Biodegradable and Biohybrid Materials for Next-Generation Brain-Computer Interfaces

Abstract

Biodegradable and biohybrid materials for nanobioelectronics offer a compelling alternative for developing next-generation brain-computer interfaces (BCIs). In this chapter, we focus on the critical need for biodegradability within nanobioelectronics and the advent of biohybrid materials as key solutions for integrating biological and synthetic components. A thorough exploration of biodegradation mechanisms, encompassing solubilization, chemical hydrolysis, and enzymatic processes, underscores the intricate pathways involved. Additionally, we investigate the utilization of biodegradable materials across bioresorbable devices such as neural interfaces, drug carrier electrodes, and intracranial pressure monitors. Moreover, we delve into the integration of living microorganisms with synthetic compounds to develop biohybrid materials, explaining their potential for enhancing functionality and biocompatibility in neural interfaces. Design considerations for both biodegradable and biohybrid devices are examined, addressing challenges and proposing strategic approaches for mitigation. Finally, we conclude with a forward-looking perspective on the future trajectory of BCIs, emphasizing the importance of ongoing research and innovation to boost the field forward.

1. Introduction

In recent decades, the convergence of nanotechnology, biotechnology, and electronics has paved the way for innovative advancements in the field of biodegradable and biohybrid materials for nanobioelectronics. At the nanoscale, materials exhibit unique properties, enabling unparalleled interactions with biological systems [1]. Nanotechnology enables the fabrication of materials and devices at dimensions comparable to biological entities, such as proteins, cells, and even subcellular structures like organelles. Biotechnology, on the other hand, leverages biological molecules and processes for designing functional materials and systems. The integration of these disciplines with electronics has led to the development of nanobioelectronic devices with enhanced sensitivity, specificity, and biocompatibility. On the other hand, the foundation of nanobioelectronics lies in the design and synthesis of nanomaterials with tailored properties for interfacing with biological organs. The nanoscale materials exhibit unique physicochemical characteristics, such as high surface area-to-volume ratio, tunable optical and electrical properties, and facile functionalization with biomolecules. Such properties enable nanobioelectronic devices to interface with biological systems at the molecular and cellular levels, facilitating applications in diagnostics, therapeutics, and regenerative medicine [2].

The advent of implantable medical devices, such as neural probes and biosensors, has encouraged the demand for biodegradable materials in nanobioelectronics. Unlike conventional electronic implants, which persist indefinitely within the body, biodegradable materials undergo controlled degradation over time, minimizing the risk of chronic inflammation and tissue damage [3, 4]. The prolonged presence of non-biodegradable implants can elicit foreign body responses (FBR), characterized by the encapsulation of the implant by inflammatory cells and fibrous tissue, ultimately compromising device performance and patient outcomes. Biodegradable materials offer a compelling alternative for implantable nanobioelectronic devices, as they can be designed to degrade into non-toxic byproducts that are naturally metabolized or excreted by the body. Moreover, biodegradable materials offer the advantage of transient functionality, obviating the need for surgical removal of the implanted devices once they have fulfilled their intended purpose. This not only reduces the risk of surgical complications and patient discomfort but also lowers healthcare costs associated with device retrieval procedures.

Biohybrid materials represent a paradigm shift in nanobioelectronics, in which synthetic components are seamlessly integrated with biological entities to confer enhanced functionality and biocompatibility. Figure 1 illustrates an overall view on different materials, design, and fabrication strategies for biohybrid materials. By harnessing the inherent properties of biological molecules, such as proteins, nucleic acids, and carbohydrates, biohybrid materials can exhibit tailored bioactivity, specificity, and self-assembly capabilities. The integration of biological components enables bidirectional communication with living systems, facilitating real-time sensing, modulation, and therapeutic interventions [13, 14]. One of the key advantages of biohybrid materials lies in their ability to interface with biological systems with high specificity and selectivity. Biological molecules, such as antibodies, enzymes, and nucleic acids, possess inherent recognition capabilities that can be harnessed for targeted sensing and manipulation of biomolecules. By immobilizing these molecules onto synthetic substrates, researchers can create biohybrid interfaces capable of detecting analytes with exquisite sensitivity and specificity. Furthermore, the dynamic nature of biological interactions enables biohybrid materials to adapt and respond to changes in the biological environment, making them well-suited for applications requiring real-time monitoring and control [15, 16]. In addition to their sensing capabilities, biohybrid materials hold promise for therapeutic interventions in nanobioelectronics. Functionalized nanoparticles, for example, can be engineered to target specific cells or tissues within the body, delivering therapeutic agents with precision and minimizing off-target effects. Furthermore, biohybrid scaffolds can provide a supportive microenvironment for tissue regeneration and repair, facilitating the integration of implanted devices with host tissues and promoting long-term biocompatibility.

Figure 1.

Materials, design, and fabrication strategies for biohybrid materials. (A) Top: fabrication and implantation processes of a biohybrid peripheral neural interface from an in vitro cell culture into an animal model. Bottom: the completed biohybrid device comprising a microelectrode array of PEDOT: PSS integrated with living tissue [5]. (B) Miniaturized metamaterial scaffolds support contracting cardiac chambers [6]. (C) Design of a bacteria biohybrid system to inhibit bacterial infection and enhance bone tissue regeneration [7]. (D) Design and principle of a nanopore extended field-effect transistor (nexFET) biosensor capable to be equipped with biological receptors such as insulin for selective detection of insulin antibodies at the single-molecule level [8]. (E) A flexible bioelectronic device fabricated by conductive polymer-based living material, and a schematic diagram for detecting system based on the fabricated living material with improved electrogenic property [9]. (F) Schematic illustration of the use of engineered cyanobacteria for creating stimuli-responsive living materials [10]. (G) Schematic for the preparation of a biomimetic piezoelectric nanomaterial-modified oral microrobots using Veillonella atypica (VA) cells and Staphylococcus aureus cell membrane-coating BaTiO3 nanocubes (VA-SAM@BTO). This biohybrid material can be used for targeted catalytic and immunotherapy of colorectal cancer [11]. (H) Top: schematic illustration for the preparation of a natural polyphenol-based single-cell coating (nanoarmor) for the protection of bacteria from antibiotics in the gastrointestinal (GI) tract. Bottom: Schematic representation of the nanoarmor on QCM chips which enables enhanced mass adsorption due to the multiple interactions between polyphenol moieties and antibiotic molecules [12].

Biodegradable and biohybrid materials also offer a compelling alternative for developing next-generation brain-computer interfaces (BCIs) that seamlessly interface with the brain, while mitigating the adverse effects associated with chronic implantation [13]. The success of BCIs hinges on the development of biocompatible electrode arrays capable of interfacing with the brain with high spatial and temporal resolution. Conventional electrode materials, such as metals, often elicit an FBR when implanted into neural tissue, leading to the formation of glial scar tissue and impedance mismatches that compromise signal fidelity [17]. Biodegradable and biohybrid materials offer a promising solution to these challenges, as they can provide a temporary interface with the brain while minimizing tissue damage and inflammatory responses. Furthermore, the integration of bioactive molecules, such as neurotransmitters, growth factors, and neural adhesion proteins, into biodegradable and biohybrid materials can enhance their biocompatibility and promote neural tissue regeneration. By mimicking the native extracellular matrix (ECM) of the nervous system, these biomimetic scaffolds can create an optimal microenvironment for neuronal growth and synaptic connectivity, facilitating the integration of implanted devices with host neural circuits.

