Basics Of Stimuli Responsive Polymers

Published Date: 02 Nov 2017

In order to sustain life around us and to carry out a number of biological functions, nature has formed and used a large number of specifically tailored molecules and interface which perform a specific function with respect to changes in their environment. Examples of such systems range from semi permeable cell membranes to photosynthetic molecules and more. Based on such a bio mimetic approach, polymer systems are often researched upon and developed so as to make surfaces and perform processes which are similar to what is present in nature. Such class of polymeric materials which can respond to changes in the external environment are called stimuli responsive or smart materials (as they can make their own decisions depending upon the external stimuli).

In this report, we first start with the basics of stimuli responsive polymers i.e. what are their types and how do they work. We then move on to the different polymers available, their characterization, applications and processing. Challenges in this area and future trends are then highlighted which is then followed by a market analysis of the material under consideration.

1.1] DEFINITION

Stimuli responsive polymers also referred to as smart polymers are materials which exhibit a change in properties when subjected to a change in the environment. The change in environment can comprise of a number of factors such as pressure, humidity, temperature, electric field, magnetic field, pH etc. Depending upon the material, the change in property could range from changes in shape, colour, conductivity etc.

This property of stimuli responsive polymeric materials makes them usable in a variety of applications which require an environment specific or targeted action. Smart polymers are widely being used in today’s world for applications such as targeted drug delivery, tissue engineering, biosensors, textiles, smart ‘optical systems’ etc. with the ultimate goal being to able to first essentially tailor the material specifically for applications as is done in nature and then also be able to manufacture such a process on a large industrial and economical scale.

1.2] SMART POLYMERS: Different Types and Chemistry

Based on the environment change to which a particular material responds to, smart polymers can be broadly classified into 7 technologically important areas:

Temperature sensitive polymers

pH sensitive polymers

Phase sensitive polymers

Light sensitive polymers

Polymers with dual stimuli-responsiveness

Magneto-responsive materials

Electro-active polymers

1.2.1] TEMPERATURE SENSITIVE POLYMERS

As their name suggests, these are polymers which show changes in properties when subjected to changes in temperature. Some of the transitions, these polymers generally show include a gel to gel transition as per changes in environmental temperature. Such solutions generally show a critical solution temperature. Changes in solubility are also observed as a function of change in temperature.

Polymers which have a single phase above a certain temperature and show phase separation below it have an upper critical solution temperature (UCST) whereas on the other hand solutions which exhibit a single phase below a certain temperature and multiple phases above it have a lower critical solution temperature (LCST) (Fig 1). Presence of such a property makes the polymer usable in a variety of applications such as smart drug release, DNA sequencing etc. Such a behaviour in these polymers are caused due to a combined effect of hydrogen bonding with water and the changes in balance between the hydrophobic/hydrophilic group due to fluctuations in the environment temperature. Solubility of the polymer in water is mainly due to hydrogen bonding. An increase in temperature results in a decrease in the effecienc of hydrogen bonding for UCST polymers. Beyond the critical point, phase separation takes place as now hydrogen bonding becomes insufficient for the solubility of the polymer. Some examples of such polymers include poly (N- isopropylacrylamide) (PNIPAAM), poly ethylene oxide etc.

http://ars.els-cdn.com/content/image/1-s2.0-S0169409X01002046-gr1.gif

[Fig 1: Temperature sensitive action in case of a LCST polymer] [7]

1.2.2] pH SENSITIVE POLYMERS

Polymers which show a transition between properties (especially solubility) when subjected to changed in the net amount of charge on the macromolecule form the class of pH sensitive polymers. Changing the pH of the solution is one very efficient way of altering the amount of charge on the polymer. Most of such polymers are polyelectrolyte in nature and they have either a very weak acidic or a very weak basic group attached to them.

http://upload.wikimedia.org/wikipedia/commons/f/f6/PH_sensitive_polymer_swelling-collapse_mechanism.jpg

[Fig 2: Variation in the property of polymer with changes in pH]

Depending upon the solvent in which the polymer is ionized, the macromolecule can either expand due to electrostatic repulsion or become tightly coiled. This change in form between tightly coiled and the expanded state (Fig 2) can be used for a variety of applications such as glucose sensing, drug delivery system etc. The interplay between the two forms is generally brought about by a change in the ionic strength, pH or the type of counter ions. Some examples of such kind of polymers include copolymers of dimethylaminethyl methacrylate and methyl methacrylate etc.

