Antibacterial, Antifungal and Antiviral Nanocomposites: Recent Advances and Mechanisms of Action

*Suchita C. Warangkar, Manish R. Deshpande, Narayan D. Totewad and Archana A. Singh*

## **Abstract**

Over the past ten years, there has been a significant increase in research into the study of nanocomposites. Nanocomposites vary in their physical and chemical properties. In today's era, eco-friendly, nontoxic, biocompatible, biobased fillers and composites should be synthesized to increase their societal value in various aspects. These materials have seen extensive use across several industries, from biosensors to biomedicine. Great strides have been made in the field of Microbiology, particularly as Antibacterial agents, among these applications. The objective of this review is to present a thorough analysis of several Nanocomposites that reveal promising antibacterial activity. Such Nanocomposites are reviewed in detail, as well as their antibacterial efficacy is discussed.

**Keywords:** antibacterial activities, antifungal activities, antiviral activities, nanocomposites, antibacterial agents

## **1. Introduction**

A composite material is referred to as a nanocomposites when it contains a phase with nanoscale morphology, such as nanoparticles, nanotubes, or lamellar nanostructure. As a result of their numerous phases, they qualify as multiphase materials, and at least one of those phases must have a diameter between 10 and 100 nm. In order to get beyond the limits of present engineering materials, nanocomposites have developed as suitable substitutes. Nanocomposites may be categorized based on their dispersed matrix and dispersed phase materials [1]. Thanks to this rapidly emerging field, it is now possible to generate a wide range of exciting new materials with distinctive properties.

The interfacial and morphological features of the originals, together with their own characteristics, had a significant impact on the so-called found's characteristics. It is evident that, parent component parts are unaware of the newly created feature in the composite material and this intricate structure enhances its applicability [2, 3]. In order to create new materials with amazing flexibility and an increase in their

physical properties, nanocomposites are based on the idea of employing building pieces that have dimensions in the nano scale range. Nanocomposites are made up of a bulk matrix and one or more nano dimensional phase(s) that differ from one another in terms of their chemical and structural makeup and properties. Inorganic nanoclusters, fullerenes, clays, and biological molecules can be mixed with a range of organic polymers, organic and organometallic chemicals, biological molecules, enzymes, and sol-gel produced polymers. Inorganic nanoclusters, fullerenes, clays, metals, oxides, or semiconductors can be mixed with a range of organic polymers, organic and organometallic chemicals, biological molecules, enzymes, and sol-gel produced polymers to produce nanocomposites.

## **2. Nanocomposites that reveal promising antibacterial activity**

Antimicrobially active products are a recent development in nanoparticle-based materials that have gained significant attention. It has been documented that nanoscaled materials, such as fabrics, plastics, and metals coated with nano-silver, as well as nanocomponents based on titanium dioxide, magnesium oxide, copper, copper oxide, zinc oxide, cadmium selenide/telluride, chitosan, and carbon nanotubes, possess biocidal or bacteriostatic properties [4]. Both gram-positive and gram-negative bacteria, including *Escherichia coli* and *Pseudomonas aeruginosa*, have demonstrated the antibacterial activity of nanosized metal compounds. These bacteria include *Staphylococcus aureus* and *Bacillus subtilis*. The most frequently used antibacterial agents are nanomaterials with a silver base [5]. The antibacterial properties of metallic, ionic, and nanoscale silver compounds added to alumina nanopowder were described. However, gram-positive and gram-negative bacteria differ in their sensitivity to silver-doped nanocrystalline material [6].

Antimicrobially effective nanomaterials exist in the form of salts, oxides, complexes, and elemental nanoparticles. Because of their small size, chemical toxicity, and distinctive shape, they are effective at damaging cell membranes. Cell membrane surface loading and permeability may be disturbed as a result of nanoparticles' detrimental effects. Probably the most frequent method by which nanoparticles affect bacteria is through the production of reactive oxygen species (ROS) [7]. On "model" bacterial strains like *E. coli*, newly developed or modified nanoparticles' antimicrobial properties are typically tested. An assay for turbidity, a microdilution method, and the disc diffusion method are the main procedures. The antimicrobial activity of some industrial products was tested using a number of ISO regulations, such as ISO 20743 for textile products and ISO 22196 for plastics and other non-porous materials [8].

In tests with *E. coli*, *P. aeruginosa*, S. aureus, and *B. subtilis*, a potential wound healing nano-based material composed of genipin-crosslinked chitosan, poly (ethylene glycol), zinc oxide, and silver produced significant antibacterial activity [9]. With the addition of silver nanoparticles to hydrogels, researchers successfully achieved a significant antimicrobial impact for chitosan films, making them potentially useful in wound dressings as well [10]. The antimicrobial effect of the combination of silver nitrate and titanium dioxide nanoparticles applied to facemasks was described [11]. After 48 hours of testing, they noticed a 100% decrease in viable *E. coli* cells. The magnetic nanocomposite film created after dispersing magnetic nano—Fe2O3 in a chitosan matrix has potential uses in biosensors and tissue [12].

The use of highly toxic chemical reagents in the production of nanoparticles for medical applications should be avoided, especially when using materials containing

## *Antibacterial, Antifungal and Antiviral Nanocomposites: Recent Advances and Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.108994*

silver (Ag). As a result, a "green synthesis approach" is taken into account. For instance, aqueous solutions of AgNO3, glucose, and starch can be used to produce starch-protected Ag nanoparticles. Using these solutions, the reduction of Ag (NH3) 2+ by carbohydrates results in the production of nano-Ag films (50–200 nm), Ag hydrosols (20–50 nm), and Ag colloids. Can also be used to reduce Ag (NH3) 2+. In tests with *E. coli*, *P. aeruginosa, S. aureus*, and *B. subtilis*, a nano-based substance with the potential to treat wounds and containing genipin-crosslinked chitosan, poly (ethylene glycol), zinc oxide, and silver, demonstrated antibacterial activity [13].

Since chitosan nanoproducts have been shown to have potential antimicrobial properties, many medical applications of nanoproducts (chitosan-carbon dots, chitosan-i-cysteine quantum dots, chitosan-based biosensors and biomarkers) [14] are based on these materials. Chitosan-poly(N-vinylpyrrolidone)-TiO2 Nanocomposite was proposed as a wound dressing material due to its significant antibacterial impact against *P. aeruginosa*, *E. coli*, S. aureus, and *B. subtilis*. In this study, the titanium dioxide nanocomponent was suggested to be responsible for the adsorption of bacteria and their inactivation [15].

By combining chitosan and 4-(ethoxycarbonyl) phenyl-1-amino-oxobutanoic acid with nano-Ag, Srivastava et al., 2011. created a nanocomposite. The effect of the obtained nano-film on bacteria like *S. aureus*, *E. coli*, and *P. aeruginosa* led to its proposal as a material for use in medicine [16]. Numerous medical applications benefit from the antibacterial properties of nanoparticle-based materials, including implants, wound and burn dressings, medical devices, filters, and dental plaque reduction materials. One of the most crucial justifications for the application of novel nanocomposites for clinical use is their potential impact on antibiotic-resistant bacteria, which pose a serious problem in current medical settings. In textile modification and impregnation, as well as "construction" elements for implants, cements, and resins, in the antibacterial coatings of external ventricular drains and venous catheters that lessen the risk of potential infections, nanocomposites can be used [4].

The most promising areas of nanotechnology applications are in the development of new antibacterial agents. Nanocluster engineering can broaden the application of Ag- and Au-based antimicrobial preparations. The commercial application of nanoproducts should also be carefully monitored because of their potential negative environmental effects. The use of Au, Ag, and Cu-based nanoclusters in medicine and biosensing is widespread. According to Zheng et al., 2016 the generation of ROS is the mechanism that most likely causes pathogenic bacteria to be destroyed in the presence of Ag-nanoclusters, whereas the core surface speciation of the nanoclusters may be related to their cellular toxicity. Due to the significantly higher surface-to-volume ratio they can achieve due to their ultra small size and interaction with intracellular components, they have a stronger antibacterial effect. It's possible that adding Ag nanoclusters to medications will enhance their therapeutic effects. In the presence of combined daptomycin-Ag nanoclusters, damage to microbial DNA was noted [17]. The nucleation and growth mechanism of Thiolate-protected Au nanoclusters with different topologies within the inner core of various clusters were described [18].

