The Osteoimmunologic Basis of Biologic and Bioengineered Therapies in Osteoarthritis

Osteoarthritis (OA) is a significant clinical problem that places a substantial burden on both patients and the healthcare system. Characterized by progressive cartilage degeneration, synovial inflammation, and subchondral bone remodeling, OA is a rapidly growing and increasingly studied disease affecting millions around the world. Growing evidence has expanded on the traditional view of OA as a mechanical "wear-and-tear" disease, highlighting that disease progression is driven not only by mechanical stress but also by chronic dysregulation of the osteoimmune environment. Activation of innate and adaptive immune pathways, macrophage M1 polarization, and dysregulated cytokine signaling all contribute to progressive joint degeneration. While current therapeutics often focus on managing symptoms or restoring joint mechanics, interventions often overlook the role of osteoimmunology in disease progression. This review summarizes the biological and bioengineering strategies emerging to address OA. These platforms include bioceramics, metal-based scaffolds, hydrogels, nanoparticles, and microsphere systems. Furthermore, small molecules, cell-based therapies, and gene-modified systems have also been shown to modulate the inflammatory microenvironment, enhance regulatory immune responses, and restore cartilage homeostasis. Together, these approaches represent the evolving research landscape, shifting away from just symptom alleviation and towards targeted disease-modifying therapies, including osteoimmunomodulation. However, significant barriers to clinical translation remain, such as limited large animal studies and species immune system differences, which need to be addressed for the development of clinically applicable interventions.