Multimodal probing of T-cell recognition with hexapod heterostructures.

Studies using antigen-presenting systems at the single-cell and ensemble levels can provide complementary insights into T-cell signaling and activation. Although crucial for advancing basic immunology and immunotherapy, there is a notable absence of synthetic material toolkits that examine T cells at both levels, and especially those capable of single-molecule-level manipulation. Here we devise a biomimetic antigen-presenting system (bAPS) for single-cell stimulation and ensemble modulation of T-cell recognition. Our bAPS uses hexapod heterostructures composed of a submicrometer cubic hematite core (α-Fe2O3) and nanostructured silica branches with diverse surface modifications. At single-molecule resolution, we show T-cell activation by a single agonist peptide-loaded major histocompatibility complex; distinct T-cell receptor (TCR) responses to structurally similar peptides that differ by only one amino acid; and the superior antigen recognition sensitivity of TCRs compared with that of chimeric antigen receptors (CARs). We also demonstrate how the magnetic field-induced rotation of hexapods amplifies the immune responses in suspended T and CAR-T cells. In addition, we establish our bAPS as a precise and scalable method for identifying stimulatory antigen-specific TCRs at the single-cell level. Thus, our multimodal bAPS represents a unique biointerface tool for investigating T-cell recognition, signaling and function.

Dissecting Biological and Synthetic Soft-Hard Interfaces for Tissue-Like Systems.

Soft and hard materials at interfaces exhibit mismatched behaviors, such as mismatched chemical or biochemical reactivity, mechanical response, and environmental adaptability. Leveraging or mitigating these differences can yield interfacial processes difficult to achieve, or inapplicable, in pure soft or pure hard phases. Exploration of interfacial mismatches and their associated (bio)chemical, mechanical, or other physical processes may yield numerous opportunities in both fundamental studies and applications, in a manner similar to that of semiconductor heterojunctions and their contribution to solid-state physics and the semiconductor industry over the past few decades. In this review, we explore the fundamental chemical roles and principles involved in designing these interfaces, such as the (bio)chemical evolution of adaptive or buffer zones. We discuss the spectroscopic, microscopic, (bio)chemical, and computational tools required to uncover the chemical processes in these confined or hidden soft-hard interfaces. We propose a soft-hard interaction framework and use it to discuss soft-hard interfacial processes in multiple systems and across several spatiotemporal scales, focusing on tissue-like materials and devices. We end this review by proposing several new scientific and engineering approaches to leveraging the soft-hard interfacial processes involved in biointerfacing composites and exploring new applications for these composites.

Probing the electronic properties of the electrified silicon/water interface by combining simulations and experiments.

Silicon (Si) is broadly used in electrochemical and photoelectrochemical devices, where the capacitive and Faradaic reactions at the Si/water interfaces are critical for signal transduction or noise generation. However, probing the electrified Si/water interface at the microscopic level remains a challenging task. Here we focus on hydrogenated Si surfaces in contact with water, relevant to transient electronics and photoelectrochemical modulation of biological cells and tissues. We show that by carrying out first-principles molecular dynamics simulations of the Si(100)/water interface in the presence of an electric field we can realistically correlate the computed flat-band potential and tunneling current images at the interface with experimentally measured capacitive and Faradaic currents. Specifically, we validate our simulations in the presence of bias by performing pulsed chronoamperometry measurements on Si wafers in solution. Consistent with prior experiments, our measurements and simulations indicate the presence of voltage-dependent capacitive currents at the interface. We also find that Faradaic currents are weakly dependent on the applied bias, which we relate to surface defects present in newly prepared samples.

Porosity-based heterojunctions enable leadless optoelectronic modulation of tissues.

Homo- and heterojunctions play essential roles in semiconductor-based devices such as field-effect transistors, solar cells, photodetectors and light-emitting diodes. Semiconductor junctions have been recently used to optically trigger biological modulation via photovoltaic or photoelectrochemical mechanisms. The creation of heterojunctions typically involves materials with different doping or composition, which leads to high cost, complex fabrications and potential side effects at biointerfaces. Here we show that a porosity-based heterojunction, a largely overlooked system in materials science, can yield an efficient photoelectrochemical response from the semiconductor surface. Using self-limiting stain etching, we create a nanoporous/non-porous, soft-hard heterojunction in p-type silicon within seconds under ambient conditions. Upon surface oxidation, the heterojunction yields a strong photoelectrochemical response in saline. Without any interconnects or metal modifications, the heterojunction enables efficient non-genetic optoelectronic stimulation of isolated rat hearts ex vivo and sciatic nerves in vivo with optical power comparable to optogenetics, and with near-infrared capabilities.