1.2.3] PHASE SENSITIVE POLYMERS

Being sensitive to changes in phase, such polymers are generally used for preparing biocompatible formulations which can be used for a controlled delivery of proteins in a biologically active and conformational stable form.

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[Fig 3: Schematic action of phase sensitive polymer] [8]

In such an approach (Fig 3), a biodegradable water insoluble polymer (such as poly (D, L-lactide) etc.) is dissolved in a medically acceptable solvent which in turn is mixed with a drug therby forming a suspension or a solution. After the formulation is injected into the human body, the water miscible solvent disintegrated and water enters into that phase. This in turn causes a phase separation and thus the drug gets precipitated at the site of the injection. Such a mechanism has a potential for usage in the controlled release of lysozyme, proteins etc.

1.2.4] LIGHT SENSITIVE POLYMERS

Polymers of this kind form an aqueous two phase system when exposed to light. Such a material is often used in case of industrial bio separation techniques. The systems that are used are biocompatible, biodegradable and polymerizable in nature.

The working mechanism of such polymers includes a polymerization of the molecules by initiators i.e. free radicals in the presence of either visible light, infra red or ultra violet wavelength. The molecule in consideration consists of at least one water soluble region, two free radical polymerizable region and one biodegradable region. Some examples of such polymers include N-isopropylacrylamide, chlorophyllin sodium copper salt, n-butyl acrylate etc.

1.2.5] POLYMERS WITH DUAL STIMULI-RESPONSIVENESS

Such kinds of materials are nothing but polymers which are sensitive to both changes in temperature and pH. They contain both the ionisable and the hydrophobic/hydrophilic functional group and thus are able to respond to changes in pH as well as temperatures. Such polymers are formed by the copolymerization of polyelectrolytes with temperature sensitive polymers resulting in the formation of dual stimuli responsive monomers. Major use of such materials is in the formation of smart core shell microgels, vehicles for peptide delivery etc.

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[Fig 4: Dual responsive Au-protein-polymer nanoparticle] [9]

1.2.6] MAGNETO-RESPONSIVE MATERIALS

Magneto responsive materials are polymer-based elastomeric materials and which undergo deformation and experience mechanical stress when magnetic field is applied. These materials are also known as magneto-rheological polymers or magneto-elasts. Magnetic polymer gels are flexible cross-linked polymers which contains magnetisable particles. These materials are used in the application of diagnostic medicine, high density memory devices and spintronics.

Common materials used are poly (vinyl alcohol) (PVA) filled with magnetite particles, magnetic polystyrene, magnetic poly (dimethylsiloxane) composites (mPDMS).

1.2.7] ELECTRO-ACTIVE POLYMERS (EAP)

These polymers undergo a change in shape or size in the presence of electric field. Electro-active polymers are used in actuators and sensors. EAP are of two types: Dielectric and Ionic.

Dielectric EAP are materials in which actuation is caused by electrostatic forces between two electrodes. Ionic EAP in which materials are actuated due to the movement of ions inside the polymer. Examples of EAP materials are ferroelectric polymers eg. Nylon 11 and Polyvinylidene fluoride, dielectric EAP, and electro- viscoelastic elastomers. Ionic EAP includes conductive polymers, ionic polymers gels, carbon nanotubes and ionomeric polymer metal composites.

Polymers are made electrically active by addition of conductive fillers. Metals, carbon fibers and carbon black are the conductive fillers. Chemical modification is done to activate ionic polymeric gels. Commonly used EAPs are poly(pyridine), poly(sulfone), poly(thipene), poly(acetylene), poly(p-phenylene), Poly (methyl methacrylate),Dendritic Poly(styrene sulphonate) and poly(p-phenylene vinylene).

Apart from the above classification, stimuli responsive polymers can also be differentiated based on their physical forms. The different types include:

Linear free chains in solution (where the polymer goes to a reversible collapse when an external stimulus is applied; widely used in protein folding)

Covalently cross linked reversible and physical gel (where shrinkage or swelling of the gel can happen due to changes in the environment; widely used in bio sensing applications and actuators)

Surface grafted copolymers (where the polymer collapses on a surface or swells as and when an external parameter is changed; widely used in tissue engineering, chemical valves etc.)

