Cardiovascular disease is still one of the leading causes of death in the world, and heart transplantation is the current major treatment for end-stage cardiovascular diseases. However, because of the shortage of heart donors, new sources of cardiac regenerative medicine are greatly needed. The prominent development of tissue engineering using bioactive materials has creatively laid a direct promising foundation. Whereas, how to precisely pattern a cardiac structure with complete biological function still requires technological breakthroughs. Recently, the emerging three-dimensional (3D) bioprinting technology for tissue engineering has shown great advantages in generating micro-scale cardiac tissues, which has established its impressive potential as a novel foundation for cardiovascular regeneration. Whether 3D bioprinted hearts can replace traditional heart transplantation as a novel strategy for treating cardiovascular diseases in the future is a frontier issue. In this review article, we emphasize the current knowledge and future perspectives regarding available bioinks, bioprinting strategies and the latest outcome progress in cardiac 3D bioprinting to move this promising medical approach towards potential clinical implementation.

Cell behavior is intricately intertwined with the in vivo microenvironment and endogenous pathways. The ability to guide cellular behavior toward specific goals can be achieved by external stimuli, notably electricity, light, ultrasound, and magnetism, simultaneously harnessed through biomaterial‐mediated responses. These external triggers become focal points within the body due to interactions with biomaterials, facilitating a range of cellular pathways: electrical signal transmission, biochemical cues, drug release, cell loading, and modulation of mechanical stress. Stimulus‐responsive biomaterials hold immense potential in biomedical research, establishing themselves as a pivotal focal point in interdisciplinary pursuits. This comprehensive review systematically elucidates prevalent physical stimuli and their corresponding biomaterial response mechanisms. Moreover, it delves deeply into the application of biomaterials within the domain of biomedicine. A balanced assessment of distinct physical stimulation techniques is provided, along with a discussion of their merits and limitations. The review aims to shed light on the future trajectory of physical stimulus‐responsive biomaterials in disease treatment and outline their application prospects and potential for future development. This review is poised to spark novel concepts for advancing intelligent, stimulus‐responsive biomaterials.

Mesenchymal stem cells (MSCs) encapsulation by three-dimensionally (3D) printed matrices were believed to provide a biomimetic microenvironment to drive differentiation into tissue-specific progeny, which made them a great therapeutic potential for regenerative medicine. Despite this potential, the underlying mechanisms of controlling cell fate in 3D microenvironments remained relatively unexplored. Here, we bioprinted a sweat gland (SG)–like matrix to direct the conversion of MSC into functional SGs and facilitated SGs recovery in mice. By extracellular matrix differential protein expression analysis, we identified that CTHRC1 was a critical biochemical regulator for SG specification. Our findings showed that Hmox1 could respond to the 3D structure activation and also be involved in MSC differentiation. Using inhibition and activation assay, CTHRC1 and Hmox1 synergistically boosted SG gene expression profile. Together, these findings indicated that biochemical and structural cues served as two critical impacts of 3D-printed matrix on MSC fate decision into the glandular lineage and functional SG recovery.

3-dimensional (3D) bioprinting technology provides promising strategy in the fabrication of artificial tissues and organs. As the fundamental element in bioprinting process, preparation of bioink with ideal mechanical properties without sacrifice of biocompatibility is a great challenge. In this study, a supramolecular hydrogel-based bioink is prepared by polyethylene glycol (PEG) grafted chitosan, α-cyclodextrin (α-CD) and gelatin. It has a primary crosslinking structure through the aggregation of the pseudo-polyrotaxane-like side chains, which are formed from the host-guest interactions between α-CD and PEG side chain. Apparent viscosity measurement shows the shear-shinning property of this bioink, which might be due to the reversibility of the physical crosslinking. Moreover, with β-glycerophosphate at different concentrations as the secondary crosslinking agent, the printed constructs demonstrate different Young's modulus (p < 0.001). They could also maintain the Young's modulus in cell culture condition for at least 21 days (p < 0.05). By co-culturing each component with fibroblasts, CCK-8 assay demonstrate cellular viability is higher than 80%. After bioprinting and culturing, immunofluorescence staining with quantification indicate the expression of Ki-67, Paxillin, and N-cadherin is higher in day 14 than those in day 3 (p < 0.05). Oil red O and Nissl body specific staining reflect strength tunable bioink may have impact on the cell fate of mesenchymal stem cells (p < 0.05). This work might provide new idea for advanced bioink in the application of re-establishing complicated tissues and organs.

Extrusion-based bioprinting (EBB) holds potential for regenerative medicine. However, the widely-used bioinks of EBB exhibit some limitations for skin regeneration, such as unsatisfactory bio-physical (i.e., mechanical, structural, biodegradable) properties and compromised cellular compatibilities, and the EBB-based bioinks with therapeutic effects targeting cutaneous wounds still remain largely undiscussed. In this review, the printability considerations for skin bioprinting were discussed. Then, current strategies for improving the physical properties of bioinks and for reinforcing bioinks in EBB approaches were introduced, respectively. Notably, we highlighted the applications and effects of current EBB-based bioinks on wound healing, wound scar formation, vascularization and the regeneration of skin appendages (i.e., sweat glands and hair follicles) and discussed the challenges and future perspectives. This review aims to provide an overall view of the applications, challenges and promising solutions about the EBB-based bioinks for cutaneous wound healing and skin regeneration.

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.