The development of polypyrrole-based nanocomposites as alternative antibacterial agents also represents a promising strategy to be applied against the prevailing multi-resistant bacteria. The composites are made up of different fillers (metal nanoparticles, carbon nanotubes, and polysaccharides) and strategies to improve their action (such as light and electrical stimulation) [19]. Graphene oxide–silver (Ag–GO) nanocomposite has emerged as a vital antibacterial agent very recently. It was successfully applied to *E. coli* to investigate antibacterial activity by varying

its dose concentration. The functional groups of GO facilitated the binding of Ag nanoparticles to silver nanoparticles. The antibacterial properties of GO-Ag nanocomposite were studied using gram-negative *E. coli* ATCC 25922 and gram-positive *S. aureus* ATCC 6538 and showed excellent antibacterial activity. In this study, results demonstrated that GO-Ag nanocomposite, as a kind of antibacterial material, had great promise for application in a wide range of biomedical applications [20].

The Cu2O-GO nanocomposites have rarely been studied before. The Cu2O-GO nanocomposites show potent antibacterial activities against both *E. coli* and *S. aureus*. Bactericidal activity was also observed for the Cu based bionanocomposite samples against both gram-positive (*S. aureus*) and gram-negative (*Klebsiella pneumoniae*) bacteria. Enhancement of antibacterial activity was observed with increasing copper content in nanocomposites. Results confirm the potential of bionanocomposites containing copper nanostructures as new antimicrobial materials [21].

Cellulose/Ag nanocomposites were prepared using two distinct methodologies and two different cellulose substrates: vegetable and bacterial cellulose. Detailed studies on their antibacterial activity were conducted on *B. subtilis*, *S. aureus*, and *K. pneumoniae*. Silver nanoparticles present in these cellulosic fibers in concentrations as low as 5.0 wt% make them effective antibacterial materials [22].

The antibacterial activity of AuNPs-COOH/AgNO3, MnFe2O4@SiO2@Au and Bi2S3 nanocomposites against a wide range of gram-negative bacteria has been demonstrated. Green synthesis methods were applied and showed good activity against some gram-negative bacterial strains. A photocatalytic system comprising TNTs/Au/ CDs was developed for a bactericidal approach. An Ag–Au/CeO2 nanostructure was produced with a maximum zone of inhibition against *S. aureus* and *E. coli* strains. The produced nanohybrid showed acceptable antibacterial activity and was applicable for marine antifouling paint and sewage treatment. Au@TiO2-NT was light-independent and applicable to the dark environment inside tissues, such as for orthopedic devices and implants [23, 24].

Nanocomposites and a composite based on poly (butylene adipate-co-terephthalate) were synthesized using commercial copper nanoparticles. The materials showed good inhibitory responses against the nonresistant strains *Enterococcus faecalis*, *Streptococcus mutans*, and *S. aureus*. They had the highest biocidal effect, even against resistant bacteria like *Acinetobacter baumannii* [25].

Magnetic cores loaded with metallic nanoparticles can be promising nano-carriers for successful drug delivery at infectious sites. The cobalt acetate was synthesized, and the decoration of AgNPs was carried out with silver acetate. The antibacterial performance of nanocomposites against *E. coli* and *B. subtilis* was found to be densitydependent. Silver nanocomposites exhibiting antiviral, antifungal, antibacterial, antiangiogenic, and antiinflammatory activities are discussed as potential candidates for several biomedical applications due to their ability to bind with the biomolecules of microbial cells [26].

In brief, the antibacterial GN/Ni (OH)2 composite has been prepared using a facile method, providing powerful antibacterial capacity, good biocompatibility, and long-term effectiveness. The antibacterial activity of GN/Ni (OH)2 was dose dependent and obviously exceeded that of rGO and GO. The GN/Ni(OH)2 could efficiently kill gram-negative or positive bacteria with a low dose and exert low toxicity toward normal cells, motivating their potential safe applications. The results revealed that the improved 3D contact between GN/Ni(OH)2 and bacteria enhanced the physical punctures on cells, causing severe leakage of intracellular components and leading to cell apoptosis. The GN/Ni(OH)2 could not induce a remarkable increase in ROS

*Antibacterial, Antifungal and Antiviral Nanocomposites: Recent Advances and Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.108994*

#### **Figure 1.**

*Various modes of antibacterial and antifungal activities of different nanocomposites.*

production, indicating that the ROS-dependent oxidative stress induced by GN/ Ni(OH)2 will not affect antibacterial efficiency [27]. Nanocomposites that reveal various modes of antimicrobial Activities were enlisted in **Figure 1**.

## **3. Nanocomposites that reveal promising antifungal activity**

Growing worldwide populations as a result of medical developments make more patients vulnerable to superficial and serious fungal infections. Dermatophytes like *Microsporum*, *Epidermophtyon*, and *Trichophyton*, as well as species from the genera *Candida*, *Aspergillosis*, and *Cryptococcus*, are among the fungi that are frequently linked to these disorders. Additionally, as the world's population rises, so do agricultural needs. Therefore, owing to food insecurity, fungal infections of preharvested crops and stored food by plant diseases such as *Magnaporthe oryzae* and *Fusarium oxysporum* might have negative socioeconomic impacts. The majority of current antifungal treatment plans are based on small molecule antifungal medications. Poor solubility and bioavailability, however, place restrictions on these medications. Additionally, there is an increase in antifungal resistance to these medications. A significant worldwide healthcare concern is the effect of fungal illnesses and the development of antimicrobial drugs against pathogenic fungus. Silver-loaded hydroxyapatite (Ag/HAP) nanocomposites (NCs) with varying Ag contents were tested against susceptible and resistant *Candida species* for their antifungal efficacy. *Candida krusei* had the inhibitory impact, followed by *Candida parapsilosis sensu stricto* and *Candida tropicalis* [28].

Antimicrobial polymers thus provide a different approach to combat fungi. The cationic regions of antifungal polymers have been reported to react with microbial phospholipids and membranes, and the hydrophobic areas are known to repel water. Such synthetic or natural polymers exhibit various antifungal activities, like fungal cell membrane permeabilization or fungal cell membrane depolarization. It might be challenging to determine their relative importance as Antifungal candidates. Due to

these polymers' chemical structure, they can be coupled to provide synergistic effects with other antimicrobial substances such as metal ions, charcoal, lipids, and current antifungal medications. In certain instances, antifungal nanocomposites and polymers surpass typical small molecule antifungal drugs in terms of antifungal efficacy or toxicity [29, 30].

Cationic antimicrobial polymers and nanocomposites with antifungal activity as well as the state of knowledge on the antifungal mode of action were studied. The innate immune response includes antimicrobial peptides (AMPs), sometimes referred to as host defense peptides. The host is shielded against encroaching diseases by these substances, which are generated by plants, animals, and microbes. These peptides have short, amphiphilic sequences with an average length of 100 amino acids. The majority of AMPs are cationic, but those with high levels of histidine have powerful antifungal properties. Cathelicidins are an illustration of this. The primary storage location for this class of antifungal AMPs in macrophages is the lysosome, which is a component of the human innate immune system. However, certain AMPs with anionic charges need metal ions to be activated biologically. For membrane permeabilization, anionic AMPs bind metal ions to create cationic salt bridges with anionic microbial membranes. Even though certain anionic AMPs are credited with this mechanism, less is known about their antibacterial action than with cationic AMPs [31, 32].

In order to study the antifungal efficacy of these peptides against *Candida albicans*, Ramamourthy et al. (2020) synthesized peptides with various numbers of lysine and tryptophan repetitions (KWn-NH2). The antifungal and biofilm-eradication abilities of these peptides increase with peptide length, with the longest peptide, KW5, exhibiting toxicity in a human keratinocyte cell line, while the smallest peptide, KW2, showed no antifungal activity by Ramamourthy et al., 2020. The membranes of fungus cells were not damaged by the KW4 peptide. However, KW4 was shown to be linked to fungal RNA in the cytoplasm of *C. albicans*, as revealed by laser-scanning Confocal Microscopy. This indicates that not all of these peptides antifungal mechanisms include membrane permeabilization. Instead, these synthetic AMPs localize within the cell where they disrupt cellular activities by attaching to specific receptors after entering fungal cells [33].

Despite synthetic AMPs showing broad-spectrum antifungal activity and low toxicity, research into antimicrobial polymers is often focused on synthetic polymers as they are considerably cheaper to produce in comparison and share functional cationic similarities with AMPs. Polyhexamethylene biguanide (PHMB) is a synthetic quarternary ammonium polymer which has been established to be an effective antimicrobial agent with the added advantages of low toxicity. It exhibits a high therapeutic index and broad-spectrum antifungal activity due to its biguanide groups and is commonly used as a preservative in cosmetics, water purification systems, and contact lens cleaning solutions. It is also used clinically for wound cleaning, where it shows excellent biocompatibility. Although PHMB shows membrane disruption abilities due to its phospholipid binding, the exact antifungal mechanism of action remains unclear. The antifungal mechanism is thought to involve cell wall destabilization and membrane permeabilization. Gene expression studies in *Saccharomyces cerevisiae* indicated an increase in the expression of cell wall integrity genes and protein kinase C, which regulates cell maintenance. This suggests PHMB also damages the β-glucan structure of the *S. cerevisiae* cell wall [34].