In this chapter, we will delve deeper into the latest developments, challenges, and future prospects of biodegradable and biohybrid materials for neural interfaces, especially for BCIs. Through an exhaustive review of the current literature and state-of-the-art research, we aim to provide a comprehensive understanding of the opportunities and challenges associated with these emerging materials and their transformative potential in shaping the future of nanobioelectronics.

2. Biodegradation: mechanisms and processes

All materials degrade, but the rate matters. In fact, achieving significant tunable degradation in a human-relevant timeframe is important. Degradation can be conducted by various processes including photo-induced, thermal, mechanochemical, and biodegradation processes. Although biodegradation has been extensively studied for various biomedical applications [18, 19, 20], it lacks a unique definition. Nevertheless, biodegradation involves four primary mechanisms: (i) solubilization, (ii) hydrolysis, (iii) charge formation followed by dissolution, and (iv) enzyme-catalyzed degradation [21].

2.1 Solubilization

Solubilization involves the dissolution of polymers in water. This phenomenon is observed in both natural and synthetic polymers, highlighting its broad applicability. Polyelectrolytes, such as poly(acrylic acid) (PAA), and polar polymers, exemplified by poly(vinyl alcohol) (PVA), are among the polymers that readily dissolve in water due to their inherent chemical properties and molecular structures [22, 23]. Upon contact with water molecules, these polymers undergo interactions that facilitate their dissolution, leading to the formation of a hydrogel. This hydrogel structure represents an intermediate state in the solubilization process, characterized by the polymer chains being partially dispersed within the aqueous medium. As water is further added, the polymer-polymer contacts are progressively disrupted, promoting the transition of the hydrogel into a more homogeneous and viscous solution. The rate at which solubilization occurs is influenced by several factors, including the molecular weight and concentration of the polymer. Higher molecular weight polymers typically exhibit slower dissolution rates due to the increased number of intermolecular interactions that must be overcome. Similarly, higher polymer concentrations may lead to slower dissolution kinetics, as the availability of water molecules for polymer-solvent interactions becomes limited [21]. Environmental conditions also play a significant role in dictating the kinetics and extent of solubilization. Factors such as temperature, pH, and the presence of salts can modulate the solvation properties of water and, consequently, impact the dissolution behavior of polymers. For instance, higher temperatures may enhance polymer mobility and facilitate faster dissolution rates, while extreme pH conditions or the presence of specific ions can either promote or inhibit solubilization depending on their compatibility with the polymer structure.

2.2 Hydrolysis

Chemical hydrolysis, in which a molecule of water breaks one or more chemical bonds, is one of the main reactions for degradation of materials to low molecular weight residues. Natural polymers like proteins and polysaccharides, as well as certain synthetic polymers, degrade via hydrolysis [24]. Water-insoluble polymers generally possess functional groups that can form hydrogen bonds, which enhance their crystalline structure and make them resistant to dissolving in water [25]. It can be found that, to enable hydrolysis, the polymer must possess hydrolytically unstable bonds and a reasonable degree of hydrophilicity. Polyesters, including PGA, PLA, and poly(ε-caprolactone) (PCL), primarily degrade via simple hydrolysis [26, 27, 28], with degradation initiating in amorphous regions before progressing to crystalline domains. Enzymes may participate in degrading hydrolysis products, although their involvement in the initial phase is limited [29].

2.3 Charge formation precedes dissolution

The mechanism of charge formation followed by dissolution represents another significant pathway in the biodegradation of materials, particularly for certain initially insoluble polymers. This process involves the ionization or protonation of pendant groups within the polymer structure, leading to a change in solubility and subsequent dissolution. Notably, polyacids and polybases are prominent examples of polymers that exhibit pH-dependent solubility characteristics, allowing for diverse applications in fields such as pharmaceutical enteric coatings. The initial step in this mechanism involves the ionization or protonation of specific functional groups present within the polymer matrix. These groups, often referred to as pendant groups, possess acidic or basic properties that render them susceptible to changes in pH conditions. For instance, polyacids contain carboxylic acid groups (-COOH), while polybases feature amino groups (-NH₂) that can undergo protonation or deprotonation reactions in response to variations in pH. Under acidic conditions, polyacids readily donate protons, leading to the ionization of their carboxylic acid groups and the formation of carboxylate ions (-COO). This increase in negative charge promotes electrostatic repulsion between polymer chains, thereby disrupting intermolecular interactions and facilitating polymer dissolution. Conversely, under basic conditions, polybases accept protons, resulting in the protonation of amino groups and the formation of positively charged ammonium ions (-NH₃). This alteration in charge distribution alters the polymer’s solvation properties, promoting its dissolution in aqueous environments [21, 30]. The pH-dependent solubility exhibited by polyacids and polybases is exploited in various applications, with pharmaceutical enteric coatings being a notable example. Enteric coatings are designed to remain intact in the acidic environment of the stomach while dissolving in the more neutral or basic conditions of the intestine. By incorporating polyacids or polybases into the coating, the solubility of the polymer can be tailored to the desired pH range, ensuring targeted drug release and enhanced therapeutic efficacy.

Water-insoluble polymers containing pendant anhydrides or ester groups have the ability to transform into a soluble form through hydrolysis [31]. The hydrolysis leads to the formation of ionized acids along the polymer chain. For example, polymers like poly(methyl acrylate) (PMA) and poly(methyl methacrylate) (PMMA), derived from PAA and poly(methacrylic acid) (PMAA), respectively, undergo this change [21]. The hydrolysis of esters within these polymers is succeeded by the ionization of carboxyl groups, making them soluble in water. Researchers developed a pH-sensitive drug delivery device using a bioerodible polymer partially esterified with 1-hexanol, which becomes water-soluble upon ionization of carboxyl groups [32]. The dissolution pH threshold increases with ester size, reaching about pH ~ 6 for hexyl esters. Poly(glutamic acid) (PGA) is a biodegradable polymer known for its labile ester functionalities, which undergo hydrolysis in vivo [33]. When PGA copolymerized with ethyl glutamate, the resulting copolymers yield hydrogels with diverse hydrophilic properties due to the differential rates of hydrolysis of ethyl glutamate esters. Specifically, copolymers containing higher proportions of ethyl glutamate exhibit slower hydrolysis rates compared to those with higher glutamic acid content. As a consequence, copolymers containing approximately 50 mol% glutamic acid tend to become water-soluble as the hydrolysis of ethyl glutamate esters progresses, leading to the liberation of hydrophilic carboxyl groups along the polymer chain. This transition to water solubility highlights the dynamic interplay between copolymer composition and hydrolytic degradation kinetics, offering opportunities for tailored design of biocompatible materials for various biomedical applications.

2.4 Enzyme-catalyzed degradation

Enzymes within the body serve as catalysts for specific biochemical degradation reactions like hydrolysis, essential for metabolizing proteins and polysaccharides [34, 35]. Each enzyme has a specific active site for binding substrates, leading to substrate-specific degradation. Natural polymers like proteins and polysaccharides, renowned for their biodegradability, were among the earliest biomaterials employed. Moreover, enzymes play an important role in the degradation of synthetic poly(α-amino acids) like poly-L-lysine and poly-L-arginine, although predicting the enzymes involved and extent of degradation is challenging [36, 37]. Even apparently, inert polymers like polyethylene and polypropylene undergo degradation to some extent under physiological conditions. Enzymes, although specific, can degrade many synthetic polymers nonspecifically, including nylon, poly(ether urethane), and poly(ethylene terephthalate). Enzyme penetration into synthetic polymers determines the mode of degradation, whether surface or bulk, influenced by enzyme size and polymer properties. Semi-crystalline polymers degrade from amorphous regions first, with blending non-biodegradable polymers with degradable ones allowing for controlled degradation. In addition, water-soluble polymers like poly(ethylene glycol) (PEG) and PVA undergo enzymatic degradation. Polyvinylpyrrolidone (PVP) degrades minimally in the body, mainly involving low molecular weight fractions [21].

