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Fundamentals and Effects of Biomimicked Stimuli Responsive Polymers for Engineering Functions Jay Milind Korde, and Balasubramanian Kandasubramanian Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.9b00683 • Publication Date (Web): 14 May 2019 Downloaded from http://pubs.acs.org on May 14, 2019

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Industrial & Engineering Chemistry Research

Fundamentals and Effects of Biomimicked Stimuli Responsive Polymers for Engineering Functions Jay M. Kordea and Balasubramanian K.*a a

Biocomposite Laboratory, Department of Metallurgical & Materials Engineering, DIAT (DU), Ministry of Defence, Girinagar, Pune-411025, India. * Corresponding author E-mail: [email protected]

Abstract: Over the past few decades, reversible responsive polymer materials has sought interest conjointly from the academia as well as the industries owing to its ability to adapt to surrounding environments, change adhesion and wettability of copious species on extraneous stimulus, or regulate transportation of molecules and ions. Stimuli responsive polymers or macromolecules also exhibit ability for converting biochemical and chemical signals into mechanical, thermal, optical and electrical signals, and vice versa due to which they are utilized in a variegated array of applications like ‘smart’ optical systems, drug delivery, diagnostics, and tissue engineering, in conjunction with coatings, textiles, biosensors and microelectromechanical systems. Extensive exploration on reversible responsive polymeric systems for variegated engineering functionalities have been probed, however, no consolidated information is available as such. This article consolidates profuse reversible responsive polymers utilized in the assorted array of functions inclusive of sensors, drug delivery, smart and self-healing coatings, etc. Keywords: Stimuli-responsive polymer; Multiple responsive polymer; 4D printing; Smart coating; Smart Polymer; Biomedical.

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1. Introduction: Mother Nature is a productive and vast workshop boasting with a database full of efficient solutions to numerous technical and scientific problems such as hierarchical organizations, miniaturization, sophistication, adaptability and environment-resistance; thus the notions from Mother Nature have inspired homo-sapiens through a series of state-of-the-art designs on highperformance systems and materials, such as hierarchically organized structures, stimuliresponsive, etc. which function from nanoscale to macroscale1–3. Numerous illustrations of stimuli-responsive materials which are available in Mother Nature such as the leaflets of Venus flytrap which snaps closed on the condemned insect victim, or the Mimosa pudica leaves which suddenly collapse when touched, or chameleons regulate color in accordance to ecological conditions and upon exposure to sunlight leaflets of Codariocalyx motorius rotate, etc. have enticed the researchers conjointly from academia as well as the industries4. In recent years, scientists have travailed and successfully mimicked the functions of such organisms into synthetic stimuli-responsive polymers owing to institution of novel polymerization techniques, wholesome perception of their structure-property relationships, and availability of unique and low-cost monomers, thus exhibiting scientific significance and promising applications4,5. Stimulus-sensitive macromolecules or polymers, also termed ‘smart’6 or ‘intelligent’7 or ‘environmentally-sensitive’ polymers8, tend to unveil dramatic and abrupt conformational and/or chemical alterations on being exposed to internal or external stimuli9–11. Reversibility is a crucial trait of the stimulus-sensitive polymers, wherein the polymer exhibits ability to return to its original state upon the counter-trigger application, owing which they have been synthesized for a range of stimuli-responses inclusive of temperature, pH12, mechanical force13, electric or magnetic fields14 or the presence of the various small biomolecules and molecules15 etc., as depicted in Figure 1, which has yielded an array of applications for the stimuli-responsive polymers in sectors extending from medicine to biology and could be utilized in sensing and bio-sensing16, environmental remediation17, for controlled and triggered drug delivery18, chemo-mechanical actuators19,20 and other versatile applications21–23. Naturally occurring biopolymers like nucleic acids and proteins are the rudimentary stimulus-sensitive constituents of the living biological structures which remains constant across an array of extraneous parameters often, however they exhibit abrupt 2 ACS Paragon Plus Environment

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severe conformational regulations at given critical points, which has ensued construction of copious man-made macromolecules which are premeditated for mimicking the malleable behavior of the naturally occurring stimuli-responsive polymers9,24.

Figure 1: Copious architectures of stimuli-responsive polymers exhibiting alterations in polymeric chains, at polymeric surfaces and interfaces, and polymeric gels produced from assorted chemical and physical stimuli.

Addition of responsive entities along polymeric chain which are pliable to an amendment in nature such as solvency, polarity and charge, where the resultant relative modifications in the chemical structure amplify synergistically, causing dramatic transformations in the characteristics of the macroscopic material. In solutions, archetypally, ‘riposte’ of a macromolecule generally tunes its secondary structure, intensity of intermolecular correlation or solubility, individual chain size or dimensions25,26. Generally, destruction or the presence of secondary forces like electrostatic interactions, hydrophobic effects, hydrogen bonding, etc., or facile counteraction such as acid – base effects of entities associated to polymeric chain, or/and the variances in the osmotic pressure are accountable to bring about such responses26. Intense modulations in macromolecular configuration like deterioration of the macromolecule on exposure of definite stimuli owing to breaking of bonds along polymeric chain or at cross-linking pendant assemblages is another type of a ‘riposte’25. Numerous times the chemical science of monomers along with their intensity or 3 ACS Paragon Plus Environment


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distribution in polymeric backbone dictate the responsivity of the stimuli-responsive polymer, owing to which it’s necessary to contour polymers exhibiting well-defined architecture and chemistry. Over the period, a range of polymerization technologies such as living cationic27,28 and anionic polymerization29,30 reversible addition fragmentation chain transfer polymerizations31,32 also controlled radical polymerizations like atom transfer radical polymerization33 and nitroxide mediated radical polymerization34,35 have been developed for contouring stimuli-responsive polymers exhibiting well-defined chemistry and architecture. Polymeric systems exhibiting stimuli-responsive characteristics can be contoured either by merging a macromolecule with sensitive moiety wherein macromolecule serves only as transferor or template for the moiety or with a responsive polymer. The most well studied and understood response of the multitude of responses to stimuli is the temperature response or the thermoresponse, wherein some polymers portray occurrence of temperature induced demixing at lowest temperature, also known as lower critical solution temperature or LCST36. Solvent molecules and polymeric chains stay in single homogeneous mixed phase below LCST, whereas phase separation arises via an entropically driven process above the LCST. The most extensively explored temperature responsive polymers is poly(Nisopropylacrylamide) or pNIPAm37 that portrays a LCST at ∼32 °C. An alteration from solvated or extended random coil to globular conformation (compact or desolvated) in the pNIPAm chains occurs as solution temperature rises above the LCST, while the coil to globule conversion can be controlled thermodynamically for individual macromolecular chains via modulation of polymeric conformation38, in other words, LCST tunes to lower or higher thermal value via copolymerization by hydrophobic or hydrophilic units respectively39,40. A wide range of polymeric macromolecule demonstrate LCSTs like poly[N-[2-(diethylamino) ethyl acrylamide]] (PDEAEAM) poly(N,Ndiethylaminoethyl

methacrylate)

(PDEAEMA)42,

poly[oligo

(ethylene

41,

glycol)

methacrylate]43,44, poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA)45–47, poly(N,Ndiethylacrylamide) (PDEAAM)48 and poly(2-(N-morpholine) ethyl methacrylate) (PMEMA)42. Furthermore, polymeric systems exhibiting multi-response could be contoured via integrating supplementary functional assemblies into thermo-sensitive macromolecule, e.g., pH sensitive amalgams like acrylic acid12,49–51 and N,N-dimethylaminoethyl methacrylate52–54, having ionizable reactive units which are proficient in accepting or donating protons on ecological pH alterations can be utilized. For generating materials exhibiting both light and temperature responsivity, light 4 ACS Paragon Plus Environment

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responsive monomers can be added, where the response of these polymers is caused owing to the photo-initiated isomerization of photo-sensitive groups assimilated into the macromolecule, with azobenzene55–57 being a common example, however different mechanisms like light triggered ionization are also possible. Lastly, systems having the capacity to riposte to stimulus which are intrinsically existent in biological models or biologically sensitive structures such as glucosesensitive macromolecules58 and enzyme-sensitive macromolecules59–61 could be contoured, where riposte is generally product of detention biomolecules restrained in polymeric interface with the objective, resulting in interlinking of network or/and ionization.

Figure 2: Graphical illustration of number of publications of stimuli-responsive polymers.

Recently review piloted on Scopus exploration platform during 2018 for evaluating the total number of research investigated and published on the stimuli responsive polymers each year ever since its initial development62, as clarified in Figure 2, evidently unveils that upon the introduction of stimuli-responsive polymers to mankind, researchers have been extensively investigating various methodologies for augmenting its characteristics for a superior performance in the wide array of functions in the biomedical and industrial sectors, thus marking the dawn of the 21st century as the emergence of “Smart Materials Age”63. Realizing this, Indian Ministry of Defence, in recent times, has sanctioned and expended comprehensively on assorted projects comprising of stimuli-responsive polymers for devising systems exhibiting functional as well as protective functions that are specifically tailored for variegated Defence applications. In existent literature, numerous review articles are available on stimuli-sensitive polymers being expended in assorted range of engineering functions, however, they are restricted to either specific class of stimulus5 ACS Paragon Plus Environment


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sensitive macromolecules or their certain engineering functions and thus no consolidated data is as such available to author’s best understanding. In this review article we briefly enumerate the operational exploitation of stimuli-responsive polymers for variegated sectors in engineering functions such as drug delivery, smart coatings, sensing and biosensing, actuators etc. In following section we highlight on elementary traits of stimuli responsive polymers trailed by profuse classification of stimuli-responsive polymers in conjunction with final section effectively highlighting utilization of the stimuli-responsive polymers for assorted engineering functions like drug delivery, smart coatings etc.

2. Fundamental Aspects of Stimuli – Responsive Polymers: Stimulus-sensitive macromolecules generally exhibit vivid as well as sudden conformational and/or chemical alterations on being exposed to internal or external stimuli9, where the responsivity of the stimuli-responsive polymers is mainly influenced by chemical science of monomers in conjunction with their intensity or distribution in polymeric backbone, render the necessity for assembling of stimuli-responsive polymers having well-defined chemistry and architecture10. Intense alterations in the characteristics of the macroscopic material brought about by the resultant relative modifications in the chemical structure which amplify synergistically owing to assimilation of the functional assemblies along polymer backbone which are pliable to variations in characteristics like solvency, polarity and charge9,11. We enumerate the fundamental aspects of the stimuli-responsive polymers in the following sections, such as the non-covalent interactions requisite for assembling of the stimuli-responsive polymers, trailed by different architectures of stimuli-responsive polymers. We later elaborate the mechanism for the assorted polymeric brushes owing to which they find themselves extensively exploited for smart coatings functions. 2.1 Non – Covalent Interfaces for Constructing Stimuli – Responsive Polymers: 2.1.1

Hydrogen bonding:

Hydrogen linkages, initially recommended by Winmill and Moore in 191264, tends to be weaker in comparison to the ionic and covalent bonds, exhibiting type of dipole – dipole attraction between proton (hydrogen atom) and electronegative atoms for instance fluorine, oxygen or nitrogen, have energy ranging typically from 5 to 30 kJ/mol65. High strength and excellent 6 ACS Paragon Plus Environment

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reversibility is provided by the hydrogen bonds, rendering them ideal non-covalent bonds for holding stimuli-responsive polymers together66–71, withal, accurate control over the reversibility and the strength of hydrogen attachment amid monomers could be elucidated via contouring arrays of hydrogen binding assemblies in monomer72–74, thereby allowing formation of multitudinous bonds for framing of the hydrogen bonded stimuli-responsive polymers. Meijer et al. developed the famous 2-ureido-4-pyrimidones (UPy) building unit, capable of dimerizing strongly in the presence of a self-complementary array of quadruple hydrogen bonds, set benchmark for assembling the stimuli-responsive polymers75–81. Based on the reversible hydrogen bond interactions, in such systems, where the viscidness of stimuli-responsive macromolecules could decline on increasing the thermal value exhibiting distinctive temperature-sensitiveness, permitting facile production of the stimulus-sensitive macromolecular constituents for effective utilization in various applications65. Park and Zimmerman69 during their investigation contrived multi-block supramolecular copolymers, wherein one block comprised of two guanosine butyl urea molecules bound at end of triethylene glycol linker or PEG chain, whereas the other block comprised of 2,7-diamido-1,8naphthyridine unit at each end of short alkane diester linker via the aid of quadruple hydrogen bonding. They validated that guanosine butyl urea represented ADDA hydrogen binding array which was complementary to DAAD array of 2,7-diamido-1,8-naphthyridine cause of which they consequence in strong complex demonstrating high propensity for alternation. Similarly, Feldman et al.80 in another investigation devised random copolymers comprising of n-butyl acrylate backbones quadruple hydrogen-bonding side chains of 2-ureido-4[1H]-pyrimidinone by means of controlled radical polymerization. They reported that reversible networks having well-defined molecular architecture exhibiting high monomer content of 2-ureido-4[1H]-pyrimidinone was owing to side chain quadruple hydrogen bindings. 2.1.2

Macrocyclic Host – Guest Interactions:

In recent times, pivotal role in contriving of supramolecular stimulus-responsive polymers has been played by macrocyclic host – guest interactions cause of their exceptional dynamic nature. General concept of designing stimulus-sensitive polymers dependent on macrocyclic host – guest interactions comprises of three approaches: (i) connecting host and guest molecules to polymeric chain; (ii) linking guest molecules to polymeric chains; (iii) linking macrocyclic host to polymeric 7 ACS Paragon Plus Environment


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chain82. Over the decades, scientific researchers have reported extensive investigations for devising stimulus-sensitive supramolecular polymers which are based on the macrocyclic host – guest interactions, wherein cyclodextrins (CDs), cucurbit[n]urils (CB[n]), calix[n]arenes, and pillar[n]arenes (PA[n]s) are most commonly expended as macrocyclic hosts83–96. Recently, Song et al.88 steered an experiment wherein they investigated the fluorescent behavior of four supramolecular assemblies via host – guest interactions, consisting of two pillararene tetramers exhibiting aggregation-induced emission properties (SH & LH) and also two different lengths of neutral guests revealing three binding sites for pillararene cavities (SG & LG), in presence organic of organic solvents. They confirmed that only LG⊂LH turned into supramolecular gel demonstrating stimulus-sensitiveness cause of their flexible arms whereas SG⊂SH exhibited utmost fluorescent enhancement in presence of chloroform owing to supramolecular assembly-induced emission enhancement. Similarly another investigation was conducted by Li et al.84 wherein they synthesized β-CD incorporated star-shaped PGMA (S5PGMA-CD) by means of ring-opening addition method that served as supramolecular gating machines with desired biocompatibility and water-solubility. They reported that S5-PGMA-CD was anchored on surface of azobenzene-modified MSNs to form hybrid nanocarrier according to the host-guest interaction amongst azobenzene derivatives and β-CD. They further stated that contrived nanovalves exhibited exceptional temperature, light and competitive binding agent responsiveness and satisfactory RhB encapsulation and controllable discharge on comparison with pristine β-CD itself as gatekeeper, in addition to their low cytotoxicity which ensure their consumption for drug delivery functions. 2.1.3

Hydrophobic Interactions:

Propensity of molecular hydrophobic fragments forming intra- or intermolecular clusters in aqueous solution can be termed as the definition for hydrophobic interactions, which similar to hydrogen bonds are weaker in comparison to the covalent bonds, are an effective route for designing stimulus-sensitive macromolecules 65. Cucurbit[n]urils (CB[n]) 97–99 and cyclodextrins (CDs) 100–104, in such cases, owing to their hydrophobic cavities are capable of selectively binding guest molecules rendering them ideal and being extensively exploited as macrocyclic hosts for supramolecular stimuli-responsive polymers. Liu et al.103 investigated the fabrication of stimuliresponsive supramolecular polymers via elegant utilization of the several host-stabilized charge8 ACS Paragon Plus Environment

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transferal interfaces amid a multifunctional monomer 3 and CB(8) wherein they elucidated that the resultant stimuli-responsive supramolecular polymers tend to develop a potassium cationsensitive supramolecular gel at small concentration ∼4mM. Thus, stimulus-sensitive macromolecular constituents, compelled via hydrophobic interfaces could be certainly acquired via tuning of the stimulus-sensitive characteristics of the self-balancing fragments. In similar fashion, another investigation was piloted by Olbert et al.105 where they contoured novel bis-urea based supramolecular stimuli-responsive polymer which demonstrated to selfassemble over extensive array of solvents comprising polarity scale from water to toluene. They testified that self-assembly of the devised stimuli-sensitive supramolecular polymer in presence of water, non-polar solvents and aprotic polar solvents was owing to the presence of both hydrogen bonding as well as the hydrophobic interactions. Brunsveld et al.106 in their experiment reported that on comparison with monofunctional ureido-s-triazines, bifunctional ureido-s-triazines supported with penta(ethylene oxide) side chains were capable of self-assembling in water which resulted in helical columns with the aid of co-operative stacking of hydrogen-bonded pairs. They reported that existence of linker for covalently fusing couple of ureido-s-triazine entities is significant as it promotes higher local concentration of aromatic units which is promising for hydrophobic stacking interactions, as stacking consequences in hydrophobic microenvironment which permits intermolecular hydrogen binding to take place at greater concentrations as hydrogen bonds are isolated from competitive hydrogen bonding with water. 2.1.4

Metal – Ligand Co-ordination:

Co-ordination linkages have been widely exploited for designing supramolecular co-ordination materials, metal–organic frameworks (MOFs) as well as other crystal structures, owing to their high directionality and great strength, wherein the ultimate aim was for contouring elevated value mono-crystals followed by analyzing their characteristics107–118. Recently, fascinating reversible non-covalent interactions have also appeared in metal – ligand co-ordination linkages, facilitating the assembling of metallo-supramolecular stimuli-responsive polymers. Simultaneously, the fascinating redox and photo-physical properties in conjunction with the tunable co-ordination binding strength of ligands and metal ions promote functioning of metallo-supramolecular stimuliresponsive macromolecules in materials science. Application of tridentate, bis(2,6-bis(1′-methyl-



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benzimidazolyl)-4-hydroxypyridine), as flexible ligand intended to produce supramolecular stimulus-sensitive polymeric tools, have been effectively probed119–122. Metallo-supramolecular polymeric stimulus-sensitive films consisting of 4-oxy-2,6-bis-(1′methylbenzimidazolyl)pyridine ditopic endcapped poly(tetrahydrofuran) incorporated with varying ratios of Eu3+ and Zn2+ were recently fabricated by Kumpfer et al.120 during their experimentation. They elucidated that a pronounced optical response on exposure to chemicals like triethyl phosphate that was utilized for mimicking of organophosphate pesticides and nerve gas agents, or to an increase in temperature was demonstrated by the contrived Eu3+-containing metallo-supramolecular polymeric systems. Likewise, McKenzie et al.122 devised chains of liquid crystalline ligand-containing monomers, which are functionalized derivatives of the 2,6bisbenzimidazolylpyridine ligand. They reported that the synthesis of mesogens exhibiting array of tunable thermal liquid crystalline transitions and phases were possible owing to the tailoring of the size of the aromatic core and length of two pairs of alkyl substituents. They further stated that transition from a liquid crystalline to isotropic state was caused owing to the binding of lanthanideand/or transition metal salts to the ligand encompassing mesogens. 2.1.5

π – π Stacking:

π – conjugated systems exhibit intermolecular overlying of p-orbitals, resulting in π – π stacking, which is a non-covalent interface among organic compounds containing aromatic moieties, thus becoming stronger with the increasing number of π – electrons 123–127. Strength of π – π stacking, however, is neither directional nor strong enough in comparison with hydrogen bond present in polar diluents. Thus, researchers have effectively explored the combination of hydrogen binding and π – π stacking for designing stimuli-responsive polymeric materials benefitting owing to inherent properties of π – conjugated monomers 125,128. Effective utilization of π – conjugated tailored oligo(p-phenylenevinylene) derived, having ureidotriazine capping one end of chiral side chains while other end being capped by a tridodecyloxybenzene via solvent-assisted nucleationelongation route, have been elucidated by Meijer et al

129,130,

for self-assembling of quadruple

hydrogen linking into helical responsive fibrillar edifices. Liu et al.131 recently demonstrated in their experiment that water-soluble supramolecular polymers can be synthesized from anthracene derivatives and cucurbit[8]uril using host-enhanced π – π interactions. They stated that primarily a ternary complex was fabricated by encapsulating 10 ACS Paragon Plus Environment

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couple of anthracene molecules in one cucurbit[8]uril cavity, following which the distance between two anthracene molecules was shortened cause of which the π – π interaction between them was enhanced considerably. Likewise recently a healable, supramolecular elastomeric polymeric blend encompassing telechelic polyurethane having pyrenyl end moieties and chainfolding polyimide which was compatibilized via aromatic π – π stacking amongst π – electron rich pyrenyl entities and π – electron deficient diimide units was devised in an investigation which was piloted by Burattini et al.132. They further stated that for contriving such elastomeric, tough, healable material, the interpolymer interaction is necessary. 2.1.6

Integrated Non–covalent Interactions:

The stability of precise stimuli-responsive macromolecular configurations is owing to amalgamation of several non-covalent interfaces in most types of the stimuli-responsive polymers 133–139.

