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Hydrogels Powering 3D Biology


 Hydrogels play a central role in advancing 3D biological systems by providing hydrated, biomimetic environments that closely resemble native extracellular matrices. Their unique ability to combine high water content, mechanical tunability, and biochemical compatibility makes them essential materials for modern cell culture, tissue engineering, and regenerative research.

                                        Irreversible bone defects resulting from trauma, infection, and degenerative illnesses have emerged as a significant health concern. Structurally and functionally controllable hydrogels made by bone tissue engineering (BTE) have become promising biomaterials. Natural proteins are able to establish connections with autologous proteins through unique biologically active regions. Hydrogels based on proteins can simulate the bone microenvironment and regulate the biological behavior of stem cells in the tissue niche, making them candidates for research related to bone regeneration. This article reviews the biological functions of various natural macromolecular proteins (such as collagen, gelatin, fibrin, and silk fibroin) and highlights their special advantages as hydrogels. Then the latest research trends on cross-linking modified macromolecular protein hydrogels with improved mechanical properties and composite hydrogels loaded with exogenous micromolecular proteins have been discussed. Finally, the applications of protein hydrogels, such as 3D printed hydrogels, microspheres, and injectable hydrogels, were introduced, aiming to provide a reference for the repair of clinical bone defects.

 In three-dimensional biology, hydrogels support cell survival, spatial organization, and functional differentiation by offering a scaffold that permits cell–cell and cell–matrix interactions. By adjusting polymer composition and crosslinking density, researchers can precisely control stiffness, porosity, and degradability, allowing cells to sense and respond to their microenvironment in physiologically relevant ways.

From stem cell expansion to organoid formation, hydrogels enable long-term culture stability while maintaining genomic integrity and phenotypic fidelity. Their permeability to oxygen, nutrients, and signaling molecules ensures efficient mass transport, supporting complex multicellular structures and dynamic biological processes.

 Beyond structural support, advanced hydrogels can be engineered to incorporate bioactive cues, such as adhesion motifs or controlled release of growth factors. These features allow hydrogels to actively regulate cellular behavior, including migration, lineage commitment, and tissue patterning.

 As 3D biology continues to evolve toward more predictive and translational models, hydrogels remain foundational materials that bridge materials science and life sciences, powering more accurate representations of living systems and accelerating discovery in developmental biology, disease modeling, and regenerative medicine.