Advanced Intelligent Systems - 2023 - Kanjilal - Bioionic Liquids Enabling A Paradigm Shift Toward Advanced and Smart

REVIEW
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Bioionic Liquids: Enabling a Paradigm Shift Toward

Advanced and Smart Biomedical Applications
Baishali Kanjilal, Yangzhi Zhu, Vaishali Krishnadoss, Janitha M. Unagolla,
Parnian Saemian, Alessia Caci, Danial Cheraghali, Iman Dehzangi,
Ali Khademhosseini,* and Iman Noshadi*
nitrate) in 1914, ILs have been a major

Ionic liquids (ILs) exhibit unique properties of good ionic conductivity, electro- scientific area, with the pace of research
chemical and thermal stability, and nonflammability, which make them promising accelerating especially within the last
candidates for biomedical applications. The limitations of their cytocompatibility decade. Increased multidisciplinary studies
have emerged, including chemistry, materi-
are enhanced by using bioionic liquids (BILs) derived from biological molecules
als science and engineering, and chemical
such as amines, sugars, and organic acids. BILs can be synthesized using tailorable and environmental engineering.[1–4] A
chemistries that enable their immobilization onto biopolymers. For example, the driving factor behind the plethora of appli-
cholinium ion and its derivatives have found significant interest in tissue engi- cations stems from the various combina-
neering and drug delivery systems. Ion-doped BIL-functionalized polymers and tions of cations and anions that can be
their composites can also be used to design pH and electrical responsive actuators used to meet the scientific definition of
ILs, which leads to a diverse range of phys-
and sensors. The cytocompatibility and low immunogenicity of BIL-functionalized
icochemical behaviors.[1,2] Their relatively
polymers enable the possibilities of their use for power storage devices as well as low vapor pressures compared to conven-
implantable devices. These devices are gaining recognition and importance in tional organic solvents make them desirable
nucleic acid delivery and molecular medicine. This review focuses on the recent for green processes where scrubbing of sol-
advances of BILs in biomedical applications. Specifically, the review explores BILs vent vapors needs elimination as a unit
as agents for biopolymer functionalization and highlights BILs as solvents for operation.[2] ILs have been further delin-
eated into applications that utilize them as
supermolecular ionic networks.
functional pendant groups in polymeric
structures, or in supported onto membranes
and metal–organic frameworks. Their
1. Introduction hybrid ionic–organic nature makes them suitable for certain cata-
lytic activities or as cocatalytic support with potential applications
Ionic liquids (ILs) are organic salts with low melting temperatures in supercapacitors, ion gels, separation, or lubrication.[1,2] ILs have
(below 100 °C), good ionic conductivity (within 104–102 S cm1 been particularly used for catalytic conversion of cellulosic and
around room temperature), electrochemical and thermal stability, lignocellulosic biomass and their valorization into biofuels and
and nonflammability, making them promising materials for many biorenewable chemicals.[2,3] Thermoresponsive ILs have been
applications.[1] Since the first report on the IL (ethylammonium used for catalyzing hydroformylation reactions proffering a dual
B. Kanjilal, J. M. Unagolla, A. Caci, I. Noshadi V. Krishnadoss

Department of Bioengineering Department of Biological Engineering
University of California, Riverside Massachusetts Institute of Technology
Riverside, CA 92521, USA Cambridge, MA 02142, USA
E-mail: inoshadi@ucr.edu
P. Saemian
Y. Zhu, A. Khademhosseini Mander Portman Woodward
Terasaki Institute for Biomedical Innovation Cambridge, UK
Los Angeles, CA 90064, USA
E-mail: khademh@terasaki.org D. Cheraghali
Center Incubator Technology Health of Medical Sciences
The ORCID identification number(s) for the author(s) of this article Shahrood University of Technology
can be found under https://doi.org/10.1002/aisy.202200306. Shahrood, Iran
© 2023 The Authors. Advanced Intelligent Systems published by Wiley- I. Dehzangi
VCH GmbH. This is an open access article under the terms of the Department of Computer Science
Creative Commons Attribution License, which permits use, distribution Rutgers University
and reproduction in any medium, provided the original work is Camden, NJ 08102, USA
properly cited.
DOI: 10.1002/aisy.202200306
Adv. Intell. Syst. 2023, 5, 2200306 2200306 (1 of 22) © 2023 The Authors. Advanced Intelligent Systems published by Wiley-VCH GmbH
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action as a solvent and catalyst.[2,3] ILs have been employed in sep- ensures a metabolic pathway for biodegradation. This biodegrad-
aration processes with high separation efficiency, particularly ability endows them with a high degree of biocompatibility,
extraction and purification of bioactive compounds and molecules which can be harnessed for further biological applications.
with complex solubility profiles.[2,3] The ability for ILs to be sup- The water-soluble cholinium cation is common in biodegrad-
ported as excellent solvents or impregnated liquid membranes able, cytocompatible, and cost-effective BIL structures.[13]
or as chemical functionalities renders them useful in liquid–liquid Choline is a precursor of cellular phospholipids, such as phos-
extraction as well as solid–liquid extraction, solid-phase extraction, phatidylcholine and sphingomyelin.[14] Choline degrades to
and induced precipitation.[2–4] The wide electrochemical small nontoxic chain molecules, which has enhanced its appeal-
window and ionic conductivity of ILs have been used in electro- ing potential for biological applications. For example, cholinium
chemistry and power storage applications.[4] Their interfacial and cation-based BILs have been investigated with various counter-
surface electrochemistry makes them suitable for usage in both anion combinations, including active pharmaceutical ingredient
composite electrode structures and high-capacitance electrolyte derivatives such as ampicillin, salicylic acid derivates, and pico-
applications.[4] linic acid derivates. These currently established systems showed
The poor biodegradability and environmental toxicity of ILs have a significant improvement in the capacity of cell membrane pen-
limited their applications in wearable and implantable devices. etration with concomitant drug delivery possibilities. Glycine
Developmental research that focuses on biocompatible ILs has thus betaine-based BILs are alternatives to cholinium-based BILs,
prompted the progress of novel compounds with enhanced toxico- owing to their abundance in sugar molasses and similarities
logical and biodegradable profiles.[5,6] Such novel IL structures that in structure with cholinium via trimethyl alkylammonium and
employ moieties from amino acids, artificial sweeteners, glucose, carboxylate structures.[15] However, their applications are limited
and organic acids are termed as bioionic liquids (BILs).[7] to acting as solvents in green synthesis to date. In this review, we
Natural or synthetically derived biomacromolecules may form focus on the use of BILs in biomedical applications, entailing tis-
either the cationic or anionic moiety of the BILs. The first BIL, sue engineering, bioprinting, and bioelectronics. The review also
made by Fukumoto et al., was amino acid (AA)-derived IL, explores BIL-based supermolecular chemistries that have been
wherein the AA was coupled as an anion, either with imidazo- utilized in the biomedical field. The review is based on searches
lium cation or with an appropriate cationic counterpart.[8] of journal articles, books, and patents over, but not necessarily
Imidazolium cation-based ILs have been derived from D-fructose limited to, the years 2001–2022, primarily searched using
as well as polysaccharides.[9,10] Similarly, lignin or hemicellulose Google Scholar, science.gov, PubMed, and ScienceDirect. The
structures have also been converted or derived into cationic or review has concentrated on biomedical applications with a par-
anionic counterparts of ILs.[11] Carboxymethylated chitosan poly- ticular focus on BILs in biomedical applications.