Polyethylenimines (PEI) are amine-containing polymers with a two-carbon (CH2CH2) spacer. At room temperature, they can be found in branched and linear polymeric forms in various states. They have been widely used in in vitro *Antibacterial, Antifungal and Antiviral Nanocomposites: Recent Advances and Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.108994*

transfections and drug delivery. Such study has demonstrated depolarization of *C. albicans* membranes for its inactivation, though the precise antifungal mechanism is unknown [35, 36].

HTCC, a chitosan derivative used as a preservative in the cosmetics industry, is an antimicrobial polymer. In a study by Hoque et al. 2016, HTCC was shown to have strong antifungal activity (MIC = 125,250 g/ml), with killing occurring in just two hours. It targets the fungal cell membrane, increasing membrane permeability, similarly to chitosan, and exhibits extremely low toxicity (HC50 = > 100 g/ml) in a mouse model [37, 38].

Polymethacrylates (PMMA) is a polymer made of methacrylic acid esters. It is used as a wrinkle filler in cosmetics and as an intraocular lens in ophthalmology. Because it is used in medical devices, it is susceptible to microbial colonization by pathogens like *C. albicans*. Undecylenic acid (UA), a monounsaturated lipid with established antifungal activity at various UA concentrations (3–12%), changed the surface of PMMA by making it more hydrophilic. At UA concentrations of 6%, *C. albicans* exposed to these PMMA-UA composites exhibited decreased attachment, growth, and increased death of these fungal cells. Despite the fact that UA concentrations of 9% showed a 95% eradication of *C. albicans*, these composites were extremely toxic to human cells, with a 50% reduction in viability [39].

Antimicrobial metal nanoparticles (NPs) are used more frequently than antimicrobial drugs because they reduce the risk of antimicrobial resistance. They do, however, have a toxic reputation. They can be incorporated into biomaterials like proteins, peptides, and sugars to increase biocompatibility. The Ag-Au alloy nanoparticles (Ag-AuNPs) with potential broad-spectrum uses, such as a coating material for medical devices or for drug delivery, were created using a green synthesis approach [7].

 The concentration of Ag used in the synthesis of NPs determines its size and shape. Due to the silver ions, these nanocomposites effectively combatted *C. albicans*. The Ag-Au alloy nanoparticles, however, displayed improved performance. Due to its broad-spectrum antibacterial activity and low toxicity toward mammalian cells, cotton is the most commonly used natural fiber for textiles today. Silver nanoparticles have recently been added to it [40].

Likewise functionalized fabric treated with a nanocomposite made of silver nanoparticles and carboxymethyl chitosan had excellent antifungal and antibacterial properties against *C. albicans* and *Aspergillus niger* (AgNPs-CMC). This fabric was functionalized to demonstrate how this fabric could be used to make hospital clothing to lower nosocomial infections. In this research, reported synthesis of silver-incorporated Chitosan nanocomposites (Ag@CS), CS was used as a reducing and stabilizing agent. The fungicide Antracol (An) was then combined with Ag@CS/ An to effectively combat *Phytophthora capsici*. Researchers discovered that Ag@CS/An was found to have significantly stronger and synergistic antifungal ability than Ag@ CS nanocomposites or Antracol nanocomposites, which had diameters upto 44.6 nm [41]. The TiO2-NPs, in particular, are also effective as antimicrobial agents due to their high aspect ratio, large surface-to-volume ratio, and reactivity [42].

Nanomaterials made upof metals or metal oxides are produced using living things or their components. AgNPs against *Candida glabrata* were made in spherical or rod shapes with crystal structures made of 80% anatase and 20% rutile. Under spherical AgNPs (with a diameter range of 1–24 nm) produced by a filtrated suspension of *Aspergillus sydowii* fungi, *C. glabrata* has demonstrated a minimum inhibitory concentration of 0.125 ppm [43]. Additionally, a hydrothermal technique was used

to decorate TiO2@ZnO nanocomposites with AuNPs that shown antifungal activity against *C. albicans* (MTCC 282) and an antiproteinase activity [44].

Hesperidin, a flavanone disaccharide extracted from orange peel, was used to make ZnONPs, which demonstrated notable antiviral activity against the *Hepatitis A* virus and *Respiratory Syndrome CoronaVirus* 2 (SARS-CoV-2). They also displayed activity that was suitable for treating HIV infection (50% inhibition at 100 ppm) [45].

Seven novel silver chromite nanocomposites were synthesized and assayed to evaluate their antimicrobial, antiviral, and cytotoxic activities. Five bacterial species were used in this study: three gram-positive (*B. subtilis*, *Micrococcus luteus*, and *S. aureus*) and two gram-negative (*E. coli*, and *Salmonella enterica*). Three fungal species were also tested: *C. albicans*, *A. niger*, and *Aspergillus flavus*. The MIC of the tested compounds was determined using the bifold serial dilution method. These tested compounds could be attractive and alternative antibacterial compounds that open a new path in chemotherapy [46].

A sustainable and green method was used to prepare silver nanoparticles (Ag-NPs), followed by their incorporation into a tertiary nanocomposite consisting of starch, oxidized cellulose, and ethyl cellulose. Ag-NC significantly suppressed the growth of tested bacterial strains (*E. coli, P. aeruginosa, S. aureus,* and *B. subtilis*) as compared with controls. It has also exhibited antiviral effects against *Herpes Simplex Virus*, *Adenovirus* and *Coxsackie B Virus* in a dose-dependent manner. In conclusion, the prepared tertiary Ag-NCs had promising antibacterial, antifungal, as well as antiviral activities [7, 40].

Binary TiO2/AgBr nanocomposites were synthesized using a facile ultrasonic irradiation route and characterized by various instruments. After adding AgBr nanoparticles, the antifungal activity was markedly enhanced. Silver ions in AgBr have a broad antimicrobial spectrum and can inhibit the growth of fungi. A sample with 20% of silver bromide represented the highest inhibitory concentration for the mycelial growth of *F. graminearum* and *S. sclerotiorum*. The inactivation rate decreased with increasing ultrasound irradiation time [47].

The negative effects of various biotic and/or biotic stresses on plants may be mitigated by silicon and its nanomaterials. For regulating the growth parameters and yield of *faba beans* infected with *Botrytis cinerea*, the antifungal role of silver/silicon dioxide nanocomposite (Ag/SiO2NC) biosynthesized using a free-cell supernatant of *E. coli* was examined. In vitro tests revealed significant in vitro activity with a minimal inhibitory concentration (MIC) of 40 ppm. These are all encouraging findings for the use of the biosynthesized Ag/SiO2NC as a secure and efficient antifungal agent against *B. cinerea* [48].

Nanocomposites that reveal various modes of antimicrobial inhibition enlisted in **Figure 1**.

## **4. Nanocomposites that reveal promising antiviral activity**

The most recent research on viruses-designed coating materials as well as potential nanocoatings to stop the spread of the contagious SARS-COV-2 virus in response to the global health outbreak was well explored. Due to viral adhesion/colonization, subsequent proliferation, and biofilm formation, the exposed surfaces are contaminated. Hence, surface contamination possibly removed using the traditional disinfecting cleaning method, but studies shown that disinfecting only offers a momentary relief. The field of antiviral coating has seen some promising work, but more study

*Antibacterial, Antifungal and Antiviral Nanocomposites: Recent Advances and Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.108994*

is undoubtedly needed. In the creation of antiviral coatings, it is thought that nanomaterials like metal oxide nanostructures, Graphene, Carbon Nano Tube, Carbon quantum dots, Titanium dioxide, bio-based nanoparticles like chitosan, capped silver, Graphene, Gold and Silicon nanoparticles could play a key role [49, 50].

A team of researchers has shown that surface-adsorbed viruses can be effectively removed from surfaces using nanoparticles. The antiviral effect, which most likely results from a "contact killing mechanism," is highly dependent on the type of polymer and the affinity of the nanoparticles for the polymer. In this regard surface coatings made of nanocomposite materials with a polymer matrix and Cu/CuO nanoparticles synthesized and shown that surface-adsorbed viruses could be effectively removed [51].

Numerous viruses can survive and maintain their infectiousness on plastics for several days when exposed to ambient conditions. Measuring the persistence of various virus types on frequently used composite materials, like carbon-epoxy and glasspolyester laminates, is necessary. The polymer composites community has received a clear message from the SARS-CoV-2 global pandemic that there are opportunities for next-generation materials with virus-resistant surfaces [52].

