Monolithic silicon for high spatiotemporal translational photostimulation.

Electrode-based electrical stimulation underpins several clinical bioelectronic devices, including deep-brain stimulators1,2 and cardiac pacemakers3. However, leadless multisite stimulation is constrained by the technical difficulties and spatial-access limitations of electrode arrays. Optogenetics offers optically controlled random access with high spatiotemporal capabilities, but clinical translation poses challenges4-6. Here we show tunable spatiotemporal photostimulation of cardiac systems using a non-genetic platform based on semiconductor-enabled biomodulation interfaces. Through spatiotemporal profiling of photoelectrochemical currents, we assess the magnitude, precision, accuracy and resolution of photostimulation in four leadless silicon-based monolithic photoelectrochemical devices. We demonstrate the optoelectronic capabilities of the devices through optical overdrive pacing of cultured cardiomyocytes (CMs) targeting several regions and spatial extents, isolated rat hearts in a Langendorff apparatus, in vivo rat hearts in an ischaemia model and an in vivo mouse heart model with transthoracic optical pacing. We also perform the first, to our knowledge, optical override pacing and multisite pacing of a pig heart in vivo. Our systems are readily adaptable for minimally invasive clinical procedures using our custom endoscopic delivery device, with which we demonstrate closed-thoracic operations and endoscopic optical stimulation. Our results indicate the clinical potential of the leadless, lightweight and multisite photostimulation platform as a pacemaker in cardiac resynchronization therapy (CRT), in which lead-placement complications are common.

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.

Exploring Present and Future Directions in Nano-Enhanced Optoelectronic Neuromodulation.

Electrical neuromodulation has achieved significant translational advancements, including the development of deep brain stimulators for managing neural disorders and vagus nerve stimulators for seizure treatment. Optoelectronics, in contrast to wired electrical systems, offers the leadless feature that guides multisite and high spatiotemporal neural system targeting, ensuring high specificity and precision in translational therapies known as "photoelectroceuticals". This Account provides a concise overview of developments in novel optoelectronic nanomaterials that are engineered through innovative molecular, chemical, and nanostructure designs to facilitate neural interfacing with high efficiency and minimally invasive implantation.This Account outlines the progress made both within our laboratory and across the broader scientific community, with particular attention to implications in materials innovation strategies, studying bioelectrical activation with spatiotemporal methods, and applications in regenerative medicine. In materials innovation, we highlight a nongenetic, biocompatible, and minimally invasive approach for neuromodulation that spans various length scales, from single neurons to nerve tissues using nanosized particles and monolithic membranes. Furthermore, our discussion exposes the critical unresolved questions in the field, including mechanisms of interaction at the nanobio interface, the precision of cellular or tissue targeting, and integration into existing neural networks with high spatiotemporal modulation. In addition, we present the challenges and pressing needs for long-term stability and biocompatibility, scalability for clinical applications, and the development of noninvasive monitoring and control systems.In addressing the existing challenges in the field of nanobio interfaces, particularly for neural applications, we envisage promising strategic directions that could significantly advance this burgeoning domain. This involves a deeper theoretical understanding of nanobiointerfaces, where simulations and experimental validations on how nanomaterials interact spatiotemporally with biological systems are crucial. The development of more durable materials is vital for prolonged applications in dynamic neural interfaces, and the ability to manipulate neural activity with high specificity and spatial resolution, paves the way for targeting individual neurons or specific neural circuits. Additionally, integrating these interfaces with advanced control systems, possibly leveraging artificial intelligence and machine learning algorithms and programming dynamically responsive materials designs, could significantly ease the implementation of stimulation and recording. These innovations hold the potential to introduce novel treatment modalities for a wide range of neurological and systemic disorders.

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.

Self-inhibition effect of metal incorporation in nanoscaled semiconductors.

