Sistema Ortopédico e Muscular: Pesquisa Atual
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Hydrogel-Based Local Release of Salubrinal Stimulates Healing of Mouse Tibia Fracture

Wenxiao Xu, Andy Chen, Yijia Zhang, Jiliang Li, Chien-Chi Lin, Jing-long Yan and Hiroki Yokota*

Background: Salubrinal is a small synthetic agent that presents beneficial effects on skeletal diseases and tumor progression. It is reported to stimulate bone formation and suppress bone resorption. In this study, we examined whether salubrinal administration can stimulate the healing of bone fracture using a mouse model of closed tibia fracture.

Materials and Methods: We administered salubrinal to mice in two different routes: one-time hydrogel injection with salubrinal-loaded Poly Lactic-Co-Glycolic Acid (PLGA) microparticles; and daily subcutaneous injection for 4 weeks. A subcutaneous injection of Bone Morphogenetic Protein 2 (BMP2) was used as a positive control. The measurement of Bone Mineral Density (BMD)/Bone Mineral Content (BMC), as well as micro-CT imaging and mechanical testing were utilized to evaluate the healing of the experimental fracture.

Results: It was shown that 4 weeks after the induction of tibia fracture no groups, including the BMP2 control group, elevated BMD or BMC. Hydrogel-based injection of salubrinal showed a higher stiffness than that of the vehicle control, as well as significant elevation of ultimate force. Although daily subcutaneous injection of BMP2 increased stiffness and ultimate force, daily injection of salubrinal did not show significant improvement of mechanical properties. Of note, the total salubrinal dose in the hydrogel group was approximately 18% of that in the subcutaneous group.

Discussion: Improvement in mechanical properties by a hydrogel-based administration of salubrinal and not by a daily subcutaneous injection indicates dependence of salubrinal’s efficacy on its administration procedure. Salubrinal is capable of suppressing tumor growth, a clear advantage over a growth factor such as BMP2. For a future clinical trial, administration frequency and optimal dosage may need to be further analyzed.