2.5 Biodegradable hydrogels

Biodegradable hydrogels undergo degradation through various mechanisms and processes influenced by their chemical composition, environmental conditions, and intended application [38]. The degradation of these hydrogels typically involves hydrolysis, enzymatic degradation, and physical erosion. As mentioned, hydrolysis is a prominent mechanism wherein water molecules infiltrate the hydrogel matrix and break the polymer chains through the cleavage of chemical bonds. In the case of biodegradable hydrogels, ester or amide bonds within the polymer backbone are commonly targeted for hydrolytic degradation. The hydrolysis proceeds more rapidly under physiological conditions, such as in the presence of enzymes or at higher temperatures. Natural polymers used in biodegradable hydrogels, such as polysaccharides (e.g., chitosan) and proteins (e.g., gelatin), are susceptible to enzymatic attack by proteases, glycosidases, or lipases [39, 40]. This enzymatic action leads to the breakdown of the polymer chains and subsequent degradation of the hydrogel. On the other hand, physical erosion involves the gradual dissolution or detachment of hydrogel components from the bulk material due to mechanical forces or fluid flow. As water penetrates the hydrogel network, swelling occurs, exerting mechanical stress on the polymer chains. Over time, this stress can lead to the fragmentation or erosion of the hydrogel structure, resulting in the release of degraded fragments into the surrounding environment. The degradation kinetics of biodegradable hydrogels depend on factors such as polymer composition, crosslinking density, and environmental conditions. Higher crosslinking densities often slow down degradation by limiting water penetration and access to cleavage sites, whereas lower crosslinking densities promote faster degradation. Additionally, environmental factors such as pH, temperature, and the presence of enzymes can significantly influence the degradation rate of biodegradable hydrogels [38]. Understanding the mechanisms and processes of degradation is essential for designing biodegradable hydrogels with tailored degradation profiles. By controlling degradation kinetics, researchers can optimize the performance and functionality of biodegradable hydrogels for sustained drug delivery, tissue engineering, wound healing, and other innovative applications [41, 42, 43]. Recently, modern materials synthesis aims to create new combinations of properties at molecular and surface levels. Modifying known polymers allows for projecting the properties of the modified product accurately. Although many polymers are not water-soluble and do not form hydrogels, they can contribute to hydrogel preparation by forming block copolymers, blends, or interpenetrating polymer networks with water-soluble polymers. These formulations, rich in hydrophilic polymers, absorb water and swell without dissolving, forming hydrogels [44]. Thus, water-insoluble polymers can effectively contribute to biodegradable hydrogel preparation, leveraging their well-characterized properties.

3. Biodegradable materials for bioresorbable devices

Bioresorbable electronics entail the development of electronic devices designed to be gradually absorbed within the body, eliminating the need for surgical removal. These devices, composed of degradable biocompatible materials, serve critical roles in temporary medical monitoring and therapeutic interventions. The controlled degradation of these materials ensures gradual absorption, minimizing inflammatory responses and adverse reactions. When designing a bioresorbable device, the first important factor to consider is its intended dissolution time, which depends on whether it is meant for long-term or short-term monitoring. The control over dissolution rates is achieved by carefully choosing appropriate materials for the device. Table 1 provides a classification of the distinct materials that make up the different components of the biodegradable device, including conductors, semiconductors, dielectrics, substrate, and encapsulation layers.

Component	Material type	Examples
Conductors	Biodegradable metals	Magnesium (Mg), Zinc (Zn), Molybdenum (Mo), Tungsten (W), Iron (Fe)
	Conductive polymers	Polyaniline (PANI), Poly(3,4-ethylenedioxythiophene) (PEDOT)
Semiconductors	Organic semiconductors	Poly(3-hexylthiophene) (P3HT), Pentacene
	Inorganic semiconductors	Zinc Oxide (ZnO), Silicon (Si)
Dielectrics	Biodegradable polymers	Polylactic Acid (PLA), Polyglycolide (PGA)
	Natural dielectrics	Cellulose, Chitosan
Substrate	Biodegradable polymers	Polylactic Acid (PLA), Polyhydroxyalkanoates (PHA), Polyvinylpyrrolidone (PVP), Silk, Rice paper, Polyvinyl alcohol (PVA), Poly(1,8-octanediol-co-citrate), Polycaprolactone (PCL)
	Biodegradable ceramics	Calcium phosphate, Tricalcium phosphate
Encapsulation Layers	Biodegradable polymers	Polycaprolactone (PCL), Poly(lactic-co-glycolic acid) (PLGA)
	Natural materials	Shellac, Beeswax

Table 1.

Classification of biodegradable materials in neuroelectronic devices.

Bioresorbable materials are also gaining prominence in the development of temporary neural interfaces designed to align with the transient nature of biological processes such as neuroregeneration, neurotherapy, and recovery. A wide range of materials, including silicon nanomembranes (Si NMs) and zinc oxide (ZnO) thin films, can serve as active semiconductor components within these interfaces. The fundamental resorption process of these materials involves hydrolytic reactions occurring in the presence of surrounding biofluids. Similarly, materials endowed with both conductive and insulating characteristics, such as magnesium (Mg), molybdenum (Mo), zinc (Zn), silicon (Si), and tungsten (W), undergo comparable chemical transformations, enabling their utilization as electrodes and interconnects [45]. For the fabrication of gate and interlayer dielectrics, substances like silicon dioxide (SiO₂), magnesium oxide (MgO), and silicon nitride (SiN_x) are utilized. Furthermore, substrates including PLGA, PLA, PVA, PCL, collagen, and silk fibroin are employed [45]. These materials, as well as comparable alternatives, naturally undergo degradation within the body without eliciting adverse biological effects.