Orthogonal amalgamations of numerous non-covalent interlinks into the same stimuli-

responsive edifices produce materials exhibiting multiple characteristics which behave smartly under copious stimuli and facilitate facile contouring of intricate architectures. Dynamic stimuliresponsive supramolecular polymers having cross-linked or linear topologies have been reported by researchers over the decades

140,

where the linear stimuli-responsive supramolecular

macromolecule was primarily contoured via self-organizing bridging ligand with heteroditopic monomer compelled by hydrogen binding, in addition to confrontational π – stacking interactions between paraquat derivative 147–153

141–146,

like guest part, N,N′-dialkyl-4,4′-bipyridinium and cryptand

host part on the monomer. The incorporation of a crosslinker in the system, such as

PdCl2(PhCN)2, co-ordinates with the triazole ligand, yielding in a crosslinked polymer network, while further incorporation of competitive ligand, like PPH3, traps cross-linker for restoring the linear chain network. Based on the integrated non-covalent interactions, numerous other advanced stimuli-responsive polymeric network materials can be designed 133,135,139. 2.2 Principle Architectures of Stimuli – Responsive Polymers: Stimuli-sensitive polymers exhibit variegated principal architectures which endure macroscopic regulations on exposure to extraneous stimulus, as illustrated in Figure 3. 2.2.1

Polymers in Solutions:



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Figure 3: Schematic illustration of macroscopic alterations in single polymeric chains, polymeric networks, and grafted polymeric brushes on sensitive surfaces respectively.

Conventional polymers can be termed as macromolecules entailing of manifold recurring entities, also known as monomers, which are held together owing to the presence of covalent bonds 154,

with Flory, Kramers, Kuhn, and Debye, laying groundwork for apprehending polymeric

behavior and characteristics in early-to-mid of 20th century

155.

One is able to calculate the

statistical length of a polymer chain, from minutest entity of macromolecule, in other words, monomer, by ignoring the faraway interfaces amongst the monomers which are distant from one another on particularized chain. Numerous investigations have validated that by developing methodologies for accounting long-range monomer interactions, magnitude of macromolecule can be further precisely identified

154,156.

Single monomer can be assumed as entities congregated

jointly as constituents, for allowing a better description of the polymer chains, wherein edifice of macromolecular sequence is deemed unaltered by milieu. Flory theory

157,

marks coarse

approximations conjointly of entropic as well as energetic influence on unbound energy, is one of utmost familiarized concepts adapted for predicting sequence configuration in suitable dissolving agent, with predictions being in decent concurrence conjointly with experimentations and supplementary sophisticated concepts. Flory theory has its limitations, however, it provides reasonable information and is simple to apply owing to which finds itself useful, and to 12 ACS Paragon Plus Environment

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supplement, also unveils unanimous power-law dependency of macromolecule having dimension ‘R’ on quantity of monomer components ‘N’, which is given as: R∼Nν

(1)

The exponent ‘ν’ accounts for the solvent quality with the value of ν being 1/3, 3/5 and 1/2 for θsolvent, athermal or good solvent and poor or non-solvent respectively. In more recent times, the interest of the researchers have been intrigued by the computer imitations processes, inclusive of Monte Carlo

158

as well as molecular dynamics

159

simulations, as they have the aptitude of

bridging experiment with theory. Scaling laws, which are utilized in the traditional non-responsive polymers, fail to easily predict the performance of stimulus-sensitive macromolecules in solution owing to additional specific monomer – solvent and monomer – monomer interfaces. Responsiveness could be contrived in a polymeric sequence by selectively choosing of monomer, such as, the electromagnetic domain photo-prompted cis to trans isomerization of azobenzene could be utilized for affecting configuration of polymeric sequences comprehensively

analyzed

sensitive

158.

macromolecule

Like stated earlier, one of extremely is

pNIPAm,

wherein

the

N-

isopropylacrylamide (NIPAm) monomer is utilized for designing the thermoresponsive polymers having an LCST of ∼32 °C. Entropy change, mainly owing to association of water with macromolecule, overwhelms suspension heat content of pNIPAm as temperature increases, producing affirmative unbound energy modulations unpropitious for suspension. Extensive investigations37,160 have been conducted for understanding structural performance of pNIPAm segments in liquid suspensions, entailing which numerous reviews have been published 161,162. For analyzing performance of individual polymeric segments in solution experimentally, numerous methodologies have been developed over time, such as atomic force microscopy (AFM), which is generally adapted for reviewing individual single polymeric chains. The first elucidation of 2-D non-uniform coil conformation of polymeric segments via aid of Langmuir-Blodgett method for casting polymeric suspensions on a surface was reported by Kumaki et al.

163,164.

Elasticity of macromolecular linkages can be likewise characterized via the aid of AFM, although, isolated segments which AFM reviews are generally in quasi 2-D or dilute condition, rendering them incomparable with assorted macroscopic marvels in actual structures comprising of numerous entangled polymer chains in 3-D bulk condition. Performance of individual fluorophore13 ACS Paragon Plus Environment


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categorized polymeric segments in mass means deprived of alteration of its physical and chemical characteristics can be investigated via a methodology termed as fluorescence imaging

165,166.

Thorough data regarding polymeric configurations in solutions can be provided by a powerful technique called light scattering, which like X-ray scattering and neutron scattering 167, is a product of the variance of contrast among the surrounding solvent and the polymer chains. Typical function in polymer science of light scattering is for quantifying polydispersity and molecular weight of polymer, nevertheless, it can also provide information regarding the polymeric chains which cannot be obtained using other methods, such as conformation (random coil vs globule), diffusion coefficients 168 and the mean square radius. 2.2.2

Polymers in Gels:

The crosslinking of polymeric chains, either chemically or physically can be termed as ‘gelation’ process, wherein on its occurrence the coupling of polymer chains produces polymers having progressively larger branching. Even superior branched macromolecules are obtained as crosslinking procedure endures, causing such a large molecule not to melt in dissolving agent but rather proliferate within it. Such an endless polymer is termed as gel and alteration from structure consisting of distributed branched macromolecules to arrangement also encompassing endless segments is termed as sol – gel conversion. When system can support an elastic stress, the transition of sol to gel occurs and the point at which this transition occurs is termed as gel point 169.

Investigations on understanding the sol – gel transition can be traced to dawning of polymer

science, with mean-field theory being the first quantitative theory on gelation formulated by Flory and Stochmayer in 1940157. Successful application of the critical percolation theory to gelation was elucidated in 1970s170,171, while the 1980s unveiled the development of numerous growth concepts such as cluster-cluster aggregation, kinetic gelation, or diffusion limited aggregation, having been advanced for describing kinematic facets of accumulation along with gelation172. Virtually every species exist connected to gel linkage structure, when macromolecule reticulation counteractions are compelled faraway past gel point. The precise definition of measurement of gelation is difficult experimentally, however, approach for measuring gelation fairly accurately by measuring viscoelastic ripostes of designed gel as function of shear rate was developed by Sacks and Sheu173.


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Table 1: Assorted Response of Hydrogels

Stimulus

Type of Polymeric Network

Thermal

Thermo-responsive

Chemical

Electron-accepting groups

species pH

Acidic or basic

Electrical

Polyelectrolyte

Ionic strength

Ionic

Enzyme substrate Magnetic Ultrasound

Immobilized enzymes

Release Mechanism Change in temperature causes a change in polymer–polymer and water– polymer interactions. This causes a change in swelling. Electron-donating compounds cause charge transfer. This causes a change in swelling. A change in pH causes swelling of the hydrogel. Applied electric field causes membrane charging. Electrophoresis of charged drug changes swelling. Change in ionic strength causes a change in the concentration of ions inside the gel. This causes a change in swelling. When a substrate is present enzymatic conversion occurs. The product causes swelling.

Magnetic particles in

An applied magnetic field causes a change in pores in gel. This results in

microspheres

change in swelling.

Ethylene-vinyl alcohol

Ultrasound irradiation causes temperature increase which results in swelling change.

Physical or chemical crosslinking of polymeric chains results in gelation, with glassy and microcrystalline stages, or triple and double helixes, being some illustrations for robust physical bonds, while thermoplastic elastomers exist as illustrations for robust physical gels22. Reversible links between polymer chains exist in weak physical gels, where these linkages have finite lifetimes, reforming and breaking continuously. Ionic associations, hydrogen bonds and block copolymer micelles above their glass transition are few examples of weak physical bonds. Chemical gelation, in contrast, encompasses the development of covalent linkages across the system always producing a robust gel. Chemical gelation can be acquired via the aid of three main processes – addition polymerization174, condensation175 and vulcanization176. Polymer networks exhibit another enticing characteristic, where they are capable of amending volume on exposure to definite solvents, such as hydrogel, as classified in Table 1, which is kind of macromolecular system that inflates on revelation of fluids. “Degree of enlargement” is typical consideration for labelling hydrogels, where its termed as ratio of swollen volume to dry volume of polymer matrix177. Flory along with Rehner178 first described the equilibrium swelling theory of neutral, 15 ACS Paragon Plus Environment


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isotropic polymer networks in the presence of small molecules. They validated that when an unimpeded macroscopic polymer system existing in certain diluent, endures enlargement, wherein swelling is constant by equal extent in all directions. The elasticity of polymer network, at swelling equilibrium, is totaled by existence of osmotic force of semi-dilute suspension of non-crosslinked polymeric linkages. Some networks expand till modulus and osmotic pressure reach equilibrium, as modulus is relational with mutable unbound energy for each entities volume178. The formation of polymeric constituents exhibiting tunable and swift riposte times owing to the chemical grafting of alkanethiols with poly(vinyl methyl siloxane) (PVMS) networks comprising of hydrophilic termination assemblies (–OH or –COOH) was reported by CroweWilloughby and Genzer179,180. They elucidated that the rapid response, evaluated by a shift to a hydrophilic condition having contact angle of 55° from a hydrophobic condition having contact angle of 110° in water, was enabled by liquefied environment of poly(vinyl methyl siloxane) backbone, that was noticed to reduce cause of decreasing magnitude of methylene insert (–(CH2)n– ) present in pendant group of alkanethiol. Another well-known attribute of porous gel networks is inflammation of permeable bulk gel networks resulting in escalation of pore dimension, whereas substrate associated permeable gel networks demonstrates contradictory behavior due to substrate restraints181. Distinctive prospect for modulation of transference via polymeric network in exceedingly extensive diffusivity array from a point in suspension down to point in solids can be provided by switching among the closed and open pores in the polymer networks on shrinking and swelling respectively182. 2.2.3

Polymers on Substrates/Solid Supports:

Combined assemblages of macromolecules having one end grafted or tethered onto a substrate can be termed as polymer brushes (PB), wherein conformation of polymeric segment on substratum relies on grafting density on the substrate, molecular weight or chain length, as well as polymer composition. Very distinctive behavior is exhibited by polymer brushes, as they sustain entropy deficiency comparative to macromolecules in suspension owing to the irreversible attachment to a surface. There are three general configurational systems probable for polymeric segments tethered to surfaces, depending on proximity to other polymers attached to surface or crowding, affinity of chain monomer to substrate, as well as solvent quality 5, as illustrated in the Figure 4. When monomer exhibits an intense attraction towards surface and if space amid two 16 ACS Paragon Plus Environment

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adjacent attaching positions is superior than chain dimension, then polymeric segments adopts ‘pancake’ conformation (as illustrated in Figure 4(b)); whereas if interaction between substrate and polymer chain is weak, then polymer chain adopts ‘mushroom’ configuration (illustrated in Figure 4(a)). As illustrated in Figure 4(c), when polymer chains are crowded on substrate, they are capable of interacting with one another owing to elevated grafting density, causing individual chains to pull away from substrate, which results in ‘brush’ regime 5. The combination of free energy of polymer chain, frozen constraints of irreversible grafting, entropic repulsion or excepted volume interface, geometry of substrate and conformational entropy loss owing to chain stretching dictate behavior of polymer brushes 183.

Figure 4: Assorted configurations of polymeric brushes grafted on sensitive substrates: (a) Mushroom (b) Pancake (c) Brush respectively.

In late 20th century, de Gennes and Milner184 pioneered theoretical designing of polymeric brush performance. Scaling law, assuming division of strained macromolecule as tension globule, is molecular designing concept adopted for predicting the polymer brush behavior. Local conformation freedom of tension blobs dictates majority of configuration entropy of segment, wherein quantity of monomers and their dimension is cautiously selected so that tension globules portray non-uniform stride5. The polymer chains start interacting with one another causing embedded polymeric segments to occur in brush-like conformation when distance between adjacent tension globules, which is given by, ~-1/2

(2)

Where  is the grafting density, is lesser than segment extent, which is given as,



R∼aNν

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(3)

Where N is number of monomer, ‘a’ is Kuhn length and ν is exponent unique for each system. Segments are effectually secluded behaving independent of each other with no supplementary osmotic pressure triggering segments to elongate faraway from substrate, when value of  is small due to which chains form mushrooms or isolated islands conformation5. The critical value for 

grafting density which is requisite for forming polymeric brushes is given by, * = a-2N-2ν

(4)

Where value of exponent ‘ν’ being 1/2, for ideal polymeric segments with no interfaces among monomers; whereas value of exponent ‘ν’ being 3/5, for genuine polymeric segment in worthy dissolving agent, where interfaces between monomer and solvent are dominant. The particle density along polymeric sequence in brush conformation cannot be quantified as particle dispersion in scaling law is dimensionless. Researchers have adopted density functional theory for probing internal configuration of polymeric brush layer for overcoming this issue, in addition to mean-field theory and self-consistent theory, which were adapted for modelling and predicting behavior of polymeric brushes. Inspection of individual molecular kinds exhibiting microscopic minutiae whilst handling intermolecular interfaces with mean field approximation is basic ideology of these theories. Although good predictive power has been shown by all of these approaches, there still exists few restrictions like the assumption of system homogeneity and lack of intermolecular correction5. The kinematics of polymeric segment configuration under extraneous stimulates is further pertinent from a practical perspective, as it aids in designing principles for promptly retorting systems. The ability of polymer chains to regulate their configuration in accordance with their surroundings, permits them to respond conjointly, which differs significantly from a single chain on a substrate. For example, interface between polymeric segments and surrounding shifts from repulsive to attractive can be regulated by modifying diluent attributes from poor to good, which ultimately consequences in conformational fluctuations from swollen to collapse5. Responsive polymeric brush coatings owing to such unique characteristics prove themselves as prodigious contenders for assorted applications like protein capture185, coatings in micro-valve for specific ions transportation186, modulating cell growth and release187 and surface wetting and dewetting188. 18 ACS Paragon Plus Environment

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The behavior or polymer brushes can be analyzed experimentally, as they are polymer chains which are tethered or grafted onto substrates, using the aid of methodologies which are capable of probing the interfaces, like reflectance spectroscopy189, surface force apparatus190, surface plasmon resonance spectroscopy (SPR)191 and AFM192. An investigation conducted by Balamurugan et al.191 elucidated that thermo-sensitive pNIPAm polymeric brushes in H2O unveil density perpendicular stage partition. They further validated that close to exterior, dense brushes undergo desiccation and disassemble over wide array of thermal values, whereas the polymeric fragments which are present in outmost zone tend to stay extremely solvated at temperatures greater than LCST of ∼32 °C. Similarly, Choi et al.193 also investigated pNIPAm scrubs structural dependence on embedding temperature along with conditions via aid of atomic force microscopy (AFM), wherein they validated that pNIPAm scrubs demonstrate intricate collapse performance in inadequate diluent, having micelle alteration condition from pancake to mushroom configuration. They further clarified that deflation of pNIPAm polymeric segments beyond LCST relies on molecular weight in conjunction with grafting density. 2.2.4

Co-ordination Polymers:

Co-ordination polymers, also known as metal-organic frameworks (MOFs), archetypally comprise of metal ions and synthetic polymers bind together to polymeric ligands via aid of coordination bondages. Anchoring positions such as sulphur, nitrogen or oxygen are generally contained via polymeric ligands that are obtained either via chemical reaction amongst polymers and low molecular weight compound unveiling coordinating ability194,195. Over the past two decades, field of metal-organic frameworks has grown tremendously after its initial instigation by Yaghi et al. in the late 1990s, wherein they coined the acronym “MOF” while simultaneously choosing the “yellow sphere” in their representation to conceptually visualize the volume of free pore in their structure194,196. An exceptional chemical versatility coupled with tunable framework and an unprecedentedly large and permanent inner porosity is offered by this intriguing genre of crystalline hybrid materials that are contoured via association of metal centers or clusters and organic linker(s)197–199. At the initial stages, scientific researchers steered most of their efforts in direction of producing new frameworks unveiling novel topologies and open configurations with biggest probable surface areas198,200,201. The aim of scientific researchers was to discover materials exhibiting remarkably 19 ACS Paragon Plus Environment


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high gas storage aptitudes, especially for storage of hydrogen. Nevertheless in more recent times, investigators have devised MOFs capable of demonstrating responsive nature (in the sense that characteristics and configurations could be regulated via an external factor such as a physical stimulus or guest molecule)202,203. Development of MOFs have increased the expectations of the investigators owing to their versatility in conjunction with comprehensive chemical functionalization with the past few years unveiling fruition of these expectations around the concepts of protection/deprotection, hybrid crystal hetero-structure approaches, isoreticular frameworks, solid-solution or multivariate structures (copolymers), and post-synthesis functionalization194. Furthermore, nowadays investigators are capable of specifically tailoring the MOFs by tuning the incorporated reactive entities along with organic linkers within a MOF. Additionally, also the probability of engineering crystal surfaces and internal interfaces, intentionally creating defects and opening metal sites have also emerged194. Recently, Chen et al.204 steered an investigation wherein they devised MOF nanoparticles based on UiO-66 that were functionalized with ample polycationic fragments as polymeric brushes on substrate for loading negatively charged functional entities comprising of aggregation-induced emissive luminogen, a tetraphenylethene (TPE) derivative and anti-tumor drug doxorubicin, trailed by additional alteration with cucurbit[7]uril (CB[7]) as supramolecular glue with purpose of pursuing pH-sensitive discharge application of loaded functional constituents. They elucidated in situ pH-responsive doxorubicin discharge via the fluorescence resonance energy transfer among the doxorubicin acceptor and TPE donor, while further stating that the CB-modification appeared to enable intracellular discharge of the doxorubicin drug and also accounting for the effective cytotoxicity towards treated cells. Likewise, Wang et al.205 during their experimentation contrived nucleic acid–metal organic framework nanoparticle conjugates based on the elucidation that clustered oligonucleotides can naturally engage scavenger receptors which facilitates cellular transfection. They stated that devised metal-organic framework nanoparticles behave as protein hosts, wherein their heavily functionalized, oligonucleotide-rich surfaces make them colloidally stable and certify easy cellular entrance. They further reported that on utilizing insulin as model protein, higher loading and 10-fold augmentation of cellular uptake could be achieved owing which they validated that this method could be generalized for facilitating delivery of copious proteins as potential therapeutics or biological probes.


