MXene-Based Elastomer Mimetic Stretchable Sensors: Design, Properties, and Applications.

Flexible sensors based on MXene-polymer composites are highly prospective for next-generation wearable electronics used in human-machine interfaces. One of the motivating factors behind the progress of flexible sensors is the steady arrival of new conductive materials. MXenes, a new family of 2D nanomaterials, have been drawing attention since the last decade due to their high electronic conductivity, processability, mechanical robustness and chemical tunability. In this review, we encompass the fabrication of MXene-based polymeric nanocomposites, their structure-property relationship, and applications in the flexible sensor domain. Moreover, our discussion is not only limited to sensor design, their mechanism, and various modes of sensing platform, but also their future perspective and market throughout the world. With our article, we intend to fortify the bond between flexible matrices and MXenes thus promoting the swift advancement of flexible MXene-sensors for wearable technologies.

Bionanotechnology and bioMEMS (BNM): state-of-the-art applications, opportunities, and challenges.

The development of micro- and nanotechnology for biomedical applications has defined the cutting edge of medical technology for over three decades, as advancements in fabrication technology developed originally in the semiconductor industry have been applied to solving ever-more complex problems in medicine and biology. These technologies are ideally suited to interfacing with life sciences, since they are on the scale lengths as cells (microns) and biomacromolecules (nanometers). In this paper, we review the state of the art in bionanotechnology and bioMEMS (collectively BNM), including developments and challenges in the areas of BNM, such as microfluidic organ-on-chip devices, oral drug delivery, emerging technologies for managing infectious diseases, 3D printed microfluidic devices, AC electrokinetics, flexible MEMS devices, implantable microdevices, paper-based microfluidic platforms for cellular analysis, and wearable sensors for point-of-care testing.

Programmable nanocomposites of cellulose nanocrystals and zwitterionic hydrogels for soft robotics.

Stimuli-responsive hydrogels have garnered significant attention as a versatile class of soft actuators. Introducing anisotropic properties, and shape-change programmability to responsive hydrogels promises a host of opportunities in the development of soft robots. Herein we report the synthesis of pH-responsive hydrogel nanocomposites with predetermined microstructural anisotropy, shape-transformation, and self-healing. Our hydrogel nanocomposites are largely composed of zwitterionic monomers and asymmetric cellulose nanocrystals. While the zwitterionic nature of the network imparts both self-healing and cytocompatibility to our hydrogel nanocomposites, the shear-induced alignment of cellulose nanocrystals renders their anisotropic swelling and mechanical properties. Thanks to the self-healing properties, we utilized a cut-and-paste approach to program reversible, and complex deformation into our hydrogels. As a proof-of-concept, we demonstrated the transport of light cargo using tethered and untethered soft robots made from our hydrogels. We believe the proposed material system introduce a powerful toolbox for the development of future generations of biomedical soft robots.

Development of a Hybrid Nanoink for 3D Bioprinting of Heterogeneous Tumor Models.

Despite the rapid progress in applying three-dimensional (3D) printing in the field of tissue engineering, fabrication of heterogeneous and complex 3D tumor models remains a challenge. In this study, we report a hybrid nanoink (AGC) composed of alginate, gelatin methacryloyl (GelMA), and cellulose nanocrystal (CNC), designed for multinozzle microextrusion 3D printing of tumor models. Our results show that the ink consisting of 2 wt % alginate, 4 wt % GelMA, and 6 wt % cellulose nanocrystals (AGC246) possesses a superior shear-thinning property and little hysteresis in viscosity recovery. The fabrication of a colorectal cancer (CRC) model is demonstrated by printing a 3D topological substrate with AGC246 and then seeding/printing endothelial (EA-hy 926) and colorectal carcinoma (HCT 116) cells on top. Direct seeding of cells by dropping a cell suspension onto the 3D substrate with distinctive topological features (villi and trenches) deemed inadequate in either creating a monolayer of endothelial cells or precise positioning of cancer cell clusters, even with surface treatment to promote cell adhesion. In contrast, 3D biopinting of a CRC model using cell-laden AGC153, coupled with dual ultraviolet (UV) and ionic cross-linking, is shown to be successful. Hence, this study brings advancements in 3D bioprinting technology through innovative material and methodology designs, which could enable the fabrication of complex in vitro models for both fundamental studies of disease processes and applications in drug screening.