mers have been used as polyanionic counterions to imidazolium A schematic of the application fields is shown in Figure 1a,b.[16]
cations.[12] The presence of either cation or anion that maintains A large amount of current research and developmental work using
the structure of the biomolecular entity from which it is derived BILs remains an indispensable asset for various biotechnological
(a) Electrochemistry (12%) (c)

Tissue Engineering (5%)
Food Industry (5%)
Biomass Processes (8%)
Chemistry and Catalysis (17%)
Pharma and Biomed (14%) Cholinium Cation
Solvents (39%)
(b)
IL as APIs DRUG DELIVERY
Conventional Drugs Solvents/ Anti
as ILs solvents
Dual Active API-ILs Co Solvents
Prodrug ILs Emulsifiers
Picolinic acid
IL: Biomed Nalidixic acid
DRUG DELIVERY
DRUG SYNTHESIS Applications SYSTEM
Additives
SYNTHESIS
Catalysis
Dispersion
Media
Agents
BIOMED ANALYTICS Catalysis
Electrochem Sensors Media
Spectrometry
Electrophoresis
Chromatography Phenytoin 4-amino salicylic acid
Extraction
Figure 1. a) Schematic illustration of the recent advances in BILs and their respective systemic applications, % of the total number of publications on the
given subject. Reproduced with permission.[15] Copyright 2019, Royal Society of Chemistry. b) Biomedical applications of ILs.[14] c) BIL structures most
often used as active pharmaceutical ingredients—cholinium cation is often paired with anions derived from the structures shown.[18]
transformations, followed by their applications in electrochemis- c (Cyt c) in its reduced state, acting as a stabilizer and preventing
try, chemical catalysis, and pharmaceutic applications. To a limited the protein from unfolding during isolation.[26]
extent, BILs have been used in tissue engineering as solubilizers BILs have been used to enhance the electrochemical response
and stabilizers in drug delivery systems because of their improved of materials with low electrochemical conductivities by either
bioavailability. The functionalization of BILs into hydrogels has physically mixing or chemically functionalizing the base material
expedited a variety of applications, such as pH and electrical stim- with BILs.[27] For example, cholinium-functionalized chitosan
uli-responsive actuators and sensors and multiresponsive systems hydrogels have been used in multiresponsive drug delivery sys-
for programmed drug delivery platforms. In addition, BILs are tems due to their superior electrical and pH sensitivities.[28] In a
incorporated into natural and synthetic polymer matrices as sup- study reported in 2014, a choline nitrate–chitosan polymer gel
ported liquids or in the form of functionalization of the polymer electrolyte was used in a thin-film battery with robust mechan-
backbone. Such structures have been used in biomedical devices icals and excellent ionic conductivity appropriate for possible
or power storage applications.[17,18] The tailorability of BIL-func- implantable applications.[29] BILs have been used in ionic gels
tionalized polymers has led to complex engineered structures, for wearable bioelectronics, such as epidermal sensors, biosu-
including artificial muscles or low immunogenic tissue engineer- tures, and neuromechanical interfaces.[27] Their hydrogen-
ing scaffolds.[7,13] bonding ability makes BILs excellent plasticizers for biopolymers
such as starch.[3,4] Figure 2 summarizes commonly used
cations, anions, and alkyl chain substituents employed in BIL
2. Cationic, Anionic, and Zwitterionic BILs structures.[30]
ILs have been used as green solvents owing to their nonflamma-

bility and low vapor pressure.[19,20] The ionic counterparts can 3. BILs as a Strategy for Enhancing Electrical
yield a wide variety of combinations, thus making ILs known Conductivity of Biopolymers
as “designer” solvents. These structures exhibit high solvation,
specificity, and selectivity for separation processes and are advan- The electronic and ionic conductivity of hydrogels and biopoly-
tageous in drug delivery, plasticization, catalysis, and polymer mers have been used widely in biomedical applications. Despite
processing. Their wide electrochemical potential window (which their low impedance, conductive polymers suffer from poor
can be as high as 5.7 V between platinum electrodes) makes mechanical performance, low cohesion, and delamination.[31]
them particularly excellent candidates for electrochemical and The conductivity of biopolymers and hydrogels has been com-
photovoltaic applications. Biocompatible anions or cations used monly improved by incorporating conductive materials such
in BILs lead to metabolic degradation products of relatively lower as gold or silver nanoparticles (AuNPs or AgNPs), graphene, car-
toxicities. For example, the cholinium cation can be metabolized bon nanotubes (CNTs), and conductive polymers (i.e., polyani-
in the body through several pathways and absorbed for essential line, polypyrrole [PPy], and thiophene polymers) into hydrogel
functions. This makes the use of choline in BIL structures a safe networks.[32–35] Despite their biodegradability, these composite
proposition for in vivo biomedical applications without incurring hydrogels have poor biocompatibility. Hydrogel-AuNP-poly
toxic or complex metabolic by-products of degradation.[19,20] In (N-isopropyl acrylamide) (PNIPAAm) nanocomposites were
1998, choline was added as a B vitamin to human vitamins.[21] reported to exhibit thermoswitchable electrical properties. The
It is a precursor to the neurotransmitter acetylcholine and par- AuNPs were functionalized with a vinyl group that would help
ticipates in several biological functions entailing muscle control them covalently bond to the polymer chains. The presence of
and memory. The cholinium cation, often used as a part of BIL these AuNPs improved the electrical conductivity of BILs by
structures, is also a segment of cellular phospholipids phospha- two orders of magnitude.[36] In another study, Dai et al. fabricated
tidylcholine, and sphingomyelin, which is often present in stimuli-responsive and self-healing AgNPs hydrogels. The rapid
bilayer cellular membranes.[22,23] response was predicated on pH and temperature sol–gel switch-
Since the early 2000s, there has been a significant increase in ing. Similar to the previous study, the incorporation of AgNPs
the research work on cholinium cation-based BILs. The tunabil- into polymeric networks has been seen to influence the mechan-
ity and bioactivity of cholinium-based BILs have enabled their ical, swelling, and thermal response of electroconductive hydro-
use as active pharmaceutical ingredients (APIs).[18,24] In such sys- gels (ECHs). [37] Despite these advantages, cytotoxicity makes
tems, the cholinium cation is accompanied by an anion derived their in vivo applications uncertain.
from the API structures such as nalidixic acid (NAL), phenytoin, Another method to improve the electrical properties of ECHs
ampicillin, niflumic acid (NIF), pyrazines acid (PYR), 4-amino- involves adding CNT dispersion to polymer solutions. Xu et al.
salicylic acid (PAS), and picolinic acid (PIC).[25] The structures developed a multifunctional ECH made of polyvinyl alcohol-
often used as APIs are shown in Figure 1c. APIs thus are conju- borax cross-linked hydrogel networks and cellulose nanofiber–
gated with cholinium cations, forming a BIL structure, display- carbon nanotube (CNF–CNT). The approach brought together
ing better solubility and cellular penetration, and therefore the conductivity of CNTs and the templating ability of CNFs.
resulting in novel and improved therapeutic platforms.[18,24] The resulting assembled solid-state supercapacitor showed a
Good’s buffers (GBs) have also been explored as counteranions 117.1 F g1 specific capacitance and a 96.4% retention of capaci-
to BILs.[19] GBs are typical zwitterionic biological hydrogen ion tance even after 1000 cycles.[34] Despite electromechanical advan-
buffers, between pH 6 and 8, with high buffering capacities and tages, the hydrophobicity of CNTs makes it challenging to
low toxicities.[24] Matias and co-workers reported novel choline- incorporate them into ECHs. Zheng et al. used hyaluronic acid
sulfonate BIL buffers with the potential to dissolve cytochrome hydrogel and single-wall CNT composites for microactuator
Figure 2. a) Commonly used cations, anions, and alkyl chain substituents for BILs. Reproduced with permission.[30] Copyright 2020, Elsevier. b) Synthetic
pathways for making BILs from various renewable/biological sources. Reproduced with permission.[15] Copyright 2019, Royal Society of Chemistry.
structures.[38,39] Intrinsically conducting polymers such as blends diffusion inside the polymer hydrogel. Ribeiro et al. reported
of poly(3,4-ethylene dioxythiophene) and poly(styrene sulfonate) improved electrical conductivity of the ionic electroactive materi-
have also been studied for sensing and stimulation. The blends als using similar PVDF–imidazolium and trimethylammonium
showed electrical conductivity of 20 and 40 S cm1 in PBS and DI IL composites, which can be used as electromechanical sen-
water, respectively. Although poor biocompatibility was the main sors.[41] Similarly, levan polysaccharides have been plasticized
disadvantage, the hydrogel composites showed high strain, flex- using cholinium malate BILs, concomitant with ester bond for-
ibility, and stability in wet physiological environments.[40] mation between levan polysaccharide and [Ch][MA] BIL under
BILs have been used to minimize the toxicity induced by con- bending.[42,43] This strategy is summarized in Figure 3.
ductive nanoparticles or polymers. The biocompatibility of BILs Other similar strategies have been employed with cholinium-
is incumbent on the structure of the counterions. Ammonium, based BILs and deep eutectic solvent (DES) structures, where
pyridinium, and imidazolium-based cation structures, such as they were used as plasticizers in polymeric matrices, in effect,
propylimidazolium (PMIM) and propylmethylpiperidinium yielding enhanced electrochemical properties in such compo-
(PMPIP), have been paired with various anions and used as dis- sites. Cholium-based BILs with low toxicity counteranions were
persants in polyvinylidene fluoride (PVDF) matrices to enable used to plasticize starch thin films, which had a significant effect
usage in sensors and actuators.[41] Electrical conductivity gener- on the conductive, thermomechanical, and recrystallization
ally decreased with the increased length of the cation alkyl chains. behavior of the films.[44] In another study, potato starch-based
The bending response in these actuators was attributed to ionic films were plasticized using a cholinium-based BIL-glycerol or
Levan
[Ch][MA]
Polysaccharide
Levan Polysaccharide E
Bo ster
nd
ing
Deformation
(Bending)
Choline-Malate IL Levan_[Ch][MA]
([Ch][MA]) Biodegradable
Electrolyte
Figure 3. Molecular structures of levan polysaccharide, cholinium malate BILs. Schematic molecular structures of biodegradable electrolyte showing the
ester bond between levan polysaccharide and [Ch][MA] IL formed under bending. Reproduced with permission.[41] Copyright 2019.
urea mix as a DES with similar results.[45] As an alternative biomedical applications of such materials in transistors, sensors,
strategy, choline dihydrogen phosphate-based BIL and 1-butyl-3- actuators, and power storage capacitors.
