Nanoenabled Bioelectrical Modulation

Abstract

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.

Figure 1

Materials engineering for stimulation of cells, tissues, and organs enables many important applications for biophysics research. Length scales of the modulation material can span through many orders of magnitude and surface nanostructuring improves compatibility with biological tissues and enables new functionalities, such as photoresponsive properties. Single free-standing nanostructures can be used to investigate cells on the subcellular level and study signal propagation pathways but can also be assembled into composite devices for tissue and organ-level studies of the electrophysiology or behaviors.

Figure 2

Recent developments in wired-up bioelectrical interfaces. (a) Multifunctional neural probes with electrical, optical, and microfluidic interrogation capability. Reproduced from ref (23). Copyright 2021 Springer Nature. (b) Modified porous platinum electrode surface with nanoscale bumps and gaps which were found to enhance cell adhesion and sealing. This surface modification method is applicable to large-scale multielectrode arrays (inset). Reproduced from ref (25). Copyright 2018 Springer Nature. (c) Biomaterial scaffolds with built-in electronics. Reproduced from ref (26). Copyright 2012 Springer Nature. (d) SEM image showing the stimulation/recording electrode was covered by a dense network of electrospun fibers as the scaffold for tissue regeneration and biological modulation. Reproduced from ref (27). Copyright 2016 Springer Nature. (e) Schematics of serpentine interconnects-enabled stretchable mesh MEAs and (f) its incorporation with an organoid. Reproduced from ref (28). Copyright 2019 American Chemical Society.

Figure 3

Silicon-based nanostructured materials for freestanding multiscale biological modulation. (a) Schematic of Faradaic currents generated by a p-i-n SiNW (left). HAADF-STEM (center) and TEM (right) images of a p-i-n SiNW. Reproduced from ref (4). Copyright 2018 Springer Nature. (b) Schematic illustration of the light-stimulated bioelectric interface of mesostructured Si (left). SEM (center) and TEM (right) images of mesostructured Si. Reproduced from ref (15). Copyright 2016 Springer Nature. (c) Schematics of Si structures for interfacing multiscale biological targets. In this selection, a multilayered p-i-n Si membrane was used for cell and tissue stimulation, and Si mesh was used for organ stimulation. (d) A cross-sectional TEM image (left) showing the p-i-n Si diode junction, a STEM image (upper right) showing the oxidation-free interface with a junction width of less than 1 nm, and a SAED pattern (lower right) indicating the nanocrystalline i-layer. (e) Optical micrograph (left), photograph (upper right), and SEM image (lower right) showing the Si mesh made of distributed holey Si membrane on porous PDMS substrate with exceptional flexibility. Reproduced from ref (29). Copyright 2018 Springer Nature. (f) Schematic illustration of internalization of SiNWs into the perinuclear region of the cell. (left) Confocal fluorescence micrograph and thin sections showing SiNWs internalization. (center) SEM micrograph of SiNW embedded under a cell membrane. (right) Reproduced from ref (36). Copyright 2016 AAAS.

Figure 4

Silicon nanowires for intra- and intercellular biological modulation. a) Schematic illustration of creation of hybrid cells and their application for intra- and intercellular interrogations. Reproduced from ref (37). Copyright 2020 American Chemical Society. b) Fluorescent image (left) of myofibroblast-silicon nanowire hybrids (MF) in co-culture with cardiomyocytes (CM). Heat maps of calcium transient propagation in the case of spontaneous action potential (AP) (middle) and AP stimulated through hybrid MF (right). Reproduced from ref (5). Copyright 2019 PNAS.

Figure 5

Synthesis of carbon-based nanostructured electronics for biological modulation. (a) Laser-ablation of PDMS turns the surface of PDMS into a SiC/porous graphite structure. (b) Photographs showing sidewall and surface electrode interfacing with an isolated rat heart for cardiac pacing. (c) H₂O₂ stimulation pathway (left) and fluorescent response of stimulated smooth muscle cells. (right). (d) A schematic of layer-by-layer assembly in the synthesis of hierarchical carbon membranes. (e) SEM of hierarchical carbon (left) and cross-sectional SEM of the biointerface formed between the material and cardiomyocytes. (f) A schematic of the fabrication approach for device patterning. (g) Stimulation of laminar retinal tissues. (h) Heart pacing setup (top) and physiology measurement during electrical pacing (bottom). (a)–(c) are reproduced from ref (41). Copyright 2020 AAAS. (d)–(h) are adapted from ref (9). Copyright 2021 Springer Nature.