Elnaz Abedini, Daver Ali
Biodegradable hydrogels are injected in situ to create scaffolds in complex tissue defects with a minimally invasive approach. The current narrative review critically discusses their design principles such as polymer type (natural, synthetic and hybrid systems), crosslinking processes (physical, chemical, and self-crosslinking strategies), and optimization of their rheological properties for clinical injectability. Various advanced biofunctionalization strategies such as cell encapsulation, spatiotemporal delivery of growth factors, extracellular matrix mimicry via fiber-reinforced composites, and active immunomodulation are assessed for their application in tissue-specific regeneration in cartilage, bone, cardiac, neural, skin, and dental applications. While there has been significant progress in preclinical work, there are significant translational challenges that remain: mechanical mismatch with load-bearing native tissues, natural polymer batch-to-batch variability, unpredictable degradation rates, and a complex regulatory pathway for combination products. We explore under-explored areas such as 4D bioprinting for dynamic shape morphing, the design of materials through artificial intelligence, and closed-loop theranostic platforms that combine real-time biosensing with on-demand therapeutic release. This review suggests that the interdisciplinary convergence of materials science, bioengineering, and regulatory science is necessary to tackle these challenges and make injectable hydrogels a standard-of-care regenerative therapeutic.