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2.2.5

Porous Organic Polymers:

Considerable amount of attention has been garnered by porous polymers over the past couple of decades from both the industries and academia owing to the development of copious novel kinds of micro- and meso-porous (2 – 50 nm) materials like crystalline covalent-organic frameworks (COFs), metal organic frameworks (MOFs), and amorphous microporous/porous organic polymers (POPs) that are archetypally constructed via catalytically active, molecular building blocks206–208. Copious names have been denoted to a variety of classes of porous polymeric materials such as porous organic frameworks (POFs), porous aromatic frameworks (PAFs), conjugated microporous polymers (CMPs), and polymers of intrinsic microporosity (PIMs)206. Even though POPs are amorphous in nature, yet they possess comparatively higher internal surface areas that are owing to the meso- and micro- pores which are formed via rigid, multitopic building blocks209,210. Initial development of POPs can be traced back to as early as 1960s, wherein researchers devised porous organic polymers via incorporation of di/multitopic monomers within well-known chain-growth and step-growth polymerization methodologies for providing crosslinks among the propagating polymeric chains, thus yielding three-dimensional network materials211. Researchers conducted numerous investigations during the late 1980s for contouring molecularly imprinted polymers (MIPs) by adopting copolymerization strategy via utilization of discrete molecular porogens, whereas in the late 1990s researchers steered attempts for producing microporous organic polymeric materials from monomers demonstrating higher valency or topicity and more intricate structures so that better molecular recognition features could be stimulated in the pores206,211. Additionally scientific investigators employed slower bond-formation reactions for synthesis of pores which were more closely matched the dimensions of potential guest molecules. POPs are typically fabricated via monomeric units which are multitopic (three or more connection points) in nature, contrary to the conventional routes of producing macroporous polymers, wherein the long chains polymerized monomers are interconnected by ditopic crosslinking monomers212. Valency/topicity of the monomer or co-monomeric unit(s) dictate the crosslinking in POPs, whereas the concentration of crosslinking molecules added control the degree of crosslinking in macroporous polymeric materials213. Similarly on comparing with crosslinks formed in polymeric gels that are generally formed amongst the side chains and flexible chains, the crosslinks in POPs 21 ACS Paragon Plus Environment


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are formed among the rigid building blocks. Permanent microporosity in porous organic polymers can be attained via relatively rigid monomers which on crosslinking result in pores with similarly rigid walls214. In recent times, researchers have moved beyond the conventional polymerization methodologies for construction of POPs towards numerous modern bond-forming techniques such as imidization, aminal formation, Pd-catalyzed coupling, amidation, imine formation, nitrile polymerization, dibenzodioxane formation, and Friedel-Crafts alkylation206. On comparison with most COFs and MOFs, POPs generally demonstrate stability advantage which is owing to this broad base of bond-formation chemistry215. POPs demonstrate proficiency on exposure to a wide range of aggressive media on comparison with the other two aforementioned classes, which exhibit well-defined and uniformly sized pores, because of their reversible coordination-bond-based (or hydrolytically unstable BO bond-based) construction often limit the situations under which they can be utilized216. Recently Chakraborty et al.217 steered an investigation wherein they fabricated novel azobenzene-based colloidal porous organic polymers which were amenable to post-synthetic loading of metallic Pd-nanocrystals for photocatalytic Suzuki and Suzuki-type couplings by means of in-built Mott-Schottky heterojunction aimed for direct harnessing of visible-to-near IR light energy. Similarly, Yang et al.218 conducted an experiment where they developed a novel strategy for synthesizing cost-effective POPs for CO2 capturing via Friedel-Crafts alkylation reaction of dichloro-p-xylene, by one-step post-synthesis functionalization with polyamines. They reported that among the devised POPs, PP-2-TEPA and PP-2-DETA demonstrated exceptional CO2 selectivity over N2, appropriate Qst, and superior high CO2 uptake capacities in conjunction with excellent stability towards both water vapor and regeneration cycles under dynamic flow conditions. 2.3 Configurational Designs of Self – Assembled Stimuli – Responsive Polymers: Stimuli-responsive polymer particles typically exhibit configurational design represented via superficial amendment of numerous elements (polymeric as well as inorganic) with reactive macromolecules or via core–shell structural design shaped by self-assemblage of amphiphilic copolymers, like polymer vesicles or micelles, as illustrated in Figure 5183. Stimuli-responsive behavior can be shown by shell-forming polymer, core-founding polymer, or both shell as well as core macromolecules, wherein external stimulus are utilized for stimulating self-assembled 22 ACS Paragon Plus Environment

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assemblies and may induce their irreversible or reversible disintegration, adsorption, swelling and aggregation, as toolbox of stimuli-sensitive polymeric colloids extends from inorganic particles,

Figure 5: Self-assembled configurational designs of stimuli-sensitive polymers.

functional polymers, and copolymers183. On altering solvent for dissimilar blocks, block copolymers can form copious array of selfassembled structures ranging from continuous bilayers to micelles, as these systems on exposure to external stimuli may result in modification in aggregate size and/or modification in aggregate structure and architecture, i.e., conversion from sphere-shaped micelles to polymersomes in liquid solution, or transaction amongst blocks in corona and core219,220. Intention of unbiased unit is for preventing realization of macroscopic polyelectrolyte system via protection of core with a hydrophilic and neutral corona, wherein polyelectrolyte micelles can be acquired with aid of stoichiometrically mixed, oppositely charged macro-ions as long as constituents are charge-neutral hydrophilic diblock copolymers220. Researchers have conducted investigations using variants such as two diblock copolymers with two dissimilar neutral blocks221, charged inorganic nanoparticles 220

otherwise self-assembled macro-ions as additional component222. Additionally, self-assembled stimulus-sensitive polymeric edifices can also be polymer

vesicles or polymersomes, wherein innermost fluidic partition is bounded by amphipathic 23 ACS Paragon Plus Environment


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copolymer pellicle223,224. Transference of fragments amid interior and exterior of vesicle is regulated by copolymer membrane, where penetrability is adjustable and dilapidation of pellicle could be prompted by extraneous stimulus223. The capability of vesicle to regulate transportation of hydrophilic particles through pellicle, which produces shells mimicking transmembrane networks of live cells, depends on incorporation of pH-responsive domains224. Exterior casing of amalgam colloidal core – casing elements are incorporated with stimulus-sensitive macromolecules, such as inanimate constituents exhibiting explicit visual or magnetic characteristics are preferred for core. Tendency of elements to accumulate in conjunction with their attraction for liquescent interactions could be reversibly regulated by tuning properties of shell with aid of physico-chemical means, where resultant reversible regulation is observed in macroscopic and microscopic characteristics of colloid dispersals, such as foams, emulsions, suspensions, and sols on engagement with appropriate extraneous stimulate183. In an investigation conducted by Motornov et al.225, wherein they reported that pH-sensitive polymeric casing that were grafted to surface of the particles of silica, controlled particles’ alterable clustering and declustering. Template production of sensitive containers by coating micrometer as well as sub-micrometer sized elements can be successfully achieved by layer-by-layer assembly or LbL assembly226. The colloidal core can be dissolved after interior is covered with layer-by-layer shell, thus leaving capsules hollow227,228. Numerous applications could be sought by stimuli-responsive polymeric particles ranging from cosmetic, coatings, chemical, food and detergent trades, in conjunction with diagnostics and drug delivery, wherein stimulus-prompted construction, fragmentation, or reversal on demand of elements and their dispersals may possibly be exploited in advancement of novel methodologies and merchandises183.

3. Stimulus – Responsive Polymers: Abrupt physiochemical shifts caused by stimuli is the underlying strategy in polymeric stimulus-sensitive systems, that are also acknowledged as ‘smart’ or ‘intelligent’ polymers, as they are capable of undergoing minute alterations which arise as response to an external triggering stimuli7,229. Detectable behavioral modifications such as degradation, bond cleavage, solubility, conformation, and hydrophilic to hydrophobic equilibrium can be adapted in polymer chains at the macromolecular level 230. Depending on the reversibility of the switchable properties produced by 24 ACS Paragon Plus Environment

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the strategy employed, stimuli-responsive polymeric systems can either be reversible or irreversible. By varying location of responsive functional groups or moieties such as junctions between blocks, chain end-groups, or side chains on units, numerous well-defined architectures are possible

231.

Nonlinear riposte prompted owing to very minor stimulate, producing clear

macroscopic modifications in their configuration, is exclusiveness of such polymeric systems. Stimulus-sensitive macromolecules could be divided in solution or solid conditions, like gel or films, depending on the material state. Similarly, they can also be classified centered on amount

Figure 6: Classification of stimulus-sensitive macromolecules

of inducements they riposte to as single stimuli-responsive, dual stimulus-sensitive , and multiple stimulus-sensitive macromolecules232. Classification of stimulate-sensitive macromolecules founded on amount of stimulus they riposte to is universally adopted for segregating the extensive array of stimuli-responsive polymeric systems, as depicted in Figure 6. Herein, in the following sections we elaborate on the classification of stimulus-sensitive macromolecules founded on amount of stimulus they riposte to, while simultaneously elaborating division based on type of stimuli in single stimulus-sensitive macromolecule subdivision. 25 ACS Paragon Plus Environment


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3.1 Single Stimulus – Sensitive Macromolecules:


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Single stimulus-responsive polymers can be broadly classified in three different kinds such as

Figure 7: Summary of operation of stimuli-responsive polymers in redox, pH, UV light and near-IR light. Reprinted with permission from Song, N.; Yang, Y. W. Molecular and Supramolecular Switches on Mesoporous Silica Nanoparticles. Chem. Soc. Rev. 2015, 44, 3474. Copyright 2015 Royal Society of Chemistry.



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physical, chemical or biological depending on the external stimuli acting on the responsive polymeric system233. Generally modification of chain dynamics, like energy level of polymer/solvent system is perceived owing to physical stimuli inclusive of temperature, mechanical, light, electrical, or ultrasound whereas modulation of molecular interactions, either amid solvent and macromolecules, or amongst polymeric chains is detected owing to chemical stimuli like pH, electrochemical, solvent or ionic strength234. Genuine implementation of fragments like receptor acknowledgement of fragments, enzymatic responses can be related to biological stimuli such as receptors or enzymes 235. Figure 7 depicts the summary of operation of stimuli-responsive polymers in pH, redox, UV light and near-IR light, while the Figure 8 depicts

Figure 8: Summary of operation of stimuli-responsive polymers in thermal, magnetic field, competition and multi-stimuli. Reprinted with permission from Song, N.; Yang, Y. W. Molecular and Supramolecular Switches on Mesoporous Silica Nanoparticles. Chem. Soc. Rev. 2015, 44, 3474. Copyright 2015 Royal Society of Chemistry.

the summary of operation of stimuli-responsive polymers in thermal, magnetic field, competition and multi-stimuli. 28 ACS Paragon Plus Environment

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3.1.1

Physical Stimulus – Sensitive Macromolecules:

3.1.1.1 Temperature or Thermo – Sensitive Macromolecules: Amongst assorted divisions of stimulus-sensitive macromolecules, temperature-responsive or thermo-responsive macromolecules highlighting pivotal solution thermal value, either higher critical solution temperature (HCST) or lower critical solution temperature (LCST), with latter having been exploited comprehensively in recent times233,236. Critical solution temperature is thermal value where phase of macromolecule as well as suspension is sporadically regulated rendering to their structure233, where in case polymeric suspension exhibits single phase below specific temperature, then they are said to exhibit LCST and when polymeric solution is nonsoluble beneath a specific temperature, then they are said to exhibit HCST230,233,237. The hydrophobic and hydrophilic interfaces amid aqueous media and macromolecular chains abruptly modulate within a minor temperature array around critical solution temperature, which induces disruption of inter- and intramolecular hydrophobic and electrostatic interactions, thus resulting in volume phase transition, either in form of chain collapse or expansion. A significant function in mechanism of temperature-responsivity, besides from interfaces amongst liquid fragments and polymeric segments, is played by intermolecular interfaces of macromolecules183. Amongst key interfaces that could be modulated via temperature is hydrogen bonding of amide group. Temperature-sensitive polymers owing to the high reversibility of the temperature-responses find themselves as excellent candidates for catalytic systems and smart devices161,238,239. Figure 9

Figure 9: Schematic illustration of thermo-responsiveness in polymeric chains with variation in hydrophobic and hydrophilic 29 transition. ACS Paragon Plus Environment


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exhibits schematic illustrations of thermo-responsiveness in polymeric chains via variation in hydrophobic and hydrophilic transition. Poly(N-isopropylacrylamide) or pNIPAm, is utmost comprehensively probed thermalresponsive macromolecule owing to its renowned LCST behavior, can be synthesized via atomtransfer radical polymerization (ATRP) or by reversible addition-fragmentation chain-transfer polymerization (RAFT) methodologies232. pNIPAm because of coil to globule conversion endures changeable volumetric phase alteration at ∼32 °C240. There exist other temperature-sensitive polymers such as poly(2-isopropyl 2-oxazoline) or PIOZ, poly(vinylmethylether) (PVME), poly(N,N-diethylacrylamide) (PDEAAM), and poly(N-vinylcaprolactam) (PVCL) which exhibit state conversion thermal value at 35 °C, 33 °C, 48 °C and 32 °C respectively, where copious thermo-responsive polymers have their LCSTs reliant on solution concentration as well as molecular weight236,241,242. Investigations conducted on temperature-sensitive macromolecules that demonstrate higher critical solution temperature or HCST largely focuses on zwitterionic macromolecules due to its biological concord and supplementary distinctive solution characteristics, as zwitterionic macromolecules unveil intra- electrostatic dipole connotation cause of affirmatively and adversely energized entities at copious compound blocks or at identical monomer component243. Some extensively exploited zwitterionic macromolecules are poly(sulfobetaine)s, owing to its insolublility or scarcely solubility in H2O, which could settle by incorporation of salts. Over the period, numerous other temperature-sensitive polymers from recognized thermo-responsive monomers have been derived for catering assorted array of applications, such as block copolymers centered on amphipathic equilibrium for their thermosensitive micellization. Other hydrophobic groups for example poly(L-lactic acid) or PLLA, poly(1,2-butylene oxide) or PBO and (DL-lactic acid-co-glycolic acid) or PLGA have been utilized as equivalent of PPO masses in copolymerization with PEO for contouring copious temperature-responsive block copolymers. 3.1.1.2 Light or Photo – Sensitive Macromolecules: In recent times, an augmentation in the investigations on light or photoresponsive polymers cause of its precise site and time control owing to which they find themselves stretched for great potential applications in reversible wettability244, recyclable catalyst245, self-healing material246, polymer viscosity control247, optical storage, and controlled drug delivery system248,249. On 30 ACS Paragon Plus Environment

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irradiation with light of suitable amplitude, photo-responsive macromolecules exhibit change in their characteristics which are typically produced cause of physical modulations of definite functional assemblages along polymeric spine or side chains250,251. Irradiation being a straightforward, noninvasive mechanism for inducing responsive behavior is imperative trait of photosensitive polymeric structures. Figure 10 schematically illustrates UV light induced isomerization of photo-responsive systems. Although the research for understanding the photoresponsive polymers has been initiated a long time ago, however expansion in efforts for developing increasingly complex macromolecular architectures have been elucidated in recent times252–254.

Figure 10: Schematic depiction of UV light induced isomerization of photo-responsive systems.