2.0] PROCESSING AND CHARACTERIZATION

2.1] THERMO- RESPONSIVE MATERIALS

2.1.1] METHOD OF PREPARATION

Thermo-responsive polymers are grafted on different substrates such as glass, silica, quartz, and polyethylene-terephthalate sheets. Grafting of these polymers on tissue culture grade poly styrene (TCPS) is common. Many types of techniques such as plasma polymerization, gamma radiation, electron beam irradiation, UV irradiation and atom transfer radical polymerization are used for grafting these materials.

2.1.1.1] ELECTRON BEAM INDUCED POLYMERIZATION

In this method NIPAAm monomer is bonded on the TCPS by the irradiation of electron beam to the monomer. The nature of the bond is covalent. This method is used for thin grafting and large scale production. This method is expensive. Monomer concentration and radiation energy are used to control the thickness.

2.1.1.2] GAMMA IRRADIATION

In this method Gamma irradiation is used in place of electron beam induced polymerization. This method is used for the batch processing and grafting of PNIPAAm.

2.1.1.3] PLASMA POLYMERIZATION

In this method thermo-responsive coatings are prepared on a solid substrate. A plasma glow of NIPAAm vapour is used to deposit on to solid substrates like glass, silica or TCPS. This method is not used for the large scale production due to problems caused by continuous treatment and size.

2.1.1.4] ATOM TRANSFER RADICAL POLYMERIZATION TECHNIQUE (ATRP)

In this method surfaces are prepared with dense polymer brushes. Surface has immobilized ATRP initiators which facilitates this surface formation. PNIPAAm brushes are formed on poly (4 vinyl benzyl chloride) coated TCPS surface using ATRP. Thinner surfaces favour attachment/detachment process.

2.1.1.5] SOLUTION CASTING METHOD

Most of the above methods are expensive and not practiced by many researchers. Thermo-responsive polymers are coated onto TCPS surface by this method. It is a simple and cost efficient method. Thickness of the coating is in the order of few microns.

2.1.2] CHARACTERIZATION

Different characterization techniques are used for evaluating physicochemical and biological properties of thermo-responsive polymers. Examples of characterization techniques are attenuated total reflectance Fourier Transform spectroscopy (ATR-FTIR), Nuclear magnetic Resonance spectroscopy (NMR), Atomic Force Microscopy (AFM), Ellipsometry, Surface Plasmon resonance and Profilometry.

ATR-FTIR and NMR are used for the quantitative and qualitative detection whereas AFM, Ellipsometry are used for determining thickness of coatings.

PNIPAAm can be detected and quantified using ATR-FTIR on the thermo-responsive surface. The presence of NIPAAm can be detected if a peak of amide carbonyl group is present around 1650 m-1. The ratio of peak intensities (I1650/I1600) is used to determine the quantity of grafted PNIPAAm in ATR-FTIR.

NMR technique gives details of structure. It also helps in understanding the polymerization mechanism better. It also provides qualitative analysis of thermoresponsive surfaces.

Differential scanning calorimetry (DSC) is used to determine the LCST. The LCST of homopolymer PNIPAAm is around 32 °C, whereas the LCST of copolymers of PNIPAAm lies above or below 32 °C depending upon the hrdrophilicity and hydrophobicity of the comonomer.

X ray Photoelectron Spectroscopy (XPS) is a qualitative technique to detect the presence of PNIPAAm on different substrates. The composition of various elements like nitrogen, oxygen and carbon on the grafted surface can be determined using this technique.

Profilometry is used to estimate surface roughness and thickness from the surface of the grafted polymer. This is also to visualize the morphology of the surface.

Ellipsometry and Surface Plasmon resonance is not used to determine the thickness because of the very close value of refractive index of PNIPAAm and polymeric substrates.

Water contact angle is measured to determine the hydrophobicity and hydrophilicity of the surface.

2.2] MAGNETO-RESPONSIVE MATERIALS

2.2.1] METHOD OF PREPARATION

Preparation of magnetic polymer gels can be done similar to other filler – loaded networks. The preparation and characterization is done separately, then the polymer solution and the magnetic sol are mixed to cross link them.

2.2.1.1] MAGNETITE-LOADED POLY (VINYL ALCOHOL) GELS

First, magnetite (Fe3O4) sol (ferrofluid) is prepared by co- precipitation. The particle can be varied by using different concentrations of reactants and by varying stirring rate. X- Ray scattering is used for determining the size and size distribution of magnetite in the ferrofluid. The magnetite sol having concentration 10% is then mixed with poly(vinyl alcohol) (PVA) solution to form magnetite loaded PVA gels. Prepared samples are kept in distilled water to remove the unreacted compounds.