Understanding Carbon Nanotube-Based Ionic Diodes: Design and Mechanism.

The rectification of ion transport through biological ion channels has attracted much attention and inspired the thriving invention and applications of ionic diodes. However, the development of high-performance ionic diodes is still challenging, and the working mechanisms of ionic diodes constructed by 1D ionic nanochannels have not been fully understood. This work reports the systematic investigation of the design and mechanism of a new type of ionic diode constructed from horizontally aligned multi-walled carbon nanotubes (MWCNTs) with oppositely charged polyelectrolytes decorated at their two entrances. The major design and working parameters of the MWCNT-based ionic diode, including the ion channel size, the driven voltage, the properties of working fluids, and the quantity and length of charge modification, are extensively investigated through numerical simulations and/or experiments. An optimized ionic current rectification (ICR) ratio of 1481.5 is experimentally achieved on the MWCNT-based ionic diode. These results promise potential applications of the MWCNT-based ionic diode in biosensing and biocomputing. As a proof-of-concept, DNA detection and HIV-1 diagnosis is demonstrated on the ionic diode. This work provides a comprehensive understanding of the working principle of the MWCNT-based ionic diodes and will allow rational device design and optimization.

3D bioprinting of bicellular liver lobule-mimetic structures via microextrusion of cellulose nanocrystal-incorporated shear-thinning bioink.

3D bioprinting of living cellular constructs with heterogeneity in cell types and extra cellular matrices (ECMs) matching those of biological tissues remains challenging. Here, we demonstrate that, through bioink material design, microextrusion-based (ME) bioprinting techniques have the potential to address this challenge. A new bioink employing alginate (1%), cellulose nanocrystal (CNC) (3%), and gelatin methacryloyl (GelMA) (5%) (namely 135ACG hybrid ink) was formulated for the direct printing of cell-laden and acellular architectures. The 135ACG ink displayed excellent shear-thinning behavior and solid-like properties, leading to high printability without cell damage. After crosslinking, the ACG gel can also provide a stiff ECM ideal for stromal cell growth. By controlling the degree of substitution and polymer concentration, a GelMA (4%) bioink was designed to encapsulate hepatoma cells (hepG2), as GelMA gel possesses the desired low mechanical stiffness matching that of human liver tissue. Four different versions of to-scale liver lobule-mimetic constructs were fabricated via ME bioprinting, with precise positioning of two different cell types (NIH/3T3 and hepG2) embedded in matching ECMs (135ACG and GelMA, respectively). The four versions allowed us to exam effects of mechanical cues and intercellular interactions on cell behaviors. Fibroblasts thrived in stiff 135ACG matrix and aligned at the 135ACG/GelMA boundary due to durotaxis, while hepG2 formed spheroids exclusively in the soft GelMA matrix. Elevated albumin production was observed in the bicellular 3D co-culture of hepG2 and NIH/3T3, both with and without direct intercellular contact, indicating that improved hepatic cell function can be attributed to soluble chemical factors. Overall, our results showed that complex constructs with multiple cell types and varying ECMs can be bioprinted and potentially useful for both fundamental biomedical research and translational tissue engineering.

Nanoparticle-Based Hybrid Scaffolds for Deciphering the Role of Multimodal Cues in Cardiac Tissue Engineering.