Moreover, bioresorbable materials find practical application in the field of chemical sensing interfaces. For instance, Fe nanoparticles show catalytic properties, acting as oxidizing agents for dopamine. For example, a bioresorbable electrochemical sensor, based on this principle, was constructed using a Si NM (doped with ∼10²⁰ cm⁻³ boron) [46]. The Si NM was coated with a hybrid catalyst consisting of carboxylated polypyrrole (CPPy) nanoparticles adorned with Fe. These nanoparticles varied in size, ranging from 5 to 100 nm, and served as functionalized electrodes within the system. Furthermore, the interconnects were crafted from Mg, with thick SiO₂ coating film serving as the interlayer dielectric, and PCL used as both the encapsulation and substrate. The operation of this sensor involves a sequence of intricate molecular interactions. Initially, dopamine molecules adhere to the surface of the CPPy hybrid. This binding occurs through a fascinating phenomenon where the six-membered benzene rings within the dopamine molecules engage in π−−π interactions with the nitrogen-containing rings present in CPPy. Subsequently, the Fe nanoparticles catalyze the conversion of dopamine to its oxidized form, known as dopamine-o-quinone. This chemical transformation is essential, as it leads to the generation of electrons. These electrons are then efficiently transferred to the Si NM electrodes. This mechanism enables the sensor to exhibit electrochemical responses across a broad spectrum of dopamine concentrations, including remarkably low picomolar levels when evaluated in controlled laboratory settings. Such sensitivity and specificity are paramount for the accurate detection and quantification of neurotransmitters such as dopamine. Actually, the versatility of these materials extends beyond their sensing capabilities. They also possess resorbable characteristics, making them ideal for temporary neural implants and biosensors. Under accelerated conditions mimicking physiological environments, such as in phosphate-buffered saline (PBS) solution at a pH of approximately 11 and a temperature of 37°C, these materials demonstrate gradual dissolution [46]. This attribute is particularly advantageous in scenarios where temporary or biodegradable sensing platforms are desired, offering compatibility with the body’s natural processes of tissue healing and regeneration. Moreover, the importance of monitoring nitric oxide (NO) levels in real time within physiological settings is underscored by its regulatory impact on neurotransmitter release, contributing to the sensing of neural activity [47]. A recently devised electrochemical sensor, designed to be bioresorbable, exhibits a notable capacity for detecting NO with a detection threshold of approximately 4 nM across a broad range (0.01–100 μM) and remarkable temporal resolution (less than 350 ms). The composition of the device involves a substrate made of poly(L-lactic acid) and poly(trimethylene carbonate) (PLLA−PTMC) with a thickness of 400 μm, ultrathin gold nanomembranes (Au NMs) serving as electrodes with a thickness of 32 nm, and a poly(eugenol) film (∼16 nm thick) functioning as a selective membrane to improve specificity and selectivity toward NO [48]. Figure 2 indicates the fabricated electrochemical sensor and its components. The resorbable nature of this sensor is attributed to the bioresorption of Au NMs, facilitated via mechanisms including phagocytosis and metabolic clearance. Within the electrochemical sensing mechanism, NO undergoes oxidation at the surface of Au NMs, yielding NO⁺ (nitrosonium ion) through the removal of a single unpaired electron. Subsequently, NO⁺ is converted to NO²⁻ within the surrounding solution. The resulting redox current can be precisely quantified to ascertain the concentration of NO. This methodology offers a robust means of detecting and measuring NO levels, vital for numerous biological analyses. The device shows the capability for real-time monitoring at both cellular and organ levels and has undergone testing in live rabbit models for a duration of up to 5 days, employing a wireless system for data acquisition [48].

Figure 2.

Flexible and biodegradable sensors for nitric oxide (NO) detection: (a) and (b) demonstrate the sensors’ flexibility under bending and stretching conditions. The sensors consist of a transient structure comprising a PLLA-PTMC bioresorbable substrate, Au nanomembrane electrodes, and a poly(eugenol) thin film as depicted in (c). Detection of NO concentration is achieved through amperometry, where an oxidation potential is applied between the working electrode (WE) and reference electrode (RE), and the resulting current between the WE and counter electrode (CE) is measured. Implanted in the joint cavity of a rabbit, these sensors provide continuous in vivo monitoring of NO concentrations, with data transmission to a user interface via a customized wireless module [48].

3.1 Neural interface device

Development of innovative bioresorbable devices marks a significant advancement, particularly in the field of neuroscience and BCIs. This advancement holds tremendous promise for understanding complex brain functions and pathologies, ultimately paving the way for improved diagnostics and treatments for neurological disorders. One of the new kind of tissue-electronic interfaces are constructed utilizing metal-oxide-semiconductor field-effect transistors (MOSFETs). The materials employed in these interfaces are carefully selected to ensure optimal performance and biocompatibility. Among these materials, highly doped Si NMs, Mo, SiO₂, and trilayers of SiO₂/Si₃N₄/SiO₂ play critical roles in enhancing device functionality and longevity [49]. The incorporation of MOSFETs, particularly utilizing biodegradable materials like highly doped Si NMs, offers several advantages. Firstly, Si NMs exhibit favorable electronic properties, ensuring reliable signal transmission and processing within the device. Additionally, these materials possess mechanical flexibility, allowing the device to conformally contact dynamic brain tissues. This conformal contact is essential for accurate and reliable recording of physiological activities, such as ElectroCorticography (ECoG) and ElectroEncephalography (EEG), both in acute and chronic experimental settings. These platforms enable researchers and clinicians to study intricate patterns of brain activity with unprecedented details, offering insights into fundamental neurophysiological processes and pathological conditions. Moreover, the ability of these devices to be bioresorbable adds another layer of utility, as they can be safely implanted and subsequently dissolve harmlessly within the body over time, minimizing the risk of long-term adverse effects associated with traditional non-resorbable implants.

Advancing neural interfaces presents significant challenges in creating next-generation systems that seamlessly integrate with living tissues, accurately record electrical signals, and naturally degrade post-operation. However, recent progress has been made with the emergence of neural interfaces leveraging organic-electrochemical-transistor (OECT) technology [50]. This approach boasts an ultrathin, lightweight, and flexible design with multiple channels, enabling precise and continuous mapping of neural signals. One of the remarkable features of this technology is its active degradation mechanisms, which enhance biosafety post-operation. Unlike traditional neural interfaces that may pose risks due to their permanent presence in the body, this system is designed to degrade once its purpose is fulfilled, mitigating potential long-term complications. The platform achieves impressive spatiotemporal resolution, and boasts an outstanding signal-to-noise ratio (SNR), indicating its ability to accurately capture neural activity amidst background noise. Importantly, the implantable OECT arrays establish stable neural interfaces in living organisms while being designed to degrade over time. This feature not only enhances safety but also eliminates the need for invasive removal procedures once the device is no longer needed. Demonstrations of the technology’s efficacy include real-time monitoring of cortical electrical activity in rats under various conditions such as narcosis, epileptic seizures, and electric stimuli. Additionally, the technology has been utilized for ECoG mapping with 100 channels, showing its potential applications in neurological research and clinical settings [50]. Figure 3 illustrates the fabricated bioresorbable OECT-based neural interface.

Figure 3.

Bioresorbable ultrathin and flexible transient OECT array as a core platform for a high-fidelity brain-machine interface: (a) Schematic illustrations depicting the setup of the transient OECT array positioned on the cerebral cortex of an animal model, facilitating the recording of micro-electrocorticography (μ-ECoG) signals, along with an illustration of the individual OECT unit. (b) A detailed schematic representation shows the transient OECT platform’s design, highlighting its capacity to capture μ-ECoG signals with exceptional spatiotemporal resolution, all within a fully biodegradable framework. (c–e) Optical images are presented to underscore the mechanical flexibility, ultrathin profile, and high-density configuration of the biodegradable OECT array, demonstrating its compatibility with biological tissues. (f) A photograph displays the OECT array seamlessly adhered to the cerebral cortex of a Sprague Dawley rat, confirming its successful integration with biological tissues. (g) A photograph offers a frontal view of the OECT platform affixed onto the rat’s brain, emphasizing its tissue-friendly mechanical properties. (h) A schematic illustration exhibits the functional regions of the brain and the specific locations of the OECT biosensors, providing a comprehensive overview of the array’s spatial distribution and functional mapping on the brain atlas [50].