2.2.1.2] SMALL ANGLE X-RAY SCATTERING

This method is used as a characterization technique. This technique is used to determine the microscale and nanoscale structure of materials. This technique is accurate, only requires minimum amount of sample. It is also non- destructive.

2.2.1.3] MAGNETIC POLYSTYRENE LATEX (mPS)

Miniemulsion polymerization method is used to prepare mPS. The magnetite particles in a ferrofluid are put into the monomer under continuous stirring to obtain stable magnetite/styrene dispersion. Co-stabilizers are used for stabilizing the styrene/water miniemulsion. Stabilization is required to reduce coalescence and diffusional degradation. Stearyl alcohol (SA) is used as co-stabilizer. Ultrasound homogenization is used for the precipitation of miniemulsion.

2.2.1.4] TRANSMISSION ELECTRON MICROSCOPY (TEM)

This is also used as characterization technique in the preparation of mPS.

2.3] ELECTRO-ACTIVE POLYMERS (EAP)

2.3.1] METHODS OF PREPARATION

2.3.1.1] POLY (METHYL METHACRYLATE) (PMMA)

PMMA clay nano composite are prepared as thermal actuators which can be used as thermal switches, in auto aeration and ventilation systems. The PMMA clay nanocomposites are prepared by melt processing on a twin roll mill, temperature is around 170 °C.

2.3.1.2] DENDRITIC POLY (STYRENE SULPHONATE)

This material is prepared by using Ï’ radiation technique. A 60Co source is used for Ï’ radiation at room temperature. This polymer is a copolymer of vinylidene fluoride and hexaflouropropylene.

2.3.1.3] CROSSLINKED POLY (VINYLIDENE FLUORIDE) (PVDF)

The monomers are vinylidene fluoride, triflouroethylene and chlorotriflouroethylene or flouroethylene. These monomers form a terpolymer. Heating at around 160- 170°C will crosslink the polymer. Crosslinking enhances chemical resistant and thermally stable. Organic peroxides with amines are used as accelerator for crosslinking. The extent of the crosslinking is determined by differential scanning calorimetry (DSC), solubility test or thermal mechanical analysis (DMA).

2.3.2] CHARACTERIZATION

The main characterization techniques are described below.

2.3.2.1] STRESS-STRAIN CURVE

Information about the mechanical properties like brittleness, yield strength and elasticity is provides by Stress-Strain Curve. In this technique a force is applied to the polymer at a constant rate and the deformation is measured. Nature of the material like (brittle, tough) can be determined. This technique is destructive because polymer will fracture at higher stress.

2.3.2.2] DYNAMIC MECHANICAL THERMAL ANALYSIS (DMA)

It is a non destructive characterization technique which is used to the mechanism of deformation at molecular level. In this method a sinusoidal stress is applied to polymer which is used to determine elastic modulus and damping characteristics. Polymer is assumed as damped harmonic oscillator.

2.3.2.3] DIELECTRIC THERMAL ANALYSIS (DETA)

This technique is similar to DMA but in this case alternating electric field is applied in place of alternating mechanical energy. Due to the application of the electric field the polymeric material gets polarized. If the polymeric material have permanent dipoles, dipoles will get aligned with the electric field. This can be used to measure permittivity and electric displacement field.

2.3.2.4] DIFFERENTIAL SCANNING CALORIMETRY (DSC)

This gives the information about the crystalline nature of the cell.

3.0] CURRENT APPLICATIONS

With even small changes in the environment (i.e. pH, ionic strength, temperature etc.), stimuli responsive or smart polymers undergo a strong chemical or conformational change. Effects such as phase separation from the aqueous solution or changes in hydrogel size (sometimes even order of magnitude different) are observed. Such effects are of great use in applications such as bioseperation, drug delivery, biocatalysis, bio mimetic actutators, natural surfaces etc. Figure 5 below shows a detailed summary of the various applications for stimuli responsive polymers. Detailed analysis of each application is followed in the subsequent subsections.

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[Fig 5: Various applications of stimuli responsive polymers] [10]

3.1] DRUG DELIVERY

When we immobilize an enzyme in a smart hydrogel, the products which are formed as a result of the enzymatic reaction can itself be used to trigger off the phase transition of the gel. This would then result into the possibility of translating the chemical signal (i.e. whether the substrate is present or not) into the environment’s signal (i.e. pH change, temperature change etc.) and in turn onto the mechanical signal (i.e. shrinkage or the swelling of the hydrogel).