Myocardial microenvironment plays a decisive role in guiding the function and fate of cardiomyocytes, and engineering this extracellular niche holds great promise for cardiac tissue regeneration. Platforms utilizing hybrid hydrogels containing various types of conductive nanoparticles have been a critical tool for constructing engineered cardiac tissues with outstanding mechanical integrity and improved electrophysiological properties. However, there has been no attempt to directly compare the efficacy of these hybrid hydrogels and decipher the mechanisms behind how these platforms differentially regulate cardiomyocyte behavior. Here, we employed gelatin methacryloyl (GelMA) hydrogels containing three different types of carbon-based nanoparticles: carbon nanotubes (CNTs), graphene oxide (GO), and reduced GO (rGO), to investigate the influence of these hybrid scaffolds on the structural organization and functionality of cardiomyocytes. Using immunofluorescent staining for assessing cellular organization and proliferation, we showed that electrically conductive scaffolds (CNT- and rGO-GelMA compared to relatively nonconductive GO-GelMA) played a significant role in promoting desirable morphology of cardiomyocytes and elevated the expression of functional cardiac markers, while maintaining their viability. Electrophysiological analysis revealed that these engineered cardiac tissues showed distinct cardiomyocyte phenotypes and different levels of maturity based on the substrate (CNT-GelMA: ventricular-like, GO-GelMA: atrial-like, and rGO-GelMA: ventricular/atrial mixed phenotypes). Through analysis of gene-expression patterns, we uncovered that the engineered cardiac tissues matured on CNT-GelMA and native cardiac tissues showed comparable expression levels of maturation markers. Furthermore, we demonstrated that engineered cardiac tissues matured on CNT-GelMA have increased functionality through integrin-mediated mechanotransduction (via YAP/TAZ) in contrast to cardiomyocytes cultured on rGO-GelMA.

Towards label-free, wash-free and quantitative B-type natriuretic peptide detection for heart failure diagnosis.

Current diagnostic systems used in clinical settings to detect protein biomarkers require highly trained experts, large volumes of blood samples, and long turnaround times. There is an immense need for a low-cost and accurate point-of-care-testing (POCT) device for home monitoring of protein biomarkers for global pandemics such as heart failure (HF). The integration of highly sensitive carbon nanotube (CNT) thin film (CNT-TF) impedance sensors with the electrochemical impedance spectroscopy (EIS) technique is a promising platform to actualize POCT systems for home use. Herein, we report such a system, NanoBot, which allows the label-free and wash-free detection of the HF antigen biomarker B-type natriuretic peptide (BNP) in blood plasma. The NanoBot system consists of two parts: a disposable test strip and a miniature electronic readout unit. The NanoBot exhibited reasonable accuracy and precision, a clinically relevant limit of detection (LOD) as low as 16 pg mL-1, a linear detection range from 0-4000 pg mL-1 and excellent correlation with a reference standard fluorescent immunoassay (FIA). A pilot clinical study with patient-derived blood plasma validated the NanoBot's strong performance compared to that of Alere Triage®, with an interclass correlation coefficient (ICC) of 98% and a square of correlation coefficient (CC) of 0.95. Furthermore, unlike the Alere Triage® that requires more than 250 µL of blood collected via venipuncture, the NanoBot only requires 50 µL of blood. Collectively, the NanoBot's high sensitivity, accuracy, precision, and self-calibration characteristics signify its promising potential as a POCT platform for heart failure diagnosis in home use.

Electrochemical methods for probing DNA damage mechanisms and designing cisplatin-based combination chemotherapy.

An electrochemical approach was devised for detecting DNA damage and differentiating two DNA damage mechanisms, which is important to the design of new chemotherapeutics. This approach combined two platforms, based on the detection of base damage and DNA strand cleavage. In this work, our approach was demonstrated for the detection of cisplatin-induced DNA damage and the enhancement effects of two electron donors, N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and reduced graphene oxide (rGO). Our results demonstrated that TMPD enhanced DNA strand cleavage, supporting the proposed dissociative electron transfer mechanism. While rGO, which is an efficient electron donor, failed to show any enhancement (suggesting the lack of free-radical generation), overall, this electrochemical approach could be implemented for discovering next-generation DNA damage-based chemotherapy drugs.

Detection of Individual Molecules and Ions by Carbon Nanotube-Based Differential Resistive Pulse Sensor.

