Prelude

Utilizing cutting-edge neurotechnology is essential to providing experimental answers to the many urgent concerns in contemporary neuroscience. lets evaluate the advantages of flexible electronics for neuroscience studies, motivated by the goal of addressing current neuroscience problems using freshly built instruments.

The renowned physicist Freeman Dyson once said, "New directions in science are launched by new tools much more often than by new concepts." This phrase captures the link between tool creation and scientific discovery. A concept-driven revolution has the effect of providing fresh explanations for established concepts. A revolution fueled by tools often results in the discovery of new phenomena that require explanation.

This is true for both physics and neurology. The bimetallic arch, which was employed by Italian scientist Luigi Galvani to activate a frog's sciatic nerve in the late 18th century and launch the fields of bioelectronics and electrophysiology, is among the first instances of a tool-driven biological discovery.

Modern neurology began several decades later when Ramón y Cajal used Golgi's technique for sparsely labeling neurons.

The field of single-neuron recording in live animals was launched more recently by Hubel's invention of the tungsten microwire electrode, which greatly advanced the study of sensory systems by illuminating the neural responses to visual stimuli.

Neher and Sakmann's patch clamp approach made it possible to measure the physiological behavior of individual ion channels and intracellular action potentials, which further shed light on the fundamental processes of the neuron.

Modern optical stimulation and recording techniques, such as optogenetics and calcium/voltage imaging methods, were developed to extend neuroscience beyond the limitations of conventional electrical methods. This opened up a new branch of orthogonal approaches for manipulating and monitoring single-neuron activity.

Given the lengthy history of advancements in neuroscience, it is reasonable to assume that the field will see previously unheard-of chances for neuroscience study in the future due to technology advancements, particularly in the areas of electrical, optical, and genetic engineering.

Complementary and subsequent paradigms of growing complexity and sophistication progress modern neuroscience, much like the conceptual conundrums that beset physics in the first half of the twentieth century. With the use of more advanced neuroengineering instruments, these paradigms are still being verified.

The study of flexible electronics minimizes mechanical mismatch when interacting with biological tissues, especially delicate brain tissue, by utilizing cutting-edge structural and functional material designs. Given the background of neuroengineering and the current state of neuroscience research, flexible electronics presents special potential for neuroscientists. The mechanical characteristics of flexible electronics are more similar to those of interfaced neural tissue because they employ materials with lower bending stiffness than their rigid counterpart, which leads to increased mechanical compliance.

These "tissue-like" electronic devices allow for both monitoring and stimulation of the brain in its most natural form since they cause very little disruption to the brain's endogenous environment.

Multiple groups have independently validated this little disruption to the brain's fundamental signaling networks and metabolic environment.

Driven by these benefits, we explore in this study the open topic of how flexible electronics can continue to tackle neurological problems of the present and future.

The history of the term "flexible electronics," and in particular, the current movements toward giving these electrical devices stretchability. We cover the following four dimensions of how flexible electronics can help solve contemporary neuroscience difficulties.

Chronic stability

In order to comprehend circuit growth in development, learning and memory, and aging, flexible electronics can interact with neuronal activity at numerous timescales, ranging from single-unit action potentials of millisecond length to extended spans of months and years.

Interfacing multiple structures

Flexible electronics offer unique ability to reach areas of the brain, spinal cord, peripheral nerves, and retina that are difficult or impossible to interface with traditional electrical neural probes. Flexible electronics can conform to diverse nervous system structures.

Multi-modal compatibility

Flexible electronics can enable many brain interface modalities, including electrical stimulation and recording, calcium/voltage imaging, optogenetic and chemogenetic/pharmacological neuromodulation, and functional magnetic resonance imaging (fMRI).

Neuron-type-specific recording

In single-neuron recording, flexible electronics can distinguish between different types of neurons, a feature that is typically available in calcium/voltage imaging but absent in traditional electrophysiological methods.

Flexible electronics engages with the neural activity at multiple timescales

Neuronal probes with chronic recording and stimulating capabilities, as well as the temporal resolution to assess single-unit action potentials, are necessary to comprehend the intricate dynamic processes and the evolution of neuronal circuits over time. While chronic recordings of single-neuron activity over weeks, months, or even years are required to comprehend the dynamic evolution, recordings of single-neuron action potentials are required to reconstruct circuit-level connections and activity.