Polymer Nano-Composites (PNC), such as polysaccharides nanocomposites, may play a significant role in the development of an antiviral drug for Covid-19. PNC could manage the health system, reduce lockdown times, and reduce social isolation while also saving money and energy [53].

The unique structure of graphene oxide sheets could contribute to the inhibition of infection by feline coronavirus with a lipid envelope. GO sheets with silver particles exhibited antiviral activity against both enveloped viruses and non-enveloped viruses. Negatively charged GO can absorb positively charged lipid membranes and induce rupture of membranes. The interactions between GO and the membrane can attract the absorption of more lipid membranes [54].

This study, proposed a blocking strategy against model respiratory viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus and porcine reproductive and respiratory syndrome virus (PRRSV) (PRRSV and SARS-CoV-2) infection by heparan sulfate analogue-modified two-dimensional (2D) transition metal carbides (MXenes) nanocomposites. The functional 2D nanocomposites with excellent physicochemical properties and abundant heparin analogue (MPS) demonstrated several unique advantages for antiviral research. Firstly, the Ti3C2-Au-MPS nanocomposites with a relatively uniform particle size and excellent biocompatibility can be synthesized in a facile method. Secondly, Ti3C2-Au-MPS nanocomposites can block PRRSV infection by inactivating PRRS virions invitro and inhibiting its adsorption and invasion in host cells. Thirdly, Ti3C2-Au MPS nanocomposites have a potent inhibitory effect on SARS-CoV-2 infection, suggesting that these materials have broadspectrum antiviral activity against PRRSV and SARS-CoV-2 [55].

According to a study, aqueous medium was used to create Ag NP/Chitosan composites with antiviral activity against the Influenza A virus. Unreacted Ag NPs were not found in the composites, which were obtained as yellow or brown flocs. The experimental results demonstrate that virions and composites interacted. The synthesis methods control the antiviral and cytotoxic properties of the silver nanoparticle or nanocomposite by modifying its size, shape, morphology, and surface charge. As discussed in this work, biological approaches have emerged as a result of the shortcomings of physical and chemical approaches [56].

Antibacterial, antifungal, and antiviral properties of ZnO NPs and Activated Carbon nanoparticles were synthesized. On the human WI38 cell line, their

#### **Figure 2.**

*Various modes of antiviral activities of different nanocomposites.*

cytotoxicity was tested. Such nanocomposites reported as lethal at minimally toxic concentration reduced the Herpes Simplex Virus1 count by about 83%. (MNTC) [57].

The suggested TiO2 PL-DNA nanocomposites can be used to effectively and specifically inhibit different subtypes of influenza A virus. The proposed TiO2 PL-DNA nanocomposites have remarkable antiviral activity, making them excellent platforms for drug development against a wide range of nucleic acid-related diseases, from infectious diseases to hereditary disorders [58]. Various Nanocomposites discussed above have shown antiviral activities against respected viruses. Possible Mechanisms of Antiviral activities were enlisted in **Figure 2**.

## **5. Conclusion**

Antibacterial nanocomposites incorporating inorganic nanoparticles present higher antibacterial activity compared with their bulk counterparts due to their higher surface-to-volume ratio, resulting in improved contact with microorganisms. Antibacterial properties have been usually tested on nonpathogenic bacterial strains like *E. coli* and *S. aureus* as model organisms, but research should focus on other bacterial pathogens of different families. This would account for the increasing antibiotic resistance among various bacteria and their association as a severe hazard to worldwide public health. Some Graphene like nanocomposites with small-sized NPs are more effective against Gram-negative bacteria since they have larger surface area in contact with the bacteria. Well-dispersed nanomaterials show stronger antibacterial activity than the aggregated ones. The main challenge is obtaining reliable information on the interaction between bacteria and nano-structures. Another challenge is to analyze the toxicity associated with them. Antifungal polymers can be combined with other anti-microbial compounds to enhance their antibacterial activity. This flexibility provides great promise for applications that range from postharvest food preservation to healthcare, according to the World Health Organization (WHO). The potential of antifungal composites to replace antifungal drugs still remained unexplored. Likewise viral infections are difficult to treat because viruses spread and multiply quickly. Numerous new, deadly viruses, including the *Coronavirus, Ebola virus, Dengue virus, HIV,* and *Influenza virus*, are already causing chaos on people. Moreover Silver and biobased polymers as Nanocomposites which are selective antimicrobial

*Antibacterial, Antifungal and Antiviral Nanocomposites: Recent Advances and Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.108994*

compounds should be explored in future to enhance its applicability. Silver biobased nanocomposites are thought to be a powerful and cutting-edge pharmacological agent with strong antiviral activity against these viruses and microorganisms. This is to be thoroughly studied in all respects.

## **Acknowledgements**

The Authors would like to thank Head, Department of Microbiology and Head, Department of Physics, Principal of our college and University stake holders for their cooperation.

## **Conflict of interest**

The authors declare that there is no conflict of Interest regarding this publication.

## **Author details**

Suchita C. Warangkar1 \*, Manish R. Deshpande2 , Narayan D. Totewad3 and Archana A. Singh4

1 Department of Microbiology, Netaji Subhashchandra Bose Arts, Commerce and Science College, Swami Ramanand Teerth Marathwada University, Nanded, MS, India

2 Department of Physics, Netaji Subhashchandra Bose Arts, Commerce and Science College, Swami Ramanand Teerth Marathwada University, Nanded, MS, India

3 Department of Microbiology, B. K. Birla College of Arts, Science & Commerce (Autonomous), Kalyan, MS, India

4 Department of Chemistry, B. K. Birla College of Arts, Science & Commerce (Autonomous), Kalyan, MS, India

\*Address all correspondence to: suchitawarangkar@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 6**

## Perspective Chapter: Tissue-Electronics Interfaces

*Shahab Ahmadi Seyedkhani and Raheleh Mohammadpour*

## **Abstract**

Tissue-electronics interfaces provide a two-way communication between biological tissue and external electronics devices to record electrophysiological signals and stimulation of the living organs. This chapter presents an overview of significant progresses in tissue-electronics interfaces. At first, we evaluate principal properties of the living tissue microenvironment important for tissue-specific equipment design. Next, we study charge transfer mechanisms in the biological tissues, bulk electrode materials, and tissue-electronics interfaces. After that, we highlight the current developing and promising advanced biomaterials for the neural electrodes, significantly leading to the development of bionanoelectronics and bionic organs. Finally, the challenges and future outlook of the neural interfaces will be discussed.

**Keywords:** bioelectronics, neural interfaces, biomaterials, composites, neural recording, electrical stimulation, charge transfer

## **1. Introduction**

The discovery that human cells are capable of producing electrical signals and responding to electrical stimulation, has encouraged researchers to develop technologies based on monitoring the body's electrophysiological activities and electrical stimulation of living tissues. To understand that how the electronic systems interact efficiently with biological tissues, dominating over the structural complexity and function of the host tissue is essential. Biological tissue often contains the cells distributed in an extracellular matrix (ECM). The ECM is a specific biochemical composition consisting of various sugars and proteins in an aqueous medium. In addition to mechanical support, the ECM has biochemical and topological properties that affect the cellular functions such as migration, proliferation, differentiation and growth mechanisms. The properties of the ECM are different according to the type of tissue. Therefore, the biomaterial's performances can be different based on the microenvironment that the biomaterial is implanted in. Accordingly, to create harmony and constructive interaction between implantable devices and living tissues in a bioelectricity system, matching the properties of each component is vital [1].

Based on this, the need for new materials to extract data through advanced, immediate and accurate methods has developed different types of materials and methods to improve the interaction of implantable equipment with the biological organs, tissues and cells. Todays, developing of the new high efficient neural interfaces is progressing

#### **Figure 1.**

*Different commercial neural electrodes: (a) an iridium (or platinum, gold) multi-arrays electrode fabricated using state-of-the-art silicon microelectromechanical systems (MEMs). (b) a vector array made of silicon (inset: optical images of the electrode size in comparison with a coin), and (c) ultra-flexible Pt electrodes on a polyimide substrate. (d, e) Cardiac surface grid on heart surface. All images are adapted with permission from products of the NeuroNexus company (USA).*

rapidly, which is mostly due to the development of new materials. Meanwhile, the current electrodes are usually made of the metals such as platinum (Pt), iridium (Ir) and other materials such as stainless steel and nickel-chromium (Ni-Cr) alloys. **Figure 1** shows various commercial electrodes that are currently used in clinical applications. However, these materials have significant shortcomings such as mechanical mismatch, low biocompatibility, and weak electrochemical performances. Therefore, various new advanced materials such as hydrogels, conductive polymers, and hybrid composites have been developed, so that they are expected to cause the great improvements in bioelectronics and online health monitoring.