Macromolecules encompassing azobenzene assemblages are utmost well probed instances of light-sensitive polymers255,256, as azobenzene is distinguished chromophore consisting lightprompted cis to trans isomerization which is supplemented with speedy as well as thorough variation in electronic edifice, geometrical figure, along with polarization. Materials exhibiting variable polarity, shape along with self-assembly performance could be achieved by incorporating azobenzene derivatives, for example light-tempted distortion of epoxy-founded azobenzenecomprehending macromolecular colloids were described by Deng et al.257. Numerous investigations have been reported where isomerization that is convoyed by varying polarity has resulted in utilization of azobenzene-encompassing block copolymers for preparing light-sensitive vesicles and micelles258–260, whereas other studies also report contouring of light-sensitive dendrimers obtained from azobenzene offshoots261. Many other polymeric systems have been 31 ACS Paragon Plus Environment


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incorporated with azo chromophores, such as pNIPAm262 and poly(N-hydroxypropyl methacrylamide) (pHPMAm)263. Azobenzene groups can be engaged for regulating supramolecular assembly of polymers coupled with ability to enable photo-switching of polymeric aggregates in solution264, surface properties265,266 and bulk material properties251. Photo-responsive behavior has been elucidated to be imparted by chromophores other than azobenzene, such as spiropyran derivatives can be incorporated pendantly267–269 or terminally270 for bringing about the light sensitivity. Irradiation with suitable wavelength of light results in a zwitterionic isomer exhibiting significant increase in the dipole moment in spiropyran groups as they are relatively non-polar in nature, but this isomerization is reversible by irradiating with visible light. A variegated array of spiropyran-containing photoresponsive polymers have been constructed based on this concept, including pNIPAm267,271, poly(acrylic acid) or PAA247 and poly(N-hydroxypropyl methacrylamide) or pHPMAm. Laschewsky and Rekai272 conducted an investigation for modifying pHPMAm by copolymerizing with elements comprising photoreactive cinnamate units, where they elucidated that the photo-isomerization of pendant trans- cinnamate groups to cis- cinnamate groups yielded macromolecules exhibiting enhanced polarization and superior cloud values. They further validated that cinnamate group is easily incorporated on evaluation with other frequently used photo-sensitive groups cause of its thermal stability in both trans- and cis- conditions and its chemical inertness. As visible and UV light are captivated willingly by the skin, the responsive systems mentioned above possess possible restrictions for many biomedical functions as they necessitate isomerization prompted via UV treatment. Thus for more applicability in photo-activation of drug transferors inside alive entities, infrared irradiation is preferred, as it penetrates the skin with less damage. Investigation conducted by Goodwin et al.273 on block copolymers of 2-diazo-1,2-naphthoquinone and hydrophilic PEG via infrared treatment revealed that infrared irradiation resulted in micelle dissociation owing to light-tempted readjustment of 1,2-naptho-quinone entities for yielding hydrophilic/anionic 3-indenecarboxylate moieties. 3.1.1.3 Electro – Responsive Polymers: A straightforward, swift and efficient mode for controlling polymeric properties and morphologies can be provided by electrical stimulus like electric voltage or potential, for example, every conducting macromolecules, inclusive of poly(carbazole), polythiophenes, polypyrroles, polyanilines, along with their offshoots, are semiconductor or electro-sensitive macromolecules, 32 ACS Paragon Plus Environment

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wherein they portray electrochromic effect232,274. Materials which bend, shrink, or swell in riposte to electrical field are termed as electro-responsive polymers, as they are capable of transforming electric power in mechanical power owing to which they find potential functions such as artificial muscle actuation, sound dampening, sensing, controlled drug delivery, biomechanics, and chemical separations275–278. A number of factors, such as salt concentration or pH of ambient media, thickness or shape of gel, mutable osmotic force founded on voltage-prompted mobility of ions in suspension, location of gel comparative to electrodes and applied voltage influence gel distortion in electrical field279. Macromolecule typically depend on collapsing of system in electrical field, electrorheological effects, ionic-polymer–metal interactions, electrically activated complex formation, electrochemical reactions or changes in electrophoretic mobility for converting applied electrical field into physical riposte275. Numerous investigations conducted on electro-responsive polymers involve polyelectrolyte hydrogels, as they distort in electrical field cause of deswelling or anisotropic inflammation when activated ions are steered toward cathodic or anodic region of hydrogel275,280–283. Electroresponsive polymers can be prepared from both synthetic as well as the natural polymers, where naturally occurring polymers include chondroitin sulfate284, alginate285, chitosan282 and hyaluronic acid286, while synthetic polymers include allylamine287, acrylonitrile288, vinyl alcohol281, 2hydroxyethyl methacrylate289, methacrylic acid281,285, aniline290, acrylic acid291, 2-acrylamido-2methylpropane sulfonic acid292 and vinyl sulfonic acids291. In an investigation conducted in recent times by Gao et al.279, wherein they stated on electro-sensitive hydrogel constructed from poly(sodium maleate-co-sodium acrylate) and PVA that the gel distortion amplified on increasing electrical voltage or intensity of NaCl. Besides polyelectrolytes, some unbiased macromolecules similarly have established electrical field sensitivity in insulating medium, wherein such networks typically necessitate existence of additionally activated or polarizable constituent with capacity responding to smeared electrical field254. Electro-sensitive macromolecules find another important application in constructing of electronic field actuators, where for example, Irvin et al.291 reported polythiophene-founded conductible macromolecule gel actuator, wherein they stated that actuator exhibited mutable shrinkage/enlargement performance initiated by smearing voltage difference and enlargement against wall generated axial stress, while further validating that produced cessation stresses can be utilized as minor-scale actuator faucet. 3.1.1.4 Ultrasound – Responsive Polymers: 33 ACS Paragon Plus Environment


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Organized liberation of therapeutic complexes at definite location or rate inside body is principle on which significant amount of proposed functions for stimuli-responsive polymers rely on, where for certain instances, changes in environmental situations are requisite for imparting sensitive drug liberation which occurs via active or passive migration of macromolecular transferor to region of body having conditions which inspire liberation, e.g., cause of intrinsic dissimilarities in pH, pH-sensitive macromolecules can liberate drugs at definite locations in digestive tract or within endosomes254. Nevertheless, it could be complex cause of incapacity for locally applying stimuli at directed location for functioning of networks which depend on supplementary stimulus, such as modification in thermal value can result in liberation of thermo-responsive macromolecular transferors in vitro, however confined heating and cooling in vivo isn’t trivial each time at positions extremely inside human body. In such cases, external application on demand of ultrasound stimulus has verified efficient at prompting drug liberation within the body. As method is non-invasive, adaptation of ultrasound-sensitive macromolecules for ordered drug distribution seems appealing as well as it finds itself being successfully utilized in other factions of medical diagnostics and treatment293. Specific macromolecular characteristics which allow response to ultrasound are very difficult to pinpoint, as extensive range of polymers with varying architecture, composition, Tg, polarity etc., exhibit modulation in their behavior on exposure to ultrasonic stimulation. Polymeric micelles, hydrogels or supplementary nonswollen perceptible solids, or layer by layer (LbL) covered microbubbles are polymeric systems which generally respond to ultrasound254. Extensive exploration have been steered for understanding ultrasound-triggered liberation rate of assimilated constituents from decomposable polymers like poly-bis(p-carboxyphenoxy)alkane anhydrides with sebacic acid, polylactides, polyglycolides, as well as non-decomposable polymers like ethylene–vinyl acetate copolymers. Release kinetics were significantly enhanced for each of these systems with increasing ultrasound intensity, as ultrasound is capable of significantly increasing degree of deterioration in decomposable macromolecules and also capable of enhancing permeation through non-erodible polymers. Investigations conducted on ultrasound-responsive polymers in drug-delivery systems include poly(HEMA-co-DMAEMA) hydrogels and poly(lactide-co-glycolide) microspheres. Norris et al.293 conducted an investigation for probing the ultrasound-responsive antibiotic release from PHEMA hydrogels, wherein gels were covered for minimalizing passive liberation with coating of C12-methylene units via interaction with 34 ACS Paragon Plus Environment

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dodecyl isocyanate. They further elucidated that smearing of low power ultrasound treatment resulted in degradation of alkane layer and subsequent drug liberation, whereas in absenteeism of ultrasound, antibiotic were preserved inside polymeric medium. Relevance of ultrasound-responsive polymers for acoustic destabilization of polymeric assemblages have been considered294–297, as macromolecular micellae are generally triggered for dissociating or adopting freely related configurations on exposure to ultrasound298. Enhancement in local cellular uptake of drugs can be elucidated owing to the application of low-frequency ultrasound, thus indicating that this method might demonstrate to be beneficial in delivery only if safety measures are adopted for preventing cavitational loss to crucial assemblies within body295. Macromolecules could promote to ultrasound sensitiveness by another method, i.e., coating and stabilization of microbubbles which are produced owing to sonication, as collapsing of microbubbles and cavitation produce confined shockwaves and micro-jets which momentarily perforate membranes for facilitating cell entrance. The application of this ‘sonoporation’ process has substantiated proficient in vitro and in vivo299,300. 3.1.1.5 Magneto – Responsive Polymers: Magneto-responsive macromolecules are those macromolecules capable of responding to absence or presence of magnetic fields where they can be immobilized to surfaces, or can exist as free chains in solution, or crosslinked within systems254, where the magneto-responsive characteristics could be incorporated by adding colloidal magnetic elements301 or carbon nanotubes302 into the polymer matrix. Extensive investigations conducted by numerous researchers are available in literature which term swift riposte of magneto-sensitive gels inflated with multifarious fluids301,303,304. A number of striking phenomena occur on exposure to magnetic fields owing to combination of elastic and magnetic characteristics such as high elasticity, anisotropic elastic, giant deformational effect and swelling characteristics, the magneto-responsive materials exhibit great potential in assorted applications301. Materials with distortion in configuration and dimension which transpires reversibly and promptly in existence of mutable magnetic field is typically owing to inorganic magnetic elements which are covalently immobilized or physically captured inside 3D cross-linked linkage. A substantial escalation in consumption of magnetoresponsive polymers for soft biomimetic actuators, sensors, separation media, membranes, switches, cancer therapy agents, artificial muscles, and drug-delivery systems305–307 owing to



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magneto-phoretic force acting on polymeric material produced cause of magnetic susceptibility of elements301. A different phenomenon is elucidated on application of constant magnetic fields, wherein there is lack of interfaces between magnetic field and elements, however particle to particle interfaces are produced owing to the creation of induced magnetic dipoles. Significant transformations in material characteristics can be observed owing to unit assemblage within enclosing macromolecular matrix254. Extensively well-documented literature on amalgamation of magnetic particles (Fe3O4) inside pNIPAm-founded micro-gels is available301,308,309. Non-covalent interfaces amid magnetic elements and macromolecular chains is prime principle on which maximum illustrations of magneto-sensitive polymeric networks rely305–307, however covalent immobilization of macromolecular chains straight to exterior of magnetic elements has been facilitated by recent synthetic advances254. Broad array of mesoscale configurations have been perceived by other researchers, extending from field aligned 1D mesostructures, arbitrarily entwined chains, as well as nematic such as liquid crystal colloidal assemblages310,311. An innovative method for constructing magneto-sensitive gels with aid of surface initiated ATRP was reported by Czaun et al.312, wherein they validated that iron particles served like crosslinker, thus abolishing necessity for traditional crosslinking means. 3.1.2

Chemical Stimulus – Sensitive Macromolecules:

3.1.2.1 pH – Sensitive Macromolecules: Polymers comprising of pendant basic or acidic moieties which are capable of either accepting or releasing of a proton as a triggered riposte to alterations in environmental pH could be termed as pH-sensitive or pH-responsive polymers231. The extension and collapsing due to charge induced electrostatic repulsions leads to the interchanges of the hydrodynamic volumes of polymer chains233. Polyelectrolytes are the polymeric material which comprise of a multitude of ionisable functionalities, which can be branched in to two categories: weak poly-bases and weak poly-acids. Weak poly-bases exhibit acceptance of protons and swelling behavior under acidic conditions whereas weak poly-acids release of protons at neutral and high pH while simultaneously accepting of protons at low pH313. If the suspended acidic group ionizes at specific pH owing to the alterations in the environmental pH, then it is known as ‘pKa’, wherein rapid modifications in cumulative charge of assemblages connected results in molecular configuration variation of 36 ACS Paragon Plus Environment

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polymeric chain, as mobile counterions neutralized by network charges exert osmotic pressure for mediating the transition to expanded state231. Figure 11 depicts pH-sensitiveness in polymeric chains, polymeric networks and surface grafted polymeric brushes.

Figure 11: Schematic illustration of pH-sensitiveness in: (a) Polymeric chains (b) Polymeric networks and (c) Polymeric brushes grafted surfaces respectively.

The pH-responsive poly-acids which have been extensively explored are poly(acrylic acid) or PAA and poly(methacrylic acid) or PMAA exhibiting pKa values around 5314–317. Another example of weak poly-acids that exhibit pH-sensitive behavior are polymers comprising of sulphonamide group having pKa values extending from 3 to 11 and the rapid ionization of H2 atom of amide nitrogen to form poly-acids. In comparison with carboxylic acid based polymers, these polymers exhibit major advantages such as good sensitivity and narrow pH range253. Extensive range of polymers could be termed as pH-sensitive polymers including gelatin, poly(methacrylic acid-g-ethylene glycol) or P(MAA-g-EG)318,319, albumin, poly(ethylene imine) or

PEI320,

chitosan321, poly(acrylic acid)/chitosan interpenetrated network or IPN, poly(lysine) or PL322 and poly(N,N-diakylamino ethylmethacrylates) (PDAAEMA). The most typical representative of polybasic group for utilization as pH-responsive polymeric bases are poly-bases exhibiting an attached amino group such as poly(N,N-diethylaminoethylmethacrylate) or PDEAEMA and poly(N,N-dimethylaminoethylmethacrylate) or PDMAEMA, as the attached amino group exhibits protonation at high pH whereas it is positively neutralized and ionized at low pH232. Inducing of 37 ACS Paragon Plus Environment


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strong hydrophobic interfaces as the aggregation force can be elucidated in poly(N,Ndiethylaminoethylmethacrylate) or PDEAEMA, where a long hydrophobic group ( e.g. ethyl groups) assisted hyper-coiled conformation is exhibited231. Investigations have been conducted on polymers including poly(vinyl-immidazole) or PVI, Poly(4 or 2-vinylpyrrolidine) or PVP and quartinized poly(propyleneimine) as introduction of a more hydrophobic element offers an increased compact conformation and a highly discontinuous phase323. 3.1.2.2 Solvent – Responsive Polymers: In general, instead of adopting a stretching conformation, a coil-like conformation is exhibited by the macromolecular chains in the solution, however, a better solvent will result in a proper stretched presentation of the polymer brush, and shrinkage is noticeable in a non-solvent232. Consequently, varying characteristics are exhibited by the block copolymers or mixed polymeric brushes consisting of differing polarities or solubility. Cause of its switchable surface properties polymeric brushes have been mainly focused for probing solvent-responsive polymers, wherein exposure to diluents with dissimilar affinities yield varied results on surface characteristics of copolymer brushes183,324,325. A good representative example of material which tunes sense of balance amid electrostatic, steric and hydrophobic forces on exposure of polymeric chain to a myriad of solvents is triple block copolymer poly(styrene-block-2-vinylpyridine-block-ethyleny oxide) or PS-b-P2VP-b-PEO. Motornov et al.326 conducted an investigation where they contoured stimuli-sensitive colloidal environment founded on PS-b-P2VPS-b-PEO copolymer brushes and validated that colloidal system exhibited a histrionic property conversion on being exposed to variety of external solvents. On a single substrate, grafting of chemically varying polymers are achieved in mixed polymeric brush system, where substrates surface characteristics are convertible relying on which polymeric brush is at exterior. Modulation of surface wettability owing to mutable, diluent enhanced phase categorization of brushes is exhibited by block co-polymer brushes and binary or mixed polymeric brushes, where the brush morphology is affected by the composition of solvent, thus enabling regulations over which phase which comes in contact with the external environment327–329. Stimuli-responsive polymeric brushes modified surfaces exhibit potential for applications in microfluidic devices or where surfaces require self-cleaning owing to their solvent driven wettability changes330,331. Oligomeric grafted, perfluorinated end cap attached polyethylene glycol 38 ACS Paragon Plus Environment

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amphiphiles (f-PEGs) were applied to substrates for obtaining greater declining contact angles for oil than advancing contact angles for water in an investigation conducted by Howarter and Youngblood330, where they further validated that this switchable surface chemistry could be applied for removing oil fouling. They also reported that the energy required for the development of water substrate-contact must overcome the energy for the loss of oil-substrate contact which aids removal of oil droplet from surface i.e. these surfaces take advantage of thermodynamic driving force of water for displacing oil droplet on surface of substrate. The alternating external stimuli using water and air instead of two liquids is another intriguing investigation regarding the solvent-responsive polymeric brushes. Numerous investigations have been conducted by other researchers based on similar outlines by polymer chain reorganization and substitution of hydrophobic functionalities at superficial layer with hydrophilic assemblies when submerged in H2O332. 3.1.2.3 Ionic Strength – Sensitive Macromolecules: Ionic strength-sensitive macromolecules can be defined as the stimuli-responsive polymers containing ionizable moieties which exhibit response to variation in ionic strength as an external stimuli, in form of variations in solubility of polymer, dimension of micelles with polymeric origin and electrolyte bound fluorescence quenching kinematics of color inducing functionalities333. A single polymer chain can be incorporated with both cationic and anionic charged entities with the aid of polyampholytes, as these polymeric systems are able to exhibit unusual rheological behavior due to the alluring Coulombic interactions of positively and negatively charged species. They are dissolvable in existence of acute intensity of electrolytes where charge interfaces are protected but are insoluble in deionized water. The polymer to ionic species ratio dictates the behavior of the polyampholytes in solution, as this relation can be moderated via synthetic approaches or via extrinsic vagaries in the water rich environment, specifically alterations in pH. These systems behave as polyelectrolytes when either of the cationic or anionic groups are available in excess, nevertheless, Coulombic attractions dominate interaction capability, as proportion of anionic to cationic groups is equitable334. Typically, reduction in the electrostatic interactions between polymers and other molecules or among copolymers owing to the addition of salt is the mechanism on which the ionic strengthresponsive polymers rely on and thus ionic strength is strongly affected by the solution 39 ACS Paragon Plus Environment


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comportment of the polyelectrolyte232. Phase transitions in ionic strength-sensitive polymers may be elucidated due to differing intensities of salts that decide ionic strength of solutions. Similarly, investigations conducted on polymers which are non-ionic in nature, such as pNIPAm hydrogel at a critical salt concentration, also exhibited a sharp volume phase transition. Investigations have been conducted by Liu et al.335,336 for understanding salts outcome on LCST comportment of temperature-responsive hyper-branched macromolecules in liquescent solution, wherein they reported definite positions of anions as well as cations in decreasing LCST. 3.1.3

Biological Stimulus – Sensitive Macromolecules:

3.1.3.1 Enzyme – Sensitive Macromolecules: Stimuli-sensitive macromolecules have sought potential in a relatively new zone of research for designing constituents which exhibit macroscopic characteristic modifications on exposure to particular catalytic activities of enzymes61,337. Special enzymes, such as reductive enzymes like azo-reductase or hydrolytic enzymes like glycosidase, are produced in Mother Nature by colon inhabiting bacteria and degrade polysaccharides, like dextrin, chitosan, , pectin, cyclodextrin, and amylase or amylopectin338–340. Enzyme-responsive polymers exhibit unique sensitivity as enzymes responding under mild conditions, are highly selective in their reactivity and the polymeric systems that comprise of enzyme-sensitive surface and other component which controls interactions producing macroscopic transitions, such as variations in designs, inflation of networks, or alteration of surface characteristics61. Figure 12 illustrates enzyme triggered cleaving in polymeric chains, polymeric gels and core shell particles respectively. Non-invasive formation of hydrogels in situ can be utilized for hydrogels which are enzyme-responsive in nature. The utilization of enzymatic dephosphorylation for inducing sol–gel conversion was reported in an investigation conducted by Yang et al.341, wherein they testified that phosphatase was interacted with fluorenylmethyloxycarbonyl

(FMOC)-tyrosine

phosphate.

