We engineered functional cardiac patches by seeding neonatal rat cardiomyocytes onto carbon nanotube (CNT) incorporated photocrosslinkable gelatin methacrylate (GelMA) hydrogel. The resulting cardiac constructs showed excellent mechanical integrity and advanced electrophysiological functions. Specifically, myocardial tissues cultured on 50 μm thick CNT-GelMA showed 3 times higher spontaneous synchronous beating rates and 85% lower excitation threshold, compared to those cultured on pristine GelMA hydrogels. Our results indicate that the electrically conductive and nanofibrous networks formed by CNTs within a porous gelatin framework is the key characteristics of CNT-GelMA leading to improved cardiac cell adhesion, organization, and cell-cell coupling. Centimeter-scale patches were released from glass substrates to form 3D biohybrid actuators, which showed controllable linear cyclic contraction/extension, pumping, and swimming actuations. In addition, we demonstrate for the first time that cardiac tissues cultured on CNT-GelMA resist damage by a model cardiac inhibitor as well as a cytotoxic compound. Therefore, incorporation of CNTs into gelatin, and potentially other biomaterials, could be useful in creating multifunctional cardiac scaffolds for both therapeutic purposes and in vitro studies. These hybrid materials could also be used for neuron and other muscle cells to create tissue constructs with improved organization, electroactivity, and mechanical integrity.
Engineering of organized vasculature is a crucial step in the development of functional and clinically relevant tissue constructs. A number of previous techniques have been proposed to spatially regulate the distribution of angiogenic biomolecules and vascular cells within biomaterial matrices to promote vascularization. Most of these approaches have been limited to two-dimensional (2D) micropatterned features or have resulted in formation of random vasculature within three-dimensional (3D) microenvironments. In this study, we investigate 3D endothelial cord formation within micropatterned gelatin methacrylate (GelMA) hydrogels with varying geometrical features (50–150 µm height). We demonstrated the significance dependence of endothelial cells proliferation, alignment and cord formation on geometrical dimensions of the patterned features. The cells were able to align and organize within the micropatterned constructs and assemble to form cord structures with organized actin fibers and circular/elliptical cross-sections. The inner layer of the cord structure was filled with gel showing that the micropatterned hydrogel constructs guided the assembly of endothelial cells into cord structures. Notably, the endothelial cords were retained within the hydrogel microconstructs for all geometries after two weeks of culture; however, only the 100 µm-high constructs provided the optimal microenvironment for the formation of circular and stable cord structures. Our findings suggest that endothelial cord formation is a preceding step to tubulogenesis and the proposed system can be used to develop organized vasculature for engineered tissue constructs.
We present the first cell-attachable and visible-light-crosslinkable bioinks based on gelatin methacryloyl (GelMA) with eosin Y (EY) photoinitiation for stereolithography three-dimensional (3D) bioprinting. To develop a visible-light-crosslinkable hydrogel, we systematically studied five combinations of GelMA and EY photoinitiator with various concentrations. Their mechanical properties, microstructures, and cell viability and confluency after encapsulation were investigated rigorously to elucidate the effects of the EY and GelMA macromer concentrations on the characteristics of the hydrogel. Experimental results show that the compressive Young's modulus and pore size are positively affected by the concentration of EY, whereas the mass swelling ratio and cell viability are negatively affected. Increasing the concentration of GelMA helps in improving the compressive Young's modulus and cell attachment. We further employed the developed visible-light-based stereolithography bioprinting system to print the patterned cell-laden hydrogels to demonstrate the bioprinting applications of the developed hydrogel. We observed good cell proliferation and the formation of a 3D cellular network inside the printed pattern at day 5, which proves the great feasibility of using EY-GelMA as the bioinks for biofabrication and tissue engineering.