Flexible electronics facilitates multiple modalities of neural interfacing

For contemporary neuroscience research, multimodal brain interfaces that go beyond electrical stimulation and/or assessment are favored. The brain is not entirely electrical in nature, despite the fact that historically, electrical technologies were frequently used to examine and modify the brain. Chemical processes, such as the release of neurotransmitters across synapses to connect with nearby cells, account for a large portion of the brain's communication.

Electrical recording can be neuron-type-specific

Finally, flexible electronics offers the opportunity for neuron-type-specific electrophysiology, a long-sought goal for neural recording devices and a last unique advantage for neuroscience studies. Understanding the various types of neurons and how they differ in terms of molecular, morphological, connectional, and functional aspects is essential to understanding the structure, function, and intricate circuits that make up the brain.

Due to its soft mechanical properties comparable to those of endogenous neural tissue, small feature sizes resembling neurons and neurites, and 3D interconnected macroporous structure resembling a neural network, flexible electronics has amply demonstrated its unique advantages for a multitude of neuroscience studies. These characteristics have provided a number of advantages, such as implantation techniques that involve less intrusive acute delivery.

Flexible electronics technologies

The special component that permits local signal amplification, potentially closed-loop interaction, and extra sensing properties is flexible electronics. Various groups suggest integrating different electronic components and materials with certain manufacturing costs and performance.

Low temperature polysilicon technology

Low Temperature Polysilicon (LTPS) technology is an attractive option among the various active electronics used in brain interfaces because it demonstrates greater electrical stability and mobility in comparison to amorphous silicon, metal oxides, and organic materials. Furthermore, the fabrication of CMOS technology is possible with polysilicon, and it can be combined with high glass transition temperature polymers such as polyimide, polykapton, and polyarylate to create extremely flexible active grids. Rapid thermal processes, like excimer laser annealing (ELA), can greatly improve LTPS performance even on ultra-thin polymeric films, providing a way to build electronics directly on plastic substrates without the need for sacrificial layers. ELA readily offers a polysilicon crystalline quality to achieve electrical mobility of roughly 50 cm2/Vs, even if all manufacturing processes are restricted to a temperature of 300°C.

These processes enable for the production of miniature electrical components with channel lengths in the tens of microns range, without affecting the underlying polymer layer, which is typically polyimide. LTPS is a well-established technology that is widely used in many commercial applications and prototypes.

It is easily integrated with commercial chips composed of crystalline silicon or other inorganic materials. Large global corporations have embraced LTPS thin film transistors (TFTs) as a successful technology, particularly for the production of AMLCDs.

Flexible sensors and ultra-flexible neural interfaces allow for the fabrication of readout circuitry and pre-amplification stages using LTPS TFT-based circuits. Additionally, this technology offers good mechanical and chemical stability. The regulation of heat dissipation during operation can be achieved by strategically modifying the dimensions of TFT and interposing certain layers (AlN, AlN/TiN, etc.).

There have been several reports of LTPS-based tiny circuits and ultra-thin sensors. These parts serve as the foundation for constructing a dependable active grid that pre-amplifies brain impulses, enabling improved performance with regard to organic electronics and a higher yield with regard to intricate crystalline silicon embedding technologies.

Crystalline silicon technology

A consolidated technology with exceptional stability, extreme downsizing, and great electrical mobility (often above 1000 cm3/Vs) is crystalline silicon-based electronics, or CSE. On the other hand, because the process temperatures are typically between 600°C and 900°C, a direct integration of CSE in flexible substrates is not viable. For local amplification using deep electrodes, CSE is still an option. Despite these drawbacks, researchers have described a few methods for integrating CSE on stretchy and flexible substrates, such as shrinking commercial chips and putting them into PDMS film, or embedding silicon islands onto polymeric substrates.