Soft materials as biological and artificial membranes.

The past few decades have seen emerging growth in the field of soft materials for synthetic biology. This review focuses on soft materials involved in biological and artificial membranes. The biological membranes discussed here are mainly those involved in the structure and function of cells and organelles. As building blocks in medicine, non-native membranes including nanocarriers (NCs), especially liposomes and DQAsomes, and polymeric membranes for scaffolds are constructed from amphiphilic combinations of lipids, proteins, and carbohydrates. Artificial membranes can be prepared using synthetic, soft materials and molecules and then incorporated into structures through self-organization to form micelles or niosomes. The modification of artificial membranes can be realized using traditional chemical methods such as click reactions to target the delivery of NCs and control the release of therapeutics. The biomembrane, a lamellar structure inlaid with ion channels, receptors, lipid rafts, enzymes, and other functional units, separates cells and organelles from the environment. An active domain inserted into the membrane and organelles for energy conversion and cellular communication can target disease by changing the membrane's composition, structure, and fluidity and affecting the on/off status of the membrane gates. The biological membrane targets analyzing pathological mechanisms and curing complex diseases, which inspires us to create NCs with artificial membranes.

Recent advances in bioelectronics chemistry.

Research in bioelectronics is highly interdisciplinary, with many new developments being based on techniques from across the physical and life sciences. Advances in our understanding of the fundamental chemistry underlying the materials used in bioelectronic applications have been a crucial component of many recent discoveries. In this review, we highlight ways in which a chemistry-oriented perspective may facilitate novel and deep insights into both the fundamental scientific understanding and the design of materials, which can in turn tune the functionality and biocompatibility of bioelectronic devices. We provide an in-depth examination of several developments in the field, organized by the chemical properties of the materials. We conclude by surveying how some of the latest major topics of chemical research may be further integrated with bioelectronics.

Gold Nanoparticles Thin Films with Thermo- and Photoresponsive Plasmonic Properties Realized with Liquid-Crystalline Ligands.

Robust synthesis of large-scale self-assembled nanostructures with long-range organization and a prominent response to external stimuli is critical to their application in functional plasmonics. Here, the first example of a material made of liquid crystalline nanoparticles which exhibits UV-light responsive surface plasmon resonance in a condensed state is presented. To obtain the material, metal cores are grafted with two types of organic ligands. A promesogenic derivative softens the system and induces rich liquid crystal phase polymorphism. Second, an azobenzene derivative endows nanoparticles with photoresponsive properties. It is shown that nanoparticles covered with a mixture of these ligands assemble into long-range ordered structures which exhibit a novel dual-responsivity. The structure and plasmonic properties of the assemblies can be controlled by a change in temperature as well as by UV-light irradiation. These results present an efficient way to obtain bulk quantities of self-assembled nanostructured materials with stability that is unattainable by alternative methods such as matrix-assisted or DNA-mediated organization.

Phototunable liquid-crystalline phases made of nanoparticles.

The properties of liquid-crystalline (LC) hybrid systems made of inorganic nanoparticles grafted with photosensitive azo compounds are presented. For materials with a large density of azo ligands at the surface, the LC structure can be reversibly melted by UV light, and the return to the LC state does not require the absorption of visible light. For systems with a lower density of azo ligands, UV light causes shortening of the distance between metal sublayers in the lamellar phase. Interestingly, the azo derivatives attached to the nanoparticle surface show very different kinetics of cis/trans conformational change as compared to the free molecules. The cis form of free ligands in solution is stable for days, whereas the isomerization of molecules attached to the nanoparticle surface to the trans form takes only a few minutes. Apparently, owing to the crowded environment, azo ligands immobilized at a metal surface behave as they would in the condensed state.

Periplasmic biomineralization for semi-artificial photosynthesis.

