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

ConspectusElectrical 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.

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.

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.

Bridging the Gap-Thermofluidic Designs for Precision Bioelectronics.

Bioelectronics, the merging of biology and electronics, can monitor and modulate biological behaviors across length and time scales with unprecedented capability. Current bioelectronics research largely focuses on devices' mechanical properties and electronic designs. However, the thermofluidic control is often overlooked, which is noteworthy given the discipline's importance in almost all bioelectronics processes. It is believed that integrating thermofluidic designs into bioelectronics is essential to align device precision with the complexity of biofluids and biological structures. This perspective serves as a mini roadmap for researchers in both fields to introduce key principles, applications, and challenges in both bioelectronics and thermofluids domains. Important interdisciplinary opportunities for the development of future healthcare devices and precise bioelectronics will also be discussed.

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.

Nanowired human cardiac organoid transplantation enables highly efficient and effective recovery of infarcted hearts.

Human cardiac organoids hold remarkable potential for cardiovascular disease modeling and human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) transplantation. Here, we show cardiac organoids engineered with electrically conductive silicon nanowires (e-SiNWs) significantly enhance the therapeutic efficacy of hPSC-CMs to treat infarcted hearts. We first demonstrated the biocompatibility of e-SiNWs and their capacity to improve cardiac microtissue engraftment in healthy rat myocardium. Nanowired human cardiac organoids were then engineered with hPSC-CMs, nonmyocyte supporting cells, and e-SiNWs. Nonmyocyte supporting cells promoted greater ischemia tolerance of cardiac organoids, and e-SiNWs significantly improved electrical pacing capacity. After transplantation into ischemia/reperfusion-injured rat hearts, nanowired cardiac organoids significantly improved contractile development of engrafted hPSC-CMs, induced potent cardiac functional recovery, and reduced maladaptive left ventricular remodeling. Compared to contemporary studies with an identical injury model, greater functional recovery was achieved with a 20-fold lower dose of hPSC-CMs, revealing therapeutic synergy between conductive nanomaterials and human cardiac organoids for efficient heart repair.

Bioadhesive polymer semiconductors and transistors for intimate biointerfaces.

The use of bioelectronic devices relies on direct contact with soft biotissues. For transistor-type bioelectronic devices, the semiconductors that need to have direct interfacing with biotissues for effective signal transduction do not adhere well with wet tissues, thereby limiting the stability and conformability at the interface. We report a bioadhesive polymer semiconductor through a double-network structure formed by a bioadhesive brush polymer and a redox-active semiconducting polymer. The resulting semiconducting film can form rapid and strong adhesion with wet tissue surfaces together with high charge-carrier mobility of ~1 square centimeter per volt per second, high stretchability, and good biocompatibility. Further fabrication of a fully bioadhesive transistor sensor enabled us to produce high-quality and stable electrophysiological recordings on an isolated rat heart and in vivo rat muscles.

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.

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.

Perspectives on tissue-like bioelectronics for neural modulation.

Advances in bioelectronic implants have been offering valuable chances to interface and modulate neural systems. Potential mismatches between bioelectronics and targeted neural tissues require devices to exhibit "tissue-like" properties for better implant-bio integration. In particular, mechanical mismatches pose a significant challenge. In the past years, efforts were made in both materials synthesis and device design to achieve bioelectronics mechanically and biochemically mimicking biological tissues. In this perspective, we mainly summarized recent progress of developing "tissue-like" bioelectronics and categorized them into different strategies. We also discussed how these "tissue-like" bioelectronics were utilized for modulating in vivo nervous systems and neural organoids. We concluded the perspective by proposing further directions including personalized bioelectronics, novel materials design and the involvement of artificial intelligence and robotic techniques.

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.

Nanoenabled Trainable Systems: From Biointerfaces to Biomimetics.

In the dynamic biological system, cells and tissues adapt to diverse environmental conditions and form memories, an essential aspect of training for survival and evolution. An understanding of the biological training principles will inform the design of biomimetic materials whose properties evolve with the environment and offer routes to programmable soft materials, neuromorphic computing, living materials, and biohybrid robotics. In this perspective, we examine the mechanisms by which cells are trained by environmental cues. We outline the artificial platforms that enable biological training and examine the relationship between biological training and biomimetic materials design. We place emphasis on nanoscale material platforms which, given their applicability to chemical, mechanical and electrical stimulation, are critical to bridging natural and synthetic systems.

Distributed interfacing by nanoscale photodiodes enables single-neuron light activation and sensory enhancement in 3D spinal explants.

Among emerging technologies developed to interface neuronal signaling, engineering electrodes at the nanoscale would yield more precise biodevices opening to progress in neural circuit investigations and to new therapeutic potential. Despite remarkable progress in miniature electronics for less invasive neurostimulation, most nano-enabled, optically triggered interfaces are demonstrated in cultured cells, which precludes the studies of natural neural circuits. We exploit here free-standing silicon-based nanoscale photodiodes to optically modulate single, identified neurons in mammalian spinal cord explants. With near-infrared light stimulation, we show that activating single excitatory or inhibitory neurons differently affects sensory circuits processing in the dorsal horn. We successfully functionalize nano-photodiodes to target single molecules, such as glutamate AMPA receptor subunits, thus enabling light activation of specific synaptic pathways. We conclude that nano-enabled neural interfaces can modulate selected sensory networks with low invasiveness. The use of nanoscale photodiodes can thus provide original perspective in linking neural activity to specific behavioral outcome.

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.

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.

Freestanding nanomaterials for subcellular neuronal interfaces.

Current technological advances in neural probing and modulation have enabled an extraordinary glimpse into the intricacies of the nervous system. Particularly, nanomaterials are proving to be an incredibly versatile platform for neurological applications owing to their biocompatibility, tunability, highly specific targeting and sensing, and long-term chemical stability. Among the most desirable nanomaterials for neuroengineering, freestanding nanomaterials are minimally invasive and remotely controlled. This review outlines the most recent developments of freestanding nanomaterials that operate on the neuronal interface. First, the different nanomaterials and their mechanisms for modulating neurons are explored to provide a basis for how freestanding nanomaterials operate. Then, the three main applications of subcellular neuronal engineering-modulating neuronal behavior, exploring fundamental neuronal mechanism, and recording neuronal signal-are highlighted with specific examples of current advancements. Finally, we conclude with our perspective on future nanomaterial designs and applications.

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.

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.

Biology-guided engineering of bioelectrical interfaces.

Bioelectrical interfaces that bridge biotic and abiotic systems have heightened the ability to monitor, understand, and manipulate biological systems and are catalyzing profound progress in neuroscience research, treatments for heart failure, and microbial energy systems. With advances in nanotechnology, bifunctional and high-density devices with tailored structural designs are being developed to enable multiplexed recording or stimulation across multiple spatial and temporal scales with resolution down to millisecond-nanometer interfaces, enabling efficient and effective communication with intracellular electrical activities in a relatively noninvasive and biocompatible manner. This review provides an overview of how biological systems guide the design, engineering, and implementation of bioelectrical interfaces for biomedical applications. We investigate recent advances in bioelectrical interfaces for applications in nervous, cardiac, and microbial systems, and we also discuss the outlook of state-of-the-art biology-guided bioelectrical interfaces with high biocompatibility, extended long-term stability, and integrated system functionality for potential clinical usage.

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.