This property of the hydrogel i.e. its ability to swell or shrink in response to small changes in pH or temperature can be used as a tool to control the release of the drug into the blood stream (since the diffusion of the drug out of the bead depends on the physical state of the gel). When such a stimuli responsive polymer is integrated into a drug delivering liposomal lipid bilayer or a microcapsule wall, the chemical/conformational change in the polymer affects the stability of the microcapsule and thereby allows for the controlled release of the drugs which have been loaded onto the microcapsule.

[Fig 6: Drug delivery mechanism using a polymer gel] [10]

3.2] CHEMICAL VALVE

For a glucose-insulin release system, the specificity of the release can be modelled in the form of a chemical valve. Glucose oxidase is first immobilized in a pH responsive layer of poly (acrylic acid) which is in turn grafted onto a porous polycarbonate membrane. In the ground state i.e. neutral pH, the polymer chains are very densely charged and thus have an extended conformation, thereby preventing the transport of insulin through the membrane as the pores have been blocked. When the system is exposed to glucose, the pH drops and the chains become much more compact as they get protonated. The pore blockage is now reduced and the insulin gets transported through the membrane thereby facilitating the function of a chemical valve.

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[Fig 7: Insulin delivery mechanism using a smart material] [10]

3.3] SMART HYDROGELS FOR DRUG DELIVERY

When a smart polymer is cross-linked to form a gel, the gel will collapse and re-swell in water as a stimulus raises or lowers it through its critical condition. If a drug is loaded into the gel, the collapse can release the drug in a burst. Smart gels could be used to entrap drugs and deliver them. They also contain entrapped enzymes and cells in smart gels, and by inducing cyclic collapse and swelling of the gel, the enzymes (or enzymes within the cells) could be turned "on" and "off. For example, smart gels containing entrapped cells that could be used as "artificial organ". pH-sensitive acrylic acid-acrylate copolymer smart gels for drug delivery. Compositions of smart gels containing phosphate groups that were used to bind cationic proteins as model drugs, which were then released by a combination of thermal stimuli and ion exchange.

3.4] ENTERIC COATINGS ON ORAL DRUG TABLETS

There are two main types of smart enteric polymer coatings. One is based on copolymers of pH-sensitive methacrylic monomers such as methacrylic acid (MAAc) and hydrophobic methacrylate monomers such as methyl methacrylate (MMA). Another type of enteric polymer is based on a cellulosic polymer backbone, where some of the -CH2OH groups are esterified with phthalic anhydride. Both types of polymers are hydrophobic at stomach or gastric pH, since the carboxyl groups are protonated and non-ionized, and they become hydrophilic at intestinal or enteric pHs where the carboxyl groups are ionized. Thus, the drug is not released in the stomach, where it could irritate or inflame the stomach lining, but is rapidly released once it reaches the intestines where the pH rises to physiologic pH levels. The coatings are also useful for protecting ‘fragile’ drugs from stomach acid and gastric enzymes.

3.5] SMART MUCOSAL DRUG DELIVERY SYSTEMS

Mucoadhesive polymers are expected to enhance the residence time of the delivery formulation on the mucosal surfaces, where they may form physical hydrogels in response to the temperature and/or pH change upon contacting the surface. The physical interactions have been taken advantage of for delivering drugs from eye-drops into the eye or from nasal sprays into the nose with T-sensitive and mucoadhesive smart polymers, and from oral formulations in the stomach or intestines with pH-sensitive and mucoadhesive smart polymers. The pH-responsive polymers are used to deliver drugs within tumor tissues, which are slightly acidic.

3.6] STIMULI-RESPONSIVE SURFACE MODIFYING SYSTEMS FOR TEXTILES

The main feature of "smart" textile materials is that they could adapt effectively (significantly and automatically) to their local environment by changing the properties due to defined influences (stimuli) from the immediate surroundings. The functional activity of these materials is an important aspect.

Functional finishing approach enables producers to continue to use conventional textile fibres and at the same time, by modifying a very thin surface layer of the material, achieve added-value by implementing "smart" features.

3.7] SMART POLYMERS AS ACTUATORS

Due to their switching properties, stimuli-responsive polymers act as elementary machines (actuators), able to convert environmental signals into a mechanical response. Their ability to undergo abrupt volumetric changes in response to the surrounding environment without the requirement of external power sources provides the polymeric integrated micro fluidic components to be autonomous. The autonomous functionality of these components has been achieved by exploiting mainly volume changes exhibited by pH- and temperature responsive hydrogels. Microfluidic actuators can be divided in those having micromechanical properties, such as micro valves, micromixers, and micropumps, and micro-optical properties, such as microlense.

