Worm Generator: A System for High-Throughput in Vivo Screening.

Large-scale screening of molecules in organisms requires high-throughput and cost-effective evaluating tools during preclinical development. Here, a novel in vivo screening strategy combining hierarchically structured biohybrid triboelectric nanogenerators (HB-TENGs) arrays with computational bioinformatics analysis for high-throughput pharmacological evaluation using Caenorhabditis elegans is described. Unlike the traditional methods for behavioral monitoring of the animals, which are laborious and costly, HB-TENGs with micropillars are designed to efficiently convert animals' behaviors into friction deformation and result in a contact-separation motion between two triboelectric layers to generate electrical outputs. The triboelectric signals are recorded and extracted to various bioinformation for each screened compound. Moreover, the information-rich electrical readouts are successfully demonstrated to be sufficient to predict a drug's identity by multiple-Gaussian-kernels-based machine learning methods. This proposed strategy can be readily applied to various fields and is especially useful in in vivo explorations to accelerate the identification of novel therapeutics.

Ultrasensitive FET biosensor chip based on self-assembled organic nanoporous membrane for femtomolar detection of Amyloid-ß.

Early diagnosis of Alzheimer's disease (AD) is critical for preventing disease progression, however, the diagnosis of AD remains challenging for most patients due to limitations of current sensing technologies. A common pathological feature found in AD-affected brains is the accumulation of Amyloid-ß (Aß) polypeptides, which lead to neurofibrillary tangles and neuroinflammatory plaques. Here, we developed a portable ultrasensitive FET biosensor chip based on a self-assembled nanoporous membrane for ultrasensitive detection of Aß protein in complex environments. The microscale semiconductor channel was covered with a self-assembled organic nanoporous membrane modified by antibody molecules to pick up and amplify the Aß protein signal. The nanoporous structure helps protect the sensitive channel from non-target proteins and improves its stability since no chemical functionalization process involved, largely reduces background noise of the sensing platform. When a bio-gated target is captured, the doping state of the polymer bulk could be tuned and amplified the strength of the weak signal, achieving ultrasensitive detecting performance (enabling the device to detect target protein less than 1 fg/ml in 1 µl sample). Moreover, the device simplifies the circuit connection by integrating all the connections on a 2 cm × 2 cm chip, avoiding expensive and complex manufacturing processes, and makes it usable for portable prognosis. We believe that this ultrasensitive, portable, low-cost Aß sensor chip shows the great potential in the early diagnosis of AD and large-scale population screening applications.

Multi-Target Neural Differentiation (MTND) Therapeutic Cocktail to Suppress Brain Tumor.

Brain tumors have been proved challenging to treat. Here we established a Multi-Target Neural Differentiation (MTND) therapeutic cocktail to achieve effective and safe treatment of brain malignancies by targeting the important hallmarks in brain cancers: poor cell differentiation and compromised cell cycle. In-vitro and in-vivo experiments confirmed the significant therapeutic effect of our MTND therapy. Significantly improved therapeutic effects over current first-line chemo-drugs have been identified in clinical cells, with great inhibition of the growth and migration of tumor cells. Further in-vivo experiments confirmed that sustained MTND treatment showed a 73% reduction of the tumor area. MTND also induced strong expression of phenotypes associated with cell cycle exit/arrest and rapid neural reprograming from clinical glioma cells to glutamatergic and GABAergic expressing cells, which are two key neuronal types involved in many human brain functions, including learning and memory. Collectively, MTND induced multi-targeted genotypic expression changes to achieve direct neural conversion of glioma cells and controlled the cell cycle/tumorigenesis development, helping control tumor cells' malignant proliferation and making it possible to treat brain malignant tumors effectively and safely. These encouraging results open avenues to developing new therapies for brain malignancies beyond cytotoxic agents, providing more effective medication recommendations with reduced toxicity.

Biohybrid Triboelectric Nanogenerator for Label-Free Pharmacological Fingerprinting in Cardiomyocytes.