There has been a persistent effort to understand and control the incorporation of metal impurities in semiconductors at nanoscale, as it is important for semiconductor processing from growth, doping to making contact. Previously, the injection of metal atoms into nanoscaled semiconductor, with concentrations orders of magnitude higher than the equilibrium solid solubility, has been reported, which is often deemed to be detrimental. Here our theoretical exploration reveals that this colossal injection is because gold or aluminum atoms tend to substitute Si atoms and thus are not mobile in the lattice of Si. In contrast, the interstitial atoms in the Si lattice such as manganese (Mn) are expected to quickly diffuse out conveniently. Experimentally, we confirm the self-inhibition effect of Mn incorporation in nanoscaled silicon, as no metal atoms can be found in the body of silicon (below 1017 atoms per cm-3) by careful three-dimensional atomic mappings using highly focused ultraviolet-laser-assisted atom-probe tomography. As a result of self-inhibition effect of metal incorporation, the corresponding field-effect devices demonstrate superior transport properties. This finding of self-inhibition effect provides a missing piece for understanding the metal incorporation in semiconductor at nanoscale, which is critical not only for growing nanoscale building blocks, but also for designing and processing metal-semiconductor structures and fine-tuning their properties at nanoscale.

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.

Perspectives on Multiscale Colloid-Based Materials for Biomedical Applications.

Colloid-based materials with tunable biophysical and chemical properties have demonstrated significant potential in a wide range of biomedical applications. The ability to manipulate these properties across various size scales, encompassing nano-, micro-, and macrodomains, is essential to enhancing current biomedical technologies and facilitating the development of novel applications. Focusing on material design, we explore various synthetic colloid-based materials at the nano- and microscales and investigate their correlation with biological systems. Furthermore, we examine the utilization of the self-assembly of colloids to construct monolithic and macroscopic materials suitable for biointerfaces. By probing the potential of spatial imaging and localized drug delivery, enhanced functionality, and colloidal manipulation, we highlight emerging opportunities that could significantly advance the field of colloid-based materials in biomedical applications.

Living myofibroblast-silicon composites for probing electrical coupling in cardiac systems.

Traditional bioelectronics, primarily comprised of nonliving synthetic materials, lack cellular behaviors such as adaptability and motility. This shortcoming results in mechanically invasive devices and nonnatural signal transduction across cells and tissues. Moreover, resolving heterocellular electrical communication in vivo is extremely limited due to the invasiveness of traditional interconnected electrical probes. In this paper, we present a cell-silicon hybrid that integrates native cellular behavior (e.g., gap junction formation and biosignal processing) with nongenetically enabled photosensitivity. This hybrid configuration allows interconnect-free cellular modulation with subcellular spatial resolution for bioelectric studies. Specifically, we hybridize cardiac myofibroblasts with silicon nanowires and use these engineered hybrids to synchronize the electrical activity of cardiomyocytes, studying heterocellular bioelectric coupling in vitro. Thereafter, we inject the engineered myofibroblasts into heart tissues and show their ability to seamlessly integrate into contractile tissues in vivo. Finally, we apply local photostimulation with high cell specificity to tackle a long-standing debate regarding the existence of myofibroblast-cardiomyocyte electrical coupling in vivo.

Optical stimulation of cardiac cells with a polymer-supported silicon nanowire matrix.

Electronic pacemakers can treat electrical conduction disorders in hearts; however, they are invasive, bulky, and linked to increased incidence of infection at the tissue-device interface. Thus, researchers have looked to other more biocompatible methods for cardiac pacing or resynchronization, such as femtosecond infrared light pulsing, optogenetics, and polymer-based cardiac patches integrated with metal electrodes. Here we develop a biocompatible nongenetic approach for the optical modulation of cardiac cells and tissues. We demonstrate that a polymer-silicon nanowire composite mesh can be used to convert fast moving, low-radiance optical inputs into stimulatory signals in target cardiac cells. Our method allows for the stimulation of the cultured cardiomyocytes or ex vivo heart to beat at a higher target frequency.

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.

Nano- and Microscale Optical and Electrical Biointerfaces and Their Relevance to Energy Research.

Different research fields in energy sciences, such as photovoltaics for solar energy conversion, supercapacitors for energy storage, electrocatalysis for clean energy conversion technologies, and materials-bacterial hybrid for CO2 fixation have been under intense investigations over the past decade. In recent years, new platforms for biointerface designs have emerged from the energy conversion and storage principles. This paper reviews recent advances in nano- and microscale materials/devices for optical and electrical biointerfaces. First, a connection is drawn between biointerfaces and energy science, and how these two distinct research fields can be connected is summarized. Then, a brief overview of current available tools for biointerface studies is presented. Third, three representative biointerfaces are reviewed, including neural, cardiac, and bacterial biointerfaces, to show how to apply these tools and principles to biointerface design and research. Finally, two possible future research directions for nano- and microscale biointerfaces are proposed.