methylimidazolium dihydrogen phosphate-based ILs were synthe-
sized in the form of a novel class of proton-conducting ionic plastic
3.1. Biomedical Applications of BILs and BIL-Modified Polymers
crystals. The plastic crystalline phase showed much higher ionic
with Enhanced Conductivity
conductivities than either BIL or IL alone, promising possible
applications in proton-conducting fuel cells that are required to 3.1.1. Transistors
have fast proton transport in the solid state.[46] A similar strategy
was used in plastic crystals made from choline dihydrogen The development of electronic devices using semiconductor
phosphate-based BILs with phosphoric acid. These plastic crystals materials needs efficient charge carrier control because such
had a higher proton conductivity compared to the pure BILs, charge accumulation can cause chemical reactions or magnetic
which was confirmed with impedance spectroscopy.[47] ordering. Additionally, the formation of electric double layers can
For in vivo applications, ECHs are employed as a possible cause issues like unwarranted discharge owing to the induced
strategy, and they are fabricated by incorporating conductive electric fields. Field-effect transistors (FETs) can employ IL-based
materials into a tunable polymer backbone. They can be fabri- gates that offer the advantages of a wide electrochemical window
cated as per structural applications while utilizing both electronic and superior physicochemical stability and transistor perfor-
and ionic conductivity.[31] These ECHs can be employed in mance.[48] BILs, in particular, can be employed in the form of
electrostimulated drug delivery systems, neural and muscle cell a supported liquid membrane or as a chemically integrated part
cultures, bioconductors, sensors and actuators, prostheses, and of the biopolymer solid-state electrolyte structure. For example,
artificial muscles.[27,29,31] For example, Noshadi et al. engineered
Kim et al. synthesized a levan polysaccharide and choline-based
ECHs by functionalizing nonconductive polymers with choli-
BIL used as electrolytes for biocompatible and biodegradable
nium cation-based BILs, which could then be photopolymerized
transistors using a solid-state electrolyte (Figure 2a). The use
to obtain a tailorable hydrogel platform. The ECH demonstrated
of BIL imparted the fabricated transistors with the advantages
electrical and biocompatible properties akin to native cardiac tis-
of low volatility—due to the intrinsic low volatility of ILs, flexibil-
sue for 2D and 3D cardiac cell cultures. The incorporation of
ity, and transparence in addition to better electromechanical
BILs onto the hydrogel platform also enhanced cardiomyocyte
properties with a specific capacitance of 40 μF cm2. Even at
beating frequency. Annabi et al. electrospun a BIL-modified gel-
low driving voltage, it supported electrochemical ion transport
atin hydrogel platform for physio-electrochemical properties akin
with negligible hysteresis and mechanical reliability.[42] For
to native myocardium without any significant changes to fiber
example, electropotential signals such as the electrocardiogram
properties upon the incorporation of BILs. The cardiopatches
(ECG) and electromyography (EMG) were effectively captured
restored impulse propagation and promoted the growth and
and measured from the human body with these transistors
function of cocultures of cardiomyocytes (CMs) and cardiac fibro-
attached to human skin. They showed stable electrical perform-
blasts (CFs) in an in vitro setup, with a superior contractile profile
ances even when bent or stretched with a superior signal-to-noise
compared to gelatin methacryloyl (GelMA) scaffolds, leading to
ratio. Therefore, BIL incorporation into polymeric networks is a
the development of patches for cardiac remodeling.[31] The for-
plausible approach to obtaining electrical conductivity in hydro-
mation of ECHs using cholinium-based BILs to functionalize
gel structures that can be used in biomedical applications.[42]
biopolymers is shown in Figure 4a,b, while (c) shows the sche-
matic of a solid-state electrolyte–organic transistor based on
cholinium-based BILs. The strategy of using BILs as a part of 3.1.2. Sensors and Actuators
the biopolymer or ECH structure with ensuing enhanced electro-
chemical as well as electromechanical properties has been delin- An ideal sensor requires a broad working range, high accuracy,
eated in the following sections and subsections exploring the and sensitivity. The use of ILs in sensors was facilitated by the
Figure 4. Electrochemical hydrogels formed from immobilizing BIL onto a biopolymer backbone using specific chemistry. The ECHs can have tunable
properties depending upon the biopolymer and extent of BIL functionalization and can be fabricated as per application requirements: a) acrylation of
choline bicarbonate to form BIL-based choline acrylate (I). The panel also shows the conductivity of the polymers functionalized with this hydrogel in a
two-probe electrical station setup (II, III). A schematic of ex vivo experiments performed using rat abdominal muscle tissues, using the BIL functionalized
biopolymeric hydrogels, is shown (IV). The panel also shows the threshold voltages at which contraction was achieved (V, VI, VII). Reproduced with
permission [25] Copyright 2014, Royal Society of Chemistry. b) A new platform of photocurable ECHs made by functionalizing nonconductive polymers
with conductive cholinium acrylate-based BILs. Reproduced with permission.[135] Copyright 2020, Elsevier. c) Schematic of a solid-state electrolyte–
organic transistor (choline-based IL as electrolyte). Reproduced with permission.[91] Copyright 2019, American Chemical Society.
development of poly (ionic liquids) (PILs), synthesized via the been studied in glucose sensors with physisorbed glucose
polymerization of monomeric IL and BIL units due to their good oxidase.[36,36,49] As another example, graphene composites with
electrochemical and electromechanical properties. While ILs and imidazolium-modified PIL or amine-terminated PIL, based on
BILs also proffer the additional advantage of low volatility hence amino acids, were employed as a highly sensitive glucose detec-
making them safer to use in electronic applications, the use of tor.[29,50] Similarly, graphene oxide (GO)–PPy-based PILs have been
PILs offers the processing advantages of a polymeric matrix with- used for dopamine sensing, where they functioned as an aid for
out the experience of the IL/BIL leaching out of the matrix and nanosheet dispersion.[35] ILs, such as 1-butyl-3-methylimidazolium
sensor device. PILs also employed AuNPs and graphene chloride ([BMIm][Cl]), dispersed in biomaterials (i.e., silk) for use
NPs, photopolymerized in imidazolium PIL matrices, thereby in electrochemical biosensors were proven to support cellular pro-
creating structural tunnels as conductive pathways. These have liferation while also being studied successfully as biocatalysts in
amperometric or voltammetric biosensing of enzymes.[51–53] For to the required electrochemical or electromechanical response to
example, heme proteins entrapped in 1-butyl-3-methylimidazo- input. While conductive hydrogels have been used for flexible
lium hexafluorophosphate ([BMIm][PF6])–agarose hydrogel films electronics and devices, some may be hesitant to use them
were used for hemoglobin (Hb), Cyt c, myoglobin, and HRP in vivo because they do not possess any antimicrobial or antifoul-
detection.[54] Composite pastes of multiwall carbon nanotubes ing properties, which makes their fouling of imminent concern.
(MWCNTs) or carbon paste electrodes (CPEs) with various Choline amino acid-based PILs have been developed to provide
imidazolium-based ILs were dispersed in biopolymer hydrogels the dual advantages of metal coordination and electrostatic inter-
that are used for the detection of dopamine, where rapid electron actions and thus exhibited excellent self-healing ability, high
transport occurs at electrodes without significant interference from fatigue resistance, and energy dissipation. The presence of the
ascorbic and uric acids.[55–58] In order to circumnavigate the cyto- choline amino acid-based PILs endowed these polymers with
toxicity of imidazolium ILs, some works have used phenylalanine antimicrobial activity and rapid strain sensing. The electrical
amino acid-based BILs for electrochemical oxidation in glucose response could remain stable even after 1000 cycles of stretching.
sensing, with the intent of being used in implanted devices.[27] These flexible devices have the ability to monitor a large number
Biopolymer–choline BILs dispersions have been used for of subtle physiological motions in the human body, like writing
in vivo detection of lactic acid. The BILs were seen to have a direct (Figure 5a–c). Their sensory ability and biocompatibility make
effect on the protein unfolding and aggregation dynamics owing these PILs promising in sensors and robotics.[60]
to the ion effects of ILs on the biocatalytic activity of the Cytocompatible PILs based on cholinium derivatives have
enzyme.[59] In addition to the advantages of low volatility, the been used to exfoliate graphene and form PILs/PPy/GO
wide electrochemical property window ensures a significantly composite structures where the synergy between lamellar GO,
large response to the electrical or chemical, or mechanical stim- conductive PPy, and cytocompatible PILs results in good electro-
ulus. This allows the BIL–biopolymer dispersion a wider experi- chemical properties with stability, linearity, and high sensitiv-
mental results window and hence superior accuracy.[59] When ity.[35] The PILs are thought to change the surface charge
BILs are incorporated in polymeric structures, the additional properties toward electropositivity with subsequent improve-
advantage of tailorability of the structure can be correlated to ment of aqueous dispersibility, electronic transmission, and
the response, and the structure may be functionalized according electrocatalysis.
Figure 5. Self-healing hydrogels and BIL-modified hydrogels as sensors and actuators. a) The self-healing process and mechanism of hydrogels and
reversible dynamic bonds among BC (bacterial cellulose), PAAc (polyacrylic acid), and Fe3þ, including hydrogen bonds and metal coordination.
b) Relative resistance response of Cho-Trp0.8 hydrogel sensor under different pressure and schematic illustration of Cho-Trp0.8 hydrogel assembled
into a flexible touch keyboard. c) Demonstration of Cho-Trp0.8 hydrogel as a flexible sensor with strain-responsive conductivity. Relative resistance
variation of Cho-Trp0.8 hydrogel sensor in response to large-scale human motions, including finger, wrist, elbow, and knee. Reproduced with permis-
sion.[60] Copyright 2022, Elsevier.
