# Designing Hydrogel-Based Bone-On-Chips for Personalized Medicine
## 5 Towards Personalized Bone-On-Chips  
Bone not only provides structural support for the body to enable movement, but it also serves as a major stem cells (mesenchymal and hematopoietic) and metabolic storage site (i.e., for calcium). The diseases affecting bone have a wide spectrum of etiology but most of them induce frailty in patients with for example higher fracture risk. The complexity of the organ (several types of tissue, highly organised matrix) and of the symptoms make it difficult to predict the efficiency of treatments or the osteointegration of orthopedic implants. To recapitulate the diseases in vitro, the physical, mechanical and biochemical microenvironment that are key elements and specific to each pathology can be varied, such as a decreasing of the pH to study cancer metastasis [105] (Figure 5). BOCs are an effective technology to build in vitro microenvironments resembling the specific pathological or physiological process under investigation. The essential components of hydrogel-based BOCs are the cellular sources, the hydrogel and the culture chamber which have been tuned to mimic the hematopoietic niche in the bone marrow [16; 101; 103; 104], cancer bone metastasis [91; 95; 97], or osteo/chondrogenic differentiation [98; 99; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124;  
tion [88; 94]. Hydrogels play an important role in engineering BOCs to mimic the specific characteristics of the microenvironment under investigation. First, hydrogels must be designed to encapsulate cells and gelate within the culture chamber without damaging the embedded cells. Collagen-based hydrogels are the most common choice in BOCs as this protein is the principal component of the mineralized bone matrix and the marrow matrix. Bone marrow niches are commonly associated to lower collagen concentrations, with lower mechanical properties, while an osteogenic microenvironment corresponded to higher collagen concentrations or by incorporating HA (Table 1). Besides collagen, fibrin hydrogels can accelerate bone healing [106], and model the early stage extracellular environment of bone diseases such as fracture healing and cancer tumor-fibrin matrix [107]. At the same time, the emergence of synthetic hydrogels have offered a wider control over the structural, chemical and mechanical properties. For example, thermo-responsive hydrogel could exponentially increase their stiffness after gelation, being an ideal model to investigate the cortical matrix or the pathological environment related to osteopotrosis. Tuning and monitoring hydrogel structural properties over time can be used to model both physiological and pathological processes of the bone tissue. For example, the bone remodelling process has direct effects on matrix architecture and BOCs provide an innovative system that requires few ressources and where osteoblasts, osteoclasts and osteocytes can be simultaneously cultured in a 3D environment while monitoring the bone formation/resorption balance. However, the bone regeneration potential cannot only be reduced to variations in the osteogenic activity of osteoblast/osteocyte embedded in a 3D matrix. In order to build relevant models of bone regeneration, further research is needed to recapitulate the structural complexity of the bone tissue, as well as its interaction with any other tissue affecting the regeneration process [11]. As for pathological mechanisms, a precise control of the hydrogel architecture could replicate trabecella thickness of single individuals,  
Figure 5: Modeling bone biology with personalized hydrogel-based bone-on-chips. Bone-on-chips aim at replicating specific functions of the bone tissue in sophisticated in vitro microenvironments. From a biological perspective, the variability associated with cell phenotype and bone diseases makes it difficult for traditional models to predict the efficacy of potential therapies.