3.2 Intracranial pressure monitoring

Intracranial pressure (ICP) is a critical parameter in assessing neurological health and managing conditions such as traumatic brain injury and hydrocephalus. Among biodegradable materials, conductive polymers (CPs) and biodegradable metallic configurations such as Si NMs emerge as ideal candidates for the real-time monitoring of ICP, due to their inherent flexibility and compatibility with biological systems. The design of Si NM-based ICP sensors incorporates several unique features aimed at optimizing performance and accuracy. Strain gauges, for instance, are strategically integrated into the sensor structure to detect subtle changes in pressure. These gauges undergo deformation in response to variations in pressure, thereby enabling the sensor to precisely measure ICP dynamics. Furthermore, the inclusion of suspended membranes within the sensor architecture serves to enhance sensitivity. By suspending the sensing elements, the device becomes more responsive to even slight pressure fluctuations, ensuring that no relevant physiological changes escape detection. This heightened sensitivity is important for capturing nuanced variations in ICP, which may hold diagnostic and prognostic significance in clinical practice. Another key component of Si NM-based ICP sensors is the incorporation of enclosed air cavities. These cavities play a vital role in augmenting the overall responsiveness of the sensor system. By encapsulating air within the device, changes in pressure exerted on the sensor membrane result in proportional alterations in air volume within the cavity, thus facilitating rapid and accurate measurement of ICP dynamics. The efficacy of these advanced pressure sensors has been rigorously validated through in vivo experiments, demonstrating their stability and reliability over extended periods. These experiments have shown that Si NM-based sensors can sustain accurate monitoring of ICP for up to 25 days, attesting to their tunable durability and long-term performance in physiological environments [51]. In general, the amalgamation of strain gauges, suspended membranes, and enclosed air cavities in ICP sensors represents a sophisticated engineering solution for pressure monitoring. Their ability to provide prolonged and precise measurements of ICP positions them as invaluable tools in clinical settings, where timely and accurate assessment of neurological parameters is critical for informing medical decision-making and optimizing patient outcomes.

3.3 Wireless operation

Wireless BCIs are developing systems designed to establish bidirectional communication between the brain and external devices without the need for physical connections. These systems aim to eliminate the wired connection between the signal acquisition and translation components by employing wireless transmission technologies like Bluetooth, ZigBee, infrared (IR), Wi-Fi, and near-field communication (NFC) modules. This removal of wires significantly enhances the portability of BCI systems. Consequently, users can move freely and maintain various postures without restrictions while wearing the acquisition component of wireless BCI systems. These advantages facilitate the transition from laboratory experiments to practical, everyday applications [52, 53]. In a recent study, bioresorbable sensors designed for monitoring the brain’s temperature employ a wireless LC-resonant passive scheme, leveraging its impressive precision and accuracy [52]. This wireless system consists of several key biodegradable components, including PLGA, candelilla wax, Mg foil, and a combination of tungsten (W) and natural wax. The LC-resonant passive scheme facilitates wireless communication, eliminating the need for physical connections and minimizing potential interference. The incorporation of PLGA and candelilla wax ensures biocompatibility and stability, while Mg foil contributes to the system’s structural integrity. The mixture of W and natural wax further enhances the sensor’s performance. Remarkably, in rat models, this wireless temperature sensor system demonstrates its capabilities by providing accurate measurements for up to four days, showing performance levels comparable to commercial sensors. This incorporation of biodegradable materials and wireless technology underscores the potential of this approach for non-invasive and precise monitoring of brain temperature in clinical scenarios [54].

Recently, researchers introduced advanced materials for use in bioresorbable electronic stimulators, which can operate effectively for extended periods within the body before gradually dissolving harmlessly into non-toxic byproducts, thus obviating the need for surgical removal. Their study addressed significant hurdles associated with bioresorbable electronic devices by achieving lifespans that align with clinical requirements. Figure 4 shows the fabricated wireless electrical stimulators. These devices leverage a bioresorbable dynamic covalent polymer that fosters strong bonding both internally and with external surfaces, serving as a flexible substrate and protective coating for wireless electronic components. The results demonstrated that these polymers facilitated reliable, enduring performance as distal stimulators in a rat model of peripheral nerve injuries, showing the potential of programmable, ongoing electrical stimulation for sustaining muscle responsiveness and promoting functional recuperation [55].

Figure 4.

(a) Schematic illustration of key characteristics, including biocompatibility, mechanical stretchability, degradability, and impermeability against biological fluids, required for the design and materials of the stimulator. (b) Expanded configuration of the fabricated device and its components. Optical images of (c) the completed device, (d) the stretched (30%), and (e) twisted (360°) configurations of the devices, demonstrating its flexibility. (f) Images depicting the accelerated dissolution of the bioresorbable stimulator within PBS (pH = 7.4) at 90°C. (g) Left: 3D computed tomography image of a mouse collected 1 week after the implantation of a bioresorbable electrical stimulator, Right: images of PLGA cuff electrodes attached to the sciatic nerve over a period of 6 weeks. These images demonstrate the detachment of the sciatic nerve from the bioresorbable stimulator after a therapeutic period [55].

3.4 Neurochemical analysis

Real-time monitoring of neurotransmitter concentrations, including dopamine, epinephrine, and noradrenaline, is crucial for evaluating degenerative brain diseases and regulating essential bodily functions. Bioresorbable electrochemical sensors serve as implantable neurochemical analyzers, enabling wireless detection of dopamine [46, 56]. For example, these sensors employ doped mono-Si NRs, 2D Transition Metal Dichalcogenides (TMDs) (MoS₂ and WS₂), Fe nanoparticles, and Mg, showing exceptional sensitivity and reliability. This wireless communication system facilitates the transmission of measured, time-dynamic neurochemical responses for 2–4 weeks in vivo [56]. The integration of bioresorbable materials in neural monitoring devices represents a significant stride toward safer and more effective diagnostic and therapeutic interventions for various brain disorders. These advancements offer a unique combination of high-performance capabilities and biocompatibility, setting the stage for the next generation of neurophysiological monitoring technologies.

3.5 Drug carrier and therapeutic electrodes

Drug delivery systems employing biodegradable electrodes and implants represent a cutting-edge approach to medical technology. These systems utilize biodegradable materials to fabricate electrodes and implants for targeted and controlled therapeutic agents and drug release within the body [4, 19]. Examples of common biodegradable materials include PLGA, PCL, chitosan, and Mg alloys. Considering the design and materials of electrodes, drug-loading processes involve various approaches, including dip and spin coating, layer-by-layer assembly, encapsulation techniques, chemical grafting, and electrochemical deposition [57, 58, 59]. On the other hand, drug-releasing mechanisms can be categorized into various strategies, including passive diffusion, electrochemical stimulation, pH-responsive behavior, and enzyme-mediated degradation. These mechanisms play fundamental roles in controlling the release of drugs from biodegradable carriers, such as nanoparticles or implants.

1. Passive Diffusion: In passive diffusion-based systems, drugs or therapeutic agents are enclosed within biodegradable carriers. Over time, as these carriers degrade, the encapsulated drug is gradually released into the surrounding environment. The rate of drug release is affected by factors such as the composition, size, and surface properties of the carrier material [60]. Smaller particles typically exhibit faster drug release rates due to their larger surface area-to-volume ratio.

2. Electrochemical Stimulation: Electrochemical stimulation employs electric fields to trigger drug release from biodegradable electrodes or implants. By applying specific electrical signals, the release of charged drug molecules can be controlled, allowing precise modulation of drug delivery kinetics. This approach enables the on-demand release of drugs, which is valuable for applications requiring temporal control over drug delivery [61].

3. pH-Responsive Behavior: Certain biodegradable materials exhibit pH-responsive behavior, where changes in local pH conditions stimulate drug release. For instance, polymers like PAA undergo conformational changes in response to pH variations, leading to the release of encapsulated drugs. This mechanism is beneficial for targeted drug delivery to sites with specific pH conditions, such as the acidic microenvironment of tumor tissues.

4. Enzyme-Mediated Degradation: Enzyme-mediated degradation involves the use of biodegradable materials that are susceptible to enzymatic hydrolysis by specific enzymes found in biological tissues. By incorporating these materials into drug delivery systems, drug release can be customized to match the physiological conditions at the target site. For example, polymers sensitive to enzymes like proteases or esterases can be engineered to degrade selectively in response to enzymatic activity, facilitating site-specific drug release.

