Kidney organoids derived from human pluripotent stem cells (hPSCs) have extensive potential for disease modelling and regenerative medicine. However, the limited vascularization and immaturity of kidney organoids have been still remained to overcome. Extracellular matrix (ECM) can provide mechanical support and a biochemical microenvironment for cell growth and differentiation. Here in vitro methods using a kidney decellularized extracellular matrix (dECM) hydrogel to culture hPSC-derived kidney organoids, which have extensive vascular network and their own endothelial cells, are reported. Single-cell transcriptomics reveal that the vascularized kidney organoids cultured using the kidney dECM have more mature patterns of glomerular development and higher similarity to human kidney than those cultured without the kidney dECM. Differentiation of 𝜶-galactosidase A (GLA)-knock-out hPSCs generated using CRISPR/Cas9 into kidney organoids by the culture method using kidney dECM efficiently recapitulate Fabry nephropathy with vasculopathy. Transplantation of kidney organoids with kidney dECM into kidney of mouse accelerates the recruitment of endothelial cells from the host mouse kidney and maintains vascular integrity with the more organized slit diaphragm-like structures than those without kidney dECM. The kidney dECM methodology for inducing extensive vascularization and maturation of kidney organoids can be applied to studies for kidney development, disease modeling, and regenerative medicine.

A wide variety of experimental models including 2D cell cultures, model organisms, and 3D in vitro models have been developed to understand pathophysiological phenomena and assess the safety and efficacy of potential therapeutics. In this sense, 3D in vitro models are an intermediate between 2D cell cultures and animal models, as they adequately reproduce 3D microenvironments and human physiology while also being controllable and reproducible. Particularly, recent advances in 3D in vitro biomimicry models, which can produce complex cell structures, shapes, and arrangements, can more similarly reflect in vivo conditions than 2D cell culture. Based on this, 3D bioprinting technology, which enables to place the desired materials in the desired locations, has been introduced to fabricate tissue models with high structural similarity to the native tissues. Therefore, this review discusses the recent developments in this field and the key features of various types of 3D-bioprinted tissues, particularly those associated with blood vessels or highly vascularized organs, such as the heart, liver, and kidney. Moreover, this review also summarizes the current state of the three categories: (1) chemical substance treatment, (2) 3D bioprinting of lesions, and (3) recapitulation of tumor microenvironments (TME) of 3D bioprinting-based disease models according to their disease modeling approach. Finally, we propose the future directions of 3D bioprinting approaches for the creation of more advanced in vitro biomimetic 3D tissues, as well as the translation of 3D bioprinted tissue models to clinical applications.

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Tremendous advances have been made toward accurate recapitulation of the human intestinal system in vitro to understand its developmental process, and disease progression. However, current in vitro models are often confined to 2D or 2.5D microarchitectures, which is difficult to mimic the systemic level of complexity of the native tissue. To overcome this problem, physiologically relevant intestinal models are developed with a 3D hollow tubular structure using 3D bioprinting strategy. A tissue-specific biomaterial, colon-derived decellularized extracellular matrix (Colon dECM) is developed and it provides significant maturation-guiding potential to human intestinal cells. To fabricate a perfusable tubular model, a simultaneous printing process of multiple materials through concentrically assembled nozzles is developed and a light-activated Colon dECM bioink is employed by supplementing with ruthenium/sodium persulfate as a photoinitiator. The bioprinted intestinal tissue models show spontaneous 3D morphogenesis of the human intestinal epithelium without any external stimuli. In consequence, the printed cells form multicellular aggregates and cysts and then differentiate into several types of enterocytes, building junctional networks. This system can serve as a platform to evaluate the effects of potential drug-induced toxicity on the human intestinal tissue and create a coculture model with commensal microbes and immune cells for future therapeutics.

Recently, respiratory systems are increasingly threatened by high levels of environmental pollution. Organ-on-a-chip technology has the advantage of enabling more accurate preclinical experiments by reproducing in vivo organ physiology. To investigate disease mechanisms and treatment options, respiratory-physiology-on-a-chip systems have been studied for the last decade. Here, we delineate the strategic approaches to develop respiratory-physiology-on-a-chip that can recapitulate respiratory system in vitro. The state-of-the-art biofabrication methods and biomaterials are considered as key contributions to constructing the chips. We also explore the vascularization strategies to investigate complicated pathophysiological phenomena including inflammation and immune responses, which are the critical aggravating factors causing the complications in the respiratory diseases. In addition, challenges and future research directions are delineated to improve the mimicry of respiratory systems in terms of both structural and biological behaviors.