For biomimetic and biocompatible actuator applications, the leak in vivo, as this would result in a loss of activity. In 2021,
material must display softness while being electroactive. Krishnadoss et al. developed a novel electrolyte based on
Though conventional ILs have been used with soft biopolymers, choline-based BIL functionalized hydrogel polymers. As the
their cytotoxicity prevents them from their further use for cholinium BIL is chemically bound to the biopolymer, it cannot
long-term implantable applications. In 2020, Elhi et al. prepared diffuse out of the biopolymer.[66] These polymers were success-
PPy–PVDF using various choline-based BILs, with low environ- fully printed into interdigitated biocompatible soft microsuperca-
mental and cytotoxic impact. The actuators were demonstrated to pacitors along with graphene hydrogel electrodes. Figure 6a–c
be viable candidates for soft robotics. Choline acetate and choline shows the electrolyte synthesis, electrical properties, photo-
isobutyrate-based BILs, among others, showed the highest strain graphs of printed microsupercapacitors, and a comparison of
difference and outperformed imidazolium IL-based systems. its energy and power densities to standards. The electrolyte
The toxicity of the BILs and the polymer composites were tested had a specific capacitance of 200 Fg1, while the supercapacitor
on bacterial strains and HeLa cells. The BIL cytotoxicity was low, had a specific capacitance of 16 μ Fg1 and cyclic stability up to
though incumbent on the counteranion. Thus, these prove to be 10 000 cycles. The energy densities were nearly as high as
promising candidates for fabricating biocompatible soft polymer implantable batteries, with the power density level of implantable
actuators.[61] In a similar study, gelatin was used as a base by Elhi supercapacitors, making these BIL functionalized structures
et al. for building blocks of soft electroactive polymer actuators, promising for in situ 3D printed flexible bioelectronics with
which have the potential for application in biomimetic applica- an integrated power source.[66]
tions. In this study, PPy–gelatin blends were used along with Another method to mitigate the hazards of leaching BILs from
choline-based BILs and compared to PVDF–imidazolium IL polymer matrices is through an ion gel structure. Researchers
blends. Molecular dynamics studies highlighted cation cluster- made gelatin-ethyl-3-methylimidazolium acetate-based
ing as a good predictor of the strain difference of the actuator. cross-linked ion gels for the purpose of developing stretchable
The group also fabricated a trilayer actuator using disk diffusion. and self-healable energy storage devices for flexible and
The gelatin choline-based BIL was more elastic and more implantable electronics.[67] These electronics showed excellent
biocompatible.[62] self-healable and mechanical properties, ionic conductivity,
and temperature-dependent specific capacitance. While polymer
matrices and solvents often cause flammability and explosion
3.1.3. Power Source and Energy Storage hazards, the issue can be mitigated using BIL–polymer ion gels.
These ion gels can be cross-linked or bonded into the biopolymer
As demand for wearable and implantable devices has risen, the to prevent poor mechanical stability and leaching.[67] Safety
research in internal energy storage systems has followed suit to concerns have prompted cholinium or ammonium BIL-based
both miniaturize and make them more biocompatible. BILs offer polymer electrolytes’ development with soft solid features
the advantage of higher capacitance that allows for rapid charg- incorporated in a lithium-ion battery. A good example of this
ing, although their energy storage capacity still remains lower would be 1-ethyl-3-methylimidazolium dicyanamide with
than that of traditional batteries.[63] In a research work reported PVDF-HFP-based thin film laminated polymer–BIL electrolyte
in 2018, GO and reduced GO (rGO) were annealed using choline structures, where the BIL is either dispersed in the polymer
chloride-based BIL and urea to make a supercapacitor with a or functionalized onto the polymer structure.[68] In this case,
capacitance of 383 Fg1. A comparative structure without the the conductivity is incumbent on the liquid phase.
use of the BIL showed capacitance of 321 and 196 Fg1, for Oftentimes, the gel matrices used with BILs are made from
nitrogen-doped reduced GO and undoped reduced graphene polyethylene oxide (PEO)/polyacrylonitrile (PAN)/polymethyl
oxide, respectively, demonstrating the possibility of application methacrylate (PMMA).[69] Similar studies have also found that,
of BILs in energy storage.[63] In a similar study, an environmen- by applying the appropriate BIL to gel matrices, the limitations
tally friendly supercapacitor was fabricated using aluminum- imposed by the presence of reactive and volatile solvents can be
coated paper as a substrate and activated carbon electrodes with mitigated.
choline chloride-based BIL and choline chloride-based DES.
These supercapacitors had a larger operating window and were
cost-effective and printable. Their charge–discharge characteris- 4. Antimicrobial Properties of BILs and Their
tics were comparable to imidazolium-based IL electrolytes. Biomedical Application
Choline chloride with ethylene glycol showed the highest capaci-
tance and power densities, performing better than imidazolium The rapid evolution of antibiotic resistance in microbes has given
IL-based structures.[64] Choline nitrate-based BIL was used in an impetus to the development of novel materials and strategies
conjunction with silk fibroin as an electrolyte in a biodegradable for its redressal. In order to meet the heightened clinical
thin-film magnesium battery. The corresponding specific capac- demand, local antibiotic applications need to balance drug deliv-
itance was 0.06 mAh cm2 and the entire device was enzymati- ery efficiency, cytotoxicity, and antibacterial efficacy.[67–70]
cally degradable. The BIL-based battery system is a promising Imidazolium-based PIL with antibacterial properties was grafted
tool for next-generation biodegradable power sources, especially on titanium dioxide (TiO2). This was photocured and ion-
for transient medical bionics.[65] exchanged with L-proline and L-tryptophan. The resulting struc-
In situ 3D printability of implantable bioelectronics needs an tures had excellent activity against Staphylococcus aureus and
integrated power source that can be bioprinted too. The power Escherichia coli cytocompatibility and blood compatibility.[71]
storage system should be based on an electrolyte that does not The common assumption is that a higher charge density of
Figure 6. Functionalization of Choline BIL to polymers and its simultaneous photocross-linking as a strategy to yield materials for high capacitance
electrolytes: a) synthesis of choline BIL and its conjugation to methacrylated gelatin and PEG to yield BIL functionalized gelatin methacrylate (BG)
and BIL-functionalized PEG diacrylate (BP). b) Galvanostatic charge/discharge curve of GH-L (working electrode) with PBS buffer, BIL-conjugated gelatin,
and PEG (with 0% and 15% BIL loadings), as electrolyte at 0.1 A cm 3 and 1 to 1 V, Tafel plot of the same hydrogels at 0–1 V, charge–discharge
characteristics of uncross-linked BIL-functionalized gelatin and PEG as electrolytes with carbon electrodes. c) Bioprinted supercapacitor structures using
the BIL-conjugated biopolymers, a sample of 3D-printed energy storage device connected to the 1 V power source to illuminate the LED, Ragone plot
comparing energy and power densities of the microsupercapacitors made from the BIL-conjugated biopolymers. Reproduced with permission.[66]
Copyright 2021, Elsevier.
imidazolium cations and longer alkyl chain length endow of PPV.[73] Other strategies, like cationic liposomes exhibit antibac-
remarkable antibacterial properties. Thermally sensitive antimi- terial effects by preferentially adsorbing the negative cell wall via
crobial hydrogels have been formed from the stereocomplexation electrostatic interactions.[74] Polyvinyl alcohol (PVA)–tetrahydroxy-
of ABA block copolymers from L-lactide and ethylene glycol and a borate (B(OH)4) hydrogel with silver ions can act as a vector to
polycarbonate triblock functionalized with ammonium.[72] These make an antimicrobial multifunctional hydrogel, thereby expand-
can create micellar structures in water, with a substantial ing its biomedical applications.[75] It is thought that borate ester
effect on the counteranion of the antimicrobial properties.[73] bonds between PVA and B(OH)4 form a network junction, which
Assembled and aggregated structures based on BILs are dis- endows the multifunctionality that spans the hydrogel’s moisture
cussed in greater detail in a later section. retention to self-healing, syringe ability, and antibacterial effects
Further development in this front is an antibiotic switch based ideal for wound healing.
on reversible supramolecular assembly between poly(p-phenylene Antimicrobial properties have often entailed incorporating
vinylene) (PPV)-ammonium PIL and cucurbit, giving rise to a metal nanoparticles as an approach of choice. Mandal et al. dem-
noncovalent complex with a hydrophilic exterior and hydrophobic onstrated that polyethylene glycol (PEG)/TritonX-100 capped
interior cavity, which encapsulates quaternary ammonium ions, AgNPs, incorporated into lyophilized collagen scaffold, showed
thus stabilizing the complex and reducing the biocidal activity gradual antibacterial activity on gram-positive and gram-negative
bacteria.[68] Similarly, Chieu et al. studied AuNPs–cellulose/wool with the gram-negative cell wall of E. coli. While CAGE has been
keratin (KER) composites and imidazolium-based ILs as sup- used for topical infections, the use of choline-based BIL
port.[49] The biocompatible composite showed bactericidal capa- increased the antimicrobial potency, owing to choline’s attraction
bilities with 97–98% growth reduction of antibiotic-resistant toward the cell membrane, which allows for easy injection of
bacteria like Enterococcus faecalis and S. aureus. These were used CAGE into the microbe, thereby terminating the cells.[83]
for controlled drug delivery and to treat ulcerous infected wounds Similar research work in 2020 reported cholinium-based BILs
as dressings. Despite advantages, biologically significant physico- with 5-dinitrosalicylate, gallate, 2-(4-isobutylphenyl)propionate,
chemical properties of NPs are challenging to manage and scale behenate, and peracetate anions. Throughout various studies,
for practical applications.[49] upon exposure to a variety of microorganisms, they were proven
Thus, ILs, particularly imidazolium-based ILs, were used as to have excellent antimicrobial resistance and cytocompatibil-
an alternative strategy. Jiang et al. synthesized quaternary ity.[84] Cholinium-based BILs have been used in conjunction with
ammonium salt of gelatin using 2,3-epoxypropyl trimethylam- zinc oxide (ZnO) nanoparticles in antibacterial formulations for
monium chloride (EPTAC). This epoxypropyl salt served as topical applications. The application of the BIL to these nanopar-
an antimicrobial polymer, containing thermoresponsive ticles both combats ZnO’s tendency to agglomerate, and has a
poly(N-isopropylacrylamide) (PNIPAM) and redox-responsive synergistic effect on ZnO’s antibacterial properties. These differ-
poly(ferrocenyl silane)-based hydrogels, which provide an excel- ences make the usage of ZnO nanoparticles in conjunction with
lent combination of antimicrobial resistance and biocompatibil- cholinium BILs promising alternatives to traditional antibiotic
ity for the targeted cells, offset only by their lack of stability.[69] therapy. This same formulation was also shown to be biocompat-
Liang et al. studied imidazolium salts by loading them into ible and nontoxic to normal keratinocyte cells, even under cocul-
hydrogels and testing for antimicrobial properties against ture conditions.[85]
S. aureus, Methicillin-resistant Staphylococcus aureus (MRSA), In another work, with choline-based BILs, aggregated micellar
E. coli, and Pseudomonas aeruginosa PA01 bacteria, with up to surfactant structures of choline laureate and choline oleate-based
96.1% efficiency.[70] Huan et al. used antimicrobial imidazo- BILs were studied by Shah et al. for antimicrobial applications.