Semiconductor-based biointerfaces are typically established either on the surface of the plasma membrane or within the cytoplasm. In Gram-negative bacteria, the periplasmic space, characterized by its confinement and the presence of numerous enzymes and peptidoglycans, offers additional opportunities for biomineralization, allowing for nongenetic modulation interfaces. We demonstrate semiconductor nanocluster precipitation containing single- and multiple-metal elements within the periplasm, as observed through various electron- and x-ray-based imaging techniques. The periplasmic semiconductors are metastable and display defect-dominant fluorescent properties. Unexpectedly, the defect-rich (i.e., the low-grade) semiconductor nanoclusters produced in situ can still increase adenosine triphosphate levels and malate production when coupled with photosensitization. We expand the sustainability levels of the biohybrid system to include reducing heavy metals at the primary level, building living bioreactors at the secondary level, and creating semi-artificial photosynthesis at the tertiary level. The biomineralization-enabled periplasmic biohybrids have the potential to serve as defect-tolerant platforms for diverse sustainable applications.

Achieving tissue-level softness on stretchable electronics through a generalizable soft interlayer design.

Soft and stretchable electronics have emerged as highly promising tools for biomedical diagnosis and biological studies, as they interface intimately with the human body and other biological systems. Most stretchable electronic materials and devices, however, still have Young's moduli orders of magnitude higher than soft bio-tissues, which limit their conformability and long-term biocompatibility. Here, we present a design strategy of soft interlayer for allowing the use of existing stretchable materials of relatively high moduli to versatilely realize stretchable devices with ultralow tissue-level moduli. We have demonstrated stretchable transistor arrays and active-matrix circuits with moduli below 10 kPa-over two orders of magnitude lower than the current state of the art. Benefiting from the increased conformability to irregular and dynamic surfaces, the ultrasoft device created with the soft interlayer design realizes electrophysiological recording on an isolated heart with high adaptability, spatial stability, and minimal influence on ventricle pressure. In vivo biocompatibility tests also demonstrate the benefit of suppressing foreign-body responses for long-term implantation. With its general applicability to diverse materials and devices, this soft-interlayer design overcomes the material-level limitation for imparting tissue-level softness to a variety of bioelectronic devices.

A soil-inspired dynamically responsive chemical system for microbial modulation.

Interactions between the microbiota and their colonized environments mediate critical pathways from biogeochemical cycles to homeostasis in human health. Here we report a soil-inspired chemical system that consists of nanostructured minerals, starch granules and liquid metals. Fabricated via a bottom-up synthesis, the soil-inspired chemical system can enable chemical redistribution and modulation of microbial communities. We characterize the composite, confirming its structural similarity to the soil, with three-dimensional X-ray fluorescence and ptychographic tomography and electron microscopy imaging. We also demonstrate that post-synthetic modifications formed by laser irradiation led to chemical heterogeneities from the atomic to the macroscopic level. The soil-inspired material possesses chemical, optical and mechanical responsiveness to yield write-erase functions in electrical performance. The composite can also enhance microbial culture/biofilm growth and biofuel production in vitro. Finally, we show that the soil-inspired system enriches gut bacteria diversity, rectifies tetracycline-induced gut microbiome dysbiosis and ameliorates dextran sulfate sodium-induced rodent colitis symptoms within in vivo rodent models.

A Multifunctional Neutralizing Antibody-Conjugated Nanoparticle Inhibits and Inactivates SARS-CoV-2.

The outbreak of 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic. Despite intensive research, the current treatment options show limited curative efficacies. Here the authors report a strategy incorporating neutralizing antibodies conjugated to the surface of a photothermal nanoparticle (NP) to capture and inactivate SARS-CoV-2. The NP is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with high-affinity neutralizing antibodies. The multifunctional NP efficiently captures SARS-CoV-2 pseudovirions and completely blocks viral infection to host cells in vitro through the surface neutralizing antibodies. In addition to virus capture and blocking function, the NP also possesses photothermal function to generate heat following irradiation for inactivation of virus. Importantly, the NPs described herein significantly outperform neutralizing antibodies at treating authentic SARS-CoV-2 infection in vivo. This multifunctional NP provides a flexible platform that can be readily adapted to other SARS-CoV-2 antibodies and extended to novel therapeutic proteins, thus it is expected to provide a broad range of protection against original SARS-CoV-2 and its variants.

Stretchable Redox-Active Semiconducting Polymers for High-Performance Organic Electrochemical Transistors.

