The adult myocardium couples extreme metabolic demand with a finely tuned coronary microvasculature. Continuous, high-work output is sustained by dense capillary networks, short diffusion distances and dominant reliance on mitochondrial oxidative phosphorylation. By contrast, current cardiac tissue engineering platforms, including scaffold-free myocardial constructs, have achieved robust contraction and basic drug responsiveness but remain constrained by fetal-like cardiomyocyte metabolism and incomplete vascular integration. As pluripotent stem cell-derived cardiomyocytes are driven toward more adult-like phenotypes using metabolic maturation strategies-such as substrate switching from glycolysis to fatty acid oxidation-oxygen consumption rises sharply, exposing the limitations of diffusion-limited culture and underspecified vascular design. This Review proposes integrative circulatory engineering as a framework in which metabolic maturation, vascular architecture and perfusion are co-designed rather than optimized in isolation. Scaffold-free myocardial tissues are highlighted as a particularly suitable platform, enabling close cell-cell contact, self-organized microvascular networks and dynamic remodeling of extracellular matrix. We examine how cell type composition, paracrine crosstalk, matrix mechanics and spatial patterning can be orchestrated to align metabolic demand with vascular supply. Perfusion bioreactors are treated as active components of the engineered circulation, providing controlled oxygen delivery, shear conditioning of endothelial networks, dynamic substrate provision and tunable mechanical loading. The concept is extended to in vitro circulatory units that couple myocardial modules to vascular beds and, in advanced implementations, to other metabolic organs. Finally, translational scenarios, disease modelling opportunities, quality control and computational design are discussed. Together, these elements outline a path toward myocardial tissues that approximate the structural, metabolic and functional complexity required for regenerative therapy and high-fidelity disease modeling.

Diabetic wound healing is a highly coordinated, multi-stage process that relies critically on the pro-regenerative microenvironment. Recently, stem cell-based therapies have emerged as a promising paradigm in regenerative medicine, largely attributable to their inherent self-renewal capacity, multilineage differentiation potential, and pro-repair secretome. Despite these advances, the therapeutic potential of neural stem cells (NSCs) in cutaneous wound repair remains largely unexplored. We systematically evaluated the pro-angiogenic, antioxidant, and mitochondrial modulatory effects of NSCs on endothelial cells. A bio-inspired hydrogel was designed for NSC encapsulation with favorable preliminary biocompatibility. The in vivo pro-healing efficacy of NSCs-armed hydrogel was then assessed in diabetic mice. NSCs enhanced angiogenesis, antioxidant capacity, and mitochondrial function in endothelial cells. The engineered hydrogel exhibited favorable preliminary biocompatibility for the encapsulation of NSCs. This platform accelerated diabetic wound healing by regulating inflammation, promoting angiogenic, and exerting neural-supportive effects. This NSC-loaded hydrogel platform offers a promising and clinically relevant strategy for diabetic wound repair.

IntroductionRegenerative medicine involves restoring natural function by replacing or regenerating human cells, tissues, or organs. Despite projections of significant market growth, venture capital (VC) investment in tissue and organ engineering has recently declined.MethodsWe conducted a mixed-methods study using structured surveys and qualitative interviews. VC investors with experience in healthcare sectors (biotechnology, tissue engineering, and medical technology) were invited to complete a survey and participate in interviews.ResultsWe received 22 survey responses and conducted 9 interviews (April–May 2025). Prior exposure to regenerative medicine was significantly associated with future investment likelihood (p = 0.0464). Investment potential strongly correlated with assets under management (ρ = 0.67) and investment stage (ρ = 0.66). Among 20 respondents, clinical validation (n = 8) and adoption (n = 8) were most often cited as major investment drivers, followed by reimbursement and regulatory challenges. Interviews emphasized four factors shaping VC interest in tissue and organ engineering: prior investment experience, time horizon misalignment, clinical risk expectations, and market readiness.DiscussionStartups can improve appeal by targeting long-horizon investors, outlining clinical and regulatory pathways, and generating robust, comparative evidence to support value-based reimbursement.

Bone regeneration is a highly coordinated process shaped by the interplay between immune responses and osteogenic mechanisms. Immune cells such as neutrophils, macrophages, T cells, and B cells dynamically regulate the local microenvironment through cytokine secretion and signaling pathways, thereby influencing osteogenesis, angiogenesis and bone remodeling, while dysregulated or prolonged inflammation can disrupt healing. Growing evidence has highlighted the potential of leveraging immunomodulation to enhance bone repair. This review synthesizes recent progress in immunoregulatory strategies by comparing cellular therapies, molecular interventions and biomaterial-based approaches in terms of their mechanisms, their effects on osteogenesis and angiogenesis, and their translational potential. Particular emphasis is placed on immune cell specific signaling pathways, biomaterial design parameters including surface topography, porosity, ion release and stiffness, and emerging technologies such as immune responsive hydrogels, programmable scaffolds and exosome based delivery systems. Current findings indicate that mesenchymal stem cells and regulatory T cells not only provide progenitor sources but also reshape the immune milieu through paracrine factors and exosomes; cytokines, small molecules, microRNAs and pro resolving mediators effectively modulate inflammatory cascades to promote vascularized bone formation; and immunomodulatory biomaterials enable spatiotemporal regulation of macrophage polarization, particularly the transition from the pro inflammatory M1 phenotype to the reparative M2 phenotype. Collectively, these advances highlight that bone repair is fundamentally an immunologically driven process, and integrating temporal immune regulation with emerging therapeutic platforms offers a promising pathway toward precise and personalized bone regeneration.