This paper presents a new method of sensing single molecules and cations by a carbon nanotube (CNT)-based differential resistive pulse sensing (RPS) technique on a nanofluidic chip. A mathematical model for multichannel RPS systems is developed to evaluate the CNT-based RPS signals. Individual cations, rhodamine B dye molecules, and ssDNAs are detected successfully with high resolution and high signal-to-noise ratio. Differentiating ssDNAs with 15 and 30 nucleotides are achieved. The experimental results also show that translocation of negatively charged ssDNAs through a CNT decreases the electrical resistance of the CNT channel, while translocation of positively charged cations and rhodamine B molecules increases the electrical resistance of the CNT. The CNT-based nanofluidic device developed in this work provides a new avenue for single-molecule/ion detection and offers a potential strategy for DNA sequencing.

Reduced Graphene Oxide-GelMA Hybrid Hydrogels as Scaffolds for Cardiac Tissue Engineering.

Biomaterials currently used in cardiac tissue engineering have certain limitations, such as lack of electrical conductivity and appropriate mechanical properties, which are two parameters playing a key role in regulating cardiac cell behavior. Here, the myocardial tissue constructs are engineered based on reduced graphene oxide (rGO)-incorporated gelatin methacryloyl (GelMA) hybrid hydrogels. The incorporation of rGO into the GelMA matrix significantly enhances the electrical conductivity and mechanical properties of the material. Moreover, cells cultured on composite rGO-GelMA scaffolds exhibit better biological activities such as cell viability, proliferation, and maturation compared to ones cultured on GelMA hydrogels. Cardiomyocytes show stronger contractility and faster spontaneous beating rate on rGO-GelMA hydrogel sheets compared to those on pristine GelMA hydrogels, as well as GO-GelMA hydrogel sheets with similar mechanical property and particle concentration. Our strategy of integrating rGO within a biocompatible hydrogel is expected to be broadly applicable for future biomaterial designs to improve tissue engineering outcomes. The engineered cardiac tissue constructs using rGO incorporated hybrid hydrogels can potentially provide high-fidelity tissue models for drug studies and the investigations of cardiac tissue development and/or disease processes in vitro.

Resonant photo-thermal modification of vertical gallium arsenide nanowires studied using Raman spectroscopy.

Gallium arsenide nanowires have shown considerable promise for use in applications in which the absorption of light is required. When the nanowires are oriented vertically, a considerable amount of light can be absorbed, leading to significant heating effects. Thus, it is important to understand the threshold power densities that vertical GaAs nanowires can support, and how the nanowire morphology is altered under these conditions. Here, resonant photo-thermal modification of vertical GaAs nanowires was studied using both Raman spectroscopy and electron microscopy techniques. Resonant waveguiding, and subsequent absorption of the excited optical mode reduces the irradiance vertical GaAs nanowires can support relative to horizontal ones, by three orders of magnitude before the onset of structural changes occur. A power density of only 20 W mm(-2) was sufficient to induce local heating in the nanowires, resulting in the formation of arsenic species. Upon further increasing the power, a hollow nanowire morphology was realized. These findings are pertinent to all optical applications and spectroscopic measurements involving vertically oriented GaAs nanowires. Understanding the optical absorption limitations, and the effects of exceeding these limitations will help improve the development of all III-V nanowire devices.

Highly Elastic and Conductive Human-Based Protein Hybrid Hydrogels.

A highly elastic hybrid hydrogel of methacryloyl-substituted recombinant human tropoelastin (MeTro) and graphene oxide (GO) nanoparticles are developed. The synergistic effect of these two materials significantly enhances both ultimate strain (250%), reversible rotation (9700°), and the fracture energy (38.8 ± 0.8 J m(-2) ) in the hybrid network. Furthermore, improved electrical signal propagation and subsequent contraction of the muscles connected by hybrid hydrogels are observed in ex vivo tests.

Carbon Nanotube-Based Supercapacitors with Excellent ac Line Filtering and Rate Capability via Improved Interfacial Impedance.