Nanowired Bioelectric Interfaces.

Biological systems have evolved biochemical, electrical, mechanical, and genetic networks to perform essential functions across various length and time scales. High-aspect-ratio biological nanowires, such as bacterial pili and neurites, mediate many of the interactions and homeostasis in and between these networks. Synthetic materials designed to mimic the structure of biological nanowires could also incorporate similar functional properties, and exploiting this structure-function relationship has already proved fruitful in designing biointerfaces. Semiconductor nanowires are a particularly promising class of synthetic nanowires for biointerfaces, given (1) their unique optical and electronic properties and (2) their high degree of synthetic control and versatility. These characteristics enable fabrication of a variety of electronic and photonic nanowire devices, allowing for the formation of well-defined, functional bioelectric interfaces at the biomolecular level to the whole-organ level. In this Focus Review, we first discuss the history of bioelectric interfaces with semiconductor nanowires. We next highlight several important, endogenous biological nanowires and use these as a framework to categorize semiconductor nanowire-based biointerfaces. Within this framework we then review the fundamentals of bioelectric interfaces with semiconductor nanowires and comment on both material choice and device design to form biointerfaces spanning multiple length scales. We conclude with a discussion of areas with the potential for greatest impact using semiconductor nanowire-enabled biointerfaces in the future.

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.

Tracking Longitudinal Rotation of Silicon Nanowires for Biointerfaces.

The rolling motion (i.e., longitudinal rotation) of nanomaterials may serve as a proxy to probe microscopic environments. Furthermore, nanoscale rotations in biological systems are common but difficult to measure. Here, we report a new tool that measures rolling motion of a nanowire with a short arm grown at one end. We present a particle detection algorithm with subpixel resolution and image segmentation with principal component analysis that enables precise and automated determination of the nanowire orientation. We show that the nanowires' rolling dynamics can be significantly affected by their surroundings and demonstrate the probes' ability to reflect different nanobio interactions. A non-cell-interacting nanowire undergoes rapid subdiffusive rotation, while a cell-interacting nanowire exhibits superdiffusive unidirectional rotation when the cell membrane actively interacts with the nanowire and slow subdiffusive rotation when it is fully encompassed by the cell. Our method can be used to yield insights into various biophysical and assembly processes.

Silicon Nanowires for Intracellular Optical Interrogation with Subcellular Resolution.

Current techniques for intracellular electrical interrogation are limited by substrate-bound devices, technically demanding methods, or insufficient spatial resolution. In this work, we use freestanding silicon nanowires to achieve photoelectric stimulation in myofibroblasts with subcellular resolution. We demonstrate that myofibroblasts spontaneously internalize silicon nanowires and subsequently remain viable and capable of mitosis. We then show that stimulation of silicon nanowires at separate intracellular locations results in local calcium fluxes in subcellular regions. Moreover, nanowire-myofibroblast hybrids electrically couple with cardiomyocytes in coculture, and photostimulation of the nanowires increases the spontaneous activation rate in coupled cardiomyocytes. Finally, we demonstrate that this methodology can be extended to the interrogation of signaling in neuron-glia interactions using nanowire-containing oligodendrocytes.

Synthesis of Metal-Capped Semiconductor Nanowires from Heterodimer Nanoparticle Catalysts.

Semiconductor nanowires (NWs) capped with metal nanoparticles (NPs) show multifunctional and synergistic properties, which are important for applications in the fields of catalysis, photonics, and electronics. Conventional colloidal syntheses of this class of hybrid structures require complex sequential seeded growth, where each section requires its own set of growth conditions, and methods for preparing such wires are not universal. Here, we report a new and general method for synthesizing metal-semiconductor nanohybrids based on particle catalysts, prepared by scanning probe block copolymer lithography, and chemical vapor deposition. In this process, metallic heterodimer NPs were used as catalysts for NW growth to form semiconductor NWs capped with metallic particles (Au, Ag, Co, Ni). Interestingly, the growth processes for NWs on NPs are regioselective and controlled by the chemical composition of the metallic heterodimer used. Using a systematic experimental approach, paired with density functional theory calculations, we were able to postulate three different growth modes, one without precedent.

