# Designing Hydrogel-Based Bone-On-Chips for Personalized Medicine
## 5 Towards Personalized Bone-On-Chips
Each physiological or pathological bone process has a specific extracellular environment, which can be replicated by using hydrogels and tuning their biochemical composition, structural and mechanical properties. Therefore, hydrogel-based bone-on-chips offer personalized bone tissue models, where a proper combination of complex 3D microenvironments and primary human cells can answer questions on bone biology and test novel treatments. which is considered a risk factor for postmenopausal bone loss [47]. Thus, BOCs could define patient-specific matrices and predict the outcome of osteoporosis based on the initial trabecula thickness. It is then clear that BOCs can help predicting the outcome of treatments by designing different bone characteristics with specific hydrogel composition. In addition, each sample can be patient-specific if a small bone explant is harvested and primary human cells extracted and seeded in a BOCs (Figure 5). Patient-to-patient variability is a critical challenge for tissue engineering and personalized therapies where patient-specific organ-on-chips offer innovative systems to predict biological variability between individuals [12; 13]. A BOC system has already compared the osteogenic activity of bone cells isolated from different patients [88]. Thus, future studies might determine how bone-related disorders alter the osteogenic activity of primary human bone cells by means of controlled experimentation with patient-specific BOCs. Furthermore, the organ-on-chip technology relies on the use of microfluidic systems to apply various mechanical stimuli on cells where the culture condition could be monitored with microscale and nanoscale biomedical sensors [108; 109]. Indeed human tissues are characterized by different mechanotransduction signals, thus organ-on-chips offer alternative solutions to apply multiple mechanical and physical cues, such as shear and interstitial flow, cyclic stretching, stiffness gradient or geometric confinement [110]. In addition, as for the bone tissue, osteocyte regulatory role of both bone formation and resorption processes is directly related to strains and fluid shear stresses in the lacunocalicular network. It is know that extracellular proteins, such as glycocalyx, bind cell receptors, such as integrins, and activate mechanotransduction pathways by stretching the cell membrane [111]. Therefore, BOC platforms could investigate the osteocyte mechanotransduction with a direct control on the 3D matrix where cells are embedded and on the interstitial fluid flow that replicates the in vivo mechanical stimuli. For future studies, BOC devices will not only be key for a precise personalized medicine, but it will also provide a great tool to study in vitro bone mechanobiology by applying mechanical stimuli. Therefore, BOCs can have a role in pre-clinical evaluation and are the ideal candidate to predict the individual mechano-sensitivity in bone regeneration in a controlled microenvironment. By reproducing around bone cells pathological conditions with the association of mechanical stimuli and circulating levels of specific factors, such as estrogen [44], in microfluidic devices, future studies might be capable to predict the individual mechano-sensitivity and bone regenerative capacity in vitro in these specific microenvironments. In conclusion, this review aims at providing essential background and guidelines on the design of hydrogel-based BOC platforms to model bone tissue. It is clear that the rapid advances in the organ-on-chip technology will allow to answer further biological questions and to test therapies in vitro at a small scale and with limited resource (cells, materials). In the near future of personalized medicine and therapies for bone disease, those major tools will allow to assess for each individual biological response with patient-specific BOCs that recreate clinically relevant scenarii in miniaturized devices and that could predict the outcome of a treatment.