lium-based BIL–PVA cross-linked hydrogel with high strength, The antimicrobial activity of the individual BIL, as well as that in
antibacterial, and antifungal abilities, which furthermore pro- a mixture, worked well against gram-positive and gram-negative
moted cutaneous wound healing. Qin et al. developed pyrrolidi- bacteria. They also displayed low cytotoxicity in vitro with human
nium-based polymeric ILs for antibacterial membranes with C2C12 cell cultures.[86]
an efficiency that increased with an alkyl chain length of
substitutions.[76] They demonstrated exceptional hemocompati-
bility and low cytotoxicity in vitro for use in topical applications. 5. Hemostatic Properties of BILs and Their
While the use of imidazolium-based ILs is sufficient for anti- Biomedical Application in Tissue Adhesives
microbial applications in topical applications, they have an inher- and Antibacterial Dressings
ent cytotoxicity that prevents the ready proliferation of cells. This
means that it cannot be readily used in corneal applications or The traditional tissue trauma repair and wound closure methods
in vivo implants, which need the proliferation of cells while are beset by improper tissue integration due to poor biocompati-
allowing microbial resistance. Cholinium-, phosphonium-, and bility. This imperfection often leads to poor wound healing and
ammonium-based ILs have been studied for their antibacterial infections, an example of which is medical-grade cyanoacrylates.
properties as possible alternatives for the ILs. Sivapragasam In addition to being biocompatible, biodegradable, or acting as a
et al. studied microbial toxicity with phosphonium/ammonium drug carrier, rigid biodegradable material adhesives need to be
cationic BILs where the anions were chosen from phenylalanine/ resilient and attach firmly to underlying tissue to prevent body
taurinate/hydroxide/ acetate.[77] The ILs exhibited EC50 values fluid leakage and minimize invasion. A vital wound-healing
from 100.2 to 1000 mg L1 and underscored that the anions were adhesive property is that of hemostasis. Clotting, a vital process
the primary contributors to the toxicity. In another study, that provides the wound with a physical barrier, is incumbent on
cholinium-based ILs like choline phenylacetate demonstrated clotting agents, such as clotting factors, thrombin, and fibrino-
excellent inhibition of all microorganisms tested.[78] Salicylate, gen. Still, most of these hemostats are suitable for very shallow
gallates, propionates, and peracetates of choline showed external wounds, and the need for hemostatic biomaterials, inter-
promising inhibitory performance on gram-positive and nal injuries, and deep cuts remains unmet.
gram-negative bacteria and yeasts, in addition to being biode- Thrombin and fibrinogen-based injectable solutions pose the
gradable, making them promising candidates for wound healing risk of activating coagulation in the circulatory system. To
applications.[79–81] address this, researchers have studied polymer-based materials
A similar work by Siopa et al. entailed choline BILs based on that can simultaneously exhibit both adhesive and hemostasis.
dimethylethanolamine monoquaternary ammonium salts and Ryu et al. made hemostatic adhesives from injectable hydrogels
methyl diethanolamine, diethanolamine, and triethanolamine using thermosensitive chitosan/Pluronic composites. The chito-
monoquaternary ammonium salts for studies on antibacterial san was functionalized using catechol groups, cross-linked with
resistance. It was revealed that the presence of a hydroxyethyl thiolated triblock Pluronic F-127.[87] Compared to the control, the
group along with a C14–C16 linker in a choline compound total blood loss was brought down by nearly 75%, with these com-
improved antimicrobial activity while also decreasing the BIL’s positions, with easy setting under body temperature and good
cytotoxicity.[82] Choline and geranate (CAGE)-based BILs adhesion to soft tissue. Lih et al. studied rapid curing of
reported by Ibsen et al. identified the interaction mechanism chitosan–PEG hydrogels as hemostatic adhesives in similar
work.[88] The hydrogels also showed improved skin incision heal- cell membranes and their inverse but identical structures in
ing relative to sutures, fibrin glue, or cyanoacrylate, suggesting the choline phosphate-based BIL that couples to the cellulose
promising applications for biomedical use. Other biopolymers membrane. The cellulose membranes were functionalized onto
like alkali polymerized, complexed, polydopaminesodium the surface with polymer brushes containing choline phosphate
alginatepolyacrylamide (PDASAPAM) hydrogels have been BIL groups using surface-initiator atom transfer radical polymer-
studied for skin tissue engineering.[89] They exhibited good adhe- ization followed by click chemistry. Red cell binding was seen to
sion to porcine skin with rapid blood coagulation, making them be proportional to the density of choline-based BIL binding on
potential candidates for skin tissue engineering. the brushes. The red blood cells (RBCs) were seen to bind like
Hong et al. studied adhesive hemostatic hydrogels for arterial a “bound pseudopodia”-membrane projections that distorted the
repair and healing heart bleeds. These adhesive hydrogels were RBC shape. This type of binding underscored the multivalent
based on photoreactive gelatin methacrylate, N-(2-aminoethyl)-4- interactions between the RBCs and the choline phosphate
(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide, BIL-functionalized cellulose membrane, with concomitant prom-
and glycosaminoglycan hyaluronic acid, which is a mimic for ising implications for hemostasis and trauma management
the extracellular matrix. The matrix was capable of withstanding (Figure 8a).[93]
pressures much higher than that of commercial fibrin glue.[90] The mechanisms of hemostasis are thought to be multifari-
The other class of material that has recently been studied in ous. One of these mechanisms is the formation of a collagen net-
biomedical applications is the BIL-based bioadhesive structures. work that traps the red blood cells. In 2020, Tarannum et al.
As a result of the abundance of positive charges in the structure, studied the effects of choline BILs as biocompatible collagen
the anions’ adhesive strength surpasses that of the cations’ and is cross-linkers and stabilizers. The hydration dynamics were
more capable of rapidly holding blood. Noshadi et al. reported probed using NMR relaxation and impedance measurements.
novel hemostatic bioinspired multifunctional photocurable adhe- Choline-based BILs cause a reorientation of the surrounding
sives with choline-based BIL-conjugated biopolymers backbones, water milieu, casing compaction of collagen, pushing it toward
displaying excellent adhesion, biodegradability, and biocompati- cross-linking. The collagen scaffolds treated with BILs showed
bility. The burst pressures increased by tenfold over the control higher crosslinking and platelet attachment levels while retaining
and over 50% lowering of blood loss from a liver cut model over their cytocompatibility. Choline-based BILs thus acted like bio-
control sutures and staples, underscoring its apparent advan- compatible crosslinkers of collagen with possible implications
tages. However, existing adhesives have limited functions and in biomedical applications (Figure 8b).[94]
applications; BILs may contribute to building a new platform
for the synthesis of novel multifunctional adhesives, augment
the utility, and broaden their applications. Figure 7 illustrates 6. Antifouling Properties of BILs and Their
the hemostatic properties of various IL/BIL-functionalized poly- Biomedical Applications
mers and composites. Antimicrobial properties are especially
important if the polymer serves as a tissue adhesive that allows Biomedical fouling is caused by the nonspecific adsorption of
for integration with the native tissue, where the polymer must cells, proteins, and microorganisms onto the scaffold and
have a structural similarity to the native tissue and must allow implant surfaces, impairing their function as bandages for
cellular proliferation in a watery body fluid-laden environment. wound healing, biomedical devices, or biosensors. General-
The choline BIL structure is a precursor of a cellular phospho- purpose antifouling strategies are challenging to be retrofitted
lipid bilayer, leading to their excellent adhesion, thus allowing for for biomedical applications. Soft hydrogel-like surfaces have
cellular proliferation and integration with the tissue over time. At been designed to avoid excessive fouling by inhibiting adherence,
the same time, the polymer also demonstrated excellent antimi- which is a property that makes them susceptible to mechanical
crobial resistance against gram-positive and gram-negative bac- damage or exfoliation after long-term use or degradation from a
teria in both in vitro and in vivo infected corneal injury models, host of environmental factors.[95–97]
making it a promising approach for tissue repairs, wound dress- ILs are gradually gaining popularity as magnets in biofilm pre-
ings, and flexible electronic attachment to tissues.[91] vention. The mechanism by which their low cytotoxicity balances
In 2021, Das et al. studied the effect of various choline this antifouling activity is still an area of study. The advantage
BILs─choline fumarate (Ch-Fu), choline adipate (Ch-Adi), cho- offered by ILs is their tunability of properties which can be mod-
line caproate (Ch-Cap), choline caprylate (Ch-Capl), choline ified to suit a given application environment. ILs range from imi-
capriate (Ch-Capr), and choline laurate (Ch-Lau)─for selective dazolium and quinolinium to cholinium cationic head structures
coagulation of κ-carrageenan from Kappaphycus alvarezii seaweed that are being used as magnets. It has been seen that the modifi-
extract obtained using water and alkali. Choline caprylate and cation of the cationic head is primarily responsible for driving the
laurate BILs displayed selectivity in coagulating the polysaccha- antifouling–cytocompatibility balance. Antifouling capability is
ride, promising implications for wound dressings.[92] Wound one of the essential requisites for the targeted delivery of thera-
dressings need a critical optimization between bleeding control peutics or diagnostic particles. Thus, in addition to being used
and wound healing. Often electrostatic interactions are utilized to for enhanced cell penetration, cholinium BILs are being increas-
drive dressing adhesion. In 2016, Yang et al. studied a choline ingly studied for their control of pathogenic biofilms.[98]
phosphate BIL-functionalized cellulose membrane for arresting Traditionally, robust solutions entailed composites like
human red blood cells with potential application in wound dress- PVA and poly(2-acrylamido-2-methyl-1-propanesulfonic acid)
ing. The bioadhesion was driven by multivalent electrostatic (PAMPS)/polyacrylamide (PAAm) double network gels, which
interactions between phosphatidyl choline lipids heads on the showed antifouling activity of hydroxy and sulfonic groups
Figure 7. Hemostatic properties of IL–polymers and composites—the application of various strategies to prompt hemostatic response in biopolymers
a) PDA–catechol adhesive: adhesive strength of hydrogels to porcine skin;[87] b) tissue adhesive made by conjugating an acrylate derivative of cholinium-
based BIL onto various biopolymer structures (gelatin methacrylate and PEG diacrylate): ex vivo and in vivo results, including puncture sealing and
patching of a porcine heart wound. Measurement of burst pressure in the explanted heart. Blood loss volume estimated from in vivo tail cut model.