Learning from Solar Energy Conversion: Biointerfaces for Artificial Photosynthesis and Biological Modulation.

Three seemingly distinct directions of nanomaterials research, photovoltaics, biofuel production, and biological modulation, have been sequentially developed over the past several decades. In this Mini Review, we discuss how the insights gleaned from nanomaterials-based solar energy conversion can be adapted to biointerface designs. Because of their size- and shape-dependent optical properties and excellent synthetic control, nanomaterials have shown unique technological advantages as the light absorbers or energy transducers. Biocompatible nanomaterials have also been incorporated into biological systems including biomolecules, bacteria, and eukaryotic cells for a large collection of fundamental studies and applications. For the photocatalytic biofuel production, either isolated bacterial enzymes or the entire bacteria have been hybridized with the nanomaterials, where functions from both parts are synergistically integrated. Likewise, interfacing nanomaterials with eukaryotic systems, whether in individual cells or tissues, has enabled optical modulation of cellular behavior and the construction of active cellular materials. Here we survey different approaches in which nanomaterials are used to elicit electrical or mechanical changes in single cells or cellular assemblies via photoelectrochemical or photothermal processes. We end this Mini Review with the discussion of future nongenetic modulation at the intracellular level.

Rational Design of Semiconductor Nanostructures for Functional Subcellular Interfaces.

One of the fundamental questions guiding research in the biological sciences is how cellular systems process complex physical and environmental cues and communicate with each other across multiple length scales. Importantly, aberrant signal processing in these systems can lead to diseases that can have devastating impacts on human lives. Biophysical studies in the past several decades have demonstrated that cells can respond to not only biochemical cues but also mechanical and electrical ones. Thus, the development of new materials that can both sense and modulate all of these pathways is necessary. Semiconducting nanostructures are an emerging class of discovery platforms and tools that can push the limits of our ability to modulate and sense biological behaviors for both fundamental research and clinical applications. These materials are of particular interest for interfacing with cellular systems due to their matched dimension with subcellular components (e.g., cytoskeletal filaments), and easily tunable properties in the electrical, optical and mechanical regimes. Rational design via traditional or new approaches, such as nanocasting and mesoscale chemical lithography, can allow us to control micro- and nanoscale features in nanowires to achieve new biointerfaces. Both processes endogenous to the target cell and properties of the material surface dictate the character of these interfaces. In this Account, we focus on (1) approaches for the rational design of semiconducting nanowires that exhibit unique structures for biointerfaces, (2) recent fundamental discoveries that yield robust biointerfaces at the subcellular level, (3) intracellular electrical and mechanical sensing, and (4) modulation of cellular behaviors through material topography and remote physical stimuli. In the first section, we discuss new approaches for the synthetic control of micro- and nanoscale features of these materials. In the second section, we focus on achieving biointerfaces with these rationally designed materials either intra- or extracellularly. We last delve into the use of these materials in sensing mechanical forces and electrical signals in various cellular systems as well as in instructing cellular behaviors. Future research in this area may shift the paradigm in fundamental biophysical research and biomedical applications through (1) the design and synthesis of new semiconductor-based materials and devices that interact specifically with targeted cells, (2) the clarification of many developmental, physiological, and anatomical aspects of cellular communications, (3) an understanding of how signaling between cells regulates synaptic development (e.g., information like this would offer new insight into how the nervous system works and provide new targets for the treatment of neurological diseases), (4) and the creation of new cellular materials that have the potential to open up completely new areas of application, such as in hybrid information processing systems.

Texturing Silicon Nanowires for Highly Localized Optical Modulation of Cellular Dynamics.

Engineered silicon-based materials can display photoelectric and photothermal responses under light illumination, which may lead to further innovations at the silicon-biology interfaces. Silicon nanowires have small radial dimensions, promising as highly localized cellular modulators, however the single crystalline form typically has limited photothermal efficacy due to the poor light absorption and fast heat dissipation. In this work, we report strategies to improve the photothermal response from silicon nanowires by introducing nanoscale textures on the surface and in the bulk. We next demonstrate high-resolution extracellular modulation of calcium dynamics in a number of mammalian cells including glial cells, neurons, and cancer cells. The new materials may be broadly used in probing and modulating electrical and chemical signals at the subcellular length scale, which is currently a challenge in the field of electrophysiology or cellular engineering.