## **2. Essential considerations**

## **2.1 Dynamics and mechanical properties**

Reducing the damage to the biological tissue and minimizing the interfering effects on the function of the organ are fundamental considerations in the design and implantation of a device in the body. From the muscle dynamics caused by heart and lung activities to peristalsis of the digestive system and the mobility of bones and joints, may affect the performance of the implant. On the other hand, the presence of biomedical implants in the body can slow down or disrupt the activity of dynamic organs. The forces caused by continuous movements around the implant can easily lead to the destruction of the bioelectronic device. In addition, the stiffness of the

## *Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

living tissue can also affect the performance of the implant. Most biological tissues, except bones and teeth, are soft and have an elastic modulus of less than 1 kPa (such as central nervous system) to higher than 100 kPa (such as lungs, kidneys, arteries) [2]. Meanwhile, pathological conditions can lead to the transformation and increase of stiffness of biological tissues [3]. Subsequently, changing the ECM's stiffness affects the behavior and function of the cells. Therefore, the soft nature of most biological organs and tissues makes them highly vulnerable when faced with biological implants. Accordingly, it is important to understand the dynamics and mechanics of the living tissues.

## **2.2 Immune responses to implants**

After implantation, a layer of proteins, such as fibronectins, collagens, laminins, are quickly absorbed on the implant's surface [4]. This layer is determined by the immune system, leading to foreign body responses (FBR) [5]. The FBR is a phenomenon in which many immune cells undergo apoptosis. This compromises the immune system that may result in formation of a biofilm around the implant and tissue infection [6]. During this process, the formed fibrotic capsule around the implant separates the electronic device from the biological target.

The immune system reactions are altered based on the tissue. In the central nervous system, which is resistant to foreign antigens and immune response [7], the FBR causes the glial scar formation. The resulting scar isolates the bioelectric implant and ultimately impairs the electrical recording/stimulation function. Infections and glial scars caused by the presence of an implant in the body are generally attributed to various reasons such as the mechanical mismatch of the implant with the host tissue [8]. Hence, tailoring the mechanical properties to minimize the FBR is a major consideration when designing an efficient implant. **Figure 2** shows the immune responses, including glial encapsulation and tissue/electrode separation processes, to the implants.

### **2.3 Chemical environment**

The chemical microenvironment surrounding the implant plays an essential role in the stabilization, interaction and performance of the bioelectricity system. Biological tissues are moist and somewhat alkaline microenvironment, which may be aggressive to electronics system components such as sulfate, chloride, carbonate, and phosphate [10]. The combination of the chemical microenvironment with reactive oxygen species (ROS), which are produced during intracellular metabolic processes, can cause the FBR caused by oxidative processes. This disrupts the implant's interaction with the biological tissue, and the subsequent entire functioning of the bioelectricity system.

Ideal biomedical implants should be compatible with the underlying living tissue. This adaptation results in a sincere but not restrictive interaction with the organ's topography. Therefore, to minimize inflammation of the immune system, bioelectronic materials and designs must be biocompatible, and neutral to proteins absorption and immune cells stimulation. For example, applying an inert encapsulating material aims to reduce the direct interaction zone between the electrode and biological tissue, reducing electrical noise and potential electrode degradation. Hence, one of the most effective ways to reduce inflammation and infection, is designing new materials and modifying the implant's surface to be more compatible with biological microenvironments.

## **Figure 2.**

*Glial encapsulation process (A) before implantation, and (B) 12 h post-implantation, (C) 1 week postimplantation, (D) 4 weeks post-implantation, (E) 12 weeks post-implantation. Panels (F), (G), and (H) represent cross-sectional of (C), (D), and (E), respectively. The figure is adapted with permission from Ref. [9] MDPI.*

## **3. Charge transfer mechanisms**

## **3.1 Charge transfer at tissue-biomaterial interfaces**

Accurate monitoring of the electrophysiological signals produced by the nervous system and operative tissue stimulation are important parameters for evaluating the performance of the tissue-electronics interface [11]. The generation and transmission of electrophysiological signals are conducted by stimulating ions to pass through the cell's membrane and changing the charge concentration in the ECM. These ions carry the charges in the ECM, so their mobility makes a local electric field. The goal of a neural electrode is to create a two-way connection between the electronics device and biological tissue to record the changes of the electrophysiological field (signal recording) or change the field (electrical stimulation). Enhancing this two-way communication is the basis of that we consider for designing and construction of bioelectricity systems [12]. **Figure 3** indicates the bioelectronics activities in the tissue-electronics interfaces and equivalent circuit models for stimulation and recording. It does not matter which communication mode (recording or stimulation) is performing at the interface, the important thing is that the applied electroactive materials ensure efficient charge transfer between electrons and ions in the bioelectricity system. Because, charge transfer in neural interfaces is done by electrons, while biological tissues transfer electrophysiological charges through ions [14].

*Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

#### **Figure 3.**

*schematic representation of (a) ions transfer through membrane channels, making (b) an extracellular potential that interacts with the electrical field produced by electrode. (c) Equivalent circuit models for (top) recording and (bottom) stimulation processes. VR shows the output of the recording with the interconnect resistance Rc. The V indicates the electric potential within ECM generated by the ionic currents applied on the electrode surface. For both recording and stimulation, the tissue-electrode interface is considered as a parallel circuit of the EDL capacitance (C), and the leakage resistance, R. VS indicates the input for stimulation with the interconnect resistance Rc. The Ve represents the electric potential within ECM generated by VS applied on the neuron's outer membrane [13].*

In a way known as capacitive charge transfer, the transfer mechanism depends on the charging/discharging process of the capacitance made by the electric double layer (EDL) formed on the electrode surface. Upon the electrode generates an electrical pulse, the electrostatic charges concentration on the implant's surface changes, which is accompanied with the alternating absorption and repulsion of ions in the ECM surrounding the implant. It is worth noting that during this process, there is no electron transfer between biomaterials and tissue. In fact, under these conditions, a layer of polarized water molecules is adsorbed on the electrode's surface and acts as a dielectric for the EDL capacitor [15]. It means, no chemicals are produced or consumed in capacitive charge transfer. Therefore, electrodes whose function is based on capacitive charge transfer are more suitable for stable interaction with physiological environments. However, the charge transfer ability of a neural interface depends on the capacitance of the surface EDL, and the capacitance is positively dependent on the surface area of the electrode. Therefore, increasing the effective surface area of neural electrodes, without increasing their size, leads to improvement of the bioelectronics systems performance.

In another charge transfer process that is based on the Faraday mechanism, charge transfer depends on chemical reactions occurring on the electrode's surface. In other words, when the electrode generates an electrical pulse, the reductionoxidation (redox) reactions occur at the tissue-electrode interface. The Faradaic charge transfer is associated with the reduction or oxidation of chemicals, which establishes as electrons pass through the interface. According to whether new stable products are produced during charge transfer or not, the Faradaic process is divided into two types of reversible or irreversible. During the irreversible Faradaic process, the redox reactions not only lead to the collapse of the electrode, but also damage the living tissue by changing the ECM's conditions such as pH and releasing harmful products into the tissue microenvironment. So, it is preferred to avoid charge transfer processes by irreversible Faradaic paths. Meanwhile, in reversible Faraday charge transfer mechanism, new materials produced on the electrode's surface are converted to their original state during the opposite electric pulse. Hence, in the

reversible Faradaic process, new products are not introduced into the living biological tissue. Accordingly, charge transfer through reversible Faradaic processes is safe and desirable. It is very important that the corresponding redox reactions occur during charge injection in the reversible Faradaic method, because they indicate that the neural interface can hold more charges. Consequently, the electrodes with a reversible Faradaic charge transfer mechanism are preferred compared to the electrodes based on irreversible charge transfer. **Figure 4** indicates capacitive and faradaic charge transfer mechanisms at tissue-electronics interfaces and their cyclic voltammetry (CV) responses.

## **3.2 Charge transfer in biomaterials (electrode)**

Due to the type mismatch of charge carriers in the biological tissues and electronics systems, the stable and effective data transmission using the neural interface is a significant challenge. So far, we have discussed charge transfer mechanisms in the biological tissues and the tissue-electrode interfaces. Next, we will describe charge transfer mechanisms in biomaterials (electrode material). Charge transfer in the electrode materials are divided into three main categories, which are:

1.Charge transfer by electrons: This type of charge transfer is often observed in traditional electrodes, which are often made of metals and carbon materials. These materials generally use free electrons as charge carriers to establish connections with biological tissues [16]. Due to the high electrical conductivity and long-term biological stability of metal and carbon electrodes, these materials have been widely used in construction of the neural electrodes [17].