The development of new drugs requires high-throughput and cost-effective pharmacological assessment in relevant biological models. Here, we introduce a novel pharmacological screening platform that combines a biohybrid triboelectric nanogenerator (TENG) and informatic analysis for self-powered, noninvasive, and label-free biosensing in cardiac cells. The cyclic mechanical activity of functional cardiomyocytes is dynamically captured by a specially designed biohybrid TENG device and is analyzed by a custom-made machine learning algorithm to reveal distinctive fingerprints in response to different pharmacological treatment. The core of the TENG device is a multilayer mesh substrate with microscale-gapped triboelectric layers, which are induced to generate electrical outputs by the characteristic motion of cardiomyocytes upon pharmaceutical treatment. Later bioinformatic extraction from the recorded TENG signal is sufficient to predict a drug's identity and efficacy, demonstrating the great potential of this platform as a biocompatible, low-cost, and highly sensitive drug screening system.

A Remotely Controlled Transformable Soft Robot Based on Engineered Cardiac Tissue Construct.

Many living organisms undergo conspicuous or abrupt changes in body structure, which is often accompanied by a behavioral change. Inspired by the natural metamorphosis, robotic systems can be designed as reconfigurable to be multifunctional. Here, a tissue-engineered transformable robot is developed, which can be remotely controlled to assume different mechanical structures for switching locomotive function. The soft robot is actuated by a muscular tail fin that emulates the swimming of whales and works as a cellular engine powered by the synchronized contraction of striated cardiac microtissue constructs. For a transition of locomotive behavior, the robot can be optically triggered to transform from a spread to a retracted form, which effectively changes the bending stiffness of the tail fins, thus minimizing the propulsion output from the "tail fin" and effectively switching off the engine. With the unprecedented controllability and responsiveness, the transformable robot is implemented to work as a cargo carrier for programmed delivery of chemotherapeutic agents to selectively eradicate cancer cells. It is believed that the realization of the transformable concept paves a pathway for potential development of intelligent biohybrid robotic systems.

Effects of in vivo exposure to polyfluorinated dibenzo-p-dioxins on organo-somatic indices and ethoxyresorufin-O-deethylase activity in mice (Mus musculus).

In this study, five different congeners of polyfluorinated dibenzo-P-dioxins (PFDDs) (1,8-di-FDD, 1,3,8-tri-FDD, 1,3,6,8-tetra-FDD, 2,3,7,8-tetra-FDD and 1,2,3,4,5,6,7,8-octa-FDD), representing different numbers and positions of fluorine substituents of all 75 PFDD congeners, were synthesized and purified to evaluate their potential environmental impact on living organisms. Their toxicity was evaluated by determining the impact on the organo-somatic indices (OSI) and ethoxyresorufin-O-deethylase (EROD) activity in mice (Mus musculus) after intragastric administration with different doses (0.5-100 µg/kg body weight) for 3 days. The results showed that these PFDDs significantly inhibited the growth and changed the OSI in mouse tissues. Notably, hepatic EROD activity was markedly induced in mice after exposure to these PFDDs, probably indicating a high affinity of binding to the aryl hydrocarbon receptor. Overall, these findings provided some preliminary but alarming toxicity data of PFDDs, and filled information gaps in the toxicological databases for living organisms.

Minimally-invasive implantable device enhances brain cancer suppression.

Current brain tumor treatments are limited by the skull and BBB, leading to poor prognosis and short survival for glioma patients. We introduce a novel minimally-invasive brain tumor suppression (MIBTS) device combining personalized intracranial electric field therapy with in-situ chemotherapeutic coating. The core of our MIBTS technique is a wireless-ultrasound-powered, chip-sized, lightweight device with all functional circuits encapsulated in a small but efficient "Swiss-roll" structure, guaranteeing enhanced energy conversion while requiring tiny implantation windows ( ~ 3 × 5 mm), which favors broad consumers acceptance and easy-to-use of the device. Compared with existing technologies, competitive advantages in terms of tumor suppressive efficacy and therapeutic resolution were noticed, with maximum ~80% higher suppression effect than first-line chemotherapy and 50-70% higher than the most advanced tumor treating field technology. In addition, patient-personalized therapy strategies could be tuned from the MIBTS without increasing size or adding circuits on the integrated chip, ensuring the optimal therapeutic effect and avoid tumor resistance. These groundbreaking achievements of MIBTS offer new hope for controlling tumor recurrence and extending patient survival.

