Recent Advances in Cryogel Applications for Musculoskeletal Regeneration.

Abstract

Hydrogels have been widely used in tissue engineering due to their high-water content and biocompatibility, yet their densely cross-linked microstructure inherently limits cell infiltration, mass transport, and mechanical support. Cryogels, formed through partial freezing and crosslinking under subzero conditions, provide unique 3D macroporous networks with excellent permeability, elasticity, and shape-memory behavior. These structural and mechanical advantages facilitate cell migration and angiogenesis, while enabling minimally invasive delivery via syringe injection and highlighting strong translational potential. In musculoskeletal tissues such as bone, cartilage, and skeletal muscle, which have distinct biomechanical requirements, cryogels allow precise control over pore size, anisotropy, hierarchical architecture, and stiffness to better emulate native functionalities. Furthermore, tunable chemical composition and surface cues enable enhanced cell-matrix interactions and biological responsiveness. In addition, recent advances that incorporate growth factors, cells, nanomaterials, and conductive or immunomodulatory elements have established cryogels as therapeutic platforms that actively contribute to regeneration. These advancements further reinforce their clinical applicability and impact. This review summarizes the principles of cryogelation, crosslinking mechanisms, and structure-property relationships and examines recent cryogel-based strategies for musculoskeletal regeneration. By comparing fabrication parameters and their regenerative outcomes, we provide engineering insights for tissue-specific scaffold design and future optimization of cryogel-based musculoskeletal repair platforms.