#### **Figure 4.**

*Schematic illustrations of the electrochemical processes at tissue-electronics interfaces. (a) Capacitive charge transfer based on the electrical double layer (EDL) consisting of the charge and discharge processes. (b) An idealized faradaic (Redox) charge transfer. (c) The capacitive charge transfer characterized by voltage (V)-independent current (I) in cyclic voltammetry, resulting in a box-like cyclic voltammogram. (d) The faradaic charge transfer features an anodic peak (corresponding to oxidation, [Red − e− → Ox], where 'Red' and 'Ox' are the reduced and oxidized forms of a species, respectively) and a cathodic peak (corresponding to reduction Ox + e<sup>−</sup> → Red) around the standard redox potential E0 of the redox couple in cyclic voltammetry.*


In the next section, we will describe the notable electrode materials based on their charge transfer mechanisms.

## **4. Current developing neural interfaces**

Tremendous production progresses of new materials, reducing dimensions while increasing efficiency of bioelectronics systems. In addition, the mechanical adaptability and improving the electrical properties of neural electrodes to better interact with biological tissues have always been on the research programs. The improvements of the conventional electrode's properties and design of new electrodes, lead the bioelectronics present in various applications such as heart pacemakers, deep brain stimulators, retinas, contact lens, electronics skin and etc. In this section, we will introduce different types of these electrode materials, manufacturing processes and their functional mechanisms.

## **4.1 Neural interfaces that transfer charge by electrons**

## *4.1.1 Metal electrodes*

Until now, most neural electrodes are mainly produced by electron conductive materials, namely metals and metal composites such as platinum (Pt), gold (Au), silver (Ag), and iridium. However, the practical applications of these materials as electronic-tissue interfaces are limited due to their weak biocompatibility and insufficient electrical activities. It should be noted that the electrical activity of the electrode depends on different electrochemical parameters such as electrochemical impedance, charge injection limit (CIL) and charge storage capacity (CSC). It means, the high electrical conductivity of metal electrodes does not necessarily mean in that they have good electrical activity. For example, it has been demonstrated that although some conductive polymers suffer from lower electrical conductivity, they show higher electrical activity than platinum [21]. Therefore, a material with low electrical conductivity is not necessarily a weak electroactive material, although increasing the electrode's conductivity usually improves its electrical activity [22]. In the following, we will discuss the recent approaches for improving the biological behaviors and electrical activities of the metal electrodes.

• Nanostructured metal electrodes

Do more with less, this is the mantra of nanotechnology. Considering the urgent need for small bioelectricity systems, increasing the number of channels and charge injection density of neural electrodes while reducing their dimensions, researchers have developed different types of electrodes with nanoscale features [23, 24]. However, these electrodes still face unavoidable limitations, which are: (I) the possibility of bending and placing in unspecified places due to the excessive fineness and frangibility. (II) To design these tiny electrodes, the materials with high hardness and stiffness are needed, which may cause activation of the immune system, formation of glial scars and tissue inflammation. (III) Nanometer electrodes may have relatively high electrochemical impedance and low charge injection capability, which leads to weakening the performance of the bioelectricity system. However, some approaches such as introducing nanopores in the electrode structure for increasing its effective surface area, can reduce the electrochemical impedance of the neural interface [25]. Recently, composite coatings made of electrodeposited iridium oxides with Pt gray were developed to fabricate IrOx/Pt gray neural electrode. It demonstrated that the large surface area of the nanoporous Pt, leading to firm adhesion of the iridium oxide to the substrate accompanying with superior mechanical and electrochemical stability of the electrode [26]. Other example are the diamond-titanium porous composites produced by deposition process to fabricate hybrid neural electrodes. These composite electrodes have demonstrated high electrochemical capacitance, low impedance, and excellent biocompatibility assessed in vitro using cortical neurons [27]. Moreover, the nanostructured electrodes have shown greater compatibility with the ECM [28]. The flexibility of nanostructured electrodes in line with the weak movements of the brain and other dynamic biological organs, is another advantage of nanometer electrodes [29].

## • Metal composite electrodes

High impedance and low biocompatibility are the unfavorable characteristics of traditional metal electrodes for monitoring electrophysiological signals and tissue stimulation. Accordingly, metal composites have been developed to overcome the mentioned challenges and improve the long-term stability of metal-based neural interfaces. Avoiding parasitic effects should be considered for design of metal composites, so combining the materials with similar characteristics is more preferable. In addition, it has been proved that the nanocomposites, which have high specific surface area and more compatibility with the ECM, improve the performance of the neural interface. Also, fabrication of nanostructured composite coatings on the electrode, could be a method to create the preferred properties. The composite coatings are usually deposited by electrochemical deposition, sputtering and thermal evaporation methods. Currently, gold (Au) is considered as a promising candidate for improving the properties of neural electrodes. The excellent biocompatibility and encouraged performance of the Au-coated electrodes have been proven [30]. Compared to the pure silver (Ag) surface, the Au-Ag nanocomposite electrodes have shown lower impedance and more biocompatibility, which has resulted in accurate, high-quality, and stable recording of electrocardiogram (ECG) and electromyogram (EMG) signals. Moreover, the traditional neural electrodes generate wide signal void (no functional magnetic resonance imaging (MRI) signal) in ultrahigh field (UHF) MRI scanners. This is an important shortcoming when simultaneous MRI signal acquisition and neural monitoring is desired, for example in studying the functional mechanisms of deep brain stimulation (DBS). Recently, new gold-aluminum (Au-Al) composites have been presented for neural interfaces to overcome the signal voids. The Au-Al composites significantly reduce the magnetic susceptibility difference

*Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

between the brain tissue and electrode, resulting in greatly reduced regions of the signal voids. The Au-Al composites produced less field distortion and signal loss compared to the pure Au and Al electrodes, leading to MRI scanners of lower magnetic field strengths as well [31].

Despite to the conventional electrode metals such as the toxic Ag nanowires [32], liquid metals (LM) have good biocompatibility, excellent mechanical flexibility, and significant electrical conductivity. The LM composites include bismuth-indium-tin (Bi-In-Sn), indium-gallium eutectic (EGaIn) and gallium-indium-tin (GaInSn), are widely used in the preparation of neural electrodes. However, these LM electrodes have obvious challenges, including (I) removing the oxide layer of LM particles inside the ink to connect the electrode paths, (II) overcoming the surface tension of the LM and converting it into desired shape, (III) solving the problem of connection fragility of the LM to other components of the bioelectricity system, and (IV) encapsulating the LM to prevent leakage into the biological microenvironment, and subsequent tissue damages.

## *4.1.2 Carbon-based electrodes*

At present, carbon-based materials such as carbon nanotubes (CNTs) and graphene, are outstanding candidates for the design and fabrication of nanoscale, flexible, and multifunctional neural interfaces.

• Graphene electrodes

Graphene is a single layer of carbon atoms that are connected to each other in the form of a two-dimensional honeycomb network by sp2 hybridization. Recently, graphene has been used as a successful high efficiency material in the neural interfaces [33]. Among the prominent features of the graphene, the following should be mentioned: (1) very high mechanical strength while maintaining extraordinary flexibility, (2) excellent electrical conductivity (single layer resistance of 100 Ω sq.−1) with a carrier mobility of ~15,000 cm2 V−1 s−1 at ambient temperature [34], (3) large surface area that provides a favorable template for cell attachment and charge transfer, thereby enhancing electrical recording/stimulation capability, and (4) biocompatibility. Additionally, the modified surface functional groups of the graphene, makes it more compatible as an operational nanostructure for various applications. By manipulating or functionalizing graphene, some modified structures such as graphene oxide (GO), reduced graphene oxide (rGO), graphene fibers and other derivatives can be produced, which brings more choices for bionanotechnology [35, 36]. Graphene can be coated on the electrodes using different methods such as chemical vapor deposition (CVD) [37], spraying [38], and electrochemical routes such as cyclic voltammetry (CV) [39]. However, weak adhesion of the graphene to the substrate, resulting in coating instability and destruction of the electrode, is one of the main challenges of the graphene electrodes.

• CNT electrodes

Carbon nanotubes (CNTs) are one-dimensional nanostructures created by twisting the graphene sheets. The CNTs have been widely used in the construction of neural electrodes, duet to their following desirable characteristics: (1) they have high electrical conductivity, facilitating the ballistic electron transfer from the electronics-tissue interface to the electrode material. (2) They have a high surfaceto-volume ratio, which can reduce the electrochemical impedance and increase the charge injection capability of the electrode [40, 41]. (3) The CNTs benefit from surface functional groups that are easily modified by biological molecules, leading to tunable anisotropic properties adequate based on the application. In addition, (4) The CNT-based electrodes have presented superior biocompatibility, mechanical strength, flexibility, and worthy adhesion to the nerve cells [42, 43].