Mitochondria dysfunction and bipolar disorder: From pathology to therapy.

Bipolar disorder (BD) is one of the major psychiatric diseases in which the impairment of mitochondrial functions has been closely connected or associated with the disease pathologies. Different lines of evidence of the close connection between mitochondria dysfunction and BD were discussed with a particular focus on (1) dysregulation of energy metabolism, (2) effect of genetic variants, (3) oxidative stress, cell death and apoptosis, (4) dysregulated calcium homeostasis and electrophysiology, and (5) current as well as potential treatments targeting at restoring mitochondrial functions. Currently, pharmacological interventions generally provide limited efficacy in preventing relapses or recovery from mania or depression episodes. Thus, understanding mitochondrial pathology in BD will lead to novel agents targeting mitochondrial dysfunction and formulating new effective therapy for BD.

Ferromagnetic Flexible Electronics for Brain-Wide Selective Neural Recording.

Flexible microelectronics capable of straightforward implantation, remotely controlled navigation, and stable long-term recording hold great promise in diverse medical applications, particularly in deciphering complex functions of neural circuits in the brain. Existing flexible electronics, however, are often limited in bending and buckling during implantation, and unable to access a large brain region. Here, an injectable class of electronics with stable recording, omnidirectional steering, and precise navigating capabilities based on magnetic actuation is presented. After simple transcriptional injection, the rigid coatings are biodegraded quickly and the bundles of magnetic-nanoparticles-coated microelectrodes become separated, ultra-flexible, and magnetic actuated for further minimally invasive three-dimensional interpenetration in the brain. As proof of concept, this paradigm-shifting approach is demonstrated for selective and multiplexed neural activities recording across distant regions in the deep rodent brains. Coupling with optogenetic neural stimulation, the unique capabilities of this platform in electrophysiological readouts of projection dynamics in vivo are also demonstrated. The ability of these miniaturized, remotely controllable, and biocompatible ferromagnetic flexible electronics to afford minimally invasive manipulations in the soft tissues of the mammalian brain foreshadows applications in other organ systems, with great potential for broad utility in biomedical science and engineering.

Novel Nano-Drug Delivery System for Brain Tumor Treatment.

As the most dangerous tumors, brain tumors are usually treated with surgical removal, radiation therapy, and chemotherapy. However, due to the aggressive growth of gliomas and their resistance to conventional chemoradiotherapy, it is difficult to cure brain tumors by conventional means. In addition, the higher dose requirement of chemotherapeutic drugs caused by the blood-brain barrier (BBB) and the untargeted nature of the drug inevitably leads to low efficacy and systemic toxicity of chemotherapy. In recent years, nanodrug carriers have attracted extensive attention because of their superior drug transport capacity and easy-to-control properties. This review systematically summarizes the major strategies of novel nano-drug delivery systems for the treatment of brain tumors in recent years that cross the BBB and enhance brain targeting, and compares the advantages and disadvantages of several strategies.

An implantable ultrasound-powered device for the treatment of brain cancer using electromagnetic fields.

Brain tumors have been proved challenging to treat. Here, we present a promising alternative by developing an implantable ultrasound-powered tumor treating device (UP-TTD) that electromagnetically disrupts the rapid division of cancer cells without any adverse effects on normal neurons, thereby safely inhibiting brain cancer recurrence. In vitro and in vivo experiments confirmed the significant therapeutic effect of the UP-TTD, with ~58% inhibition on growth rate of clinical tumor cells and ~78% reduction of cancer area in tumor-bearing rats. This UP-TTD is wireless ultrasound-powered, chip-sized, lightweight, and easy to operate on complex surfaces, with a largely boosting therapeutic efficiency and reducing energy consumption. Meanwhile, various treatment parameters could be tuned from the UP-TTD without increasing its size or adding circuits on the integrated chip. The tuning process was simulated and discussed, showing an excellent agreement with the experimental data. The encouraging results of the UP-TTD raise the possibility of a new modality for brain cancer treatment.

