Hyun-Wook Kang

Ischemic diseases, characterized by impaired blood flow and progressive tissue necrosis, remain a major challenge in regenerative medicine. Surgical revascularization remains the gold standard for restoring blood flow in major vessels, but still shows limited effects on microvascular regeneration. To address this unmet need, various strategies in therapeutic angiogenesis have been explored to induce microvascular formation, including delivery of bioactive molecules, stem cells, or pre-vascularized grafts. However, injection-based approaches often suffer from off-target effects, and conventional implantable grafts lack sufficient angiogenic secretory activity. To address these limitations, we aimed to develop a dual-function prevascularized graft that accelerates neovascularization and promotes vascular integration to restore tissue perfusion in ischemic conditions. The graft was engineered by combining a microvascular pattern (µVP) with spatially organized mesenchymal stem cell (MSC) spheroids, fabricated via high-precision coprinting of endothelial cells and MSCs. Optimization of spheroid density and spatial arrangement enhanced VEGF secretion and increased host capillary infiltration nearly two-fold. In a murine critical limb ischemia model, implantation of these engineered grafts achieved a 60% limb salvage rate and reduced limb loss by ~ 15%, representing a 4.5-fold improvement over conventional grafts. Histological and morphometric analyses confirmed reduced muscle degeneration, enhanced neovascularization, and seamless anastomosis between engineered and host vessels. These findings demonstrate a dual-functional graft that couples paracrine stimulation with structural vascular support, providing a promising regenerative strategy to promote therapeutic angiogenesis and ischemia therapy, while indicating its potential for preclinical and future clinical applications in ischemic disease. Schematic illustration of engineered grafts designed to enhance secretion and vascular integration, thereby promoting therapeutic angiogenesis and restoring blood perfusion in hindlimb ischemia The online version contains supplementary material available at 10.1007/s10456-026-10059-3.

Autologous adipose tissue (AT) grafting is often compromised by insufficient early vascularization, leading to ischemia, fibrosis, and inconsistent long-term volume retention. Incorporating platelet-rich plasma (PRP) into AT bioinks offers a clinically accessible means to enhance vascular recruitment, but the in vivo impact of PRP dosage remains unclear. Here, we investigated how PRP concentration, uniformly integrated into a previously reported clinically relevant AT bioink, regulates vascular infiltration, tissue remodeling, and overall graft survival. High-dose PRP markedly improved graft performance, including an 8-fold increase in highly perfused regions, a 3.8-fold enhancement in adipocyte survival, a 1.67-fold reduction in fibrosis, and a 2.51-fold increase in collagen III deposition compared with PRP-free AT grafts. Histological analysis further demonstrated that PRP mitigates the adverse effects of poor perfusion, reducing regional disparities in survival and extracellular matrix (ECM) remodeling. High-dose PRP also maximized graft retention, preserving 103% of graft mass relative to 50.6% in native AT. Together, these results establish a clear in vivo dose–response relationship for PRP-enhanced AT grafts and highlight platelet concentration as a key design parameter for soft-tissue reconstruction. This work provides a translational framework for optimizing PRP-functionalized bioinks to improve clinical outcomes in reconstructive surgery.

The human vascular system is a sophisticated hierarchical network branching from large‐diameter vessels to fine capillaries. Recapitulating this hierarchy remains a major biofabrication challenge, as oxygen diffusion from the nearest capillary is limited to ≈200 µm in native tissues, while current vascularized constructs struggle to maintain stable perfusion and functional multiscale architectures. To address this, a hybrid fabrication strategy is introduced that combines top‐down microfabrication of tubular scaffolds via electrospinning with bottom‐up bioprinting of cell‐laden bioinks. This approach enables the engineering of spatially programmable endothelialized tubular networks across three scales: macrovessels (≈3 mm), mesovessels (500–2000 µm), and capillaries (10–25 µm). Electrospun macrovessels exhibit artery‐like mechanical properties in longitudinal and circumferential directions. Bioprinting enables precise control over meso‐ and capillary‐scale vessels, facilitating the hierarchical patterning of complex architectures. Integrated triple‐scale endothelialized tubular networks formed interconnected, perfusable architectures comprising spatially patterned capillaries and enhanced diffusive transport by more than fivefold. Dynamic culture within endothelialized tubular networks of 5 mm thick tissue constructs supports high cell viability, rapid capillary formation, and in vivo‐like endothelial phenotypes under moderate flow. This work uniquely enables scalable vascular–mimetic architectures with artery‐like mechanical properties and spatially defined capillaries, representing a previously unattainable integration in angiogenesis, bioprinting, electrospinning, scaled‐up tissue constructs, vascular tissue engineeringlarge‐scale vascular constructs.

