Engineering patient-derived organotypic bone models for skeletal disease and osteoanabolic therapy testing

Patient-derived organotypic bone models offer insights into the pathomechanisms of genetic skeletal disorders and can act as platforms to study the osteoanabolic effect of drug therapies toward precision medicine. Here, we developed a mechanically stimulated 3D bioprinted organotypic bone model using autologous cells from clinical bone samples, replicating both osteoblastic and osteocyte-like phenotypes through a two-step 3D bioprinting and cell seeding process. First, osteoblasts were isolated from patient bone, encapsulated within a bioink for extrusion 3D bioprinting, and subjected to mechanical loading for 4 weeks until mineralized. These mineralized cell-laden constructs were top-seeded with fresh osteoblasts and cultured for an additional 4 weeks. Using osteogenesis imperfecta (OI) patient-derived osteoblasts and osteoblasts from a metabolically healthy patient undergoing femur osteotomy (FO), we investigated the effects of Dickkopf-1 antibody (DKK1Ab), a Wnt pathway modulator, on gene expression, collagen dynamics, mineralization, and mechanical properties. Time-lapsed micro-computed tomography revealed hypermineralization, increased fragility and structural deformities in OI constructs, while transcriptomics, collagen quantification, and immunohistochemistry demonstrated the model's ability to capture differential patient-specific responses to treatment. This model offers a powerful platform for predicting disease progression and treatment outcomes in skeletal disorders, with the potential to transform orthopaedic care from reactive fracture management to proactive, personalized intervention strategies.