BIL conjugation renders them highly efficient tissue adhesives with hemostatic properties. Reproduced with permission.[91] Copyright 2019, American
Chemical Society. c) Schematic synthesis of PAA/Laponite NC gels. Reproduced with permission.[136] Copyright 2014, American Chemical Society.
against barnacles.[97] Self-healing coatings made using disulfide hydrogels.[100] Yang et al. studied salt-responsive zwitterionic
functionalized hydrogels were reported for their antifouling antifouling polymer brushes of poly(3-(1-(4-vinyl benzyl)-1H-
activity. Some antifouling hydrogels were made from PEG meth- imidazole-3-ium-3-yl)propane-1-sulfonate).[19] At appropriate
acrylates or N-hydroxyethyl acrylamide and 2-(methacryloyloxy)- ionic conditions, the brushes switched to yield surfaces with very
ethyl trimethylammonium chloride.[99] Researchers also little (<0.3 ng cm2) protein adsorption and hence fouling and
developed mussel-inspired self-healing antifouling hydrogels, extremely low friction (u 103), thereby demonstrating their
which were based on ABA triblock copolymers in which cate- promising versatility in the medical field.
chols and other aromatics provided them with rapid self-healing None of these traditional approaches satisfactorily achieved
capabilities via hydrogen bonding.[97–102] the antifouling cytocompatibility trade-off that biomedical appli-
The poor mechanical properties of hydrogels that limit their cations entail. Thus, cholinium BILs were studied for the pur-
practical application were circumnavigated using BIL functional- poses of enhancing antifouling capabilities in liquid-infused
ization. Kostina et al. studied zwitterionic carboxy betaine meth- porous surfaces.[13] Wylie et al. reported that slippery, super
acrylamide and 2-hydroxyethyl methacrylate (HEMA)–Laponite hydrophilic surfaces that had been infused with polyvinyl
dispersions as antifouling, self-healing, robust, and tough chloride (PVC) substrates were roughened by phosphonium
Figure 8. a) Cellulose membrane functionalized with polymer brushes bearing multiple choline phosphate BIL groups—used as excellent hemostatic
agents. Reproduced with permission.[92] Copyright 2016, Elsevier; b) choline-based BILs as a biocompatible cross-linker for collagen. Reproduced with
permission.[93] Copyright 2020, Elsevier.
and cholinium BILs, which could reduce bacterial adherence by manufacturing has been gaining popularity as a means of device
up to four orders of magnitude within 24 h.[101,102] fabrication, particularly in tissue engineering, flexible electron-
Targeted delivery of therapeutic and diagnostic particles is one ics, sensors, actuators, and power storage. PILs offer physical
of the most challenging applications to tackle, given the rapid and viscoelastic properties along with the advantages of the
in vivo fouling that prevents the particles from achieving intrinsic properties of polymer’s processability, mechanical sta-
their targeted efficacy or reaching their destination. Another bility, and biocompatibility, thus making them popular in the
issue is the rapid clearance of intravenously administered bioprinting field as a versatile material.
nanoparticles (NPs) from the in vivo system or bloodstream. PILs offer flexibility in molecular design for bioprinting that
Hamadani et al. used a special biocompatible protein-avoidant needs a delicate balance of processing and synergistic properties.
ionic liquids (PAILs) based on choline hexanoate BIL, as an PILs can be homopolymers, copolymers, or even cross-linked
NP surface modifier to stably coat poly(lactic-co-glycolic acid) structures, including IPNs and SIPNs. Tethered and mobile
(PLGA) NPs. The NPs showed a marked increase in resistance charges allow for conductivity and charge stability, which are
to in vitro protein adsorption and hence greater retention in the essential for device and energy storage applications. When utiliz-
blood of mice. The choline hexanoate BIL also successfully redir- ing 3D printing, the IL monomer can be polymerized with a cat-
ected NP biodistribution to preferentially accumulate in the alyst, or a PIL structure can be cross-linked into an infinite
lungs, thus increasing possibilities of enhanced bioavailability network; for example, choline-functionalized methacrylate
with lower adjunct cytotoxicity, making it a promising candidate BILs could be in situ photocross-linked while being 3D
for targeted cancer drug delivery systems.[103] In another study, printed.[42] Traditionally, when 3D printing phosphonium ionic
choline-based BIL monomeric units were radically polymerized monomers, the monomers are polymerized with diacrylate.[105]
into various biopolymer chains to deliver salicylates. These graft Click chemistry, which allows orthogonal combinatorial synthe-
structures are assembled into spherical superstructures. The use sis, has been used in copper-catalyzed azide-alkyne cycloaddition
of choline BIL significantly reduced the antifouling of these or thiol–ene and thiol–yne reactions for triazolium PILs.
aggregates. The biodistribution was dependent on the chain Sequential azide–alkyne coupling and Menshutkin reactions
length of the polymer.[104] have been employed for a complex sequence of ions in PIL
structures.[105]
Imidazolium tetrafluoroborate PILs have also been 3D
7. BILs and BIL-Functionalized Polymers in printed into piezoresistive tactile sensors.[106] PILs such as
Bioprinting 1-ethyl-2-methylimidazolium tetrafluoroborate ([EMIM][BF4])/
2-[[(butylamino)carbonyl]oxy]ethyl acrylate (BACOEA) can con-
Owing to trends toward the miniaturization of implantable trol composition and processing parameters, thus making it
and wearable biomedical devices, 3D bioprinting or additive an appropriate choice for printable devices.[106–108] The ILs that
have been used ranged from biocompatible choline structures to 8. The Applications of BILs in Tissue Engineering
imidazolium and a wide variety of combinatorial anions and cat-
ions, which offer flexibility to circumnavigate the biomedical In order to successfully engineer tissues, the materials used need
challenges in drug delivery and the bioavailability of drug to mimic biological materials. A common strategy entails cultur-
insolubility. BILs can be easily applied in inkjet 3D printing ing harvested autologous chondrocytes on collagen membrane
for biomedical applications such as printing of tissues and and implanting them at the site of the injury. While insufficient
organs or even device printing of actuators and sensors (i.e., cel- vascularity acts as a hurdle to this approach, it can be improved by
lulose impregnated with phosphonium/cholinium or even engineering microvasculature into the membrane scaffolds before
[EMIM] acetate ([EMIM][OAc])).[109] implantation. By engineering these scaffolds to provide regenera-
The primary issue with the usage of other ILs is their cytocom- tive signals to cells, one can repair and regenerate tissues.
patibility. Sometimes, this can be offset by using a biopolymer as This approach requires complex biomimetic biomaterials with
the counterpolyanion with an imidazolium cation. However, it is multifunctional capability, in addition to bioinstructive, stimuli-
the cation head that is primarily responsible for an IL’s cytotox- responsive abilities. Biomaterials must transmit appropriate stim-
icity. In order to diminish its cytotoxicity, a true BIL must be uli at tissue, cell, and subcellular levels with critical pathways,
based on a biocompatible cation. For example, PVDF [EMIM] hence entailing cell adhesion complexes or contractile forces.