Organic electrochemical transistors (OECTs) represent an emerging device platform for next-generation bioelectronics owing to the uniquely high amplification and sensitivity to biological signals. For achieving seamless tissue-electronics interfaces for accurate signal acquisition, skin-like softness and stretchability are essential requirements, but they have not yet been imparted onto high-performance OECTs, largely due to the lack of stretchable redox-active semiconducting polymers. Here, a stretchable semiconductor is reported for OECT devices, namely poly(2-(3,3'-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-[2,2'-bithiophen]-5)yl thiophene) (p(g2T-T)), which gives exceptional stretchability over 200% strain and 5000 repeated stretching cycles, together with OECT performance on par with the state-of-the-art. Validated by systematic characterizations and comparisons of different polymers, the key design features of this polymer that enable the combination of high stretchability and high OECT performance are a nonlinear backbone architecture, a moderate side-chain density, and a sufficiently high molecular weight. Using this highly stretchable polymer semiconductor, an intrinsically stretchable OECT is fabricated with high normalized transconductance (≈223 S cm-1 ) and biaxial stretchability up to 100% strain. Furthermore, on-skin electrocardiogram (ECG) recording is demonstrated, which combines built-in amplification and unprecedented skin conformability.

Bridging the gap - biomimetic design of bioelectronic interfaces.

Applied bioelectronic interfaces have an enormous potential for their application in personalized medicine and brain-machine interfaces. While significant progress has been made in the translational applications, there are still concerns about the safety and compliance of artificial devices interacting with cells and tissues. Applying biomimetic design principles enables developing new devices with improved properties in terms of their signal transduction efficiency and biocompatibility. Learning from the paradigms of biological architecture, we can define four cornerstones of biomimetics, which can guide designing new bioelectronic devices or providing improved solutions to challenging biomedical problems. Recent progress shows how these paradigms were successfully employed, for example, to create neuron-like electronics and assemble electronic materials in situ onto the cell membranes using genetic targeting.

Nanoenabled Bioelectrical Modulation.

Studying the formation and interactions between biological systems and artificial materials is significant for probing complex biophysical behaviors and addressing challenging biomedical problems. Bioelectrical interfaces, especially nanostructure-based, have improved compatibility with cells and tissues and enabled new approaches to biological modulation. In particular, free-standing and remotely activated bioelectrical devices demonstrate potential for precise biophysical investigation and efficient clinical therapies. Interacting with single cells or organelles requires devices of sufficiently small size for high resolution probing. Nanoscale semiconductors, given their diverse functionalities, are promising device platforms for subcellular modulation. Tissue-level modulation requires additional consideration regarding the device's mechanical compliance for either conformal contact with the tissue surface or seamless three-dimensional (3D) biointegration. Flexible or even open-framework designs are essential in such methods. For chronic organ integration, the highest level of biocompatibility is required for both the materials and device configurations. Additionally, a scalable and high-throughput design is necessary to simultaneously interact with many individual cells in the organ. The physical, chemical, and mechanical stabilities of devices for organ implantation may be improved by ensuring matching of mechanical behavior at biointerfaces, including passivation or resistance designs to mitigate physiological impacts, or incorporating self-healing or adaptative properties. Recent research demonstrates principles of nanostructured material designs that can be used to improve biointerfaces. Nanoenabled extracellular interfaces were frequently used for either electrical or remote optical modulation of cells and tissues. In particular, methods are now available for designing and screening nanostructured silicon, especially chemical vapor deposition (CVD)-derived nanowires and two-dimensional (2D) nanostructured membranes, for biological modulation in vitro and in vivo. For intra- and intercellular biological modulation, semiconductor/cell composites have been created through the internalization of nanowires, and such cellular composites can even integrate with living tissues. This approach was demonstrated for both neuronal and cardiac modulation. At a different front, laser-derived nanocrystalline semiconductors showed electrochemical and photoelectrochemical activities, and they were used to modulate cells and organs. Recently, self-assembly of nanoscale building blocks enabled fabrication of efficient monolithic carbon-based electrodes for in vitro stimulation of cardiomyocytes, ex vivo stimulation of retinas and hearts, and in vivo stimulation of sciatic nerves. Future studies on nanoenabled bioelectrical modulation should focus on improving efficiency and stability of current and emerging technologies. New materials and devices can access new interrogation targets, such as subcellular structures, and possess more adaptable and responsive properties enabling seamless integration. Drawing inspiration from energy science and catalysis can help in such progress and open new avenues for biological modulation. The fundamental study of living bioelectronics could yield new cellular composites for diverse biological signaling control. In situ self-assembled biointerfaces are of special interest in this area as cell type targeting can be achieved.