Islet transplantation is a promising treatment for type 1 diabetes. However, treatment failure can result from loss of functional cells associated with cell dispersion, low viability, and severe immune response. To overcome these limitations, various islet encapsulation approaches have been introduced. Among them, macroencapsulation offers the advantages of delivering and retrieving a large volume of islets in one system. In this study, we developed a hybrid encapsulation system composed of a macroporous polymer capsule with stagger-type membrane and assemblable structure, and a nanoporous decellularized extracellular matrix (dECM) hydrogel containing pancreatic islet-like aggregates using 3D bioprinting technique. The outer part (macroporous polymer capsule) was designed to have an interconnected porous architecture, which allows insulin-producing β-cells encapsulated in the hybrid encapsulation system to maintain their cellular behaviors, including viability, cell proliferation, and insulin-producing function. The inner part (nanoporous dECM hydrogel), composed of the 3D biofabricated pancreatic islet-like aggregates, was simultaneously placed into the macroporous polymer capsule in one step. The developed hybrid encapsulation system exhibited biocompatibility in vitro and in vivo in terms of M1 macrophage polarization. Furthermore, by controlling the printing parameters, we generated islet-like aggregates, improving cell viability and functionality. Moreover, the 3D bioprinted pancreatic islet-like aggregates exhibited structural maturation and functional enhancement associated with intercellular interaction occurring at the β-cell edges. In addition, we also investigated the therapeutic potential of a hybrid encapsulation system by integrating human pluripotent stem cell-derived insulin-producing cells, which are promising to overcome the donor shortage problem. In summary, these results demonstrated that the 3D bioprinting approach facilitates the fabrication of a hybrid islet encapsulation system with multiple materials and potentially improves the clinical outcomes by driving structural maturation and functional improvement of cells.

In vitro organ models allow for the creation of precise preclinical models that mimic organ physiology. During a pandemic of a life-threatening acute respiratory disease, an improved trachea model is required. We fabricated a modular assembly of the blood vessel and trachea models using 3D bioprinting technology. First, decellularized extracellular matrix (dECM) were prepared using the porcine trachea and blood vessels. A trachea module was fabricated based on the tracheal mucosa-derived dECM and microporous membrane. Further, a blood vessel module was manufactured using the prepared vascular-tissue-derived dECM. By assembling each manufactured module, a perfusable vascularized trachea model simulating the interface between the tracheal epithelium and blood vessels was fabricated. This assembled model was manufactured with efficient performance, and it offered respiratory symptoms, such as inflammatory response and allergen-induced asthma exacerbation. These characteristics indicate the possibility of manufacturing a highly functional organ model that mimics a complex organ environment in the future.

Despite encouraging progress in the development of in vitro cancer models, in vitro cancer models that simultaneously recapitulate the complexity of the tumor microenvironment and its diverse cellular components and genetic properties remain lacking. Here, an advanced vascularized lung cancer model is proposed, which includes patient-derived lung cancer organoids (LCOs), lung fibroblasts, and perfusable vessels using 3D bioprinting technology. To better recapitulate the biochemical composition of native lung tissues, a porcine lung-derived decellularized extracellular matrix (LudECM) hydrogel was produced to offer physical and biochemical cues to cells in the lung cancer microenvironment. In particular, idiopathic pulmonary fibrosis-derived lung fibroblasts (iLFs) were used to implement fibrotic niches similar to actual human fibrosis. It was shown that they increased cell proliferation and the expression of drug resistance-related genes in LCOs with fibrosis. In addition, changes in resistance to sensitizing targeted anti-cancer drugs in LCOs with fibrosis were significantly greater in LudECM than in that Matrigel. Therefore, assessment of drug responsiveness in vascularized lung cancer models that recapitulate lung fibrosis can help determine the appropriate therapy for lung cancer patients accompanied by fibrosis. Furthermore, it is expected that this approach could be utilized for the development of targeted therapies or the identification of biomarkers for lung cancer patients accompanied by fibrosis.