They

further

validated

that

supramolecular assemblages by π moeties of fluorenyl groups, decrease in electrostatic repulsions, and inevitable gelation was elucidated owing to the removal of phosphate groups. Assimilation of functional groups which react as a response to explicit enzymes is another approach for conveying enzymatic-sensitivity in a polymeric system, as revelation of assemblies to definite enzyme may cause establishment of novel covalent associations which triggers alterations in the macroscopic properties25. 40 ACS Paragon Plus Environment

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Figure 12: Illustration of enzyme triggered cleaving in polymeric chains, polymeric gels and core shell particles respectively.

Researchers have conducted investigations where they have validated that transglutaminase exhibits crosslinking of side chains of lysine residues with glutamine deposits across peptide segments342, whereas others validated the utilization of proteases for instigating the self-assembly of hydrogels by the means of reversed hydrolysis of peptides61. Similarly, interlinking of natural macromolecules in existence of cellular unit can be brought about by the aid of transglutaminase343, which are active in the vicinity of calcium ions and can result in activating enzymatic cross-linking61. Researchers have extensively investigated over the years and strategically contoured copious routes for constructing hydrogels which exhibit a macroscopic response to proteases25. Generally, the subsequent release of cased contents owing to the gel degradation caused due to the hydrolysis of peptide- and protein- based cross-linkers in the network is exhibited by the hydrogel on being exposed to a protease enzyme. An investigation was conducted by Thornton et al.337 where enzyme reducible tri-peptide encompassing amalgamations of phenylalanine, positively charged arginine, and glycine remains which caused enlargement as consequence of electrostatic repulsions led to modification of copolymers that comprised of acrylamide and PEG macro-monomers. They further stated that the loss of arginine groups caused by the cleaving of tripeptide, upon addendum of proteases, ensued in decrease in electrostatic repulsions causing consequent collapse of hydrogel. They also proposed the protease-responsive 41 ACS Paragon Plus Environment


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hydrogels for possible functions in the entrapment of medically relevant drugs or in the removal of toxins. 3.1.3.2 Antigen – Responsive Polymers: Multifarious immune-based riposte which aid evaluation and neutralization of extraneous infection instigating entities within body, are offered by antigen-antibody exchanges, as they are explicit in nature. Copious array of non-covalent exchanges, like electrostatic attraction or repulsion, van der Waals forces, hydrogen bonding and hydrophobic interfaces decide the binding among the antibodies and antigens25. For yielding an array of responsive synthetic polymeric systems, high attraction along with specificity of interfaces of antibodies and antigens can be utilized, as antibodies are deployed for numeral immune established endeavors in recognition and quantification of non-biological and biological constituents344. In numerous investigations, hydrogels have been prepared for inducing responses to antigen-antibody binding via chemical conjugation of antigen or antibody to system, by physically entrapping antigens or antibodies in system or utilizing antigen-antibody sets as mutable interlinkers within system345. An investigation was conducted by Miyata et al.346 for constructing hydrogels which were antigen-sensitive in behavior by conjugating N-succinimidylacrylate or NSA with rabbit immunoglobulin G or Rabbit IgG, wherein mutated elements were polymerized in vicinity of MBA, acrylamide and antibody of goat anti-rabbit IgG, which resulted in production of hydrogel interlinked conjointly by covalent interfaces as well as through the antigen-antibody interfaces. They further reported that with addendum of rabbit IgG as a free antigen results in curtailing antigen-antibody cross-linkers and concomitant enlargement of hydrogel owing to viable attachment of rabbit IgG with goat anti-rabbit IgG antibodies. Similarly, a comparable hydrogel which was reversibly responsive was reported by Miyata et al.347, wherein antibody (goat antirabbit IgG) in conjunction with antigen (rabbit IgG) were functionalized for containing vinyl groups. They further stated that regulated antigen underwent polymerization with aid of MBA and acrylamide in existence of antibody which was polymerized using acrylamide, for synthesizing of hydrogels portraying antigen-antibody semi-interpenetrating network. They also validated that the disruption of antigen-antibody crosslinks which produced swelling of hydrogel was perceived owing to viable binding of antibodies with free rabbit IgG antigen. They finally testified that the swelling was reversible as mutually antigen as well as antibody were covalently bound within 42 ACS Paragon Plus Environment

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semi-interpenetrating network and also that stepwise alterations in antigen intensity prompted pulsatile infusion of protein through system. 3.1.3.3 Thiol – / Redox – Responsive Polymers: Another class of biologically-responsive polymeric systems which exhibit remarkable prospective in the sector of ordered drug distribution systems are the thiol- or redox-responsive polymers348–351. In many biological processes, inter-conversion of thiols and disulfides is important reaction, owing to its importance in rigidity as well as stability of inherent proteins within active cells, which have also been exploited for contouring copious array of bioconjugation protocols352. During introduction of various reducing agents disulfide bonds are reversibly converted to thiols and in existence of supplementary thiols, they undergo disulfide exchange owing to which polymers that comprise of disulfide linkages are generally thiol- or redox-responsive in nature353,354. Direct incorporation of redox-responsive disulfide groups into backbones or side chains could be achieved with aid of an appropriate chain transfer agent, monomer or initiator355– 357.

Thiol-/redox-responsive polymers were constructed by Tsarevsky and Matyjaszewski358 in an

experiment, with the aid of disulfide-containing difunctional ATRP initiator, whereas in another experiment they utilized a disulfide-functional dimethacrylate monomer for fabricating redoxresponsive gels by using inverse miniemulsion ATRP359, wherein they validated that integrating cleavable disulfides with both micelle cores and shells is a feasible procedure for alleviating multimolecular clusters.. Although examples mentioned above mainly rely on self-assembly of block copolymer within vesicles or micelles which can subsequently be stabilized/destabilized by using thiol-disulfide chemistry, however, redox sensitive could be prompted in clusters which doesn’t consist block copolymers. Similarly, other investigations have also been reported in the literature on redoxsensitive gels and block copolymers, where for example, polyacrylamide hydrogels were fabricated by means of tetrapeptide interlinker sensitive to reducing agents like TCEP by Plunkett et al.360, whereas in another experiment, a redox triggered gel was formed through reversible addition fragmentation chain transfer polymerization of NIPAm facilitated via polysaccharide (pullulan)-founded chain transfer agent by Morimoto et al.361. Numerous experiments have been reported in literature by various researchers362,363 for fabrication in conjunction with redoxresponsivity of reversible interlinked polystyrene systems, where aminolysis of using reversible 43 ACS Paragon Plus Environment


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addition fragmentation chain transfer produced macromolecules prompted telechelic thiol macromolecules which can reversibly accumulate into sensitive bicyclic, cyclic, multi-block, as well as network designs. On incorporation of redox-mutable connections at block junction positions, block copolymers such as star, block, and multi-block copolymers could be rendered as thiol-sensitive in behavior. Application of RAFT for fabricating three-armed star polymers that were thiol-sensitive and biodegradable in nature via -both ‘arm-first’ and ‘core-first’ approaches were reported by Liu et al.364. Similarly, numerous investigations have been conducted by Napoli et al.365–367 for designing and characterizing block copolymers of hydrophobic poly(propylene sulfide) (PPS) tethered to hydrophilic poly(ethylene glycol) (PEG) via disulfide bridges, as novel class of oxidation-responsive copolymers. They further validated that these responsive materials could be possibly utilized in bio-sensing and as carriers in drug delivery. 3.1.3.4 Sugar – Sensitive Macromolecules: Proficiency of mimicking usual endogenous insulin emission for minimalizing diabetic impediments and simultaneously releasing bioactive compound in meticulous means is exhibited by glucose-sensitive polymers25. Glucose-responsive polymers exhibit variability in their response on exposure to glucose, as they are sugar-sensitive, owing which they had acquired significant concern for its application in both insulin-delivery and glucose-sensing functions231. Responsive polymeric systems which exhibit macroscopic response on exposure to glucose are typically based on combining of glucose with lectins, mutable covalent linkage realization amid glucose and phenyl-boronic acid moieties or enzymatic glucose oxidation via glucose oxidase (GOx)25,231. Figure 13 illustrates glucose binding triggered disintegration of polymeric micelles. Stereotypically, straightforward interface of glucose with sensitive macromolecules does not induce glucose-sensitivity, but is rather induced owing to reaction of polymer with derivatives which effect from enzymatic glucose oxidation, as enzymatic exploitation of GOx on glucose is extremely precise that results in derivatives of gluconic acid and H2O2254. Thus, the addition of a macromolecular entity which exhibits response to these trivial fragments can indirectly result in a glucose-sensitive polymeric system. In numerous investigations researchers have reported that when GOx systems are conjugated with poly(acrylic acid) or PAA, glucose is converted into gluconic acid owing to increase in blood glucose level, which results in protonation of PAA carboxylate units and in reduction of pH, thus facilitating the release of insulin, whose release 44 ACS Paragon Plus Environment

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pattern mimics that of endogenous secretion of insulin25,368. Investigations have also been reported by researchers for fabricating similar hydrogels by copolymerizing sulfadimethoxine monomer with N,N-dimethylacrylamide (DMA)369 or via N-isopropylacrylamide (NIPAm) with methacrylic acid370.

Figure 13: Glucose binding triggered disintegration of polymeric micelles.

Glucose-sensitive macromolecular structures can also be fabricated by utilizing distinctive carbohydrate binding characteristics of lectins, as they are multivalent proteins which trigger responses specifically for glucose and mannose231. One such type of lectin which has been extensively exploited in insulin-modulated drug delivery owing to its four binding sites is Concanavalin A or Con A. Chemical modification of the insulin molecules is generally carried out in such systems by incorporating glucose molecule or a functional group, which is then attached to a carrier or supports via precise interfaces capable to be interrupted only by glucose itself. Viable binding performance of Con A with glucose and glycosylated insulin is exploited by glycosylated insulin-Con A complex, as free glucose molecules are bioactive and cause translation of glycosylated Con A-insulin conjugates interior of the surrounding tissues254. Investigations have been conducted on assorted polymers which exhibit glucose-response based on competitive binding amid glucose and lectins. Takemoto et al.371 conducted an investigation for contouring insulin and glucosyl-terminal poly(ethylene glycol) (G-PEG) mono-substituted conjugates, where 45 ACS Paragon Plus Environment


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they testified that G-PEG-insulin conjugates were covalently linked to Con A which were further bound to a PEG–poly(vinylpyrrolidine-co-acrylicacid) backbone, and they further validated that successive attachment of glucose to Con A resulted in dislodgment and liberation of G-PEG insulin conjugates owing to an augmentation in the concentration of glucose. Investigations have also been reported for fabricating glucose-responsive polymers by other approaches including polymers comprising phenyl-boronic groups & polyol polymers which result in a gel via arduous configuration amid hydroxyl groups & pendant phenyl-borate372. Insulin is generally unconfined from eroded gel owing to reduction in crosslinking density of complex caused by escalation in glucose intensity. Borate-polyol crosslinking renders the glucose exchange reaction reversible, thus permitting the reformation of the gel25. Glucose-responsive polymers based on reversible covalent linkage configuration inbetween glucose and boronic acid moieties find themselves being extensively utilized as glucose sensors & as ligand moieties all through chromatography owing to the capacity of boronic acids to mutable system thru sugars373. 3.2 Combinational Stimuli – Responsive Polymers: 3.2.1

Dual Stimuli – Responsive Polymers:

Hypothetically, a dual stimuli-responsive polymeric system can be termed as the combination of any two single stimuli-responsive system which exhibit a triggered macroscopic response on exposure to more than one external stimuli. There exist copious classes of dual stimuli-sensitive polymers comprising combinations of several stimulus such as light, magnetic field and pH with temperature-responsive polymers owing to their extensive exploitation232,374. 3.2.1.1 Temperature and pH – Responsive Polymers: Adoption of pH and temperature as suspension variates has conjointly intrigued scientific researchers as well as academia, as they are capable of voluntarily modifying an archetypal structure236,375. An additional trigger in form of pH can be incorporated within the thermo-sensitive polymeric systems due to which these polymers have sought devotion in the drug delivery sector, as both variates subject themselves to alterations within the cancer tissue for triggering an autonomous response376,377. The association of pH-sensitive characteristics can perpetually be elucidated via polyelectrolytes, as charges present along polymeric chains produce complex interas well as intra-molecular interactions, which always has intense influence on rheological, dynamic, as well as structural characteristics of network374. In recent times, numerous approaches 46 ACS Paragon Plus Environment

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including alteration of pH have been engaged for tailoring thermal value of prompted phase conversion for variegated functions, as its eminent that addition of altered magnitude of charged monomers is proficient approach for modulating the phase transition temperature378. In a system comprising of a pH-tunable phase transition temperature, the hydrogen-bonding interactions play a vital role. Carboxylic acids or tertiary amines are the typical examples of functional groups that are assimilated into the LCST polymer backbone in such dual stimuli-sensitive systems, which upon protonation, can either form ionic groups or dissociate into ionic groups, however, some homopolymers like poly(2-(dimethylamino) ethyl methacrylate) exhibit a temperature- and pHsensitive behavior, having cloud point in span of 50 °C in unbiased liquescent suspension42,379. Although, the protonation of amino-functionality on augmenting the pH, shifts the cloud point to greater numbers, thus representing the dual stimuli-responsive system. Numerous investigations have been conducted by the researchers for constructing dual stimuli-responsive systems for wide array of functions380. Zhou et al.381 piloted an experimentation for contouring a stable and smart polymer brush interface founded on pNIPAm, poly(acrylic acid) and poly(N-isopropylacrylamideco-acrylic acid). They testified that polymeric brush interface was competent to reversibly riposte to temperature, as well as pH, simultaneously or independently, owing to mutable alteration in hydrogen binding amongst two constituents (NIPAm and AA) and water, and ionization of carboxylate units in altered ambient conditions which ensued in the dual stimulus-responsive behavior. Dual stimuli-sensitive polymeric arrangements founded on combination of temperature and pH, also exhibit great potential in the oil-gas industries as shear-thickening resources379. 3.2.1.2 Temperature and Light – Sensitive Macromolecules: One of utmost significant dual stimulus-sensitive polymeric systems are the polymers which respond by exhibiting a macromolecular tuning to either temperature- and/or light-55. Numerous investigations have been conducted in recent times by researchers for fabricating dual stimuliresponsive systems which trigger responses to the combination of temperature in conjunction with light, for synergistically manipulating the materials characteristics375,382,383. Light responsiveness of such polymer systems is cause of the chromophores which undergo structural isomerization, ring-opening or cyclization upon radiation at a specified wavelength, and on exposure to light at a distinct wavelengths, some of these photo-induced alterations are able to unveil reversibility382. 47 ACS Paragon Plus Environment


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Figure 14 illustrates transition of hydrophobic or hydrophilic phases in dual surface grafted polymeric brushes on exposure to temperature or light. An archetypal paradigm of chromophore

Figure 14: Transition of hydrophobic or hydrophilic phases in dual surface grafted polymeric brushes on exposure to temperature or light.

is the azobenzene moiety, which experiences a swift trans-to-cis photo-isomerization on irradiation, resulting in the increase of the dipole moment (0 D to 3 D) which subsequently augments the LCST of the polymer chain384. Extensive investigations exhibiting a serial interplay have been conducted based upon this seminal work for functionalizing the thermo-responsive polymers with azobenzene moieties385– 387.

Researchers have also utilized other photo-responsive moieties like fulgimides, spiropyran, o-

nitrobenzyl groups and coumarin388,389, as spiropyran and fulgimides are photochromic molecules which undergo photo-isomerization, whereas ortho-nitrobenzyl units are cleaved upon radiation and coumarin is benzopyrone molecule which could uncrosslink and crosslink on radiation at distinct wavelengths. Shiraishi et al.271 piloted a trial for devising block copolymer system comprising of pNIPAm as thermal-responsive block and spiropyran entities as photo-sensitive block.

They

testified

that

cause

of

temperature-sensitive

reversible

and

linear

hypochromic/bathochromic alteration of absorption spectra within broad range of temperature


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under UV irradiation, constructed block copolymer system could potentially be utilized for temperature sensor functions. 3.2.1.3 Supplementary Dual Stimuli – Responsive Polymers: Researchers have also endeavored for devising stimuli-responsive polymeric systems exhibiting dual responsive nature with other combinations for practical functions. Dual stimuliresponsive polymer systems comprising combinations of magneto-sensitive and thermo-sensitive characteristics find themselves being exploited for functions like artificial muscle301 and for protein separation390. Ding et al.390 steered experimentation for investigating desorption and adsorption conduct of human serum albumin (HSA) protein on magnetic elements blanketed by temperature-sensitive pNIPAm polymer via seed polymerization methodology, wherein they elucidated that on increasing temperature, devised particles were able to deswell and were liable

Figure 15: Dual-stimuli effect resulting in entrapped cargo release from the stimuli-responsive polymers. Reprinted with permission from Li, Q.-L.; Fang, L.; Yang, Y.-W.; Chen, Q.; Lu, H.; Gu, W.-X.; Gao, H. Construction of Stable Polymeric Vesicles Based on Azobenzene and Beta-Cyclodextrin Grafted Poly(glycerol Methacrylate)s for Potential Applications in Colon-Specific Drug Delivery. Chem. Commun. 2015, 51, 4715. Copyright 2015 Royal Society of Chemistry.



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for absorbing superior quantities of proteins that might be desorbed at inferior temperature. They also validated that the magnitude of adsorption was reliant on the incubation time, protein concentration and pH value, where amplifying the initial protein concentration or the incubation time augmented the favorability for the adsorption of proteins, whereas at greater pH, lesser extent of proteins could be adsorbed owing to the electrostatic repulsive forces amongst the surface particles and the proteins. Figure 15 illustrates the dual-stimuli effect resulting in the entrapped cargo release from the stimuli-responsive polymers Similarly, dual stimuli-responsive polymeric systems based on other combinations such as temperature- and redoxsensitive polymers have also been probed by the researchers over the period. An investigation was piloted by Phillips and Gibson391 for devising dual stimuli-responsive polymeric systems based on pNIPAm macromonomers that were linked with the aid of disulfide units for triggering the dual responsive behavior. In the presence of gluthathione, the redoxsensitive disulfide unit could be cleaved causing the pNIPAm bits to exhibit cloud point behavior dependent on molecular weight392. Block copolymer comprised of vinylferrocene and alkylacrylamide entities is another example of serial interplay between both stimuli, i.e. temperature and redox, as polymer exhibits distinctive LCST, that could be reversibly augmented via ferrocene units once its transferred into hydrophilic cationic condition. Likewise, researchers have been extensively conducting experimentation for contriving dual stimuli-sensitive polymer systems based on other than the thermo-responsive polymers12,393–400. Jackson and Fulton396 steered an investigation for formulating polymeric units, which exhibited dual response to variation in pH and redox, by crosslinking aldehyde/disulfide-functionalized and copolymers amine/disulfide-functionalized copolymers via development of disulfide and benzoic imine binds. Researchers have also exploited dual redox stimuli-responsive assemblies for biomedical applications like regulated drug delivery upon specific biological events like physiological oxidative stress400. 3.2.2

Multiple Stimuli – Responsive Polymers:

The strength of merging numerous stimuli within one polymer has been demonstrated impressively by the assorted combinations of dual stimuli-sensitive polymers owing to which in recent times, the researchers have been extensively endeavoring for contriving stimuli-responsive polymers revealing one additional stimulus, i.e., triple or multiple stimuli responsive 50 ACS Paragon Plus Environment

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polymers254,374. Higher degree of accuracy, enlargement of

switching window or uniform

regulation of switching conditions, can be achieved by the addition of one more stimulus, which yields a higher level of intricacy of polymer232. Figure 16 depicts schematic illustration of triggered release of drug particles on exposure to multifarious stimuli.

