A 3D spheroid model of quadruple cell co-culture with improved liver functions for hepatotoxicity prediction.

Drug-induced liver injury (DILI) is one of the major concerns during drug development. Wide acceptance of the 3 R principles and the innovation of in-vitro techniques have introduced various novel model options, among which the three-dimensional (3D) cell spheroid cultures have shown a promising prospect in DILI prediction. The present study developed a 3D quadruple cell co-culture liver spheroid model for DILI prediction via self-assembly. Induction by phorbol 12-myristate 13-acetate at the concentration of 15.42 ng/mL for 48 hours with a following 24-hour rest period was used for THP-1 cell differentiation, resulting in credible macrophagic phenotypes. HepG2 cells, PUMC-HUVEC-T1 cells, THP-1-originated macrophages, and human hepatic stellate cells were selected as the components, which exhibited adaptability in the designated spheroid culture conditions. Following establishment, the characterization demonstrated the competence of the model in long-term stability reflected by the maintenance of morphology, viability, cellular integration, and cell-cell junctions for at least six days, as well as the reliable liver-specific functions including superior albumin and urea secretion, improved drug metabolic enzyme expression and CYP3A4 activity, and the expression of MRP2, BSEP, and P-GP accompanied by the bile acid efflux transport function. In the comparative testing using 22 DILI-positive and 5 DILI-negative compounds among the novel 3D co-culture model, 3D HepG2 spheroids, and 2D HepG2 monolayers, the 3D culture method significantly enhanced the model sensitivity to compound cytotoxicity compared to the 2D form. The novel co-culture liver spheroid model exhibited higher overall predictive power with margin of safety as the classifying tool. In addition, the non-parenchymal cell components could amplify the toxicity of isoniazid in the 3D model, suggesting their potential mediating role in immune-mediated toxicity. The proof-of-concept experiments demonstrated the capability of the model in replicating drug-induced lipid dysregulation, bile acid efflux inhibition, and α-SMA upregulation, which are the key features of liver steatosis and phospholipidosis, cholestasis, and fibrosis, respectively. Overall, the novel 3D quadruple cell co-culture spheroid model is a reliable and readily available option for DILI prediction.

Magneto-Thermomechanically Reprogrammable Mechanical Metamaterials.

Future active metamaterials for reconfigurable structural applications require fast, untethered, reversible, and reprogrammable (multimodal) transformability with shape locking. Magnetic control has a superior advantage for fast and remotely controlled deployment; however, a significant drawback is needed to maintain the magnetic force to hold the transformation, limiting its use in structural applications. The shape-locking property of shape-memory polymers (SMPs) can resolve this issue. However, the intrinsic irreversibility of SMPs may limit their reconfigurability as active metamaterials. Moreover, to date, reprogrammable methods have required high power with laser and arc welding proving to be energy-inefficient control methods. In this work, a magneto-thermomechanical tool is constructed and demonstrated, which enables a single material system to transform with untethered, reversible, low-powered reprogrammable deformations, and shape locking via the application of magneto-thermomechanically triggered prestress on the SMP and structural instability with asymmetric magnetic torque. The mutual assistance of two physics concepts-magnetic control combined with the thermomechanical behavior of SMPs is demonstrated, without requiring new materials synthesis and high-power energy for reprogramming. This approach can open a new path of active metamaterials, flexible yet stiff soft robots, multimodal morphing structures, and mechanical computing devices where it can be designed in reversible and reprogrammable ways.

Inverse design of 3D reconfigurable curvilinear modular origami structures using geometric and topological reconstructions.

The recent development of modular origami structures has ushered in an era for active metamaterials with multiple degrees of freedom (multi-DOF). Notably, no systematic inverse design approach for 3D curvilinear modular origami structures has been reported. Moreover, very few modular origami topologies have been studied to design active metamaterials with multi-DOF. Herein, we develop an inverse design method for constructing 3D reconfigurable architected structures - we synthesize modular origami structures whose unit cells can be volumetrically mapped into a prescribed 3D curvilinear shape followed by volumetric shrinkage to construct modules. After modification of the tubular geometry, we search through all the possible geometric and topological combinations of the modular origami structures to attain the target mobility using a topological reconstruction of modules. Our inverse design using geometric and topological reconstructions can provide an effective solution to construct 3D curvilinear reconfigurable structures with multi-DOF. Our work opens a path toward 3D reconfigurable systems based on volumetric inverse design, such as 3D active metamaterials and 3D morphing devices for automotive, aerospace, and biomedical engineering applications.