bis(trifluoromethylsulfonyl)imide ([TFSI]) ([EMIM][TFSI]) This is especially true for muscle and neural cell development,
electrospun fibers have been used for tissue engineering, signif- which show significant differences when grown on rigid gels that
icantly affecting cell viability while maintaining their noncytotox- mimic bone structure or brain tissue mechanicals. Heart cells
icity.[41] The same combination has been used in a polymer require synchronous beating to grow, which paves the way for
electrolyte–biocompatible magnesium-based implantable battery the requisite of a mechanosensitive scaffold. Additionally, the scaf-
device.[110] The electrolyte also incorporated chitosan biopolymer, fold must permit biochemical signaling and deliver growth and
which enhanced its biocompatibility, ionic conductivity, and vol- angiogenic factors for vascularization, cytokines, and adhesion
umetric power density, pointing at a capability of supporting peptides for the neural supply.[41] Beyond these is the ability of
small implantable medical devices. Transparent and stretchable a scaffold to keep itself from fouling and infection or, for that mat-
ter, be used as a system for delivering therapeutic genes.[41,90]
ionic conductors have been developed, based on poly(MMA-butyl
Due to their porosity and high surface-to-volume ratio, nano-
acrylate) with IL [EMIM][TFSI] as an ionic skin-type strain sen-
fibers have been acknowledged as promising tissue engineering
sor, to be used for human movement sensing, with remarkably
candidates. They are fabricated via electrospinning, which is
high elongation limits and a recovery ratio of >96% even after
commonly used for its simplicity and scalability.[41,90] Despite
500 cycles.[111] Figure 9 illustrates IL and BIL-based formulations
their difficulties in spinning, polyelectrolytes have been used
in sensors, power sources, and bioprinting.
to mimic natural extracellular matrix. The limitation of using
ECHs have gained popularity in bioprinted biomedical appli-
them is their jet instability, which makes scaling a complex pro-
cations as well. They are hydrated networks that can be modu-
cess. As most polyelectrolytes are water-soluble, electrospinning
lated into highly tunable structures by the functionalization or
and process scaling become difficult due to the low volatility of
incorporation of nanoparticles and conductive polymers.
water and its high surface tension as well as ion dissociation,
Biocompatible ECHs are often based on either blends or func-
leading to poor rheological control.[116] Often BILs or other salts
tionalized ILs with biocompatible polymers, where ILs can be are added to nonpolar polymers to alter their electrical properties,
grafted to the structure of hydrogels. Choline BIL grafted hydro- allowing their solutions to become conducting despite their insu-
gels combine the requisite properties of the BIL with the easy lating nature and hence facilitate their electrospinning. Herein,
processability of the polymer for bioprinted applications such the electrospinning of biocompatible PIL could provide a
as tissue engineering, biosensors, flexible electronics, and other superior recourse to materials that are adequately responsive
implantable medical devices. For example, Walker et al. synthe- to electrical stimulus while being spinnable, owing to their
sized a photocross-linked GelMA prepolymer, which was acry- unique architecture.[30] Only a few PIL structures have been
lated using a modified choline BIL structure. The hydrogels electrospun, even though PILs are organic soluble and suitable
were accessible to bioprint and demonstrated tunable electrical candidates for electrospinning. Poly(3-cyanomethyl-1-vinyl-
conductivity within the range of native cardiac tissue. It was used imidazolium bis(trifluoromethanesulfonyl)imide) in blends with
to bioprint scaffolds with and without encapsulated cells, and PVP, PVA, or PEO have been used to increase chain entangle-
maintained excellent viability of the cells encapsulated. The ments without viscosity alteration.[97] In electrospun fibers, the
seeded cardiac cells displayed a higher beating frequency relative solvent also has a tremendous effect on the polymer’s structure.
to the control GelMA hydrogel scaffolds, indicating that bio- In this context, electroactive electrospun PVDF fiber mat compo-
printed BILs can be adapted to biomedical technology.[112–115] sites with 5–10% of and IL-based on 1-ethyl-3-methylimidazo-
In a similar study, choline BILs were grafted onto PEG and lium bis(trifluoromethanesulfonyl)amide were developed for
gelatin structures to enhance the mechanical and electrical prop- biomedical applications.[41] Around 10% IL caused complete
erties of the polymers. These were bioprinted into microsuper- PVDF crystallization in the piezoelectric β-phase. This estab-
capacitors and studied as subcutaneous implants. The flow lished that PVDF fiber properties could be tailored by differenti-
properties and ensuing device performance were seen to be ating the IL connect for integrated sensor and electromechanical
directly correlated to BIL functionalization.[65,66] Figure 9 shows actuator devices. Nevertheless, again, the limitation of cytocom-
applications of various bioprinted conductive hydrogels and pol- patibility makes cellular proliferation and implantation an issue
ymers functionalized with BILs. of concern.
Figure 9. a) BIL-based formulations in sensors, power sources, and bioprinting: biosensors: PIL-gold nanocomposites, nano PIL-graphene sheets, glucose
sensing using glucose oxidase embedded poly(ionic liquid) microgels, PIL/PPy/GO nanosheets for dopamine detection. Reproduced with permission.[137]
Copyright 2016, John Wiley & Sons. b) Pressure sensors were fabricated by 3D printing a conductive self-healing hydrogel and used as sensing devices.
Reproduced with permission.[111] Copyright 2019, Elsevier. c) Printing of energy storage device using ALLEVI2 bioprinter and a choline BIL-functionalized
conductive hydrogel on porcine skin, subcutaneous supercapacitor implantation. Reproduced with permission.[65] Copyright 2019, Elsevier.
BILs, as an alternative strategy, have also been used in muscle modified and are highly responsive to dynamics encountered
regeneration by employing active scaffolds with mechanoelectrical by self-assembled nanoarchitectures with concomitant enhanced
stimuli in a biomimetic microenvironment. In a study by Meira sensitivity toward environmental stimuli─this, along with their
et al., imidazolium ILs and cholinium BILs acted as composites simplicity and ease of modification, makes them particularly
or blends with PVDF and were cast into thin films to fabricate ionic alluring in controllable drug release and bioimaging applications.
electroactive materials. The BILs employed were 2-hydroxyethyl-tri- While they have been used as solvents and plasticizers, BILs
methylammonium dihydrogen phosphate [Ch][DHP]. Researchers and ILs have also been grafted onto the structures of a vast assort-
witnessed an increase in electrical conductivity and heightened ment of polymers to enhance biocompatibility.[28,122] These
PVDF crystallization in the polar β-phase. While the imidazolium blends and grafted polymers often create aggregates and self-
ILs’ performance overall surpassed that of the BILs’, it was offset by assemble formations that can be adapted to drug delivery sys-
the excellent cytocompatibility shown by the BILs with exceptional tems.[122] For example, cellulose-poly(L-lactide) grafts synthesized
C2C12 cell proliferation.[117] Chitosan is a well-received cationic in imidazolium-based ILs were self-assembled into micelles and
polyelectrolyte polymer that has been used in a wide variety of bio- used for sustained drug release. These assemblies had cores and
medical applications. In 2013, Brett et al. used chitosan, a cationic shells as hydrophobic PLA and hydrophilic cellulose segments,
polyelectrolyte, with choline dihydrogen phosphate and choline respectively.[122,123] Similar imidazolium IL–polyacrylamide-
chloride BILs to develop biocompatible and biodegradable materi- based aggregated structures have been used for thermal and
als for improved electrical and pH-sensitive properties. It was pH stimulus-responsive drug delivery.[124,125] ILs protonating
observed that a low pH (acidic) enhanced conductivity and the actu- groups like N,N-dimethylaminoethyl groups gave rise to the
ation capacity of the films, which was more pronounced with decontraction of the brush structure, reduced micellar diameter,
[Ch][DHP]. These were studied as stimuli-responsive scaffolds and induced rupture of the micelle at a higher pH, thus making it
for tissue engineering and other biomedical applications. The a viable structure for pH-sensitive drug delivery.[126] Similar
simultaneous effects of ILs on the electrical response of the films concepts have been used for drug uptake with chitosan–lilial con-
allowed for the development of biocompatible and biodegradable jugates made in imidazolium-based ILs, where the aggregate
integrated iontophoretic systems for tissue engineering.[28] structure was seen to disintegrate at lower pH and could be
Polylactides (PLAs) are biopolyesters that possess promising used for lysosomal or endosomal uptake as a gradually acidified
biocompatible and biodegradable characteristics. However, their process.[127] ILs like (1-octyl-3-methylimidazolium acetate
high hydrophobicity is of primary concern in tissue engineering ([OMIM][Ac]) have been used for making biopolymer-particle
applications. In a recent study, these limitations were circum- suspension-based delivery systems that overcome the limitations
vented by blending them with isotactic acid and choline taurinate. of the size issue of NPs.[127,128] These structures were used in
This blending caused partial aminolysis of the ester bonds of the drug burst release studies with up to 80% sustained drug release
polymer by the taurine amino group and led to the stabilized dis- for 10 h. Figure 10 illustrates some assembled and aggregated
persion of oligomers. The grafted choline taurinate allowed for the structures based on BIL-modified chitosan for biomedical
modulation of pore dimensions in porous scaffold structures and applications.
the enhancement of hydrophilicity, thus making cellular prolifer- In recent studies, cholinium and other ammonium ILs have
ation attainable.[118] Choline BILs have been used earlier in collag- been used as biocompatible alternatives to imidazolium ILs in
enous matrices. They acted as cross-linkers for the collagen aggregated structures. Drug nanocarriers composed of linear
structure and exhibited excellent cytocompatibility with the possi- copolymers contained different contents of cholinium-based
bility of being used for biomedical applications.[119] Choline ace- ILs like 2-[(methacryloyloxy)ethyl]trimethylammonium chloride.
