Bacterial infection, excessive inflammation and damaging blood vessels network are the major factors to delay the healing of diabetic ulcer. At present, most of wound repair materials are passive and can't response to the wound microenvironment, resulting in a low utilization of bioactive substances and hence a poor therapeutic effect. Therefore, it's essential to design an intelligent wound dressing responsive to the wound microenvironment to achieve the release of drugs on-demand on the basis of multifunctionality. In this work, metformin-laden CuPDA NPs composite hydrogel (Met@ CuPDA NPs/HG) was fabricated by dynamic phenylborate bonding of gelatin modified by dopamine (Gel-DA), Cu-loaded polydopamine nanoparticles (CuPDA NPs) with hyaluronic acid modified by phenyl boronate acid (HA-PBA), which possessed good injectability, self-healing, adhesive and DPPH scavenging performance. The slow release of metformin was achieved by the interaction with CuPDA NPs, boric groups (B-N coordination) and the constraint of hydrogel network. Metformin had a pH and glucose responsive release behavior to treat different wound microenvironment intelligently. Moreover, CuPDA NPs endowed the hydrogel excellent photothermal responsiveness to kill bacteria of >95% within 10 min and also the slow release of Cu²⁺ to protect wound from infection for a long time. Met@ CuPDA NPs/HG also recruited cells to a certain direction and promoted vascularization by releasing Cu²⁺. More importantly, Met@CuPDA NPs/HG effectively decreased the inflammation by eliminating ROS and inhibiting the activation of NF-κB pathway. Animal experiments demonstrated that Met@CuPDA NPs/HG significantly promoted wound healing of diabetic SD rats by killing bacteria, inhibiting inflammation, improving angiogenesis and accelerating the deposition of ECM and collagen. Therefore, Met@CuPDA NPs/HG had a great application potential for diabetic wound healing.

Three-dimensional (3D) printing holds great potential for preparing sophisticated scaffolds for tissue engineering. As a result of the shear thinning properties of an alginate solution, it is often used as 3D printing ink. However, it is difficult to prepare scaffolds with complexity structure and high fidelity, because the alginate solution has a low viscosity and alginate hydrogels prepared with Ca²⁺ crosslinking are mechanically weak. In this work, chitosan powders were dispersed and swelled in an alginate solution, which could effectively improve the viscosity of an alginate solution by 1.5–4 times. With the increase of chitosan content, the shape fidelity of the 3D printed alginate–chitosan polyion complex (AlCh PIC) hydrogels were improved. Scanning electron microscope (SEM) photographs showed that the lateral pore structure of 3D printed hydrogels was becoming more obvious. As a result of the increased reaction ion pairs in comparison to the alginate hydrogels that were prepared with Ca²⁺ crosslinking, AlCh PIC hydrogels were mechanically strong, and the compression stress of hydrogels at a 90% strain could achieve 1.4 MPa without breaking. In addition, human adipose derived stem cells (hASCs) adhered to the 3D printed AlCh PIC hydrogels and proliferated with time, which indicated that the obtained hydrogels were biocompatible and could potentially be used as scaffolds for tissue engineering.

Hydrogel scaffolds are attractive for tissue defect repair and reorganization because of their human tissue-like characteristics. However, most hydrogels offer limited cell growth and tissue formation ability due to their submicron- or nano-sized gel networks, which restrict the supply of oxygen, nutrients and inhibit the proliferation and differentiation of encapsulated cells. In recent years, 3D printed hydrogels have shown great potential to overcome this problem by introducing macro-pores within scaffolds. In this study, we fabricated a macroporous hydrogel scaffold through horseradish peroxidase (HRP)-mediated crosslinking of silk fibroin (SF) and tyramine-substituted gelatin (GT) by extrusion-based low-temperature 3D printing. Through physicochemical characterization, we found that this hydrogel has excellent structural stability, suitable mechanical properties, and an adjustable degradation rate, thus satisfying the requirements for cartilage reconstruction. Cell suspension and aggregate seeding methods were developed to assess the inoculation efficiency of the hydrogel. Moreover, the chondrogenic differentiation of stem cells was explored. Stem cells in the hydrogel differentiated into hyaline cartilage when the cell aggregate seeding method was used and into fibrocartilage when the cell suspension was used. Finally, the effect of the hydrogel and stem cells were investigated in a rabbit cartilage defect model. After implantation for 12 and 16 weeks, histological evaluation of the sections was performed. We found that the enzymatic cross-linked and methanol treatment SF₅GT₁₅ hydrogel combined with cell aggregates promoted articular cartilage regeneration. In summary, this 3D printed macroporous SF-GT hydrogel combined with stem cell aggregates possesses excellent potential for application in cartilage tissue repair and regeneration.

Microgel assembly, a macroscopic aggregate formed by bottom-up assembly of microgels, is now emerging as prospective biomaterials for applications in tissue engineering and regenerative medicine (TERM). This mini-review first summarizes the fabrication strategies available for microgel assembly, including chemical reaction, physical reaction, cell-cell interaction and external driving force, then highlights its unique characteristics, such as microporosity, injectability and heterogeneity, and finally itemizes its applications in the fields of cell culture, tissue regeneration and biofabrication, especially 3D printing. The problems to be addressed for further applications of microgel assembly are also discussed.