Vascularized neural constructs for ex-vivo reconstitution of blood-brain barrier function.

Ex-vivo blood-brain barrier (BBB) model is of great value for studying brain function and drug development, but it is still challenging to engineer macroscale three-dimensional (3D) tissue constructs to recapitulate physiological and functional aspects of BBB. Here, we describe a delicate 3D vascularized neural constructs for ex-vivo reconstitution of BBB function. The tissue-engineered tissue construct is based on a multicomponent 3D co-culture of four types of cells, which typically exist in the BBB and were spatially defined and organized to mimic the in vivo BBB structure and function. A porous polycaprolactone/poly (d,l-lactide-co-glycolide) (PCL/PLGA) microfluidic perfusion system works as the vasculature network, which was made by freeze-coating a 3D-printed sacrificial template. Endothelial cells were seeded inside the channels of the network to form 3D interconnected blood vessels; while other types of cells, including pericytes, astrocytes, and neurons, were co-cultured in a collagen matrix wrapping the vasculature network to derive a vascularized neural construct that recapitulates in vivo BBB function with great complexity and delicacy. Using this model, we successfully reconstituted BBB function with parameters that are similar to the in vivo condition, and demonstrated the identification of BBB-penetrating therapeutics by examining the molecular delivery to neuronal cells when relevant biologic molecules were applied to the vasculature circulation system of the neural construct.

Injectable Nanoreinforced Shape-Memory Hydrogel System for Regenerating Spinal Cord Tissue from Traumatic Injury.

Traumatic injury in the central nervous system can lead to loss of functional neurons. Transplantation of neural progenitors is a promising therapeutic strategy. However, infusion of dissociated cells often suffers from low viability, uneven cell distribution, and poor in vivo engraftment that could be reinforced by a better cell delivery system. Here, we develop an injectable composite hydrogel system for use as a minimally invasive treatment of spinal cord injury (SCI) using motor neurons (MNs) derived from embryonic stem cells (ESCs). The composite hydrogel is based on a modified gelatin matrix integrated with shape-memory polymer fibers. The gelatin matrix creates a local microenvironment for cell assembly and also acts as a lubricant during injection through a fine catheter. Notably, shape-memory fiber scaffolds are able to recover to maintain the microstructures even after dramatic deformation from injection operation, providing the necessary support and guidance for motor neuron differentiation. We find that the composite hydrogel with an aligned fiber scaffold greatly improves the viability of ESCs and their differentiation toward MNs both in vitro and in vivo. When transplanted to SCI animals by injection, the ESC-loaded composite hydrogels are identified to significantly enhance tissue regeneration and motor function recovery in mice. With this proof-of-concept study, we believe that the injectable composite hydrogel system provides a promising solution for in vivo cell delivery with minimum invasiveness and can be readily extended to other stem-cell-based regenerative treatments.

High-throughput three-dimensional chemotactic assays reveal steepness-dependent complexity in neuronal sensation to molecular gradients.

Many cellular programs of neural development are under combinatorial regulation by different chemoattractive or chemorepulsive factors. Here, we describe a microfluidic platform that utilizes well-controlled three-dimensional (3D) diffusion to generate molecular gradients of varied steepness in a large array of hydrogel cylinders, allowing high-throughput 3D chemotactic assays for mechanistic dissection of steepness-dependent neuronal chemotaxis. Using this platform, we examine neuronal sensitivity to the steepness of gradient composed of netrin-1, nerve growth factor, or semaphorin3A (Sema3A) proteins, and reveal dramatic diversity and complexity in the associated chemotactic regulation of neuronal development. Particularly for Sema3A, we find that serine/threonine kinase-11 and glycogen synthase kinase-3 signaling pathways are differentially involved in steepness-dependent chemotactic regulation of coordinated neurite repellence and neuronal migration. These results provide insights to the critical role of gradient steepness in neuronal chemotaxis, and also prove the technique as an expandable platform for studying other chemoresponsive cellular systems.

