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Pretreatment using various types of biophysical stimuli could provide appropriate potential to cells during construction of the engineered tissue in vitro. We hypothesized that multiple combinations of these biophysical stimuli could enhance osteogenic differentiation in vitro and bone formation in vivo. Cyclic strain, an electromagnetic field, and ultrasound were selected and combined as effective stimuli for osteogenic differentiation using a developed bioreactor. Here we report the experimental evaluation of the osteogenic effects of various combinations of three different biophysical stimuli in vitro and in vivo using human adipose-derived stem cells (ASCs). Osteogenic differentiation of ASCs was accelerated by multiple-combination biophysical stimulation in vitro. However, both single stimulation and double-combination stimulation were sufficient to accelerate bone regeneration in vivo, while the osteogenic marker expression of those groups was not as high as that of triple-combination stimulation in vitro. We inferred from these data that ASCs appropriately differentiated into the osteogenic lineage by biophysical stimulation could be a better option for accelerating bone formation in vivo than relatively undifferentiated or completely differentiated ASCs. Although many questions remain about the mechanisms of combined effects of various biophysical stimuli, this approach could be a more powerful tool for bone tissue regeneration.

Biophysical stimuli may be an effective therapy to counteract age-related changes in bone structure that affect the primary stability of implants used in joint replacement or fracture fixation. The influence of controlled mechanical loading on osseointegration was investigated using an in vivo device implanted in the distal lateral femur of 12 male rabbits. Compressive loads (1 MPa, 1 Hz, 50 cycles/day, 4 weeks) were applied to a porous titanium foam implant and the underlying cancellous bone. The contralateral limbs served as nonloaded controls. Backscattered electron imaging indicated that the amount of bone ingrowth was significantly greater in the loaded limb than in the nonloaded control limb, whereas the amount of underlying cancellous periprosthetic bone was similar. No significant difference in the mineral apposition rate of the bone ingrowth or periprosthetic bone was measured in the loaded compared to the control limb. Histological analysis demonstrated newly formed woven bone in direct apposition to the implant coating, with a lack of fibrous tissue at the implant-periprosthetic bone interface in both loaded and nonloaded implants. The lack of fibrous tissue demonstrates that mechanical stimulation using this model significantly enhanced cancellous bone ingrowth without the detrimental effects of micromotion. These results suggest that biophysical therapy should be further investigated to augment current treatments to enhance long-term fixation of orthopedic devices. Additionally, this novel in vivo loading model can be used to further investigate the influence of biophysical stimulation on other tissue engineering approaches requiring bone ingrowth into both metallic and nonmetallic cell-seeded scaffolds.