Mechanical Load Modulates the Stimulatory Effect of BMP2 in a Rat Nonunion Model

Abstract

Introduction:

Local application of bone morphogenetic proteins (BMPs) at the fracture site is known to stimulate bone regeneration. However, recent studies illustrate that the BMP-initiated mineralization may be enhanced by additional mechanical stimulation. Therefore, bone healing was monitored in vivo in order to investigate the effect of mechanical loading on the initiation and maturation of mineralization after cytokine treatment. We hypothesized that the mechanical stimulation would further enhance the efficacy of BMP2 treatment.

Method

: Female Sprague-Dawley rats underwent a 5-mm defect, stabilized with an external fixator. Type I collagen scaffolds containing 50 μg of BMP2 diluted in a solvent or solvent only were placed into the defects. The BMP2-treated specimens and control specimens were then each divided into two groups: one that underwent mechanical loading and a nonloaded group. In vivo loading began immediately after surgery and continued once per week for the entire 6-week experimental period. For all groups, the newly formed callus tissue was quantitatively evaluated first by in vivo microcomputed tomography at 2, 4, and 6 weeks and further by histologic or histomorphometric analysis at 6 weeks postoperation.

Results:

Mechanical stimulation with BMP2 treatment significantly enhanced mineralized tissue volume and mineral content at 2 weeks. Histological analysis demonstrated a significantly greater area of fibrous connective tissue including bone marrow in the stimulated group, suggesting reconstitution of the endosteal canal and more advanced bone remodeling present in the mechanical loaded group. Both groups receiving BMP2 underwent massive bone formation, achieving bony bridging after only 2 weeks, while both control groups, receiving solvent only, revealed a persisting nonunion, filled with fibrous connective tissue, prolapsed muscle tissue, and a sealed medullary canal at week 6.

Conclusion:

Mechanical loading further enhanced the efficacy of BMP2 application evidenced by increased mineralized tissue volume and mineralization at the stage of bony callus bridging. These data suggest that already a minimal amount of mechanical stimulation through load bearing or exercise may be a promising adjunct stimulus to enhance the efficacy of cytokine treatment in segmental defects. Further studies are required to elucidate the mechanistic interplay between mechanical and biological stimuli.