tacrolimus and Tibial-Fractures

There is a dearth of therapies that are safe and effective for the treatment of volumetric muscle loss (VML), defined as the surgical or traumatic loss of muscle tissue, resulting in functional impairment. To address this gap in orthopedic care, we developed a porous sponge-like scaffold composed of extracellular matrix (ECM) proteins (e.g., gelatin, collagen, and laminin-111) and an immunosuppressant drug, FK-506. While the majority of VML injuries occur in orthopedic trauma cases, preclinical models typically study muscle injuries in isolation without a concomitant bone fracture. The goal of this study was to investigate the extent to which FK506 loaded biomimetic sponges support functional muscle regeneration and fracture healing in a composite trauma model involving VML injury to the tibialis anterior muscle and osteotomy (OST) to the tibia. In this model, implantation of the FK-506 loaded biomimetic sponges limited the extent of inflammation while increasing the total number of myofibers, mean myofiber cross-sectional area, myosin-to-collagen ratio, and peak isometric torque compared to untreated VML+OST muscles on Day 28. Although all tibia fractures were bridged by Day 28 post-injury, fracture healing was impaired in response to an adjacent VML injury. Sponge treatment increased bone callus volume, yet the bridged mineralized bone volume was not significantly different. Taken together, these results suggest that biomimetic sponges primarily benefitted muscle repair and may provide a promising therapy for traumatized muscle.

Topics: Biomimetics; Fracture Healing; Humans; Muscle, Skeletal; Tacrolimus; Tibial Fractures

Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration.. We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle).. The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production CONCLUSION: Collectively, these findings support the administration of FK506 to ameliorate healing of fractures with severe muscle trauma comorbidity. The results suggest one potential mechanism of action is a reduction in local T lymphocytes within the injured musculoskeletal tissue, though other mechanisms to include direct osteogenic effects of FK506 require further investigation.

Topics: Adaptive Immunity; Animals; Biopsy; Bone Nails; Bone Regeneration; Bony Callus; Disease Models, Animal; Fracture Fixation, Intramedullary; Fracture Healing; Humans; Immunity, Innate; Immunosuppressive Agents; Macrophages; Male; Muscle, Skeletal; Muscular Diseases; Osteotomy; Rats; Rats, Inbred Lew; Soft Tissue Injuries; T-Lymphocytes; Tacrolimus; Tibial Fractures; Torque

Immunosuppressant drugs like cyclosporine A and FK506 are widely used for solid organ transplantation. They are accelerating bone remodeling but cause net bone loss. The aim of this study was to investigate the effect of FK506 on fracture healing in the rat. Eighty Lewis rats were divided into four groups, which received FK506 (1 mg/kg BW) or no treatment for 2 or 4 weeks, beginning after production of a closed, nondisplaced unilateral tibial fracture. Radiographic, histological, and biomechanical studies were used to evaluate fracture healing and histomorphometric analysis of the tibial metaphysis of the intact contralateral side was performed. Radiographs revealed no difference of the healing of the control fractures compared with the fractures in the FK506-treated group at 2 and 4 weeks. The mechanical parameters of the tested contralateral intact tibiae and of the fracture callus demonstrated no difference between control and immunosuppressed animals. Tibial bone histomorphometry revealed increased measures of bone formation and bone resorption, accompanied by a significant reduction of percent trabecular area. At 4 weeks, the fractures showed osseous healing with woven bone at the fracture site and only minimal amounts of cartilage. Histological grading was not different between the control and the FK506 group at both time points. We conclude that systemic application of FK506 has no biomechanical and histological effects of experimental fracture healing in the rat. However, resorption far in excess of formation leads to a net bone loss in the trabecular bone of the tibia that has no effect on the stability of the intact bone.

Topics: Animals; Fracture Healing; Immunosuppressive Agents; Male; Radiography; Rats; Rats, Inbred Lew; Tacrolimus; Tibia; Tibial Fractures