As mechanical end-effectors, microgrippers enable the pick-transport-place of micrometer-sized objects, such as manipulation and positioning of biological cells in an aqueous environment. This paper reports on a monolithic MEMS-based microgripper with integrated force feedback along two axes and presents the first demonstration of forcecontrolled micro-grasping at the nanonewton force level. The system manipulates highly deformable biomaterials (porcine interstitial cells) in an aqueous environment using a microgripper that integrates a V-beam electrothermal microactuator and two capacitive force sensors, one for contact detection (force resolution: 38.5 nN) and the other for gripping force measurements (force resolution: 19.9 nN). The MEMS-based microgripper and the force control system experimentally demonstrate the capability of rapid contact detection and reliable force-controlled micrograsping to accommodate variations in size and mechanical properties of objects with a high reproducibility.
Microfabrication technology provides a highly versatile platform for engineering hydrogels used in biomedical applications with high-resolution control and injectability. Herein, we present a strategy of microfluidics-assisted fabrication photo-cross-linkable gelatin microgels, coupled with providing protective silica hydrogel layer on the microgel surface to ultimately generate gelatin-silica core–shell microgels for applications as in vitro cell culture platform and injectable tissue constructs. A microfluidic device having flow-focusing channel geometry was utilized to generate droplets containing methacrylated gelatin (GelMA), followed by a photo-cross-linking step to synthesize GelMA microgels. The size of the microgels could easily be controlled by varying the ratio of flow rates of aqueous and oil phases. Then, the GelMA microgels were used as in vitro cell culture platform to grow cardiac side population cells on the microgel surface. The cells readily adhered on the microgel surface and proliferated over time while maintaining high viability (∼90%). The cells on the microgels were also able to migrate to their surrounding area. In addition, the microgels eventually degraded over time. These results demonstrate that cell-seeded GelMA microgels have a great potential as injectable tissue constructs. Furthermore, we demonstrated that coating the cells on GelMA microgels with biocompatible and biodegradable silica hydrogels via sol–gel method provided significant protection against oxidative stress which is often encountered during and after injection into host tissues, and detrimental to the cells. Overall, the microfluidic approach to generate cell-adhesive microgel core, coupled with silica hydrogels as a protective shell, will be highly useful as a cell culture platform to generate a wide range of injectable tissue constructs.
Gelatin methacrylate (GelMA) hydrogel is a promising bioink for biofabrication applications due to its cost-effectiveness, ease of synthesis and biocompatibility to allow cell adhesion. However, the GelMA synthesized from a widely used porcine skin gelatin has a thermal gelation problem at room temperature. Here, we present thermally stable GelMA hydrogels at room temperature while maintaining the mechanical and biological properties comparable to porcine GelMA. The novel GelMA hydrogels were synthesized from fish skin and cold soluble gelatin. We systematically characterized the properties of the GelMA hydrogels from different sources. The properties include the degree of methacrylation, compressive Young's modulus, mass swelling ratio, viscosity, and cell adhesion and proliferation in 2D and 3D microenvironments. It has been found that the cold soluble GelMA was comparable to the porcine skin GelMA but could offer low viscosity and thermal stability at room temperature. We performed a droplet generation experiment to demonstrate the benefit of using the cold soluble GelMA for biofabrication. The cold soluble GelMA showed a more reliable and stable droplet fabrication process. Taken together, the cold soluble GelMA is a promising bioink solution and may greatly benefit the research in biofabrication.
Over the past decade, synthesized nanomaterials, such as carbon nanotube, nanoparticle, quantum dot, and nanowire, have already made breakthroughs in various fields, including biomedical sensors. Enormous surface area-to-volume ratio of the nanomaterials increases sensitivity dramatically compared with macro-sized material. Herein we present a comprehensive review about the working principle and fabrication process of nanowire sensor. Moreover, its applications for the detection of biomarker, virus, and DNA, as well as for drug discovery, are reviewed. Recent advances including self-powering, reusability, sensitivity in high ionic strength solvent, and long-term stability are surveyed and highlighted as well. Nanowire is expected to lead significant improvement of biomedical sensor in the near future.
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