Although numerous organ‐on‐a‐chips have been developed, bone‐on‐a‐chip platforms have rarely been reported because of the high complexity of the bone microenvironment. With an increase in the elderly population, a high‐risk group for bone‐related diseases such as osteoporosis, it is essential to develop a precise bone‐mimicking model for efficient drug screening and accurate evaluation in preclinical studies. Here, we developed a high‐throughput biomimetic bone‐on‐a‐chip platform combined with an artificial intelligence (AI)‐based image analysis system. To recapitulate the key aspects of natural bone microenvironment, mouse osteocytes (IDG‐SW3) and osteoblasts (MC3T3‐E1) were cocultured within the osteoblast‐derived decellularized extracellular matrix (OB‐dECM) built in a well plate‐based three‐dimensional gel unit. This platform spatiotemporally and configurationally mimics the characteristics of the structural bone unit, known as the osteon. Combinations of native and bioactive ingredients obtained from the OB‐dECM and coculture of two types of bone cells synergistically enhanced osteogenic functions such as osteocyte differentiation and osteoblast maturation. This platform provides a uniform and transparent imaging window that facilitates the observation of cell–cell interactions and features high‐throughput bone units in a well plate that is compatible with a high‐content screening system, enabling fast and easy drug tests. The drug efficacy of anti‐SOST antibody, which is a newly developed osteoporosis drug for bone formation, was tested via β‐catenin translocation analysis, and the performance of the platform was evaluated using AI‐based deep learning analysis. This platform could be a cutting‐edge translational tool for bone‐related diseases and an efficient alternative to bone models for the development of promising drugs.

An extracellular matrix (ECM) utilized as a biomaterial can be obtained from organs of living organisms. Therefore, it has some limitations in its supply because of insufficient organs. Furthermore, therapeutic efficacy of ECMs varies depending on factors such as donor’s health condition and age. For this reason, ECMs obtained from a cell line could be a good alternative because they can be produced under a controlled environment with uniform quality. Thus, the purpose of this study was to investigate the potential of the MC3T3-E1 cell line-derived ECM as bone graft. The optimized decellularization process was developed to separate the ECM from MC3T3-E1, osteoblast cell line, using Trypsin–EDTA and Triton X-100. The decellularized ECM was partially digested using pepsin. Also, human bone marrow-derived mesenchymal stem cells induced faster osteogenesis on the ECM-coated surface than on the collagen-coated surface. Partially digested ECM fragments were embedded on the polyethylene glycol scaffold without additional chemical modification or crosslinking. Micro-computed tomography and histological analysis results showed that the ECM in the scaffold promoted actual bone regeneration after in vivo implantation to a mouse calvarial defect model. This study suggests that the bone-specific ECM derived from the cell line can replace the ECM from organs for application in tissue engineering and regenerative medicine.

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