Innovative strategies for delivering anti-cancer drugs directly to brain tumors have garnered considerable attention in recent years, with researchers exploring various approaches to enhance therapeutic outcomes while minimizing adverse effects. One promising method involves the use of biodegradable wafers implanted adjacent to the surgical site in the brain. These wafers serve as localized drug delivery systems, effectively bypassing the brain’s natural protective mechanisms, including the blood–brain barrier (BBB), to target residual tumor cells. Despite the advancements achieved through this approach, there is still a lot of opportunities for improvement in optimizing patient outcomes. To address this, researchers have introduced novel materials and device technologies designed to enhance drug delivery specifically to brain tumors. One such innovation is a biodegradable, flexible, and adhesive patch loaded with therapeutic agents and equipped with wireless electronics for precise drug administration within the brain [62]. Figure 5 illustrates an overview on materials and device design applied for this biodegradable wireless patch. The fabricated patch boasts a dual-sided structure, allowing it to securely attach to the surgical site while ensuring the controlled release of drugs to the tumor area. Importantly, its design minimizes the unintended dispersion of drugs into the cerebrospinal fluid, thereby enhancing targeting precision. As the patch gradually degrades, the risk of neurological side effects associated with prolonged drug exposure is mitigated. This feature is critical for improving patient safety and tolerability of the treatment. Experimental studies conducted on animal models, including mice and larger animals like canines, have demonstrated promising results. These studies have shown that the patch effectively inhibits tumor growth and improves survival rates, underscoring its potential as a therapeutic tool for managing brain tumors in human patients [62].

Figure 5.

The bioresorbable electronic patch (BEP) integrates advanced materials and wireless technology for biomedical applications: (a) The BEP comprises various components, including a flexible substrate, electronic circuits, and drug-infused oxidized starch (OST) patches. The OST structure enables controlled drug release. (b) Over time, the BEP degrades into hydrolyzed products, ensuring biocompatibility and eventual absorption by the body. (c) A photograph displays the BEP with its constituent parts: a bioresorbable wireless heater, temperature sensor, and drug-infused OST patch. (d) Prior to implantation, the BEP undergoes sterilization to prevent infection. (e) In vivo studies in a canine model demonstrate the feasibility of BEP implantation, with images depicting brain craniotomy before and after implantation. (f) The BEP facilitates localized and penetrative drug delivery to deep glioblastoma multiforme (GBM) tissues, utilizing wireless mild-thermic activation for targeted therapy [62].

Local stimulation of peripheral nerves can inhibit the propagation of action potentials, providing a non-pharmacological option for acute pain treatment. Traditional devices for nerve stimulation often come with drawbacks, such as the potential for nerve tissue damage and the necessity of surgical removal post-treatment, adding costs and risks. To overcome these issues, researchers have developed a new kind of bioresorbable nerve stimulator [63]. This device offers electrical nerve block and pain relief, bypassing the disadvantages associated with conventional devices. Figure 6 shows detailed configuration and application of the fabricated stimulator. The bioresorbable nerve stimulator employs materials that gradually dissolve in the body, negating the need for surgical removal. These materials are chosen for their ability to provide stable nerve blocking while minimizing mechanical, electrical, or biochemical side effects. The device’s design ensures it remains functional for the required duration before safely disintegrating. Studies conducted on animal models have demonstrated the device’s efficacy in achieving complete nerve block. These studies highlight several key features of the device, such as its ability to deliver targeted stimulation and its biocompatibility. Animal studies have shown that the stimulator can effectively block nerve signals, providing substantial pain relief without the risks associated with traditional methods. In clinical contexts, this technology holds significant potential. It can reduce or eliminate the need for opioids, which are highly addictive and come with a risk of dependence and other adverse effects [63]. By providing a reliable alternative to opioids for pain treatment, the bioresorbable nerve stimulator could play a fundamental role in addressing the opioid crisis. Its use could be particularly beneficial in postoperative pain treatment, chronic pain conditions, and other scenarios where long-term pain relief is needed. The development of the bioresorbable nerve stimulator represents a significant advancement in pain treatment technology. By leveraging bioresorbable materials, the device offers a safer, more effective way to manage pain without the drawbacks of traditional nerve stimulation devices. The successful animal model studies pave the way for future clinical trials, which will further assess the device’s efficacy and safety in human patients.

Figure 6.

(A) Illustration of detailed configuration and components of nerve stimulator fabricated using biodegradable materials. (B) Concept of blocking the nerve conduction by the nerve stimulator—Mo microelectrodes, which wrap around the nerve, inhibit action potential propagation. (C) Schematic illustration of the usage, release, and bioresorption of the stimulator by different stages of its lifetime. Degradation of (D) extension Mg/PA electrode and (E) Mo/PLGA nerve cuff in PBS at 37°C. (F) Illustration for implantation of the device. (G) Experimental arrangement of stimulating system for in vivo studies. (H) Cross-sectional micrographs of the sciatic nerve before (left) and after (right) stimulation (scale bars, 200 μm) Inset: Magnified images of each axon. Scale bars, 50 μm [63].

4. Biohybrid materials for neural interfaces

The field of electronic and electrochemical interface materials has experienced significant progress by integrating living cells into various components, such as electrodes, substrates, and protective layers. This innovative approach, extensively researched over the years, relies on two primary strategies. Firstly, cells can be introduced onto electrodes using ECM proteins like collagens, fibronectin, and laminin. These proteins play an essential role in facilitating cell adhesion and growth on the electrode surface. The ECM acts as a supportive scaffold, mimicking the natural cellular environment and promoting favorable interactions between living cells and electronic components. Alternatively, the second strategy involves cells penetrating and growing through the electrodes, forming what is referred to as “living electrodes.” This is achieved through the development of microtissue-engineered neural networks (microTENNs) [14]. In this scenario, living cells not only adhere to the electrode but actively extend their presence by growing through the electrode structure. This unique configuration enables dynamic interactions between living cells and the electronic interface, holding promise for diverse applications in biotechnology and neural interfacing. The exploration of these strategies highlights the versatility of electronic and electrochemical interface materials in accommodating the integration of living cells. The incorporation of ECM proteins and the creation of living electrodes represent innovative approaches that go beyond traditional materials science, opening up possibilities for enhanced biocompatibility and functionality across various technological applications [16, 64, 65].

4.1 Integration of living cells

Living neural electrodes are compelling due to their capacity to facilitate the natural growth of cells, seamlessly integrating into biological systems and forming electrically active neurite bridges. This integration is particularly noteworthy for its potential to mitigate adverse reactions associated with FBR. Unlike traditional electrodes, living neural electrodes promote a harmonious interface with the biological environment, reducing inflammation and tissue damage. This living electronic interface has garnered significant interest for its ability to record and modulate electronic signals within the biological system, opening up possibilities for applications in neural recording and modulation. Overall, the appeal of living neural electrodes lies in their dual ability to integrate with biological systems while offering functional capabilities for advancing neuroscientific research and medical interventions. For example, ECM-based probes have been observed to induce minimal immune responses and serve as implanted hybrid interfaces for monitoring neural activities, particularly in rat models. These probes are composed of microelectrodes featuring Au electrodes and conductive traces, each approximately 100 nanometers thick. These components are encased within parylene layers, each about 5 micrometers thick, which act as upper and lower protective layers. The overall dimensions of these probes are approximately 100 micrometers in width, 30 micrometers in height, and 5 millimeters in length (W × H × L). Notably, these microelectrodes coated with ECM proteins, excluding collagen, exhibit superior cell viability in comparison to those lacking these proteins [65].