Figure 16: Schematic illustration of triggered release of drug particles on exposure to multifarious stimuli.

3.2.2.1 Temperature, pH and Light – Responsive Polymers: In recent times, researchers have been extensively probing experimentations for contriving stimuli-responsive polymers capable of responding on exposure to combinations of three different stimulus. Combining building blocks which are both pH & temperature sensitive, such as PDMAEMA, with a different responsive entity is one way for contriving triple stimuli-responsive polymers having serial interplay374. Light-responsive entities, such as azobenzene have been utilized by researchers in conjunction with PDMAEMA, for devising responsive polymeric systems, which can respond to three different stimulus (light, pH and temperature). Recently, an experimentation piloted Tang et al.401 for contriving a triple stimuli-responsive system comprising of an azobenzene terminated PDMAEMA polymer with aid of ATRP, which exhibited 51 ACS Paragon Plus Environment


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responsiveness on exposure with pH, temperature and light. They reported that LCST characteristics of system could be modulated by altering pH value, i.e. at pH value of 4, dimethylamino functionality was completely protinized, producing augmented polarity owing which no LCST was elucidated, however, with increasing pH value, the LCST was elucidated to be lowered to 68 °C for pH value of 7 which further reduced to 30 °C for pH value of 11, which was ascribed to consecutive deprotonating of dimethyl amino group. They also reported that photoisomerization of azobenzene end-group yielded marginally higher LCST upon radiation with UV in contrast to LCST at equivalent pH prior to irradiation, which was fully reversible. Researchers have also carried out experimentations for better understanding influence of azobenzene entities positioned at series end of stimulus-sensitive polymer’s, where all researches have testified that sum of azobenzene is equal to variance in LCST prior and after radiation, however, it is to be noted that association is merely binding for azobenzene end-assemblage functionalized polymer’s, where light-prompted isomerization is entirely autonomous from different side assemblage consequences374,402,403. The phase transition behavior is not necessarily effected in a direct association for statistical copolymers containing azobenzene as side groups256,404. Sumaru et al.405 conducted an experiment where they functionalized pNIPAm with spirobenzopyran. They validated that devised polymer behaved as logic gate cause of sensitive behavior towards pH, temperature and light, wherein pNIPAm polymer delivered common thermo-responsive behavior, while spiropyran represented dualistic nature as pH and light sensitive entity. Likewise, an enticing approach was demonstrated recently by Zhang et al.406, wherein they exploited a pH, thermal & light sensitive hyper-branched macromolecule on foundation of hyper-branched polyethylenimine or HPEI. They validated that configuration exhibiting serialized sensitiveness to altogether 3 stimulus, and parallel to linear copolymer was devised on cessation of HPEI by isobutyramide units, trailed by complexation of 4(phenylazo)benzoic acid. 3.2.2.2 Supplementary Multiple Stimuli – Responsive Polymers: Similarly, numerous other investigations have been piloted by researchers for devising multiple stimuli-responsive polymeric systems exhibiting copious combinations239,407–414. Roy et al.407 conducted an experiment where they devised a boronic acid block copolymer from boronic acid acrylamido monomer (APBA) with NIPAm with the aid of RAFT polymerization, which 52 ACS Paragon Plus Environment

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validated to self-assemble as retort to modulations in concentration of sugar, pH & temperature. They reported that copolymer dissolved as unimers beneath LCST of pNIPAm block, whereas at temperature above LCST of pNIPAm block instigated PAPBA-b-pNIPAm block copolymer to dehumidify & coagulate into micelles in fluid mixture, while further stating that PAPBA block is neutralized & water attractive under low pH condition and polyanionic and hydrophilic under high pH condition. They validated that PAPBA-b-pNIPAm copolymer exhibited its multi-sensitive behavior by demonstrating reversible particle aggregation and disintegration as per the glucose concentration, pH and temperature. Likewise, Klaikherd et al.408 conducted an experiment where they contoured a block copolymer which was responsible for alterations in pH, temperature, and redox-potential having micellar characteristics and being able to encapsulate guest molecules consisting of pNIPAm block affiliated with THP-secured HEMA block by disulfide linker. They reported that following THP deprotection under acidic conditions, THP-protected HEMA block converts to water attractive from water repulsive, while rate of liberation of encapsulated Nile red was elucidated to have enhanced with time owing to acetal cleaving on decreasing the pH. They also stated that the cleaving of block copolymer into its individual homopolymers under mild conditions can be caused owing to the reduction of disulfide linker which was confirmed by GPC analysis. They finally validated that on treating Nile red containing block copolymers with acid and DTT tailed by incubation did not cause solution to become cloudy as expected owing to pNIPAm dehydration, which they testified was owing to hydrogen bonding among HEMA blocks and pNIPAm that affected alteration in LCST behavior. Similarly, researchers have also been endeavoring for contriving multiple stimuli-responsive metallo-supramolecular polymers. Beck and Rowan409 steered an experimentation for contriving multi-sensitive metallo-supramolecular polyelectrolyte gel-like constituents which exhibited thermal, chemical and mechanical ripostes, by utilizing amalgamation of metallic ions with bisligand monomer. They reported that pentaethylene glycol linked tridentate ligand bis(2,6-bis(10 methyl-benzimidazoyl)-4-hydroxypyridine) or BIP–PEG–BIP, was interspersed with Zn (II) or Co (II) ions as lineal series bound moieties or with Eu (III) or La (III) ions as crosslinking entities. They further stated that using bis-ligand monomer, they devised 4 gel-like metallo-supramolecular constituents – 1:Zn/Eu, 1:Zn/La, 1:Co/Eu and 1:Co/La, which showed a thixotropic, i.e. shear53 ACS Paragon Plus Environment


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thinning behavior, supporting that they are also mechano-sensitive, whereas alterable gel–sol change was elucidated for heating of 1:Co/La to 100 °C. They also validated that lanthanidecontaining structures were chemo-sensitive, as accumulation of formic acid to 1:Zn/Eu dissociated gel-like constituent cause of bounding of lanthanides to carboxylic acids, where method can be overturned via dehydrating and re-inflating constituent.

4. Applications of Stimuli – Responsive Polymers: In recent times, stimulus-sensitive macromolecular materials has sought interest conjointly from academia as well as industries owing to its ability to adapt to surrounding environments, change adhesion and wettability of copious species on extraneous stimulus, or regulate transportation of molecules and ions, while simultaneously boasting of ability to convert biochemical and chemical signals into mechanical, thermal, optical and electrical signals, and vice versa due to which they are utilized in variegated array of applications like ‘smart’ optical systems, drug delivery, diagnostics, and tissue engineering, in conjunction with coatings, textiles, biosensors and microelectromechanical systems25,183,415. In following sections, we extensively elaborate array of industrialized engineering functions of stimulus-sensitive macromolecules like controlled drug delivery, smart coatings, sensing and bio-sensing, artificial muscles and actuators, bio-interfaces and bio-separation, etc. 4.1 Smart Coatings: Smart coatings can be broadly termed those coatings which are capable of exhibiting a triggered macroscopic response on exposure to stimuli owing to the incorporation of responsive entities in the coatings. For the swiftly evolving field of smart coatings, polymeric brushes or reconstructable polymeric surfaces exploit as toolbox, as they permit the programming of the structure of the coatings during formulation416. The phase separation of the constituents is affected after deposition by an external stimuli for self-assembling into a coating exhibiting encoded characteristics. Misra et al.417 conducted an investigation in which they contoured colloidal particles contrived by means of emulsion co-polymerization of fluorinated acrylate and acrylate monomers for formation of stratified film morphologies, wherein fluorinated phase could be compelled to film/substrate or film/air borders owing to which they validated that kinetic and static coefficients of friction could be regulated at film/air border, thus yielding water-repelling surfaces. 54 ACS Paragon Plus Environment

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Similarly, Motornov et al.418 steered an experimentation wherein they stabilized colloidal particles in a low pH solution by grafting triblock copolymers of PS-b-P2VP-b-PEO, wherein they elucidated a textured coating, at higher pH, on casting of the particle suspension, which resulted in film comprising of particle aggregates. They further validated that the polystyrene blocks migrate to the upper coating layer, on heating beyond the Tg of polystyrene blocks, owing to which the coating exhibits superhydrophobic behavior. Figure 17 depicts copious functions of smart coatings.

Figure 17: Copious functions of smart coatings.

In recent times, the swift developments in the field of smart coatings have appealed the researchers for contriving smart coatings exhibiting hydrophobic or superhydrophobic behavior owing to the responsive moieties incorporated within the systems, which have exhibited serious potential for an assorted array of applications extending from waste water treatment to oil-water separation to removal of heavy and toxic metal ions from drinkable water415,419–446, as illustrated in Table 2. Sahoo et al.447 critically reviewed on copious bio-inspired multifunctional materials possessing hierarchical complex structures with self-cleaning and water repellant characteristics. 55 ACS Paragon Plus Environment


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For possessing the attributes of a smart coating, he focused his review on the influence of hierarchical structure, microstructures and nanopillar structure by analyzing the amount of air pocket formation, static WCA and WCA hysteresis for advancing robust superhydrophobic surfaces. In another review, Sahoo et al.432 critically scrutinized the consequence of the temperature of substrate on the superhydrophobicity of hierarchical multiscale structures fabricated by spin coated and spray coated candle soot/expanded polystyrene foam and camphor soot/expanded polystyrene foam composite potraying WCA of 165o and roll-off angle 2o. They also decisively revealed the influence of pressure and heat energy cultivated by water droplets during the spreading stage where the spray coated expanded polystyrene foam/camphor soot composite, at significant pressure of 200 Pa, astoundingly sustained the super hydrophobicity of the structures. Table 2: Assorted applications of stimuli-responsive polymers in smart coatings.

Smart Coating Function

Reference

Waste Water Treatment

419, 430, 438

Oil – Water Separation

440, 444–446

Oil – Organic Solvent Separation

433, 434

Uranium Adsorption

423, 425,426,428

Hydrogen Adsorption

420, 421, 431

Arsenic Adsorption

429, 440, 442

Thorium Adsorption

441, 443

The expulsion of debris of radioactive materials into the aquatic ecology is an anxious obsession causing extreme dilemma to the living organisms, thus compelling the researchers to look for some mitigation approaches. Gore et al.443 explored innocuous and biocompatible molecularly imprinted nanofibers of RTIL/chitosan for confiscation of Thorium (IV) ions, wherein they obtained a maximum efficacy of 90% adsorption of Thorium (IV) ions at temperature of 298 K within 2 hours from the mimicked effluent waste. Similarly, Sharma et al.430 synthesized a novel platform of molecularly imprinted camphor soot functionalized poly(acrylonitrile) nanofibers for the reclamation of Thorium(IV) ions with decent adsorption capacity of 93% in pH 7, wherein the resulting adsorbent exhibited reusable and re-generable attributes even after 4 cycles of adsorptiondesorption, with effectual desorption of 97%. 56 ACS Paragon Plus Environment

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In another research, Gore et al.442 presented resorcinol formaldehyde/polyvinyl alcohol core-shell nanofibers for probing the adsorption characteristics of Arsenic(III) ions from mimicked effluents. They testified that the fabricated nanofibers demonstrated 97.46% efficacy of adsorption on protracted exposure along with 93.1% reclamation at higher temperatures. For the exclusion of same radioactive material, Sharma et al.429 synthesized a novel microporous adsorbent, Fe2O3 impregnated crosslinked matrix of cellulose acetate for the elimination of As(V), wherein they recorded the optimized adsorption of up to 65% in the pH range of 5. They further reported that the efficaciousness of the adsorbent was obtained up to 5 cycles without substantial decrease in the efficiency. Similarly, Rule et al.423 utilized Fe2O3 impregnated cellulose based adsorbents for retrieval and amputation of Uranium(VI) ions from waste water in trace quantities wherein exceptional adsorption efficiency of 100% was acquired at 7 pH value with adsorption capacity of 7.6 mg/g. The smart hybrid adsorbent possessed well defined micro-pores that signified the aptitude for capillary action and well-defined flow lines for the adsorption of Uranium(VI) ions which caused disappearance of flow lines and rupture of the surface upon Uranium(VI) adsorption. Likewise, Singh et al.425 developed a cost effective technique based on functionalized cellulose electrospun nanofibers by camphor soot for efficient reclamation of Uranium(VI) from mimicked solution of nuclear wastewater with a maximum rapid uptake of up to 97% adsorption in 2 hours. They stated that the effectual adsorption capacity of 410 mg/g with 96% adsorption was attained as a result of the increased porosity of the nanofibers owing to the incorporation of camphor soot ensuing the spontaneous uptake. In recent periods, leaching of oil into huge oceans recently has ascended as global issue owing to spoilage of marine ecosystem, thus compelling need of counter measures for advanced oil-water separation. As a result, Gupta et al.440 piloted an experiment wherein non-ionic nano-sized dispersion polymerized PTFE was impregnated on surface tailored modified Janus membrane exhibiting superhydrophobic/superoleophilic attributes with exceptional efficiency of up to 98% separation of petroleum stuffs while upholding the inherent characteristics for not less than 30 recurrences. They reported that the remarkable efficacy was obtained as a result of nano-spindles (polymeric brushes) that were irregularly patterned onto the micro-fibral cotton surface for developing a hierarchical architecture that yielded a superhydrophobic surface exhibiting WCA of 168° ± 3o. They validated that owing to the dual scale hierarchical rough surface, several regimens such as Wenzel, Cassie-Baxter and impregnated Cassie wetting regime have been proclaimed, 57 ACS Paragon Plus Environment


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where the Wenzel’s regime asserted that upon contact of the hierarchical rough surface and water droplet, complete impregnation of water into the pores occurs and the enhanced WCA is as a result of only surface roughness leading to equation given below: cos θ= Rf cos θo

(5)

wherein, θo is Young's contact angle of smooth surface, Rf is roughness factor defined as ratio of actual to projected surface area and θ is contact angle of rough surface They further stated that, if the capillary action doesn’t occur on the rough surfaces, air pockets are formed into the pores amidst solid-liquid interface leading to enhanced WCA of hierarchical surface which can be given by Cassie-Baxter equation: cos θ= Rf fSL cos θo - 1 + fSL

(6)

wherein, fSL is fraction of projected area representing interface of solid-liquid Also, upon partial impregnation of rough surface pores with water leading to WCA amongst Wenzel and Cassie-Baxter, then WCA by Cassie wetting regime can be given by: cos θ= 1 + fSL (cos θo-1) Similarly, Gore et al.

444

(7)

fabricated an in-situ surface modified nanoclay functionalized

heterogenous wettable Janus fabric of cellulosic-substrate based with biodegradable poly(lactic acid) or PLA exhibiting superhydrophobicity of WCA ~152° exhibiting excellent separation efficacy of upto 99.16% for oil-water separation. They testified that the superhydrophobicity, superoleophilicity and low adhesion to ice of this smart coating were as a result of its hierarchical textured morphology that played an extremely crucial role in maintaining the fabrics reusability. Analogously, Gore et al.434 also presented a tunable and self-driven, wettability modified nanofibrous PVDF engineered cellulosic janus membrane for one-step selective oil absorption function, wherein they reported that this durable fabric possessed high separation efficacy owing to the fine porous interconnected nanofibers resulting in porous structure, thereby enhancing hydrophobicity of the smart coatings. 4.2 Controlled Drug Delivery:


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Researchers from past few decades are attempting to mimic the behavior of living systems to react to exterior stimulus by adapting and retorting to altering extraneous conditions, by devising the so called ‘smart’ polymers, as they exhibit promise for biomedical applications like targeted/triggered/controlled drug delivery vehicles, bio-separation apparatus, cell culture supports, tissue engineering scaffolds, biosensors, and artificial muscles/actuators448. In late 1970s, Yatvin et al.449 demonstrated conception of stimulus-sensitive polymer-based drug dispensing techniques for the first time, wherein they utilized temperature-responsive liposomes for the confined discharge of drugs via hyperthermia. Consequently researchers have conducted numerous investigations, especially on the application and design of the stimulus-sensitive polymers in drug

Figure 18: Self-assembling of PGMA-CD particles and their subsequent cargo release for colon-specific drug delivery. Reprinted with permission Li, Q.-L.; Fang, L.; Yang, Y.-W.; Chen, Q.; Lu, H.; Gu, W.-X.; Gao, H. Construction of Stable Polymeric Vesicles Based on Azobenzene and Beta-Cyclodextrin Grafted Poly(glycerol Methacrylate)s for Potential Applications in Colon-Specific Drug Delivery. Chem. Commun. 2015, 51, 4715. Copyright 2015 Royal Society of Chemistry.



