# Designing Hydrogel-Based Bone-On-Chips for Personalized Medicine
###### Abstract  
The recent development of bone-on-chips (BOCs) holds the main advantage of requiring a low quantity of cells and material, compared to traditional In Vitro models. By incorporating hydrogels within BOCs, the culture system moved to a three dimensional culture environment for cells which is more representative of bone tissue matrix and function. The fundamental components of hydrogel-based BOCs, namely the cellular sources, the hydrogel and the culture chamber, have been tuned to mimic the hematopoietic niche in the bone aspirate marrow, cancer bone metastasis and ostee/chondrogenic differentiation. In this review, we examine the entire process of developing hydrogel-based BOCs to model In Vitro a patient specific situation. First, we provide bone biological understanding for BOCs design and then how hydrogel structural and mechanical properties can be tuned to meet those requirements. This is followed by a review on hydrogel-based BOCs, developed in the last 10 years, in terms of culture chamber design, hydrogel and cell source used. Finally, we provide guidelines for the definition of personalized pathological and physiological bone microenvironments. This review covers the information on bone, hydrogel and BOC that are required to develop personalized therapies for bone disease, by recreating clinically relevant scenarii in miniaturized devices. bone-on-chip; bone microenvironment; bone hydrogels; tunable hydrogels; microfluidic bone treatments; bone models +
Footnote †: journal: Medical  
Moreover, a high number of parameters can be tested with one single batch. Yet, traditional 2D in vitro models are not suitable for long-term studies and may fail in recapitulating a clinically relevant environment due to the absence of all factors present in vivo [9], but their high output and outcome balance this weakness. The lack of clinical relevance of 2D or the experimental challenge of large scale 3D in vitro models, which includes the high number of cells necessary and necrosis in the core of large scaffold, led to the development of the organ-on-chip field. The organ-on-chip technologies have recently emerged from the synergy of microfabrication techniques and tissue engineering, aiming to replicate specific processes of organ functionality in sophisticated in vitro microenvironments and reduce the amount of cells required. While the use of organ-on-chips for drug screening is steadily increasing [10], the combination of microengineered systems with primary patient cells is inspiring the field of regenerative medicine [11] as well as personalized medicine, since they facilitate the use of cells isolated from individual patients [12]. Different organ-on-chips were recently developed to predict the variability between individuals associated to specific biological processes, such as the permeability of the blood-brain barrier [13], the inflammation of the human airways [14], the proliferation of multiple myeloma cells [15] and the drug-induced hematotoxicity [16]. Compared to other tissues, Bone-On-Chip (BOC) platforms have mostly emerged in recent years. The first literature review on the development and challenges of BOC systems has been recently published, showing the main technical solutions adopted to study bone cell function, bone regeneration and its interaction with multiple tissues [17]. Starting from a monolayer of mouse osteocyte-like cell line to study mechano-regulation under oscillatory fluid flow [18], BCCs moved to three dimensional (3D) culture systems that investigated the osteocytic network formation [19; 20] or the bone matrix mineralization process [21]. Indeed, 3D culture environments mimicking the extracellular matrix (ECM) provide representative systems of tissue function where hydrogels are an ideal candidate to reflect the matrix topography and properties. The focus of this specific review is to describe the entire process to design BOC and to provide an informed perspective of the type and characteristic of hydrogels and cellular environment required to reproduce a disease state.