There is a trade-off between the size of the neural electrode and its electrochemical impedance, so that by decreasing the electrode size decreases, its impedance increases. It should be noted that for high resolution and accurate recording of the electrophysiological signals, the small electrodes with low impedance are needed. Although the size and electrochemical properties of neural electrodes have been continuously improved, weakening the mechanical performances during miniaturization have always been an important challenge for practical applications [44]. Therefore, the CNTs are suitable nanomaterials to overcome this challenge. In addition, the improvement of biocompatibility, reduction of impedance, promotion of more stable micro-environmental ability of the conventional electrodes modified with the CNTs have also been reported [45]. The researchers have evaluated conductive CNTs/collagen composites for studying the cellular responses on the neural interfaces. The results indicated that by increasing the collagen content, the cells show enhanced attachment on the electrode's surface, which could be due to the high ability of the collagen to improve the adhesion and viability of the nerve cells [46].

## **4.2 Neural interfaces that transfer charge by ions**

Signal transmission in biological media is conducted through the movement of ions and small molecules, contrary to the electron-hole in electronic devices. Accordingly, the ion-conducting neural interfaces can interact more efficient with the living tissue. The finding this tissue-electronics charge transfer interaction has caused the ion-based interfaces to receive more attentions. However, the use of liquid ion-conducting materials such as electrolyte solutions and ionic liquids, which have high ion transfer capability, are limited due to the need for a mold to maintain the shape of the electrode [47]. As a result, the solid ion conductors have attracted more attentions. Recently, hydrogels have been broadly applied in biological applications, including cell culture, smart drug delivery, tissue repair and regeneration, due to their intrinsic biocompatibility, biological functionality, flexibility, and adaptation to living nerve tissue. The outstanding capabilities of the hydrogels have caused these materials to be considered promising candidates for designing and manufacturing flexible bioelectronic systems [48].

## *4.2.1 Hydrogels*

Hydrogels are soft solid ion-conducting materials that are composed of interconnected polymeric configuration. This polymeric structure can absorb water that enables free ion movement in aqueous-based network, creating ionic conductivity. This ability has caused hydrogels to be used in various applications such as artificial muscles, ionic skin, artificial axons and connections of the central nervous system, whose functions are performed through ion conduction. Conductive hydrogels are usually synthesized by (1) constructing distinct component networks through

*Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

#### **Figure 5.**

*Different types of conductive hydrogels, preparing by using CPs, conductive fillers, free ions, and their composites. According to the composite's materials and properties, the fabricated hydrogels can be classified as electronic, ionic, and the hybrid electron−ion conducting hydrogels. The figure is adapted with permission from Ref. [49] American Chemical Society.*

self-assembly or self-polymerization CPs/fillers, (2) building interpenetrating networks by doping CPs/fillers, (3) diffusing free ions, and (4) embedding conductive fillers/free ions into an existing non-conductive hydrogel matrix (**Figure 5**). Depending on the additives and dominant conducting mechanisms, the synthesized hydrogels can be classified as electron-based, ion-conducting, and hybrid electron− ion conductive hydrogels.

The ionic conduction is mainly based on a non-Faradaic (capacitive) charge transfer mechanism, without materials or charges passing through the neural interface. This transmission possesses the transmitting high-frequency electrical signals over long distances [50].

There are three types of widely used hydrogels for the electronic-tissue interfaces, which are (1) ion-conducting hydrogels (ICHs), (2) ion-conducting organohydrogels (ICOHs), and (3) hydrogel composites. In the following, we will focus on hydrogels in which the electrical conduction is conducted only through ions. Other hydrogels in which the charge transfer process is carried out by hybrid electron-ion transfer will be discussed in the next section.

The ICHs are classified as highly hydrophilic gels with a massive three-dimensional (3D) hydrated network structure [51]. Since ions can move freely in this 3D network, ICHs can achieve high ionic conductivity in the range of 3.4–5.5 Sm−1 [52, 53] by permeating salts such as NaCl, LiCl, FeCl3, acids such as HCl, H3PO4, or ionic liquids [54–56]. In addition, the ion conduction mechanism of hydrogels is similar to biological tissues, so they can efficiently exchange data through ion diffusion [48]. This makes hydrogels immune to the challenges of converting electronics and ion-based signals to each other and related problems [50, 57]. It should be noted that this group of hydrogels contain large amounts of water, which can act as a buffer environment during the side effects, to prevent adverse problems for the living tissue. Most ICHs are adhesive, transparent, and self-healing, so their applications in bioelectronic systems such as wearable sensors, implantable epidermal electrodes, digital tattoos, and many others are being developed [58, 59].

#### *Biocomposites - Recent Advances*

However, the prepared ICHs by salt compounds, have unfavorable biocompatibility and low stability due to the release of excess ions, which can lead to the damage of bioelectronic devices. It has been proven that compared to traditional metal electrodes, the ICH-based electrodes can generate contractile forces using lower voltages, which indicates the capability of the electrodes for bioelectrical stimulation. In addition, it should be noted that the undesired gaps formed between the electronic interface and the biological tissue, resulting by muscle contraction or skin bending (surface electromyography abbreviated to sEMG), leads to significant noise/error in the identification of electrophysiological signals. These gaps can be eliminated using soft hydrogel interfaces and making electrostatic interactions between the electrode's surface and tissue [60]. However, the ICH-based electrodes lose conductivity, flexibility, and even morphology due to rapid water loss, which limits their practical applications [61]. At present, some solutions have been proposed to overcome this problem, including (I) addition of dehydrating reagents [62, 63], (II) mixing of ionicpolymeric liquid gels [59], (III) binding of sealing materials [64], and (IV) mixing of deep eutectic solvents (DESs).

As mentioned, the water losing is one of the major shortcomings of hydrogels in practical applications. Recently, adding organic solvents to hydrogels for producing the ion-conducting organohydrogels (ICOHs) has been considered to overcome the dehydration of hydrogels. This modification is based on the premise that the organic solvents can compensate some of the lost water of hydrogels, and enhance their dry immunity and maintain ionic conductivity [65]. In addition, the ICOHs retain some advantages of the hydrogels, including biocompatibility, soft mechanical properties, and considerable shape design ability [66, 67]. Adding organic solvents to hydrogels can be conducted through three methods, which are (1) solvent replacement [68]; (2) the desorbed hydrogel network is injected with organogel precursors, and then is subjected to in situ polymerization [69]; and (3) gelation in a binary solvent [70].

It is worth noting that although the solvent displacement method could be done easily, the ICOHs prepared by this method have relatively weak forces between the hydrogel's polymer network and the replaced solution, resulting in solvent leakage and tissue damages [71]. Meanwhile, ICOHs synthesized by the gelation method in binary solvents have overcome this challenge and also presented the advantage of high electrical conductivity. While, high electrochemical impedance and insufficient long-term adhesion to biological tissue are some problems of the ICOHs, which have limited their usage in the bioelectronics.

## **4.3 Neural interfaces with hybrid electron-ion charge transfer mechanism**

An ideal tissue-electronics interface should provide the charge transfer requirements of biological tissues and electronics devices simultaneously. Hence, the materials with hybrid electron-ion charge transfer are more appropriate for design and construction of the neural interfaces. Recently, conducting polymers (CPs) have attracted many attentions to create neural interfaces due to their hybrid electron-ion charge transfer capability.

## *4.3.1 Conductive polymers*

The CPs benefit from unique features, which include (1) simultaneous electron-ion conductivity [72], leading to reduction of the electrochemical impedance and improvement of the electrical recording/stimulation. (2) Their inherent adaptive mechanical

## *Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

properties lead to bridging at electronic-tissue interfaces. (3) Fibers and nanostructures of the CPs, which could be synthesized by low-cost and simple methods, have high specific surface areas that result in facilitating electron-ion exchange at neural electronics-tissue interfaces. (4) Mixing the CPs with different materials such as polyelectrolytes (polystyrene sulfonic acid, polyacrylic acid, polymethacrylic acid) and bioactive molecules [73] can be easily conducted, which improves the biocompatibility and stability of the CPs-based electrodes [74]. In the following, some well-known CPs materials, which have shown promising performances as the neural electrodes, will be presented.

• Neural electrodes made from polypyrrole

Polypyrrole (PPy) is an intrinsic CP that has high conductivity, biocompatibility, facile processing, water solubility, and slight potential for its monomers oxidation, which has made it a capable candidate for the neural interfaces [75]. An ideal CP should have independent decent properties and performances as much as possible, without adding extra reinforcements. To achieve this goal, the CPs need to have mechanical and chemical stabilities in biological microenvironments. However, contrary to the mentioned worthy properties of the PPy, it is prone to irreversible oxidation and easily fails under the change of chemical conditions such as pH and disrupts the bioelectronics interfaces. This characteristic has limited the PPy applications, resulting in more attentions to alternative CPs such as the poly (3,4-ethylenedioxythiophene) (PEDOT).

