A Vascularized Bone-on-Paper Platform To Study Periosteum-Vascular Crosstalk and Angiogenic Remodeling

Osteoarthritis (OA) is a common degenerative joint disease in the elderly. It is characterized by articular cartilage degradation and periosteal bone spur formation. These changes often lead to pain, tissue compression, and disability. Periosteum-derived progenitor cells (PDPCs) play a crucial role in periosteal reactions, relying on vascular endothelial cells (VECs) for signal transduction through vascular networks. While bone-related studies often emphasize tissue regeneration, the intercellular signaling mechanisms driving OA progression remain underexplored. This study developed a vascularized bone-on-paper platform to simulate a three-dimensional (3D) periosteum-vascular tissue microenvironment. The platform consisted of a paper substrate sandwiched between a PDPCs/hydrogel construct and a Matrigel layer seeded with VECs. This configuration enabled coculture under inflammatory conditions to mimic the periosteum-vascular interface. The platform facilitated the investigation of cellular crosstalk and vascular development during bone degeneration. Results revealed that this platform effectively analyzed key signaling factors, including IFN-γ, TNF-α, IL-1β, IL-6, IL-10, IL-8, and VEGFA, at different stages of bone inflammation. Neutralizing and vascular development assays further demonstrated the significant role of these factors in the aberrant proliferation of PDPCs and vascular development. This platform provides a novel approach for studying intercellular signaling in bone degenerative progression and offers valuable insights for developing targeted therapies. By linking extracellular symptoms with signaling mechanisms, it advances understanding of OA pathogenesis and therapeutic innovation.