We report the fabrication of high-performance, self-standing composite sp(2)-carbon supercapacitor electrodes using single-walled carbon nanotubes (CNTs) as conductive binder. The 3-D mesoporous mesh architecture of CNT-based composite electrodes grants unimpaired ionic transport throughout relatively thick films and allows superior performance compared to graphene-based devices at an ac line frequency of 120 Hz. Metrics of 601 µF/cm(2) with a -81° phase angle and a rate capability (RC) time constant of 199 µs are obtained for thin carbon films. The free-standing carbon films were obtained from a chlorosulfonic acid dispersion and interfaced to stainless steel current collectors with various surface treatments. CNT electrodes were able to cycle at 200 V/s and beyond, still showing a characteristic parallelepipedic cyclic votammetry shape at 1 kV/s. Current densities are measured in excess of 6400 A/g, and the electrodes retain more than 98% capacity after 1 million cycles. These promising results are attributed to a reduction of series resistance in the film through the CNT conductive network and especially to the surface treatment of the stainless steel current collector.

Aligned carbon nanotube-based flexible gel substrates for engineering bio-hybrid tissue actuators.

Muscle-based biohybrid actuators have generated significant interest as the future of biorobotics but so far they move without having much control over their actuation behavior. Integration of microelectrodes into the backbone of these systems may enable guidance during their motion and allow precise control over these actuators with specific activation patterns. Here, we addressed this challenge by developing aligned CNT forest microelectrode arrays and incorporated them into scaffolds for stimulating the cells. Aligned CNTs were successfully embedded into flexible and biocompatible hydrogel exhibiting excellent anisotropic electrical conductivity. Bioactuators were then engineered by culturing cardiomyocytes on the CNT microelectrode-integrated hydrogel constructs. The resulting cardiac tissue showed homogeneous cell organization with improved cell-to-cell coupling and maturation, which was directly related to the contractile force of muscle tissue. This centimeter-scale bioactuator has excellent mechanical integrity, embedded microelectrodes and is capable of spontaneous actuation behavior. Furthermore, we demonstrated that a biohybrid machine can be controlled by an external electrical field provided by the integrated CNT microelectrode arrays. In addition, due to the anisotropic electrical conductivity of the electrodes provided from aligned CNTs, significantly different excitation thresholds were observed in different configurations such as the ones in parallel vs. perpendicular direction to the CNT alignment.

Layer-by-layer assembly of 3D tissue constructs with functionalized graphene.

Carbon-based nanomaterials have been considered as promising candidates to mimic certain structure and function of native extracellular matrix materials for tissue engineering. Significant progress has been made in fabricating carbon nanoparticle-incorporated cell culture substrates, but limited studies have been reported on the development of three-dimensional (3D) tissue constructs using these nanomaterials. Here, we present a novel approach to engineer 3D multi-layered constructs using layer-by-layer (LbL) assembly of cells separated with self-assembled graphene oxide (GO)-based thin films. The GO-based structures are shown to serve as cell adhesive sheets that effectively facilitate the formation of multi-layer cell constructs with interlayer connectivity. By controlling the amount of GO deposited in forming the thin films, the thickness of the multi-layer tissue constructs could be tuned with high cell viability. Specifically, this approach could be useful for creating dense and tightly connected cardiac tissues through the co-culture of cardiomyocytes and other cell types. In this work, we demonstrated the fabrication of stand-alone multi-layer cardiac tissues with strong spontaneous beating behavior and programmable pumping properties. Therefore, this LbL-based cell construct fabrication approach, utilizing GO thin films formed directly on cell surfaces, has great potential in engineering 3D tissue structures with improved organization, electrophysiological function, and mechanical integrity.

In situ hybridization of superparamagnetic iron-biomolecule nanoparticles.