## • PEDOT electrodes

The PEDOT is an intrinsically CP that appears to be more attractive than PPy due to several reasons, including (1) PEDOT has a narrow band gap [76], changing charges in the polymer chains. (2) PEDOT has a higher electrical conductivity that increases the electrode's capabilities [22, 77]. (3) PEDOT has shown great electrochemical stabilities [78], which are necessary for the electrical recording/excitation stabilization in a bidirectional communication. In addition, (4) the PEDOT has better biocompatibility than PPy [79, 80]. Although the CPs have many advantages in bioelectronics, their brittleness and excessive stiffness have limited their use in neural electrodes. Therefore, the design and construction of soft and elastic composites based on conductive elastomers (such as PEDOT:PSS) distributed in a soft elastomer matrix (such as polyurethane, PU), and or using the laser micromachining technology for converting the CPs into a flexible electrodes array, have been proposed [81].

• CPs composite electrodes

In addition to the CPs-based electrodes, surface modification of traditional electrodes using the CPs and their composites has given innovative capabilities to the electrical recording/stimulation processes. Improving the performance of electrodes with the CPs-based coatings, could be due to (1) reducing the electrochemical impedance of the electrode, (2) making a soft compatible surface for the electrode while being strong to improve the tissue-electronics interface. In addition, (3) increasing bioactivity in comparison with the bio-inert metallic electrodes, results in decreasing immune responses, tissue inflammation and implant infections. The CPs not only increase the electrode's stability, but also their highly porous structures, such as electrospun fibers, can improve the electrochemical performances [82]. The biological

fluids can flow in the pores of fibrous structures and interact with a high surface area to increase the electrophysiological signal transmission efficiency. Additionally, making porous composites such as fibrous CPs/CNTs can also enhance the polymer's conductivity and increase the electrode's effective surface area. The results have also shown that the neural interfaces based on the CPs/CNTs composites have lower impedance and more charge storage capabilities. These improvements can be due to the presence of CNTs as impurities to make a strong interaction with the CP chains, leading to fast electron transfer processes, formation of three-dimensional structures, and increasing the effective surface of the composite electrode [83].

• Neural electrodes made from hydrogel composites

Hydrogels can make ionic conductivity through the absorption and transfer of the ions present in their structural water, which is a process similar to the transfer of electrophysiological signals. Although this hydrogel's property has made them attractive, activation electron transfer mechanisms is the key for successful bioelectronics application of the hydrogels [84, 85]. Fortunately, the hydrogel's porous structure provides adequate space to incorporate with the electron-conducting materials such as metals, carbon-based materials, conductive polymers, etc. with the aim of forming a composite of hybrid electron-ion transfer network. Accordingly, it is possible to improve the electrochemical properties of the hydrogels, including electrochemical impedance and CIL, without weakening their excellent biological properties [49, 86].

The CPs are ideal materials for making hydrogel-based composites, because (1) the similar soft and high flexible mechanical properties of the CPs and hydrogels, avoiding mismatch dynamics and extra stresses to the electrode. (2) The CPs have high compatibility and affinity to the hydrogels that results in potential hybridization. In addition, (3) the unique polymeric and organic properties of the CPs make them facile to be modified. It should be noted that (4) some CPs such as PEDOT have a hydrogel-like form in wet environments, which corresponded to their hygroscopicity or swelling properties when exposed to water [13]. This behavior makes this kind of CPs more similar to the hydrogels' properties, leading to more integrated and consistent composites.

The CPs are usually used as the electron conducting additives in hydrogel composites. The polymeric nature of CPs allows the molecular scale structures, forming interpenetrating network (IPN) hydrogels. The IPNs not only minimize potential trade-offs in mechanical properties, but also meaningfully reduce probable heterogeneity in electrical and mechanical behaviors. The IPN-based hydrogels could be generally synthesized via three main approaches, including (a) direct mixing of CPs and the hydrogel's precursors, (b) in-situ polymerization on CPs in the hydrogel matrix, and (c) in-growth polymerization of CPs into the hydrogel matrixes. **Figure 6** shows schematic illustrations of the IPNs production processes.

Making nanocomposite using electron-conducting nanostructures, including carbon nanotubes, liquid metals, graphene, metal nanowires, is another approach to increase the hydrogels' conductivity. Carbon-based materials are preferred candidates for mixing with hydrogels, because their excellent conductivity, high effective surface area, good chemical stability in wet environments, and especially the ability to form covalent bonds with different polymeric network groups. In addition, under the premise of satisfying improved biocompatibility and electrochemical behavior,

*Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

#### **Figure 6.**

*The main synthesis methods towards the CPs IPN hydrogels. (a) direct mixing of CPs and the hydrogel's precursors, (b) in-situ polymerization on CPs in the hydrogel matrix, and (c) in-growth polymerization of CPs into the hydrogel matrixes [13].*

the bioelectronics interfaces created by the materials with hybrid electron-ion charge transferring, shows more efficient signal transmission between the biological tissues and the external bioelectronics systems.

## **5. Conclusion and outlook**

Tissue-electronics interfaces are the key component of bioelectronics systems. These interfaces provide a two-way communication between biological tissue and external electronics devices to record electrophysiological signals and stimulation of the living organs. In biological tissues, the charge transfer is done through ions, while the electronic systems generally use the electrons as electric charge carriers.

Accordingly, the neural interfaces with a hybrid electron-ion charge transfer mechanism can improve the charge transfer processes at bioelectronics. There are two main charge transfer mechanisms at the tissue-electronic interfaces, including capacitive (based on EDL) and Faraday charge transfer. In addition, the biocompatibility, which can reduce FBR and glial scar formation, is an essential parameter for tissue-electrode adhesion improvement that results in accurate and stable signal transmission. Recent general methods to increase the biocompatibility of neural interfaces include reducing the biomaterial's stiffness and elastic modulus, biocompatible coatings, and developing new bioactive materials and composites. Although significant progress has been made in the design and fabrication of tissue-electronic interfaces, some challenges must be overcome before the bioelectronics interfaces can be efficiently operated, including (I) the weak adhesion of the neural electrode materials to biological tissues. This problem may be due to the high hydrophobicity and insufficient biocompatibility of the current interfaces. (II) Inadequate biocompatibility of the electrode materials that leads to FBR, glial scar formation and subsequent tissue-electronics separation. The challenge is that although the electrode materials should have low stiffness and elastic modulus to avoid mechanical mismatch with host living tissue, the weak mechanical properties, especially in dynamic organs, can lead to electrode destruction and failure. Therefore, adapting the properties of the implant to the host living tissue, is important for successful implantation and long-term stability of the electrode. The efficiency of the neural recording/stimulation process depends on the biocompatibility, electrochemical properties such as impedance, charge storage capability, and charge injection limitation of the electrode. High electrochemical impedance reduces the accuracy of electrophysiological signals recording. Reducing methods of the electrochemical impedance mainly include the following: (1) enhancing the conformal capability between the neural interfaces, (2) improving the tissueelectronic adhesion, and (3) modifying the electrode's surface characteristics to adapt with the ECM. In summary, the prospect of developing high efficient tissue-electronic interfaces due to rising the new materials and strategies is expected. To achieve this goal, the main neural biomaterials' properties such as biocompatibility and electrochemical performance must first be improved. It is believed that the development of neural interfaces can contribute to the progress of bioelectronics medicine, neuroscience, and online health monitoring.

## **Conflict of interest**

The authors declare no conflict of interest.

*Perspective Chapter: Tissue-Electronics Interfaces DOI: http://dx.doi.org/10.5772/intechopen.108129*

## **Author details**

Shahab Ahmadi Seyedkhani\* and Raheleh Mohammadpour Institute for Nanoscience and Nanotechnology (INST), Sharif University of Technology, Tehran, Iran

\*Address all correspondence to: sh.ahmadi@sharif.edu

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## *Edited by Magdy M.M. Elnashar and Selcan Karakuş*

This book discusses the synthesis, characterization and applications of biocomposites and nano-biocomposites. It focuses on recent studies, applications, and new technological developments in the fundamental properties of biocomposites. The book includes six chapters that address topics such as the biomedical applications and characterization of biopolymers, biocomposites, and nano-biocomposites.

Published in London, UK © 2023 IntechOpen © Cavan Images / iStock

Biocomposites - Recent Advances

Biocomposites

Recent Advances

*Edited by Magdy M.M. Elnashar and Selcan Karakuş*