Advanced biomanufacturing technologies are rapidly transforming the development of microphysiological systems (MPS), which serve as sophisticated in vitro platforms to model human organ structure and function with high fidelity. This review highlights cutting-edge biofabrication strategies, including 3D bioprinting technologies (such as inkjet, extrusion-based, digital light processing, stereolithography, and laser direct writing), microfluidics, modular tissue engineering, and electrohydrodynamic manufacturing that enable precise fabrication of complex, multicellular, and physiologically relevant tissue models. The integration of microfluidic systems enhances MPS by supporting dynamic perfusion, mechanical stimulation, and real-time monitoring, while modular approaches such as cell spheroid, organoid, and cell sheet assembly facilitate scalable and reproducible tissue engineering. Electrohydrodynamic techniques like electrospinning and melt electrowriting are emphasized for their ability to fabricate nanostructured scaffolds that closely mimic native extracellular matrix properties. This review also examines the selection and application of biomaterials, ranging from natural and synthetic polymers to hybrid composites and stimuli responsive hydrogels, that underpin the structural and functional integrity of MPS. Finally, the broad applications of advanced biomanufactured MPS in drug screening, toxicology, disease modeling, and regenerative medicine are discussed, emphasizing their potential to reduce reliance on animal models and accelerate biomedical discoveries toward clinical translation. The convergence of real-time sensing, smart materials, and modular design principles is identified as a key driver for the next generation of physiologically relevant and patient specific in vitro models.

Mesenchymal stem cell (MSC)‐derived exosomes (MSC‐exosomes) are emerging as promising cell‐free therapeutic agents that address many challenges associated with traditional cell‐based therapies. However, conventional methods for isolating MSC‐exosomes using 2D culture systems are often limited in their efficiency, posing challenges to large‐scale production. This study introduces a novel approach to boost MSC‐exosome production by promoting cell–cell and cell–extracellular matrix (ECM) interactions. Specifically, ECM‐integrated MSC spheroid bioprinting technology is employed to optimize exosome secretion, analyzing the effects of spheroid size and ECM composition on exosome production. It is demonstrated that smaller spheroids constructed using MSCs exhibit an enhanced production of exosomes. Additionally, incorporating ECM components, such as fibrin, Matrigel, and collagen, particularly at higher concentrations, further boosts exosome production. Among these, MSC spheroids with a 150 μm diameter and 0.6% w/v collagen integration demonstrate the highest exosome secretion, achieving an 18.4‐fold increase compared to traditional 2D culture systems. Furthermore, exosomes derived from ECM‐enhanced MSC spheroids exhibit strong efficacy in an in vitro scratch wound assay, underscoring their therapeutic potential. Thus, the newly developed ECM‐incorporated spheroid bioprinting technology offers a highly effective strategy for scaling up MSC‐exosome production, paving the way for exosome‐based therapeutic applications.

Adipose tissue (AT) grafts are widely used in clinical procedures including soft‐tissue augmentation and post‐trauma reconstruction. However, the slow vascularization of conventional AT grafts poses a challenge to their in vivo preservation. To address this challenge, an innovative AT graft is engineered using adipose‐derived stem cell (ADSC) spheroids to enhance blood vessel infiltration. A polycaprolactone (PCL) framework containing precisely positioned ADSC spheroids is 3D bioprinted, and mechanically dissociated fat tissue is loaded into the framework to produce AT grafts. The spheroid diameter and pattern are optimized to significantly enhance the secretion of angiogenic factors from ADSCs in vivo. During an eight‐week in vivo experiment, the bioprinted and transplanted AT grafts demonstrated an impressive 8 fold increase in neo‐vessel formation compared to those in conventional grafts. This heightened neovascularization is directly correlated with a substantial improvement in transplanted AT survival and a 70% reduction in fibrous tissue formation. These findings underscore the pivotal role of ADSC spheroid‐mediated paracrine signaling in facilitating robust integration with the host vascular system. The novel approach significantly enhanced the long‐term viability and preservation of AT grafts by promoting blood vessel infiltration, paving the way for the development of highly vascularized AT grafts for clinical applications.