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dispensing function93,253,450–453. For meeting the challenges allied with administration in the body, approaches and design of the new systems must be (i) composed of biodegradable, non-toxic, and biocompatible components; (ii) simply administered; and (iii) proficient of delivery to the vital localities in response to a stimuli451. Scientists have utilized an array of stimuli-sensitive polymerderived constituents such as non-crosslinked block copolymer assemblies and crosslinked gel networks for this application. Figure 18 depicts the self-assembling of PGMA-CD particles and their subsequent cargo release for colon-specific drug delivery. Crosslinked polymeric linkages like micro-gels and hydrogels are one of the utmost essential categories of stimulus-sensitive polymers utilized in regulated delivery of drug. Hydrogels owing to their water swellability and porous structure have exhibited to be valuable for an expansive array of applications in biomedical field, as their porosity facilitates drugs loading in the gel matrix along with consequent discharge of medication at a degree reliant on the coefficient of diffusion of micro- or macromolecule in the gel complex, in conjunction with their ability to alter their swellability rate in response to modulations in their surroundings177,454,455. Majority of the hydrogels depending on their characteristics and structure have been utilized for transdermal or injectable drug deliverance systems. Microneedles have been exploited in transdermal delivery of drug, as they augment permeability of the drug into the skin by offering a clean entrance path, which enriches the efficiency of the delivery of pharmaceutical agents and vaccines like small molecules, protein, DNA456,457. Hydrogel-based microneedle arrays in comparison to the solid microneedles, are able to swiftly imbibe the skin’s liminal fluid for establishing distinct in situ hydrogel bulbs for regulating the management of drug at a quicker rate than the conventional reinforcement systems utilized in controlled drug release458. The swelling induced release mechanism is the utmost significant characteristic of the hydrogel-forming microneedle arrays459, as the incorporation of stimulus-sensitive entities into them, permits one to activate the on-demand discharge of antidote by maneuvering the exterior stimulus460,461. Hardy et al.462 conducted an investigation wherein they fused the light-sensitive drug conjugates with hydrogel-forming microneedles for contriving innovative apparatuses capable of performing on-demand transdermal drug delivery. They constructed microneedles by crosslinking ethyleneglycol dimethacrylate with poly (2-hydroxyethylmethacrylate) via micro-molding for exhibiting the desired mechanical characteristics. They validated that on exposure to light, the 60 ACS Paragon Plus Environment

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devices exhibited the liberation of ibuprofen drug over a long duration and liberation of the drug could be modulated by turning light on and off. Similarly, Yang et al.463 conducted an experiment in which they devised biphase microneedle arrangements which intertwines with tissue, mechanically, via inflatable microneedle tips for enhancing adhesion strength, by imitating endoparasite Pomphorhynchus laevis which fixes to its host’s intestinal wall. Chen et al.464,465 steered investigations, wherein they incorporated photo-sensitive moieties having light-triggered release characteristics into the microneedles yielded patches for providing chemotherapy and photo-thermal therapy. They confirmed that for several cycles photo-triggered heating and liberating nature could be accurately regulated and swapped off and on during demand. In recent times, researchers have also endeavored for devising microneedle array-based patches exhibiting sensitive characteristics for controlled antibody466 and smart insulin467,468 delivery. In recent investigation piloted by Yu et al.468, in which they proposed glucose-responsive insulin delivery apparatus in regard to microneedle array patches assimilated with glucose oxidase (GOx) and hypoxia-sensitive hyaluronic acid (HS-HA) vesicles encompassing insulin, wherein by seizing benefit of localized initiation of hypoxia, they triggered discharge of insulin in riposte to hyperglycemia. They elucidated that upon conversion of water repelling 2-nitroimidazole to waterloving 2-aminoimidazoles in hypoxic atmosphere, this hypoxia responsive transduction could be achieved. They further stated that self-assembled vesicles capable of encapsulating both GOx and human insulin were constructed from the amphiphilic hyaluronic acid, which they observed to dissociate and subsequently release the encapsulated insulin when the blood glucose level was high owing to the reduction of 2-nitroimidazole in a local hypoxic environment caused by the rapid consumption of dissolved oxygen resulting from the glucose oxidation reaction. They further demonstrated painless and continuous administration of insulin by integrating the vesicle into the microneedle array, thus validating prospect of enclosed-loop delivery of insulin. Several studies have been investigated by researchers where they have endeavored for contriving biocompatible micro-gels, as they exhibit numerous advantages, such as a faster rate of response to exterior stimulus, owing to their small size on comparison with macro-gels451,469. For circulating in the blood stream for longer durations and for biodegradability on persistent discharge, the micro-gels can be tuned chemically with responsive entities, as the biodegradability permits the micro-gels to be swiftly cleared from the body. Furthermore, they also exhibit the 61 ACS Paragon Plus Environment


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potential of being utilized for the construction of biomedical apparatuses revealing enhanced and/or novel functions, as building blocks470. For contouring controlled drug delivery systems, these many advantages make micro-gels the ideal candidates469–471. Researchers have conducted numerous investigations for acquiring unique micro-gel founded assemblies or reservoir devices, as a new platform for drug distribution techniques472–476. Gao et al.472 steered an experimentation for contriving a reservoir device, as a unique platform for triggered and controlled micromolecule delivery, comprising of pNIPAm-co-AAc micro-gel coating sandwiched amongst two thin coatings of gold. They reported that the micro-gel layer of the device was loaded with positively charged tris (4-(dimethyl amino) phenyl) methylium chloride, which was released at a rate that might be regulated by the height of the gold coating covering the micro-gel, in a pH reliant fashion, and further validated that the model drug can be given-off in an “on–off” method, by methodically tuning the solution pH. Table 3 illustrates pH value of copious cellular/tissue sections231. Table 3: pH values of copious cellular/tissue sections.

Cellular/Tissue Section

pH Value

Stomach

1.0 – 3.0

Lysosome

4.5 – 5.0

Duodenum

4.8 – 8.2

Late endosome

5.0 – 6.0

Early endosome

6.0 – 6.5

Golgi

6.4

Tumor, extracellular

6.5 – 7.2

Colon

7.0 – 7.5

Blood

7.35 – 7.45

Block

copolymer self-assembled configurations, like micelles, vesicles, and liposomes, are another significant stimuli-sensitive polymeric architectures utilized in controlled drug delivery systems, wherein thermo-sensitive polymeric micelles have enticed substantial interest cause of their abrupt modulation of characteristics in response to a slight variation in ecological temperature204,477–480. Core-shell micelle assembly forms beyond LCST, on utilization of thermo-sensitive polymers as hydrophobic core-forming segment, owing to hydrophobic interface amid dehydrated polymeric chains481–483. Qin et al.484 steered an experiment in which they utilized block copolymers of poly(ethylene oxide)-block-poly(N-isopropylacrylamide) for contouring micellas proficient of 62 ACS Paragon Plus Environment

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liberating minor molecules as function of temperature, wherein they stated that above body temperature (37 °C), polymers became amphiphilic in water and self-assembled into micellas which could capsulize both hydrophobic and hydrophilic particles, and with a reduction in temperature, the micellas disassembled and released the matters.

Figure 19: Illustration of specific drug delivery for anti-tumor functions. Reprinted with permission from Ye, M.; Han, Y.; Tang, J.; Piao, Y.; Liu, X.; Zhou, Z.; Gao, J.; Rao, J.; Shen, Y. A Tumor-Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers. Adv. Mater. 2017, 29, 1. Copyright 2017 Wiley-VCH.

Researchers have also exploited photochromic molecules as responsive constituents for contriving photo-sensitive polymeric systems for controlled drug delivery functions485,486. Wang 63 ACS Paragon Plus Environment


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et al.485 piloted investigation in which they stated construction of photochromic polymersomes unveiling photo-switchable and reversible bilayer permeability via novel poly(ethyleneoxide)-bPSPA dual block copolymers, in which SPA was spiropyran-established monomer encompassing distinctive linkage of carbamate, wherein they elucidated that on self-assembly into polymersomes, spiropyran entities inside vesicle bilayers experience mutable light-activated isomerization between water repelling spiropyran and zwitterionic merocyanine states. They further observed that owing to co-operative non covalent interactions from water-repelling interfaces, π–π stacking, hydrogen bonding, and zwitterionic or paired electrostatic interfaces, microstructures of spiropyran and zwitterionic merocyanine polymersomes are stabilized synergistically.

They

simultaneously

determined

and

validated

the

photo-switchable

spatiotemporal liberation of 4′,6-diamidino-2-phenylindole inside alive HeLa cells on exposure to UV light. Figure 19 depicts schematic representation of specific drug delivery for anti-tumor functions. Another potential candidate for developing smart responsive systems for controlled drug delivery are the disulfide bonds, as they unveil a high tendency to be reduced into thiols487. In an investigation piloted recently by Wang et al.488, they contrived multi-block copolymers by numerous enes as well as disulfides in water-repelling blocks followed by alteration of enclosed doxorubicin by core-crosslinking and conjugation reactions. They detected that under physiological conditions, the attained prodrug micelles bestowed persistent spherical particles, whereas on exposure to D,L-dithiothreitol (DTT), they undergo rapid dissociation. Similarly An et al.489 steered experimentation in which they reported unique block copolymer based on rosin intended for self-assembling into micellar carriers with situated disulfides at boundaries of hydrophilic poly(ethylene glycol) (PEG) coronas and hydrophobic rosin cores. They detected that an enhanced liberation of the encapsulated drugs by this block copolymer-based self-assembled micellar carriers because of the existence of glutathione (GSH)-responsive entity, wherein the consequential micelles comprising of PEG coronas demonstrated an exceptional colloidal stability in the occurence of proteins, thus proposing the persistent circulation of blood in vivo. They reported that the destabilization of the micelles was caused by the effective cleaving of the disulfides located at the core or corona interfaces in riposte to 10 mM GSH as biotic reducing means, thus eventually augmenting liberation of Dox encapsulated within the micelles. They finally testified that great adaptability as intra-cellular drug distribution carriers in cancer treatment 64 ACS Paragon Plus Environment

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is offered by fabricating of sensitive block copolymers along with their self-compiled configurations comprising of reduction-sensitive characteristics. In recent times, researchers have also have successfully demonstrated in their investigations that smart stimuli-sensitive polymers could be utilized as smart anti-tumor drug carriers for cancer therapy functions490–494. Li et al.491 piloted an experiment wherein they fabricated dynamically crosslinked supramolecular system of poly(glycidyl methacrylate)s derivative chains on nanoparticles of mesoporous silica by means of ion-dipole interactions and disulfide bondages among protonated diamines and cucurbit[7]urils in polymeric chains. Under simulated intracellular tumor environment (pH = 5.0, CGSH = 2~10 mM), they detected that constructed supramolecular network exhibited good release performance of doxorubicin hydrochloride (Dox), with the release value increasing on lowering pH value of the solution and increasing the concentration of glutathione (GSH). They further reported that against cancer cell lines, the constructed Dox-laden hybrid nanomaterials exhibited evident cell-growth inhibition because of which they validated that formed multifunctional organic-inorganic hybrid material unveiling glutathione and pH sensitiveness could be potentially utilized in anti-cancer drug delivery and controlled release. Similarly recently Yu et al.494 also synthesized an effective triple stimulisensitive (temperature, pH and redox) Dox-laden drug delivery system based on methyl methacrylate, poly(N-isopropylacrylamide) and N,N’-bis(acryloyl)cystamine for precise therapeutic effect of cancer treatment and improve the utilization of drugs. They stated that the constructed Dox-loaded nano-carriers exhibited tumor accumulation, tumor penetration and controlled drug release, under the influence of the three trigger factors, owing which the fabricated multi-sensitive nano-carriers are ideal candidates for development of effective novel anti-tumor drug delivery systems. Abundant flexibility in designing of stimulus-sensitive drug dispensing methods is provided by extensive array of stimulus which can be employed for triggering drug liberation at correct position and time, in conjunction with range of sensitive constituents and other functional constituents which could be constructed in diverse configurations254. 4.3 Sensors and Biosensors: An assimilated self-enclosing invention adept of converting an output signal into a readable outcome on the basis of an input received from its surroundings, can aptly be adopted as a broad 65 ACS Paragon Plus Environment


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definition for a ‘sensor’, whereas a ‘biosensor’ can be aptly defined as a gadget proficient of measuring as well as distinguishing concerned biomolecular species, or in other words, a biosensor must be proficient in recognizing a species of concern (analyte) from a multifarious fusion comprehending an array of interfering species, and providing precise outcomes in short time448,495,496. The ability to trigger an observable physical or chemical modulation on exposure to environmental stimuli has enticed the researchers for utilizing stimuli-sensitive polymers as sensing motifs in the responsive polymer-based sensors183. Toma et al.497 endeavored an investigation for contriving copolymer hydrogel network of poly(N-isopropyl acrylamide)-comethacrylic acid or pNIPAm-co-MAAc, that was deposited on an optical sensor substrate having indium tin oxide micro-heaters inserted in it that permitted optical signal tuning. They validated that temperature-photosensitive constant of dn/dT = 2 × 10−2 RIU K−1, was yielded owing to the triggered rapid thermal responses, that is, swelling and de-swelling of the pNIPAm-based material on application of micro-heaters. They also reported that the hydrogel network exhibited potential to aid as 3-Dimensional connecting matrix for biosensor functions by immobilizing biomolecules into polymeric linkage, which they validated by altering hydrogel with mouse immunoglobulin G (mIgG) with aid of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) coupling, that were capable of recognizing goat antimouse IgG labeled with Alexa Fluor 647 dye. They also stated that the enhanced electric field by Surface Plasma Resonance (SPR) resulted in an augmentation in the fluorescence strength that was detected by the SPR resonance angle which was elucidated to be temperature dependent, as tuning the temperature led to the diminishing of the fluorescence intensity in conjunction with a little shifting of the resonance contact angle owing to the collapsing of the binding matrix. Thus they testified that by enlarging and compressing of hydrogel binding matrix, the SPR-excited fluorescence signal at the resonance angle can be modulated.


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Figure 20: Copious dimensions of order in photonic crystals.

Similarly, investigators have also conducted experimentations where they have utilized stimuli-responsive polymers as building blocks for constructing photonic crystals, as they tend to exhibit structural color by means of the interaction of light with periodic configuration of the material that results in constructive or destructive interference of specific wavelengths of light448,498. Depending on the number of dimensions, the photonic crystals can be typically classified as 1-D, 2-D and 3-D, as depicted in Figure 20. Visual color of material along with wavelength of light ‘reflected’ from gadget is principally revealed by matter’s lattice spacing, that can also be tuned by applying external stimuli, if the photonic crystals are compiled of stimulisensitive macromolecule building blocks498. Widespread explorations have been conducted over the period by researchers for pioneering the advancement of 3 Dimensional sensors based on photonic crystal by inserting ordered crystalline colloidal arrays in biomolecule-sensitive hydrogel structures which were utilized for detection of temperature, ionic strength, solution pH, and the existence of chemical or biological targets499–504. Holtz and Asher499 steered experimentation for devising 3-D photonic crystal-based sensing apparatus for metal ions by copolymerizing 4acryloylaminobenzo-18-crown-6 into gel comprising of organized assortment of spheres of polystyrene, wherein they testified that when metal ions connected with crown ether of 4acryloylaminobenzo-18-crown-6, hydrogel would swell owing to the enhancement in charge density of the polymeric complex, thus causing upsurge in network swelling and osmotic pressure by means of which spheres of polystyrene in gel complex parted from each other causing alteration of ‘reflected’ light.



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In a different investigation piloted by Chiappelli and Hayward505 wherein they contrived colorimetric temperature sensor via banking discontinuous deposits of low and high refractive index polymers on substrate for developing 1-D Bragg mirror, wherein smaller refractive index macromolecule was thermo-sensitive poly(N-isopropylacrylamide)-co-acrylic acid, whereas higher refractive index macromolecule was non-sensitive poly(para-methyl styrene) or PpMS. They elucidated that the macromolecule stack exhibited an orange color and a Bragg peak at 710 nm upon room temperature immersion in water, whereas on heating, the pNIPAm-based polymer coatings shriveled, which resulted in waylay of the PpMS coatings and an affiliated transference in reflected light to inferior wavelengths yielding regulation in color. They also validated that the color modulation of the system was completely revocable with temperature. Serpe et al. have been conducting experimentations for contriving etalons, which are a basic 1-D photonic material, capable of triggering response on exposure to a variety of stimuli like electric field506, pH507, nerve agents508, light509, temperature50 as well as copious biomolecules510, by thin layer deposition of gold on surface of a substrate of glass via thermal vaporization tailed by ‘painting’ a coating of micro-gels onto the gold, and subsequently additional gold layer deposition on top of the microgel coating. They validated that consequential edifice permitted light to move in dielectric cavity and reverberate amid two reflective Au coatings, wherein this reverberating light produces destructive and constructive interference. They also stated that one can predict the wavelength of the reflected light by utilizing equation (8): λ𝑥 = 2𝑑𝑦 cos θ

(8)


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wherein 𝑥 = peak order, y = refractive index of dielectric, λ = specific wavelength maximum of reflected peak, θ = angle of incidence and 𝑑 = spacing between mirrors. In case of etalons, dielectric layer and mirrors are served by the pNIPAm-based micro-gel layers and the Au

Figure 21: Typical illustration of Bio-sensor

respectively, where these devices have been exhibited to be capable to recognize proteins511, glucose512, DNA513, CO2514 and triacyl glycerols515. Figure 21 represents schematic for typical biosensor. An experimentation was piloted by Zhang et al.515 for contriving triacylglycerol-sensitive micro-gels

by

conjugating

poly(N-isopropylacrylamide-co-4-vinylpyridine-co-N-

acryloxysuccinimide) micro-gels with lipase, wherein they elucidated that upon the penetration of triolein into the micro-gel layer, it would hydrolyze into a long fatty acid chain via lipase in the micro-gels, which could consequently fasten to the micro-gels by acid–base interactions amidst Table 4: Assorted applications of stimuli-responsive polymers for sensing and bio-sensing functions.

Function Sensors

Reference pH

500, 501, 506

Metal Ions

498, 499, 501



Bio-sensors

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Ionic Strength

500

Electric Field

505

Temperature

501, 503, 504, 509

Light

508

CO2

513

Antigen

496

Protein

509, 510

Glucose

495, 498, 499, 511

DNA

512

Triacylglycerols

514

Galactose

499

Nerve Agent

502, 507

fatty acid and micro-gel’s pyridine assemblies. Etalon’s reflectance points that resembled to intensity of triolein resulted in a blue shift upon dissociation owing to which they testified that these gadgets were capable to determine the physiologically pertinent triolein range. Table 4 depicts assorted applications of stimuli-responsive polymers in sensing and bio-sensing functions. 4.4 Artificial Muscles and Actuators:


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The complex process of transforming chemical energy into mechanical energy in biological organs is generally performed via the ‘natural muscles’, as it involves an electrical pulse from the brain which initiates chemical reactions such as adenosine triphosphate hydrolysis or ATP

Figure 22: Schematic representation of artificial muscle actuation.

hydrolysis owing to the liberation of ions inside the sarcomere and the subsequent conformational alterations along the natural muscle fibers516. For the past few decades, extensive array of experimentations have been ventured by the investigators for mimicking such behavior on bilayers, which are the utmost communal polymer-bedded actuator systems, comprising of one actuating conducting macromolecular layer accumulated on electromechanically inert coating517–521. Similarly, researchers have also endeavored experiments for devising artificial muscles comprising tangible responsivities from macroscopic and electrochemo-mechanical appliances by generating bilayers and trilayers from poly(pyrrole) films on a double-sided tape522–524. Nevertheless in recent times, development of supramolecular chemistry has observed investigators shifting their focus of experimentations on switchable supramolecular materials for development of artificial muscle systems525–531. Chen et al.530 conducted an experimentation recently wherein by means of hierarchical self-assembly of photo-responsive amphiphilic molecular motor, they developed a macroscopic contractile muscle-like motion of supramolecular network which contained 95% of water. They reported that primarily molecular motor assemble in nanofibers that subsequently assemble into aligned bundles which form long strips in dimensions of centimeters, 71 ACS Paragon Plus Environment


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while further stating that contraction of fibers towards the light source is consequence of irradiation inducing rotary motion of molecular motors. They furthermore testified that constructed system demonstrated large amplitude motion, precise control over shape, quick response in conjunction with weight-lifting studies in air and water. Figure 22 represents stimuli-responsive polymer based artificial muscle actuation5. Jiang et al.532 piloted an experiment wherein they reported the impulsive development of a poly(pyrrole) or PPy and partially-reduced graphene oxide film (PPy-prGO film) by using selfredox stratagem, as this reaction transpired on direct revelation of the graphene oxide film to pyrrole vapor at ambient temperature deprived of some additional additives. They validated that such convenient approach for devising asymmetric GO/prGO-PPy hybrid films could be utilized as electrochemical or moisture actuators in advanced actuation systems. As they are able to operate under an assortment of environments including copious salt suspensions, urine, cell culture medium, and blood plasma, PPy-based actuators and micro-actuators exhibit potential for functions in cell biology and biomedicine533,534. Unusual humidity-sensitive self-bending bilayerbased actuators have been contoured by researchers535,536 on a flexible substrate via deposition of layers comprising of the polyelectrolyte polydiallyldimethylammonium chloride or PDADMAC and the poly(N-isopropylacrylamide)-founded micro-gels. They elucidated that upon drying, responsive material exhibits bending, which is dependent on atmospheric moistness and that dehydrated PDADMAC coating comprises of both crystalline and amorphous segments, where crystalline layer templates specific bending features of device, whereas amorphous segments can voluntarily captivate water, thus resulting in actuation. Based on understanding of bending mechanism, researchers utilized them as humidity sensors and artificial muscles, wherein humidity response was measured by connecting assembly to circuit consisting of battery and LED, which accumulated LED light concentration as function of moisture. They further reported that when assembly was attached to multi-meter that was ascribed on gold surface of strain sensing apparatus, light intensity was perceived to be inversely dependent on humidity. In recent times, researchers have also conducted experiments by utilizing photo-responsive polymers for producing polymer gels, liquid crystalline polymers (LCP) and shape memory polymers as they are liable for translating the light energy into mechanical energy

537,538.

