCLUSIONS: Bioengineered hydrogels can be utilized for local delivery of cells, proteins, and small molecules. The hydrogels do not degrade immediately, which allows for extended, local release of therapeutic molecules. Results presented here indicate that hydrogel delivery of suramin, a TGF-β antagonist, can enhance muscle regeneration after injury although its effects on bone repair are less clear. Supported by the Orthopaedic Trauma Association.