Heterogeneity and the absence of a tumor microenvironment (TME) in traditional patient‐derived organoid (PDO) cultures limit their effectiveness for clinical use. Here, Embedded Bioprinting‐enabled Arrayed PDOs (Eba‐PDOs) featuring uniformly arrayed colorectal cancer (CRC) PDOs within a recreated TME is presented. This model faithfully reproduces critical TME attributes, including elevated matrix stiffness (≈7.5 kPa) and hypoxic conditions found in CRC. Transcriptomic and immunofluorescence microscopy analysis reveal that Eba‐PDOs more accurately represent actual tissues compared to traditional PDOs. Furthermore, Eba‐PDO effectively capture the variability of CEACAM5 expression—a critical CRC marker—across different patients, correlating with patient classification and differential responses to 5‐fluorouracil treatment. This method achieves an uniform size and shape within PDOs from the same patient while preserving distinct morphological features among those from different individuals. These features of Eba‐PDO enable the efficient development of a label‐free, morphology‐based predictive model using supervised learning, enhancing its suitability for clinical applications. Thus, this approach to PDO bioprinting is a promising tool for generating personalized tumor models and advancing precision medicine.

The interaction between breast cancer and stromal tissues varies significantly from patient to patient, greatly impacting cancer prognosis. However, conventional models struggle to accurately replicate these patient‐specific interactions. Herein, a novel breast cancer–adipose composite tissue model capable of precisely adjusting the inter‐tissue interaction is developed. The composite tissue model is produced through precise embedded bioprinting of breast‐cancer spheroids and live‐adipose‐tissue ink. This model possessed not only precisely patterned cancer spheroids but also well‐preserved intrinsic extracellular matrices (ECMs) and heterogeneous cell populations of adipose tissue (AT). Evaluation results successfully demonstrated that the bioprinted composite model can precisely regulate adipokine secretion, drug resistance, and cancer‐cell invasion characteristics by adjusting the distance between the cancer spheroids and adipose tissue. The utility of the model is validated using adipokine‐targeted therapies (C‐compound/SC600125 (SC), AG 490 (AG), and Metformin (MET)). Interestingly, the inhibition of cancer cell proliferation and invasion by these adipokine‐targeted drugs nearly doubled as the tissue distance decreased. This suggests that the efficacy of the drugs can be precisely evaluated using the new model. These findings underscore the potential of the developed composite model to replicate patient‐specific crosstalk, thereby offering a promising platform for the sophisticated evaluation of various breast‐cancer therapies.

Autologous fat is widely used in soft tissue reconstruction; however, significant volume reduction owing to necrosis and degradation of the transplanted adipose tissue (AT) remains a major challenge. To address this issue, a novel live AT micro‐fragment–based bio‐ink (ATmf bio‐ink) compatible with precision 3D printing, is developed. Live AT micro‐fragments of ≈280 µm in size are prepared using a custom tissue micronizer and they are incorporated into a fibrinogen/gelatin mixture to create the ATmf bio‐ink. AT micro‐fragments exhibit high viability and preserve the heterogeneous cell population and extracellular matrix of the native AT. The developed bio‐ink enables precise micropatterning and provides an excellent adipo‐inductive microenvironment. AT grafts produced by co‐printing the bio‐ink with polycaprolactone demonstrate a 500% improvement in volume retention and a 300% increase in blood vessel infiltration in vivo compared with conventional microfat grafts. In vivo engraftment of AT grafts is further enhanced by using a stem cell–laden ATmf bio‐ink. Last, it is successfully demonstrated that the bio‐ink is enabled for the creation of clinically relevant and patient‐specific AT grafts for patients undergoing partial mastectomy. This novel ATmf bio‐ink for volumetric soft tissue reconstruction offers a pioneering solution for addressing the limitations of existing clinical techniques.

Pancreatic islet macroencapsulation systems for subcutaneous transplantation have garnered significant attention as a therapy for Type I diabetes due to their minimal invasiveness and low complication rates. However, the low vascular density of subcutaneous tissue threatens the long‐term survival of islets. To address this issue, prevascularized systems are introduced but various challenges remain, including system complexity and vascular‐cell immunogenicity. Here, a novel prevasculature‐free macroencapsulation system designed as a multilayer sheet, which ensures sufficient mass transport even in regions with sparse vasculature, is presented. Islets are localized in top/bottom micro‐shell layers (≈300 µm thick) to maximize proximity to the surrounding host vasculature. These sheets, fabricated via bioprinting using rat islets and alginate‐based bio‐ink, double islet viability and optimize islet density, improving insulin secretion function by 240%. The subcutaneous transplantation of small islet masses (≈250 islet equivalent) into diabetic nude mice enable rapid (120 days. Additionally, antifibrotic drug‐loaded multilayer sheets facilitate blood glucose regulation by rat islets at the subcutaneous sites of diabetic immunocompetent mice for >35 days. Thus, this macroencapsulation system can advance the treatment of Type I diabetes and is also effective for islet xenotransplantation in subcutaneous tissue.