Investigators have incorporated photo-sensitive entities in polymers for crosslinking liquid 72 ACS Paragon Plus Environment

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crystalline polymers, as they are able to persuade photochemical interactions and noticeable macroscopic consequences on macromolecule cause of which they find themselves also being exploited as actuators539–543. Finkelmann et al.544 steered an experiment wherein mono-domain nematic liquid crystalline polymers (LCP) were introduced with azobenzene units as crosslinker for generating films which exhibited noteworthy shriveling on exposure to 365 nm radiation. Similarly, Ikeda et al.545–547 conducted an experiment wherein they demonstrated photo-compelled bending of azobenzene-LCPs can be attained via production of asymmetric deterioration amid surface and bulk of film on exposure to UV light. In another investigation steered by Yamada et al.547 contrived photo-compelled soft actuators with aid of azobenzene-LCP/polyethylene laminated films, wherein they validated that mono-domain LCP exhibiting in-plane arrangement of mesogens bent along arrangement path towards radiation source. In recent times, Kumar et al.548 conducted an experiment wherein they constructed a LCP film doped with visible photo-sensitive fluorinated azobenzene which exhibited unremitting ‘chaotic’ oscillatory motion on exposure with ambient sunlight in air by simultaneous illumination of blue and green light. They validated that motion is autonomous of location of light source and that it is regulated via molecular association in macromolecular film, making this component possibly beneficial for outdoor functions such as self-cleaning surfaces and coatings in conjunction with self- morphing/propelling soft actuators that can be utilized for harvesting and converting solar energy. Hydrogels which are able to exhibit volume alteration on being triggered by a stimuli are an another very important class of actuators, as they are 3-Dimensional linkages which could captivate water and inflate and shrink in riposte to assorted extraneous stimulus like pH, chemicals, ionic strength, light, temperature, and electricity8,549. Macroscopic modulations upon swelling and shrinking are produced by hydrogel actuators177,550–552. In an experimentation conducted recently by Kim et al.553, wherein they constructed layered hydrogel comprising of co-facially oriented electrolyte sheets, which they elucidated to produce substantial anisotropic electrostatic revulsion in inside of hydrogel. They reported that on modulating its electrostatic anisotropy, material could be operated in riposte to alterations of electrostatic permittivity, which can be regulated via alteration of material’s solvation state that relied on temperature of solution. Recently, a computational model for demonstrating an innovative reversible shape-altering constituent design theory empowered by 3 Dimensional printing of stimulus sensitive 73 ACS Paragon Plus Environment Table 5: Application of stimuli-responsive polymers for artificial muscles and actuator functions.


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macromolecules, shape memory polymers (SMP) and hydrogels was recently devised by Mao et al.554, wherein they reported that this methodology practices inflation of gel as driving force for shape modification, and temperature-reliant modulus of shape memory macromolecule for regulating time of such figure alterations. They further stated that switching between two stable configurations could be achieved by controlling temperature and aqueous environments and that assemblies are comparatively rigid and could carry load in each configuration without mechanical charging for apparatus preparation. For validating design model, they constructed and verified nature of numerous shape-altering edifices by applying the design principles, which exhibited adjustable shape modulations based on origami, folding and curling concepts. Table 5 consolidates data on stimuli-responsive polymers being utilized for artificial muscles and actuators. To summarize, stimuli-responsive polymer-based actuators are resources which are proficient of transforming energy from extraneous stimulus, like electricity, light and heat, to mechanical powers; and can be developed from a range of entities such as LCP, shape memory polymers and hydrogels. Depending on intended function material could be utilized, where for instance, rigid shape memory polymers could be exploited for elating or moving hefty masses, whereas soft hydrogels could be expended for delicate biological functions. Function

Reference

Artificial

Bilayered – based

516–520

Muscles

Trilayered – based

521, 522

Hydrogel – based

177, 549–553

Electrochemical

524

Actuators

Moisture

524, 534, 535

Mechanical Stimulation

532, 533

Light – driven

538–547

4.5 Bio-Interfaces and Bio-Separation: The stimuli-sensitive characteristics of the reconfigurable polymeric brush layers exhibit relevancy in numerous biomedical and biotechnological functions, as they are able to undergo dynamic modulations in accordance with alterations in biological structures18,555,556. Stimuliresponsive polymeric bio-interfaces have enticed the researchers owing to several key aspects, such as the possibility of switching and tuning adhesion amongst stimulus-responsive polymers 74 ACS Paragon Plus Environment

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and cells and proteins which have been reconnoitered for the cell control557 and protein558,559 adhesion, also bio-separation, in conjunction with the possibility of revealing and concealing functional entities at the bio-interface for demonstration of regulatory signals and affiliated modulation of biomolecule activity for bioengineering and cell research functions560. Figure 23 depicts representation of separation of biomolecules at bio-interface.

Figure 23: Schematic representation of separation of biomolecules at bio-interface.

Researchers have conducted numerous investigations in recent times for constructing entities that are able to interact with cell components by functionalizing pNIPAm and its copolymers with recognition moieties558–561. The utilization of temperature-sensitive poly(N-isopropylacrylamideco-2-carboxyisopropylacrylamide) for exposing or masking arginine–glycine–aspartic acid (RGD) determination sequences for cell binding function was demonstrated in an experimentation by Ebara et al.561, wherein they grafted the thermo-responsive units onto TCPS (tissue culture grade polystyrene) dishes which permitted immobilization of RGDS. They reported that by exploiting surface chemistry of stimulus-responsive polymer, the specific interactions between the immobilized RGDS cell adhesion peptides and cell integrin receptors positioned on cell membranes can be regulated in vitro, while further stating that dependent on surface content of RGDS at 37 °C, these exteriors enable scattering of human umbilical vein endothelial cells (HUVECs) without serum. They elucidated that by dropping culture temperature beneath LCST, hydrated grafted copolymer chains disconnect restrained RGDS from cell integrins, causing cells distributed on RGDS-restrained exteriors at 37 °C to separate impulsively. They finally testified that by utilizing weak atmospheric stimulus, like temperature, without chemical or enzymatic 75 ACS Paragon Plus Environment


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action, attachment of cell integrin to restrained RGDS on cell culture surfaces could be overturned impulsively. Alarcon et al.558 conducted an investigation wherein they constructed poly(Nisopropylacrylamide) or pNIPAm polymeric brushes exhibiting micro-patterned domians superficially and analyzed them for performance of these functionalized surfaces for short-term bio-adhesion assays under variegated surroundings. They elucidated that the pNIPAm polymeric brushes exhibited temperature dependent behavior at surfaces, which was expounded by an alteration in contact angle from 65.5° at 12 °C to 89.8° at 40 °C. They further reported that AFM adhesion forces measured in the aqueous solutions confirmed the switching of the hydrophobic– hydrophilic, where the reversibility of the polymer response exhibited alteration in the average brush layer thickness over the LCST transition. They finally validated that well-defined and thermally-facilitated connection of model protein, BSA, and oral bacteria Streptococcus mutans, was resulted owing to ripostes of polymeric brushes. Table 6: Assorted basis of separation in bio-separation processes.

Factor

Nature of Separation

Density

Centrifugation, Sedimentation, Floatation

Polarity

Extraction, Chromatography, Adsorption

Size

Filtration, Membrane Separation, Centrifugation

Diffusivity

Membrane Separation

Electrostatic Charge

Adsorption, Membrane Separation, Electrophoresis

Solubility

Extraction, Precipitation, Crystallization

Shape

Centrifugation, Filtration, Sedimentation

Volatility

Distillation, Membrane Distillation, Pervaporation

Another important aspect of stimuli-responsive polymeric bio-interfaces is its ability to dynamically control the chemical permeation through the interaction of ions and biomolecules with receptive surfaces454,559,562 or through porous membranes177,181,182,455,563, thus exhibiting its unique potential for bio-separation functions562,564. Table 6 consolidates assorted basis of separation in bio-separation processes. Exciting means for regulating permeation of drug via micro- and nanoporous membranes is provided by the surface-grafted stimuli-responsive 76 ACS Paragon Plus Environment

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polymers. Researchers have piloted experiments for exploring the intricate inter-relationship between the polymer molecular weight, pore size, drug permeation flux and the grafting density562– 564.

In an investigation steered by Nagase et al.564, where they developed a range of poly(N-

isopropylacrylamide) (pNIPAm)-embedded silica bead substrates with aid of surface-initiated ATRP process by altering brush chain lengths and grafting densities. They stated that by merely varying ATRP reaction time at constant concentration of catalyst, chain length of grafted pNIPAm could be regulated, in addition to further elucidation that longer holding intervals for steroids were witnessed on sparingly attached pNIPAm surfaces in comparison to that on dense pNIPAm brushes at low temperature, owing to the water-repelling interactions amongst exposed phenethyl assemblies of self-assembled monolayers on silica surfaces and steroid molecules, however, retention times for steroids on dense pNIPAm brush column augmented with temperature, as solvated polymeric fragments inside dense brush layer experience dehydration. They validated that pNIPAm grafting density exhibits vital effect on elution nature of steroids owing to distinctive dehydration of pNIPAm in dense-pack brush surfaces and also cause interaction of analytes with silica bead interfaces. Table 7 illustrates function of stimulus-sensitive macromolecules for biointerface and bio-separation applications.

Function

Reference Cell

556, 560

RNA

559

Table 7: Functions of stimuli-sensitive polymers for bio-interface and bio-separation applications.

Bio – Interface

Protein Bio – Separation

557, 558

Responsive Surfaces

451, 558, 561, 563

Porous Membranes

177, 181, 182, 454, 562

5. Future Perspectives and Applications of Stimulus – Sensitive Polymers:



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Recent advancements in field of science and technology for devising novel methodologies has yielded in the development of “additive manufacturing (AM)” technique, also known as 3D printing, solid-freeform (SFF) or rapid prototyping (RP)565–567. Additive manufacturing was initially portrayed in 1986 by Charles Hull as a ‘procedure of combining materials to construct entities from 3D model data in a layer by layer mechanism’, following which researchers have been piloted extensive investigations, as additive manufacturing enable a less-expensive free-form fabrication of customized, complex, and multiscale 3 Dimensional geometries for assorted applications and also provides adaptable technology stage for fusing computer-assisted design (CAD) and rapid manufacturing processes 3. In more recent times, considerable interest has been given to novel idea of “4D printing” by converging 3D printing with smart materials, where under an external stimulus, the form and characteristic of 3D printed component can regulate as function of time and time is the fourth dimension in the 3D space co-ordinates568,569. ‘The contouring of 3D

Figure 24: Illustration of 4D printing process.


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printed edifices with programmable and adaptable forms, characteristics or functionality as function of time, wherein time-dependent tuning of shape, characteristic or functionality can aptly be prompted by copious types of stimulus’, was the reported definition of 4D printing when it was originally introduced by a research group from MIT570. Figure 24 schematically depicts 4D printing process. The stimuli-responsive polymers like self-healing polymers or shape memory polymers, which collects, conveys, or processes a stimuli and react by generating a beneficial effect including an actuation mechanism or a signal that the materials are acting upon it are the one of the most crucial factors of 4D printing. Researchers have been conducting experimentations over the past few years for devising such smart materials owing to their potential for functions ranging from tissue engineering to biomedical devices and robotics571–574. Self-healing polymers, wherein the self-healing characteristics of polymer can be attained by few types of reactions including supramolecular chemistry, π–π stacking, ionic interactions, covalent bonding and hydrogen bonding575,576, are contrived as smart material for enabling structural refurbishment and functions retrieval upon damages, that augments material dependability and extends its lifespan577–579. There are typically two categories of self-healing polymers – intrinsic self-healing polymers and extrinsic self-healing polymers, wherein extrinsic self-healing polymers rely on encapsulated healants in microcapsule580 or in microvascular networks581, that are released and polymerized on crack intrusion for healing micro-cracks, whereas intrinsic self-healing polymers use intrinsic chemical or physical attributes of macromolecule, like chemical reactions in secondary bonds or dynamic covalent bonds for repairing micro-cracks582,583. In more recent times, great potential for variegated array of functions, such as deployable smart medical devices, soft actuators, and flexible electronics, has been revealed by self-healing polymers, which has enticed the interest of researchers584–588. Bauer et al.584 steered an experiment wherein they validated that the self-healing materials exhibit great potential for constructing soft actuators comprising augmented resilience owing to their aptitude of self-repairing damage extending from surface scratches to bulk cracks. An investigation piloted by Highley et al.585 demonstrated the successful utilization of self-healing hydrogels as ‘inks’ for additive manufacturing methodology for developing a self-healing 4D printing system.



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Similarly, another investigation was steered by Kuang et al.588, wherein they contrived a unique ink which could be utilized for 3D printing of highly stretchable, shape memory and selfhealing elastomer with the aid of UV light-assisted direct-ink-write (DIW) printing. They reported that the ink was developed for 3D printing of a semi-interpenetrating polymer network (semi-IPN) elastomer which could be stretched by up to 600%, by using urethane diacrylate and a linear semicrystalline polymer. They elucidated that fascinating functional characteristics, such as high strain shape memory and shape memory assisted self- healing capability was exhibited by the 3D printed complex structures, following which they validated that such 3D printed shape-memory selfhealing elastomer demonstrate potential for biomedical devices, like vascular repair devices, thus paving new pathways for the advancement of 4D printing in biomedical devices and soft robotics. Researchers have also conducted experiments for smart self-healing coatings, by incorporating self-healing stimuli-responsive entities in coatings, which fall under classification of intelligent coatings with preset configuration and riposte589. Andreeva et al.590 piloted an experiment in which they contoured a multi-layered layer-by-layer coating comprising of polyelectrolytes and corrosion inhibitor which could heal corrosive region on metal substrate and liberate inhibitor in course of corrosion attack. They validated that instigation of such self-healing nature relies on rupturing and re-establishing of polyelectrolyte complexes in riposte to alterations in corrosive environment, i.e., high ionic strength. Such smart self-healing coatings exhibit great potential for coatings on a ship’s hull for corrosion mitigation functions, however, a better understanding is requisite prior to being subjected for practical functions.

6. Conclusion: Even though existence of stimuli-sensitive polymeric systems has been known to mortal world for few decades, however, it wasn’t until a few years ago that immense endeavors were dedicated to area of stimulus-sensitive resources, which was determined by necessity of accurately manageable material functions. In beginning, the emphasis was dedicated to polymers evincing only one sensitive entity, however, focus has budged over years towards multiple responsive entities amalgamated inside single macromolecule, wherein this expansion is not only owing to enhanced miscellany of multi-stimulus materials, but is also substantiation for consequential advancement in macromolecular synthesis with development of novel processes such as reversible addition-fragmentation chain transfer (RAFT) and atom transfer radical polymerization (ATRP) 80 ACS Paragon Plus Environment

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over past few decades. Important sectors such as biomedical sciences, biochemistry and environmental sciences would greatly benefit from further advancement of functions of stimulussensitive polymeric materials, as stimulus-sensitive polymeric systems have already exhibited proficiency in an array of functions like protective coatings which can adapt to environment, swapping surfaces and adhesives, artificial muscles, sensors and drug delivery. In the presented review article, we have attempted to outline the stimuli-responsive polymeric systems by encompassing both the introduction to history of polymer, and the functions of stimulus-sensitive polymers. Initially, we have thoroughly described the fundamental aspects of the stimuli-responsive polymers which undergo macroscopic responses on exposure to environmental stimuli by sophisticatedly altering the dynamically reversible non-covalent interactions at the utmost fundamental level, while simultaneously consolidating the existing literature of the stimuli-sensitive polymer-based systems being expended in a copious array of functions such as smart coatings, sensors and biosensors, controlled drug delivery, artificial muscles/actuators and for bio-interfaces/bio-separation. It was elucidated from a broad literature survey that massive number of researches have excelled themselves from the original areas of single stimuli-responsive polymer systems and extended to designing of dual and multiple stimulisensitive systems exhibiting well-defined configuration and precisely controllable characteristics within one polymer for an assorted range of applications mentioned above. Recent progress in 3D printing with the so called “4D printing”, exhibit genuine promise for generating complex edifices with simplicity in view of augmenting the intake of the stimuli-sensitive polymer-based systems for biomedical and protective coating functions, however a better understanding of such systems is requisite.

7. Acknowledgement: The authors would like to thank Dr. C. P. Ramanarayanan, Vice-Chancellor, DIAT (DU), Pune, for constant encouragement and support. The authors would also like to acknowledge Mr. Swaroop Gharde, Mr. Deepak Prajapati, Mr. Prakash Gore, Mr. Kalpesh Kakulite, Mr. Giridhar Gudivada and Mr. Rushikesh Ambekar for technical discussions and support.

8. References: (1)

Bhushan, B. Biomimetics: Lessons from Nature - an Overview. Philos. Trans. R. Soc. A 81 ACS Paragon Plus Environment


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Math. Phys. Eng. Sci. 2009, 367, 1445. (2)

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