Implantable neural interfaces face significant challenges in achieving both functional efficacy and clinical viability, largely due to the inherent limitations of traditional inorganic microelectrodes. These constraints are primarily evident as reduced specificity in neural signal detection and instability over time. To overcome these issues, there is a need for innovative approaches that can enhance both the precision and longevity of neural interfaces. One promising strategy involves the biohybrid electrodes designed by the integration of biological components as intermediaries between electronic devices and the brain. By leveraging the natural synaptic connectivity of living neurons, these biohybrid interfaces offer the potential for enhanced specificity in neural signal detection and modulation. Additionally, the use of soft hydrogel matrices facilitates easy access to the brain surface, enabling seamless integration with neural tissue. Of particular interest is the incorporation of optogenetic control mechanisms into these living electrodes, enabling precise modulation of neural activity through light-based stimulation. This capability not only allows for real-time monitoring of neural dynamics but also provides unprecedented control over neural circuits with spatial and temporal precision. To realize the potential of this approach, researchers have developed implantable “living electrodes” comprised of living cortical neurons and axonal tracts encapsulated within soft hydrogel cylinders [66]. Figure 7 illustrates the fabricated biohybrid microelectrodes. In vitrostudies have demonstrated the feasibility of this approach, showing rapid axonal growth, consistent cytoarchitecture, and the ability to perform simultaneous optical stimulation and recording. Moreover, the in vivo experiments in rodent models have provided compelling evidence of the feasibility and efficacy of these biohybrid microelectrodes. Transplantation of living electrodes into the rat cortex has resulted in robust survival, integration, and functionality, paving the way for their translation into clinical applications [66].

Figure 7.

Panel (A) Schematic representation for fabrication process of biohybrid microelectrodes comprised of living cortical neurons and axonal tracts encapsulated within soft hydrogel cylinders. Panel (B) Electron microscopy images of the prepared living microelectrodes (scale bar, 200 μm). Panel (C) Left: dimensions of biohybrid microelectrode, Middle: unidirectional microTENNs synapse host neurons (blue) to transmit external inputs to cortical regions, and Right: host neurons synapse bidirectional microTENNs, transmitting signals from host cortex for monitoring through the dorsal aggregate. Pane (D) Optogenetically responsive microTENNs function as implantable input–output channels. Phase image (E) and confocal reconstruction (F) of the microTENN in vitro show that the left aggregate expresses ChR2 (optical actuator) and the right aggregate expresses the calcium reporter RCaMP, enabling simultaneous control and monitoring with light (scale bars, 100 μm) [66].

The concept of biohybrid implants has been extensively investigated across various tissues, including the central nervous system and muscle tissue. Here, we categorize these studies according to their location within the host tissue and subsequently analyze the predominant challenges and potential future directions. Our comprehensive overview focuses specifically on neural biohybrid implants, which are summarized in Table 2.

Type of biohybrid Neural Electrode	Challenges
Electrode permeable to cells	Cell viability post-implantation within the device. Attaining precise direction of implanted cells via microsieve apertures [64].
Cells attached to electrode surface	Attaining strong cell adhesion to electrodes to prevent cell migration and minimize the gap between electrodes and neurons [67, 68, 69, 70].
Electrodes formed by host cells	The extent of signal amplification across the muscle tissue. The quantity of signal conveyed via the muscle graft regenerative peripheral nerve interface [71, 72].
Long-distance cell electrode	Removing implanted living electrodes, if they fail, presents challenges due to their strong integration with host tissue, unlike conventional electrodes. The extent to which axons can extend through tracts to reach the target tissue. The effectiveness of axonal integration with the host following implantation [73].

Table 2.

Varieties of biohybrid neural interface configurations.

4.2 MicroTENNs and functional axonal tracts

Ongoing scientific investigations have yielded advancements in the creation of microTENNs characterized by the presence of well-defined functional axonal tracts. Within these constructs, the axonal tracts are strategically embedded in agarose-collagen hydrogels, forming cylindrical microcolumns that extend toward specific target tissues. This innovative design facilitates a more intricate understanding of neural connectivity and function. The microTENNs are engineered to include a diverse array of neurons, encompassing both excitatory and inhibitory types. This inclusivity enables researchers to exert precise control over neural activity, enhancing the adaptability of these microscale probes for experimental manipulation. Notably, the incorporation of various neuron types can contribute to a more comprehensive and detailed investigation of neural circuitry. These neural probes exhibit diameters spanning several hundred micrometers, a critical feature that allows for minimally invasive yet highly targeted interventions. The cylindrical microcolumns, with lengths ranging from 5 to 10 centimeters, enable deep penetration into the intricate structures of the brain. This extended reach facilitates the study of neural circuits in deeper brain regions, providing researchers with unprecedented access to study and manipulate neural activity in diverse anatomical locations. In essence, the development of microTENNs represents a significant stride in neuroscience research, offering a sophisticated toolset for investigating neural connectivity and function with unparalleled precision and depth. The strategic incorporation of diverse neurons, coupled with the unique design of these microscale probes, positions them as valuable assets in unraveling the complexities of the brain’s intricate neural networks [14, 74].

4.3 Optogenetic capabilities

The living electrodes undergo modification with optogenetic proteins, which respond to light. This modification allows for optical modulation, meaning the neural activity can be controlled or influenced by exposure to light. Optogenetic proteins are typically derived from microbial organisms, such as algae or bacteria, and they are engineered to be sensitive to specific wavelengths of light. When these proteins are introduced into the living electrodes, they confer light sensitivity to the neural tissue surrounding the electrodes. The optical modulation facilitated by the optogenetic proteins enables the elicitation of neural responses within the host brain. Essentially, by exposing the modified living electrodes to light, it is possible to control the activity of nearby neurons. This is particularly valuable in the field of neuroscience and neuroengineering, as it provides a means to manipulate neural circuits with high precision. For example, to monitor the effectiveness of these optical manipulations and the resulting neural responses, calcium imaging techniques are employed. Calcium imaging involves the use of fluorescent indicators that respond to changes in intracellular calcium levels, which is a key signaling molecule in neural activity. By visualizing these calcium changes, researchers can gain insights into the patterns and dynamics of neural responses triggered by the optical modulation of the living electrodes [66].

Recent advancements in neural implant technology have encouraged the development of novel bioresorbable implants, which could potentially eliminate the need for secondary surgeries to remove existing implants. In this regard, researchers have introduced a novel bioresorbable flexible hybrid opto-electronic system, which not only records electrophysiological signals but also provides optogenetic stimulation simultaneously [75]. This innovative device, composed of recently developed biodegradable materials, establishes a direct optical and electrical connection with the curved surface of the cerebral cortex, ensuring remarkable biocompatibility. The device was engineered to minimize losses in light transmission and interference from photoelectric artifacts, ensuring accurate signal recording and stimulation. Figure 8 shows the prepared bioresorbable hybrid opto-electronic neural implant system. The results demonstrated that the fabricated neural electrode was chronically implanted into the brains of transgenic mice, where it successfully stimulated the somatosensory area using light while simultaneously recording local field potentials. This demonstrates the feasibility and efficacy of the hybrid neural implant system in both monitoring neural activity and providing therapeutic interventions. The integration of biodegradable materials in neural implants not only addresses the issue of secondary surgeries for removal but also paves ways for diverse biomedical applications. These implants offer a promising platform for monitoring neural activity and delivering targeted therapies, with the added benefit of being naturally absorbed by the body over time, reducing the risk of long-term complications [75].

Figure 8.