Anti-counterfeiting patterns encrypted with multi-mode luminescent nanotaggants.

Anti-counterfeiting patterns are encrypted with nanotaggants that are selectively excited at distinct wavelengths. Decryption is realized by examining the temporal color or graphic responses of the pattern under various illumination wavelengths. The covert color and graphic codes that are designable through control of the nanotaggant composition are expected to provide high-level security.

Investigation of the Subcellular Neurotoxicity of Amyloid-ß Using a Device Integrating Microfluidic Perfusion and Chemotactic Guidance.

Alzheimer's disease (AD) is a neurodegenerative disorder with the histopathological hallmark of extracellular accumulation of amyloid-ß (Aß) peptide in brain senile plaques. Though many studies have shown the neural toxicity from various forms of Aß peptides, the subcellular mechanisms of Aß peptide are still not well understood, partially due to the technical challenges of isolating axons or dendrites from the cell body for localized investigation. In this study, the subcellular toxicity and localization of Aß peptides are investigated by utilizing a microfluidic compartmentalized device, which combines physical restriction and chemotactic guidance to enable the isolation of axons and dendrites for localized pharmacological studies. It is found that Aß peptides induced neuronal death is mostly resulted from Aß treatment at cell body or axonal processes, but not at dendritic neurites. Simply applying Aß to axons alone induces significant hyperactive spiking activity. Dynamic transport of Aß aggregates is only observed between axon terminal and cell body. In addition to differential cellular uptake, more Aß-peptide secretion is detected significantly from axons than from dendritic side. These results clearly demonstrate the existence of a localized mechanism in Aß-induced neurotoxicity, and can potentially benefit the development of new therapeutic strategies for AD.

Ultrathin MXene-Micropattern-Based Field-Effect Transistor for Probing Neural Activity.

A field-effect transistor (FET) based on ultrathin Ti3 C2 -MXene micropatterns is developed and utilized as a highly sensitive biosensor. The device is produced with the microcontact printing technique, making use of its unique advantages for easy fabrication. Using the MXene-FET device, label-free probing of small molecules in typical biological environments and fast detection of action potentials in primary neurons is demonstrated.

Ozonation of indigo enhanced by carboxylated carbon nanotubes: performance optimization, degradation products, reaction mechanism and toxicity evaluation.

As a promising disinfection technique to replace chlorination, ozonation has been demonstrated to be efficient in water treatment. This paper describes an effective way to enhance the ozonation of indigo by using carbon nanotubes functionalized with carboxyl groups (CNTs-COOH) as catalysts. The result of kinetic studies showed that the presence of CNTs-COOH dramatically increased the decolorization rate of indigo. Different types of catalysts were compared to further elucidate the internal mechanism of the catalytic reaction and the special nanostructure and the functional ­COOH groups are considered to play an important role in the catalytic ozonation process. Four aromatic intermediate products were identified using an electrospray time-of-flight mass spectrometer and further rationalized by the frontier electron density calculations. Ion chromatography analysis revealed that the nitrogen atom of indigo was released predominantly as ammonium and to a lesser extent as nitrate. The presence of the catalyst CNTs-COOH leads to a higher mineralization degree than single ozonation, as suggested by the total organic carbon (TOC) measurement. Three major carboxylic acids (i.e., oxalic, formic and acetic acids) were also identified as oxidation by-products, and they contributed significantly to the residual TOC after 2 h of ozonation. In addition, the toxicity evolution during the degradation was investigated through two aquatic model species to evaluate the potential ecological risks of the intermediate products.