Anything thin enough may theoretically become flexible. Thus, it is possible to bend crystalline silicon to a thickness of just a few microns. We can envision silicon membranes or islands integrated deeply into a plastic sheet where stresses tend to zero, based on the judgment that the bending strains fall linearly with thickness and taking into account that the bending strains are largest at the device's surface. These constructions have a very small bending radius and can withstand strains that are less than the limit of the material's fracture.

By using these techniques, it is possible to take advantage of the better qualities of crystalline silicon technology and create functional circuitry in close proximity to the electrodes. Large electrode arrays may be addressed and controlled with CSE, and it can also be used to switch on or off particular neural interface functionalities. The real yield of the devices, the intrinsic mechanical stress of the various chip stack layers (particularly during the wafer thinning process), and the ultimate substrate thickness—which, in the case of an ultra-thin chip package, exceeds 50 µm—are the limitations of this technology.

Another crucial thing to take into account is biological fluid penetration into CSE, which presents serious safety risks and, in any event, is the primary cause of electronics degradation because of the poor etching action between silicon and cerebrospinal fluid. In the typical active electrode array arrangement, silicon dioxide barriers can both operate as a gate dielectric for the transistors and lessen these effects, especially for log-term implantation.

The work of Rogers and others, in which silicon islands are integrated in flexible substrates to build a network of crystalline silicon transistors for generating an active array of recording sites, is responsible for some of the most well-known uses of CSE technology in neuroscience. According to other studies, it may be possible to create stretchable electronics by integrating silicon islands into PDMS substrates or designing sensor networks specifically for use on human skin.

Nature neuroscience copyrighted flexible high-density active electrode array. Electronics based on organic electrochemical transistors correspondence of a copyright nature. Stretchable array of CMOS inverters with free deformation in PDMS copyright National Academy of Sciences, 2008. Copyright IEEE Spectrum ultra-thin undetectable e-skin. Colorized SEM picture of a sophisticated material with epidermal electronics that is protected by copyright. 

Metal oxides

Another class of materials that are ideal for flexible electronics are metal oxides. Scientists have been studying the characteristics and capabilities of several alloys since the 2000s in an effort to develop a strong rival to silicon technology for the consumer electronics sector. Hosono (2003) presented a model based on Indium Gallium Zinc Oxide (IGZO) that explains the behavior of ZnO and its alloys. This model also shows the first high mobility TFT. The success of zinc oxide-based alloys is then made possible by Hosono, Carcia, Martins, and Fortunato's explanation of the slight variations between amorphous and polycrystalline structures.

When Ju showed in 2007 that it was possible to deposit inorganic materials using a solution process method, which enabled the roll-to-roll manufacture of flexible electronics devices, it was another significant advancement for the field of metal oxide technology. Additional simple procedures include the spray pyrolysis of metal oxides and the solution processing of metal oxide blends containing two-dimensional nanostructures.

Transparency in the visible range is these materials' most alluring feature. Prins and Seager were the first to demonstrate this property by presenting the first In2O3 non-volatile memory TFT and a totally transparent TFT with SnO2, respectively.

Transparency in a certain light spectrum may, in theory, make it possible to monitor brain activity by fusing recordings with visual methods like two-photon calcium imaging. There are still certain problems, like the challenge of locating high-quality p-type semiconductors and the electrical and optical instability of TFTs.

In the first scenario, a hybrid solution could result from integrating high-performing IGZO n-type transistors with organic pentacene-based TFTs or semiconducting single-walled CNTs, albeit at the expense of the circuitry's overall speed. This is true even though scientists have focused a great deal of effort on p-type materials like CuxO and SnOx. When it comes to metal oxide TFT instabilities, passivation layers or a particular UV treatment can aid to lessen the physio-sorption of oxygen and the formation of surface states.

Organic electronics

The fundamental soft material quality of organic materials is the main benefit of using them in electronics. A low Young's modulus indicates more mechanical compliance with living things and a high degree of stretchability for devices that incorporate moving body parts. The combined ionic and electrical conductivity of these materials is yet another distinctive quality. This characteristic makes low-impedance electrodes possible and is essential for identifying biological signals. Once more, consumer electronics has been at the forefront of organic electronics research, offering flat panel displays with excellent contrast and brightness that rely on organic light-emitting diodes (OLEDs).