A comprehensive overview of a flexible, biodegradable neural implant system designed for simultaneous electrophysiology and optogenetics applications. (a) Schematic representation of the fully bioresorbable neural interface, comprising of Mo/Si bilayer nanomembrane electrode array stacked on a soft and flexible PLGA waveguide for simultaneous electrophysiology and optogenetics. (b) Expanded configuration, electrical and optical characterizations of the Mo/Si electrodes and PLGA waveguide for optimizing light transmission efficiency. (c) Images of the biodegradable neural interface having PLGA waveguide and 4-channel electrode array implanted at the cerebral cortex when the laser is off (top) and on (bottom). (d) Schematic illustration of the system implanted in the cerebral cortex of a mouse. (e) Spontaneous and (f) spiking activities captured by the bioresorbable and Au control electrodes [75].

5. Challenges and future directions

The development and application of biodegradable and biohybrid materials in nanobioelectronics present numerous challenges and offer exciting avenues for future investigations. Addressing these challenges and navigating toward promising directions are important for advancing the field and realizing its full potential. This section discusses some of the key challenges and outlines future directions for research and development.

5.1 Materials performance and stability

One of the primary challenges in the utilization of biodegradable materials for nanobioelectronics is ensuring their performance and stability over time. Biodegradable materials must maintain their structural integrity and functionality throughout their intended lifespan, while also degrading at a controlled rate once their purpose is fulfilled. Achieving this balance requires a comprehensive understanding of material properties, degradation kinetics, and environmental factors that influence degradation processes. For example, although biodegradable neuroelectronic devices are designed for temporary utilization, a stable power system is vital for device functionality during monitoring or treatment. Device components require traits like water corrosion resistance, conductivity, and sufficient electrical power generation capacity for optimal performance. However, dynamic body movements can challenge device integrity, leading to component disconnection and instability. While conductive solutions have been considered, limited biocompatibility and biodegradability hinder their widespread adoption. Developing biodegradable power systems is challenging for in vivo and ex vivo applications. In vivo electric generation technologies, like cardiac pacemakers, use lead batteries to regulate heartbeats but may cause cytotoxicity, require surgical interventions, and mandate device removal [76]. While ex vivo electric generation systems, using wireless power-transducing mechanisms such as radio frequency (RF), magnetic fields, and ultrasound, are still in the early stages of development. Future research efforts should focus on optimizing material compositions, refining fabrication techniques, and conducting tunable stability assessments to enhance the reliability and performance of biodegradable devices.

5.2 Biocompatibility and tissue response

Another critical challenge is ensuring the biocompatibility of biodegradable and biohybrid materials within the biological environment. While these materials are designed to degrade harmlessly within the body, their degradation products and interactions with surrounding tissues can impact biocompatibility and provoke immune responses. Future studies should aim to elucidate the mechanisms underlying tissue-material interactions, optimize surface properties to minimize inflammatory reactions, and develop strategies for modulating the biocompatibility of biodegradable devices. Additionally, advancing our understanding of host responses to biohybrid materials and integrating living cells with synthetic substrates represent promising avenues for enhancing tissue integration and functional outcomes.

5.3 Scalability and manufacturing

Scalability and manufacturing processes pose significant challenges in the widespread adoption of biodegradable and biohybrid devices for clinical applications. Current fabrication methods often lack scalability, precision, and cost-effectiveness, hindering large-scale production and commercialization. Future research should focus on developing scalable manufacturing techniques, such as 3D printing, microfabrication, and additive manufacturing, to enable the mass production of biodegradable devices with reproducible performance and quality. Moreover, interdisciplinary collaborations between materials scientists, engineers, and biomedical researchers are essential for streamlining manufacturing processes and translating laboratory discoveries into practical clinical solutions.

Designing biohybrid neural interfaces poses challenges in fabrication, functional characterization, and clinical translation due to its technological and biological complexity. Balancing device functionality with tissue-engineered component viability is essential. Soft biomaterial coatings can promote neuronal survival but may swell, delaminate, or detach upon insertion. Various techniques enhance coating adhesion, like surface roughening or chemical pre-treatment. Design should maximize the synergy between experimental approaches, such as scaffold mechanics, targeted electrical stimulation, or leveraging neurotrophic support. Flexible organic materials are being explored, integrating cellular components directly into neural interface structures. For instance, silk films patterned with cells and electrodes or viscoelastic conductive hydrogels supporting cell growth and differentiation show promise for targeted electrical stimulation [73, 77]. The microTENNs can guide neural aggregate growth, offering the potential for modulating tissues via synaptic connections with the host nervous system [15, 66, 78, 79].

5.4 Integration with advanced technologies

The future of biodegradable and biohybrid materials in nanobioelectronics lies in their seamless integration with advanced technologies and emerging paradigms. Incorporating functionalities such as wireless communication, real-time monitoring, and artificial intelligence into biodegradable devices can revolutionize healthcare delivery, diagnostics, and therapeutics. Future research directions should explore synergistic collaborations between material scientists, electrical engineers, computer scientists, and biomedical researchers to develop next-generation biodegradable and biohybrid platforms with enhanced capabilities and versatility. Additionally, interdisciplinary training programs and knowledge-sharing initiatives can foster innovation and accelerate the translation of research findings into practical applications.

6. Conclusions

The study of biodegradability within nanobioelectronics holds paramount importance across various biomedical applications, encompassing tissue engineering, drug delivery systems, and advanced BCIs. Biodegradation involves complex processes such as solubilization, hydrolysis, and enzymatic action occurring at molecular to macroscopic scales. Moreover, chemical hydrolysis coupled with enzymatic degradation underscores the complexity and importance of biodegradation processes, necessitating further research for the advancement of biodegradable materials and their practical implementations. Also, biodegradable hydrogels undergo degradation via hydrolysis, enzymatic degradation, and physical erosion, which are influenced by composition and environmental factors. Hydrolysis breaks polymer chains, while enzymes catalyze degradation, particularly targeting natural polymers like polysaccharides and proteins. Utilizing water-insoluble polymers in hydrogel preparation enhances their versatility. The integration of biodegradable materials in biomedical devices facilitates the development of bioresorbable electronics for temporary medical monitoring and therapeutic interventions, obviating the need for surgical removal. Notably, bioresorbable electronics find utility in temporary neural interfaces for neuroregeneration, neurotherapy, and recovery, as well as in chemical sensing interfaces for detecting neurotransmitters. Advancements in neural interfaces leverage materials such as highly doped Si NMs and Mo for high-resolution mapping of electrical activity in the cerebral cortex, while implantable biodegradable electrodes enable controlled drug release within the body, enhancing therapeutic efficacy while minimizing systemic toxicity. These innovations underscore the transformative potential of bioresorbable materials in shaping the future of biomedical technologies.

The field of nanobioelectronics has found remarkable progress through the integration of living organisms into various electronic components, including electrodes, substrates, and protective layers. This innovative approach relies on two primary strategies: introducing cells onto electrodes using extracellular matrix proteins as supportive scaffolds or creating living electrodes through microTENNs. Living neural electrodes demonstrate potential for promoting natural cell growth, mitigating adverse reactions associated with FBR, and facilitating neural recording and modulation. Advancements in microTENNs enable precise control over neural activity and deeper investigation of neural circuits. Despite these strides, challenges persist, including ensuring materials’ performance and stability, enhancing biocompatibility and tissue response, addressing scalability and manufacturing issues, navigating regulatory and ethical considerations, and integrating with advanced technologies. Future researches should prioritize overcoming these challenges to unlock the full potential of biodegradable and biohybrid materials in nanobioelectronics with particular focus on BCIs.

Conflict of interest

The authors declare no conflict of interest.