Cong Xu

The placenta forms the maternal-fetal interface to protect the developing fetus from xenobiotics or pathogens. However, the understanding of complex placental features and responses to pathogens are hindered due to the lack of near-physiological models. Here, we present an engineered human placental organoid microphysiological system (MPS) incorporated with vascular endothelium, which allows to recapitulate early placental features in a vascular niche. The MPS comprises a customized insert-based organ chip and a rocker, enabling in situ differentiation and formation of placental organoids from human trophoblast stem cells under dynamic culture conditions. By incorporating vascular endothelium, trophoblast organoids (TOs) maintain improved cell viability, long-term trophoblast proliferation and differentiation. Moreover, trophoblast organoids cocultured with endothelium (EndTOs) show the activation of innate immune-related signaling pathways and high-level secretion of distinct immunomodulatory factors, including antiviral type I and III interferons and trophoblast-specific factors. We further demonstrate that EndTOs exhibit attenuated susceptibility to Zika virus (ZIKV) than single cultured TOs, indicating the crucial role of vascular niche in enhancing intrinsic antiviral defenses functions of trophoblasts. This bioinspired placental organoid MPS provides a useful platform for studying placental physiology and relevant diseases.

The burden of liver diseases is increasing worldwide, accounting for two million deaths annually. In the past decade, tremendous progress has been made in the basic and translational research of liver tissue engineering. Liver microtissues are small, 3D hepatocyte cultures that recapitulate liver physiology and have been used in biomedical research and regenerative medicine. This review summarizes the recent advances, challenges, and future directions in liver microtissue research. Cellular engineering approaches are used to sustain primary hepatocytes or produce hepatocytes derived from pluripotent stem cells and other adult tissues. 3D microtissues are generated using scaffold‐free assembly or scaffold‐assisted methods such as macroencapsulation, droplet microfluidics, and bioprinting. Optimization of the hepatic microenvironment entails incorporating the appropriate cell composition for enhanced cell–cell interactions and niche‐specific signals, and creating scaffolds with desired chemical, mechanical, and physical properties. Perfusion‐based culture systems such as bioreactors and microfluidic systems are used to achieve efficient exchange of nutrients and soluble factors. Taken together, systematic optimization of liver microtissues is a multidisciplinary effort focused on creating liver cultures and on‐chip models with greater structural complexity and physiological relevance for use in liver disease research, therapeutic development, and regenerative medicine.

Organized cardiomyocyte alignment is critical to maintain the mechanical properties of the heart. In this study, we present a new and simple strategy to fabricate a biomimetic microchip designed with an onion epithelium-like structure and investigate the guided behavior of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) on the substrate. The hiPSC-CMs were observed to be confined by the three dimensional surficial features morphologically, analogous to the in vivo microenvironment, and exhibited an organized anisotropic alignment on the onion epithelium-like structure with good beating function. The calcium imaging of hiPSC-CMs demonstrated a more mature Ca²⁺ spark pattern as well. Furthermore, the expression of sarcomere genes (TNNI3, MYH6 and MYH7), potassium channel genes (KCNE1 and KCNH2), and calcium channel genes (RYR2) was significantly up-regulated on the substrate with an onion epithelium-like structure instead of the surface without the structure, indicating a more matured status of cardiomyocytes induced by this structure. It appears that the biomimetic micropatterned structure, analogous to in vivo cellular organization, is an important factor that might promote the maturation of hiPSC-CMs, providing new biological insights to guide hiPSC-CM maturation by biophysical factors. The established approach may offer an effective in vitro model for investigating cardiomyocyte differentiation, maturation and tissue engineering applications.

Human induced pluripotent stem cells (hiPSCs) and appropriate scaffolds are of great interest in cardiac tissue engineering. In this work, we present a simple and new strategy to produce a thin collagen membrane with a natural microstructure from porcine tendons and reconstruct the functional cardiac tissues by recellularizing hiPSC-derived cardiomyocytes onto the membrane, for the first time. The collagen membrane maintained its intact properties after decellularization, the composition of which was identified as collagen I. The cardiomyocytes grown on the thin membrane strongly expressed the cardiac-specific marker cardiac troponin T and exhibited the specific morphology guided by the natural microstructure of the collagen fibers. The formed cardiac tissue could maintain a strong beating function spontaneously for over one month and respond rapidly to the two types of anti-arrhythmic drugs with opposed effects. The proposed approach is very simple, and easy to operate with a low cost. The obtained thin collagen membrane with a natural microstructure is analogous to the in vivo extracellular matrix structure and functions, supporting the good function of the engineered cardiac tissue. We envision that this work would open a new way for a wide range of applications in cardiac tissue engineering, drug testing and regenerative medicine.

A novel and simple chip-based microfluidic strategy is proposed for continuously controlled spinning of desirable hollow microfibers. These fabricated fiber-shaped materials exhibit extraordinary morphological and structural complexity, as well as a heterogeneous composition. The resulting specific hollow microfibers have potential applications in numerous chemical and biomedical fields.

This work presents a new and multifunctional organs-on-a-chip device that allows for the characterization of the multi-step metabolism processes of pro-drug CAP in liver cells and its resultant efficacy in multiple target cells simultaneously and quantitatively.

There is a growing interest in using paper as a biomaterial scaffold for cell-based applications. In this study, we made the first attempt to fabricate a paper-based array for the culture, proliferation, and direct differentiation of human induced pluripotent stem cells (hiPSCs) into functional beating cardiac tissues and create “a beating heart on paper.” This array was simply constructed by binding a cured multi-well polydimethylsiloxane (PDMS) mold with common, commercially available paper substrates. Three types of paper material (print paper, chromatography paper and nitrocellulose membrane) were tested for adhesion, proliferation and differentiation of human-derived iPSCs. We found that hiPSCs grew well on these paper substrates, presenting a three-dimensional (3D)-like morphology with a pluripotent property. The direct differentiation of human iPSCs into functional cardiac tissues on paper was also achieved using our modified differentiation approach. The cardiac tissue retained its functional activities on the coated print paper and chromatography paper with a beating frequency of 40–70 beats per min for up to three months. Interestingly, human iPSCs could be differentiated into retinal pigment epithelium on nitrocellulose membrane under the conditions of cardiac-specific induction, indicating the potential roles of material properties and mechanical cues that are involved in regulating stem cell differentiation. Taken together, these results suggest that different grades of paper could offer great opportunities as bioactive, low-cost, and 3D in vitro platforms for stem cell-based high-throughput drug testing at the tissue/organ level and for tissue engineering applications.