Subsequently, organic materials have been widely used in thin-film transistors (OTFTs) and organic solar cells. The electronic skin, which is a collection of soft temperature and pressure sensors, and electronic tattoos are well-known examples of the sophisticated sensor arrays and ultra-flexible electronic platforms that OTFTs have expanded from single devices.

In the past 20 years, a vast array of polymers have been studied and produced, offering excellent conductors, semiconductors, and dielectrics with extra properties like biodegradability, printability, and even self-healing capabilities. Chemists have discovered interesting ways to improve the stability and operability of materials, particularly for semiconductors. Among the several polymers that fall under this category are tiny conjugated molecules like polythiophene, rubrene, and blends of pentacene and its derivatives.

The local amplification of brain signals is one important use of organic electronics. We can bring up the use of the Malliaras group's PEDOT-based organic electrochemical transistors (OECTs). Furthermore, the tactics and arrangements that researchers have tried to create incredibly thin, undetectable electronics for cutting-edge wearable applications represent a significant advancement that can be utilized in the field of neuroscience. Someya and colleagues provide an excellent illustration of the potential of organic electronics in this context.

Hybrid electronic interfaces

While flexible electronics provides a range of effective methods for creating a complete brain interface, technological challenges continue to restrict its application. However, a number of groups are showing interest in hybrid solutions, wherein certain system components (such digitalization and communication modules) are built using specialized chips or ordinary commercial electronics. A hybrid solution maintains soft contact between the brain and the grid while utilizing efficient powering, real-time processing of massive amounts of data, implementing dependable communication protocols, etc.

However, the hybrid approach adds a difficult component to the neural interface, thus it must be minimized in size. In order to do this, the method is typically centered on optimizing the device for a single application, occasionally creating ad hoc integrated circuits with a few restricted features especially for the job.

The hybrid system must be housed in an external container that serves as both a barrier against biological fluids and a disguise for the electronics from the body's immune system, or bio-inert, in order for it to be implantable. These factors emphasize how crucially important proper exterior case design is to the success of a neural interface, especially for long-term implantation.

Interconnects for flexible electronics

Interconnections and linking mechanisms require a separate discussion in every flexible system. Actually, because of the device's intricacy, a neural interface is typically constructed by connecting several foils to one another.

The goal of these interconnections is to endure elongation and deformation without losing their electrical qualities; traditional bonding techniques are inadequate on polymers or ultrathin metal layers to achieve this goal, and it is not an easy task to provide strong adhesion between several layers.

However, more sophisticated methods like flex-to-flex bonding, metal-based liquid deposition, conductive paste, ink-jet or screen printing, etc. can be used to complete this difficult task.

This is a significantly more difficult task with stretchable electronics. In actuality, according on the required elongation and component size, various designed geometries must be used in these devices.

For this reason, buckled films ensure better performance at the microscale, conductive sponge and nano-mesh represent the most promising geometries at the nanoscale, and beehive or horseshoe shapes can guarantee a reliable conductance for elongation up to 20% and 100%, respectively, at the millimeter scale.

Applications

In addition to governments, who are investing heavily in neural interfaces through a number of national and international projects, private investors are now beginning to show interest in the development of intrusive BCI. Forecasts for the next ten years are all optimistic, with significant implications for neurorehabilitation and advancements in clever treatments for long-term neurological illnesses.

Indeed, studies on freely roaming animals are made possible by advancements in wireless communication and electronics downsizing. Intrusive prototypes have also been proposed for use on humans to operate robotic arms or treat patients who are locked in or tetraplegic. Although completely flexible implants are not yet on the market, hybrid methods have been shown to work. Furthermore, hybrid systems for optogenetic and electrophysiological research are developing, providing fresh insights into our understanding of how the brain works.

It seems realistic to suggest that neural interfaces will naturally evolve in the future given the rapid technological advancements we are currently seeing. Implants and probes are becoming smaller and more feature-rich due to scalability and miniaturization. By integrating functions like data processing, pattern recognition, digitalization, multiplexing of signals, and classification of data, latency can be significantly reduced and real bidirectional brain interaction is made possible.

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