The increase in interest in the integration of organic-inorganic nanostructures in recent years has promoted the use of hybrid nanoparticles (HNPs) in medicine, energy conversion, and other applications. Conventional hybridization methods are, however, often long, complicated, and multistepped, and they involve biomolecules and discrete nanostructures as separate entities, all of which hinder the practical use of the resulting HNPs. Here, we present a novel, in situ approach to synthesizing size-specific HNPs using Fe-biomolecule complexes as the building blocks. We choose an anticancer peptide (p53p, MW 1.8 kDa) and an enzyme (GOx, MW 160 kDa) as model molecules to demonstrate the versatility of the method toward different types of molecules over a large size range. We show that electrostatic interaction for complex formation of metal hydroxide ion with the partially charged side of biomolecule in the solution is the key to hybridization of metal-biomolecule materials. Electrochemical deposition is then used to produce hybrid NPs from these complexes. These HNPs with controllable sizes ranging from 30 nm to 3.5 µm are found to exhibit superparamagnetic behavior, which is a big challenge for particles in this size regime. As an example of greatly improved properties and functionality of the new hybrid material, in vitro toxicity assessment of Fe-GOx HNPs shows no adverse effect, and the Fe-p53p HNPs are found to selectively bind to cancer cells. The superparamagnetic nature of these HNPs (superparamagnetic even above the size regime of 15-20 nm!), their biocompatibility, and the direct integration approach are fundamentally important to biomineralization and general synthesis strategy for bioinspired functional materials.

Controlling mechanical properties of cell-laden hydrogels by covalent incorporation of graphene oxide.

Graphene-based materials are useful reinforcing agents to modify the mechanical properties of hydrogels. Here, an approach is presented to covalently incorporate graphene oxide (GO) into hydrogels via radical copolymerization to enhance the dispersion and conjugation of GO sheets within the hydrogels. GO is chemically modified to present surface-grafted methacrylate groups (MeGO). In comparison to GO, higher concentrations of MeGO can be stably dispersed in a pre-gel solution containing methacrylated gelatin (GelMA) without aggregation or significant increase in viscosity. In addition, the resulting MeGO-GelMA hydrogels demonstrate a significant increase in fracture strength with increasing MeGO concentration. Interestingly, the rigidity of the hydrogels is not significantly affected by the covalently incorporated GO. Therefore, this approach can be used to enhance the structural integrity and resistance to fracture of the hydrogels without inadvertently affecting their rigidity, which is known to affect the behavior of encapsulated cells. The biocompatibility of MeGO-GelMA hydrogels is confirmed by measuring the viability and proliferation of the encapsulated fibroblasts. Overall, this study highlights the advantage of covalently incorporating GO into a hydrogel system, and improves the quality of cell-laden hydrogels.

Cell-laden microengineered and mechanically tunable hybrid hydrogels of gelatin and graphene oxide.

Incorporating graphene oxide inside GelMA hydrogels enhances their mechanical properties and reduces UV-induced cell damage while preserving their favorable characteristics for 3D cell encapsulation. NIH-3T3 fibroblasts encapsulated in GO-GelMA microgels demonstrate excellent cellular viability, proliferation, spreading, and alignment. GO reinforcement combined with a multi-stacking approach offers a facile engineering strategy for the construction of complex artificial tissues.

Fabrication of three-dimensional carbon nanotube and metal oxide hybrid mesoporous architectures.

Three-dimensional (3D) vertically aligned carbon nanotube (CNT) patterns were utilized as templates for fabricating mesoporous hybrid architectures composed of CNTs and various crystalline metal oxide (MO; M = Co, Zn, Mn) nanoparticles by a microwave-assisted chemical approach. Post-synthesis thermal treatment of the CNT/MO patterns culminated in structural reorganization, depending on the treatment conditions. In air, CNTs were removed by oxidation. The remaining MO architectures preserved the shape and alignment of the original 3D CNT patterns, but with different porosity characteristics and improved MO crystallinity. Elastocapillary condensation and bending were demonstrated to be useful tools for further architecture alternation. The mesoporous nature of the CNT/MO hybrids and the MO materials were confirmed by N2-BET measurements. CNT/Co3O4 aligned strips were used as an example to demonstrate the potential application of the CNT/MO architectures as electrode materials for supercapacitive storage. Galvanostatic measurements showed that the CNT/Co3O4 strips were stable up to 1000 charge-discharge cycles at a current density of 377 µA/cm(2) with a specific capacitance as high as 123.94 F/g.