Silicon Nanowires and Optical Stimulation for Investigations of Intra- and Intercellular Electrical Coupling.

Myofibroblasts can spontaneously internalize silicon nanowires (SiNWs), making them an attractive target for bioelectronic applications. These cell-silicon hybrids offer leadless optical modulation capabilities with minimal perturbation to normal cell behavior. The optical capabilities are obtained by the photothermal and photoelectric properties of SiNWs. These hybrids can be harvested using standard tissue culture techniques and then applied to different biological scenarios. We demonstrate here how these hybrids can be used to study the electrical coupling of cardiac cells and compare how myofibroblasts couple to one another or to cardiomyocytes. This process can be accomplished without special equipment beyond a fluorescent microscope with coupled laser line. Also shown is the use of a custom-built MATLAB routine that allows the quantification of calcium propagation within and between the different cells in the culture. Myofibroblasts are shown to have a slower electrical response than that of cardiomyocytes. Moreover, the myofibroblast intercellular propagation shows slightly slower, though comparable velocities to their intracellular velocities, suggesting passive propagation through gap junctions or nanotubes. This technique is highly adaptable and can be easily applied to other cellular arenas, for in vitro as well as in vivo or ex vivo investigations.

Micelle-enabled self-assembly of porous and monolithic carbon membranes for bioelectronic interfaces.

Real-world bioelectronics applications, including drug delivery systems, biosensing and electrical modulation of tissues and organs, largely require biointerfaces at the macroscopic level. However, traditional macroscale bioelectronic electrodes usually exhibit invasive or power-inefficient architectures, inability to form uniform and subcellular interfaces, or faradaic reactions at electrode surfaces. Here, we develop a micelle-enabled self-assembly approach for a binder-free and carbon-based monolithic device, aimed at large-scale bioelectronic interfaces. The device incorporates a multi-scale porous material architecture, an interdigitated microelectrode layout and a supercapacitor-like performance. In cell training processes, we use the device to modulate the contraction rate of primary cardiomyocytes at the subcellular level to target frequency in vitro. We also achieve capacitive control of the electrophysiology in isolated hearts, retinal tissues and sciatic nerves, as well as bioelectronic cardiac sensing. Our results support the exploration of device platforms already used in energy research to identify new opportunities in bioelectronics.

Quiet Brainstorming: Expecting the Unexpected.

The COVID-19 lockdown has given us time to reconsider some of the approaches we use for generating research ideas. We propose a set of three critical "E" processes-extract, expose, and evaluate-for an individual researcher to replicate team brainstorming.

Size-Dependent Thermo- and Photoresponsive Plasmonic Properties of Liquid Crystalline Gold Nanoparticles.

Achieving remotely controlled, reversibly reconfigurable assemblies of plasmonic nanoparticles is a prerequisite for the development of future photonic technologies. Here, we obtained a series of gold-nanoparticle-based materials which exhibit long-range order, and which are controlled with light or thermal stimuli. The influence of the metallic core size and organic shell composition on the switchability is considered, with emphasis on achieving light-responsive behavior at room temperature and high yield production of nanoparticles. The latter translates to a wide size distribution of metallic cores but does not prevent their assembly into various, switchable 3D and 2D long-range ordered structures. These results provide clear guidelines as to the impact of size, size distribution, and organic shell composition on self-assembly, thus enhancing the smart design process of multi-responsive nanomaterials in a condensed state, hardly attainable by other self-assembly methods which usually require solvents.

A Neutralizing Antibody-Conjugated Photothermal Nanoparticle Captures and Inactivates SARS-CoV-2.

The outbreak of 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic. Despite intensive research including several clinical trials, currently there are no completely safe or effective therapeutics to cure the disease. Here we report a strategy incorporating neutralizing antibodies conjugated on the surface of a photothermal nanoparticle to actively capture and inactivate SARS-CoV-2. The photothermal nanoparticle is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with neutralizing antibodies. Such nanoparticles displayed efficient capture of SARS-CoV-2 pseudoviruses, excellent photothermal effect, and complete inhibition of viral entry into ACE2-expressing host cells via simultaneous blocking and inactivating of the virus. This photothermal nanoparticle is a flexible platform that can be readily adapted to other SARS-CoV-2 antibodies and extended to novel therapeutic proteins, thus providing a broad range of protection against multiple strains of SARS-CoV-2.