tate BIL and chitin have been used in the form of α-chitin-based The chloride anions of the polymer chain were used for ion
3D tissue engineering structures with porous morphology, inter- exchange with the pharmaceutical anions. These characteristics
connectivity, and excellent hydrophilic character. The cytotoxicity demonstrated that the polymer-drug ionic conjugates are suitable
assays also underscored the biocompatibility of choline-based BIL drug carriers with potential medical applications, particularly in
when seeded with human adipose stem cells.[120] treating lung and respiratory diseases. [129]
In a 2018 work, therapeutic DES, based on choline chloride BIL Nevertheless, another approach to the formation of aggregates
and ascorbic acid, was reported. Throughout a 6-month span of is the novel use of ester-functionalized surface-active ionic
maintenance during which these BILs were applied to the solvents, liquids (SAILs) based on nicotine BILs. These aggregates have
researchers were able to stabilize dexamethasone and improve its been characterized for their micelle-forming capability as well
cellular solubility while also sustaining cell viability. They pro- as cytotoxicity toward C6-Glioma cells, making them potential
ceeded to dope a starch blend with the dexamethasone solubilized future candidates for diverse biomedical applications.[130]
eutectic solvent structure to yield a blend with encouraging traits Choline citrate BILs have been used for the transdermal delivery
that may be applied to the biomedical field in the future.[121] of hyaluronic acid. The skin is difficult to breach the barrier for
drug delivery. In order to improve this process, BILs synthesized
by neutralization reactions were used to form aggregates with
9. Aggregated and Assembled BIL–Polymer hyaluronic acid and enhance transdermal delivery, which
Structures in Biomedical Applications remained the same even with dilution. No irritation was noted
in cutaneous mice studies, while the superficial moisture reten-
Supramolecular self-assembly has the potential to produce tion of the skin was enhanced, showing the potential use for facil-
responsive materials by tailoring building blocks and fabricating itating the delivery of a wide variety of drugs, such as antiaging
nanosystems. Organic building blocks are simple and easily products to antivirals and antifungal drugs.[131] Figure 11 shows
Figure 10. Assembled and aggregated BIL–chitosan structures for biomedical applications. a) Schematic diagram of the hydrogel formed by imidazolium,
Gemini surfactant ([C14-4-C14IM][Br2]), and β-cyclodextrin (β-CD); b) schematic diagram of ionic gelation of IL ions with chitosan chains via different
interactions, which finally forms chitosan–IL complexes. Reproduced with permission.[127] Copyright 2018, Royal Society of Chemistry.
the application of cholinium BIL-based supermolecular aggre- on protonated choline BILs is their application in the preparation
gate strategies for nucleic acid and drug delivery applications. of nanofibers via electrospinning. These fibers showed excellent
Similar works have studied cationic vesicles for the encapsulation hydrophilic characteristics and tunable morphology owing to
of curcumin. These vesicles were formed using imidazolium-based aggregated structures. These have excellent potential for applica-
ILs and cholinium-based BILs through synergistic interaction tions in tissue engineering.[134]
between sodium butyrate. By increasing the hydrophobic character-
istics of the vesicles, researchers discovered that it was directly
related to the loading capacity and stability of the curcumin. The 10. Conclusions and Future Outlook
modification of the choline BIL cation could be used for enhanced
potential sustained drug delivery or anticancer drug delivery.[132] Research on BILs has picked up significant steam in the last few
A novel frontier of aggregated structure application is the years due to their multifarious, biocompatible, and green appeal
encapsulation and delivery of nucleic acids. For example, in transformations and biomedical applications. The capacity to
DNA amphiphiles conjugated with tocopherol groups were chemically transform them by employing their tunability allows
self-assembled into choline-based BIL composed of lyposomic for them to be incorporated into larger polymeric structures.
phospholipid bases containing hydrophilic and hydrophobic Our review focused on BILs and their biomedical engineering
segments. These aggregates had a higher DNA density on the applications by discussing their properties relevant to the
surface, biological stability as well as highly efficient cell internal- medical field. These ranged from antimicrobial and adhesive
ization and showed the possibility of forming large polymer- applications to power sources, devices, and tissue engineering.
somes.[133] Another novel use of deep eutectic solvents based The review also described the various aspects of chemistry
Figure 11. Application of cholinium BILs in encapsulation and targeted delivery. Usage of cholinium BILs enhances the biocompatibility of aggregated
structures lowering the propensity of attack and metabolic breakdown by the immune system prior to reaching the targeted delivery spot. a) Encapsulation
and delivery of nucleic acids using DNA amphiphiles, self-assembled with lysosomal phospholipid base choline BIL. Reproduced with permission.[133]
Copyright 2020, John Wiley and Sons. b) Ester-functionalized SAILs based on nicotine BILs forming aggregates. Reproduced with permission.[130]
Copyright 2017, Elsevier. c) Cholinium and other ammonium IL-based drug nanocarriers where chloride anions of the polymer chain ion are exchanged
with the pharmaceutical anions for improved drug delivery. Reproduced with permission.[129] Copyright 2021, MDPI.
and aggregated superstructures employed in specific biomedical cells, which suffer from limitations. An example of this would be
vistas. Their ionic conduction capabilities, which are produced the removal of RNA by BILs for prodrug platforms that are self-
by their polymeric structures, rapidly expand their entry into delivering oligonucleotides.[120] Herein, such a complex structure
electrochemistry, power storage, and devices. would be capable of delivering oligonucleotides on its own with
The pace of drug development research has been adversely exceptional skin penetration, driving up the on-site bioavailability
affected by poor therapeutic efficiency and in vivo drug degrada- of the nucleotide. It was also proven by the experiment that the
tion. BILs can be a tool in the evolution of pharmaceutical small interfering RNA (siRNA) showed cellular cytoplasmic
growth, by advancing current drug delivery strategies that use localization. As an alternative control, BIL-mediated transfection
BILs in liposomes, metallic nanoparticles, soft polymeric of RNA caused the extraction of the nucleic acid, clearly establish-
micellar vesicles, polymer dendrimers, polymer nanoparticles, ing this as the preferable procedure. This approach is due to the
or carbon nanostructures. BILs are being studied to improve advancement in both gene therapy and the functional targeting of
drug stability in colloidal dispersions and enhance drug solubil- malignancies.
ity. This is especially valuable for lipid-soluble drugs, as they are Another breakthrough in this research is the employment of
delivered to their targets via closed lipid vesicles composed of biopolymeric IL structures or copolymers, which are either based
polymeric structures. For therapeutic solids, such strategies on ILs or polymers that have been functionalized by ILs.[120] DNA
are also being studied to reduce aggregation, thus enhancing binding is strengthened by higher charge densities and the pres-
their viability. ence of hydroxyl groups, but this asset oftentimes comes with
A new frontier of BILs application is that of nucleic acid han- cytotoxicity. Contemporary structures based on polyethylenei-
dling and delivery. Nucleic acids offer a window into gene func- mine and complexed with ammonium or phosphonium ILs
tion and to development of strategies for molecular medicine. can bypass this side effect, making it easier to apply them to bio-
This is predicated on the delivery of nucleic acid into eukaryotic medical treatments.
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Baishali Kanjilal is a researcher at the University of California, Riverside, with the Noshadi group. Her
expertise lies in process engineering and chemistry and synthesis of polymers for biotechnological and
biomedical applications. She obtained her Ph.D. from the University of Connecticut synthesizing ionic
liquid-based functional polymers for separation and catalytic processes, following which she worked in
the nanotechnology industry on polymer-based antiviral platforms. Dr. Kanjilal obtained her B.Sc. (Hons.)
in chemistry and polymer sciences from the University of Calcutta, India.
Yangzhi Zhu is an assistant professor at the Terasaki Institute for Biomedical Innovation (TIBI). He was
previously a postdoctoral researcher in the Nanoengineering Department at the University of California,
San Diego (UCSD). He received his Ph.D. degree in the Department of Chemical Engineering at the
University of California, Riverside. His recent work focuses on soft materials and wearable bioelectronics
for personalized and digital healthcare.
Ali Khademhosseini is the CEO/director of the Terasaki Institute for Biomedical Innovation. Formerly, he
was Levi Knight Professor of Bioengineering, Chemical Engineering, and Radiology at the University of
California-Los Angeles (UCLA) and, before that, a professor and center director at Harvard Medical
School and the Wyss Institute for Biologically Inspired Engineering. His studies have been cited more
than 100 000 times (H index ¼ 162). He is recognized as a leader in biomaterials, tissue engineering,
and bioprinting.
Iman Noshadi is an assistant professor of bioengineering at the University of California Riverside. His
research entails the development of biomaterials for biomedical application. His doctoral thesis from the
University of Connecticut focused on developing poly(ionic liquid) porous materials for catalytic
transformation of biomass. During his postdoctoral research at Harvard and MIT, he worked on
biomaterials for regenerative biomedical applications. He has served as a faculty at Rowan university,
where his group developed bioelectronics for regenerative medicine. Dr. Noshadi obtained his bachelor’s
from Shiraz University in Shiraz, Iran and his master’s from University Technology, Malaysia.

Advanced Intelligent Systems - 2023 - Kanjilal - Bioionic Liquids Enabling A Paradigm Shift Toward Advanced and Smart

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Bioionic Liquids: Enabling a Paradigm Shift Toward

nitrate) in 1914, ILs have been a major

B. Kanjilal, J. M. Unagolla, A. Caci, I. Noshadi V. Krishnadoss

(a) Electrochemistry (12%) (c)

ILs have been used as green solvents owing to their nonﬂamma-

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