Engineering a 3D bone marrow adipose composite tissue loading model suitable for studying mechanobiological questions

Tissue engineering strategies are widely used to model and study the bone marrow microenvironment in healthy and pathological conditions. Yet, while bone function highly depends on mechanical stimulation, the effects of biomechanical stimuli on the bone marrow niche, specifically on bone marrow adipose tissue (BMAT) is poorly understood due to a lack of representative in vitro loading models. Here, we engineered a BMAT analog made of a GelMA (gelatin methacryloyl) hydrogel/medical-grade polycaprolactone (mPCL) scaffold composite to struc-turally and biologically mimic key aspects of the bone marrow microenvironment, and exploited an innovative bioreactor to study the effects of mechanical loading. Highly reproducible BMAT analogs facilitated the suc-cessful adipogenesis of human mesenchymal bone marrow stem cells. Upon long-term intermittent stimulation (1 Hz, 2 h/day, 3 days/week, 3 weeks) in the novel bioreactor, cellular proliferation and lipid accumulation were similar to unloaded controls, yet there was a significant reduction in the secretion of adipokines including leptin and adiponectin, in line with clinical evidence of reduced adipokine expression following exercise/activity. Ultimately, this innovative loading platform combined with reproducibly engineered BMAT analogs provide opportunities to study marrow physiology in greater complexity as it accounts for the dynamic mechanical microenvironment context.