Micropumps and micromixers: In micro fluidic systems, micromixers and micropumps are essential components for fluidic handling. Micropumps can be classified as either mechanical or non-mechanical. Mechanical micropumps need physical actuators or mechanisms to achieve pumping; they include electrostatic, piezoelectric, thermo pneumatic and electromagnetic type. Non-mechanical micropumps have the ability to transform non-mechanical energy into movement, so that the fluid can be driven.

Micro valves: A conventional active valve consists of a deformable diaphragm coupled to an actuator that controls the on/off state. The mechanical or electrical control of these systems relies on their intrinsic responsiveness to thermal, chemical, or electro-optical stimuli. Therefore, smart polymers show promising ways of flow control for micro fluidic devices based on stimuli-responsive properties.

[Fig 8: Schematic overview of two types of membrane valves]

Microlenses: Micro-optical components such as microlenses have been recently benefited from the use of stimuli-responsive hydrogels. In contrast to traditional optical systems, microlenses based on smart polymers have the potential to allow for autonomous focusing without the need for mechanical parts, and above all to achieve a higher degree of integration with other optical components. There are smart liquid microlenses which are able to adjust their shape and focal length by taking advantage of temperature and pH-responsive hydrogels.

3.8] TWO PHASE SYSTEMS

Polymers such as poly (ethylene oxide -co- propylene oxide) being thermo responsive in nature have been used to form a di-phase system with Dextran and thus have been used to purify proteins. The protein under consideration partitions into the phase which is formed by the polymer and the phases are then subsequently separated. The phase which contains the target protein is then heated so that precipitation occurs leaving the target protein behind in the supernatant fluid.

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[Fig 9: Schematic of protein purification using two phase extraction] [10]

3.9] IMMOBILIZED BIOCATALYSTS

The property of stimuli responsive polymers to show transition between the soluble and the insoluble state has been used to develop soluble biocatalysts which are reversible in nature. These biocatalysts are used to catalyse a reaction in their soluble state and thus can be used in systems where either the substrate or the product is insoluble in nature. What happens is that as soon as the reaction is completed and the products have been removed, the conditions of the system are changed to cause the catalyst to precipitate out thereby enabling its usage in the next cycle.

Some common examples of such an application include the immobilized beads of Arthrobacter simplex cells etc.

3.10] USE OF THERMORESPONSIVE SURFACES FOR SEPARATION

Polymeric materials which have thermo responsive surface alongwith hydrophobic/hydrophilic properties can also be used in the separation of drugs and steroids. An example of such a process is the interaction between poly (N-vinyl caprolactam) and Cibacron Blue for the separation of mammalian cells from their substrate.

4.0] CHALLENGES AND FUTURE TRENDS

4.1] STIMULI RESPONSIVE POLYMERS IN BIOMEDICAL APPLICATIONS

4.1.1] KEY CHALLENGES

There are many polymer drug delivery, diagnostic and tissue engineering applications which have not come to practice. The main challenges that biochemical industry is facing is development of materials which are bio-compatible and have adequate association properties with various inherent bio-materials. The infection related issues are common problem in the use of polymers in bio-devices. Many of the smart polymers use acrylamide or acrylic acid type polymers (PNIPAAm and PPAAc) which are potentially toxic and they are not hydrolytically degradable. Further, many of these smart polymer carriers are most effective in delivering drug at their cellular targets when they are of higher molecular weights; such polymers are not readily excreted via the kidneys after delivering the drug, and are not biodegradable, so they would tend to accumulate in the body. The main challenge faced in developing biosensors is very small intensity of bio-stimuli and nano molar concentration of markers. Although Mathematical modelling of transport processes in various biological barriers of human bio-system is most important in understanding and development of bio-devices, still enough data is not available for evaluations and predictions of various parameters for polymer device development. Further, the stringent approval requirements of FDA also make companies to think twice before investing into new venture.

4.1.2] CURRENT AND FUTURE TRENDS

There are a number of examples where smart polymers are used in in -vitro operations but the recent developing interest and demand of advanced medical science has opened new avenues to think in. The world’s research trend is shifting towards development of advanced materials for bio-sensing and improving the available polymers for broader implantation. The area of polymers specific to antigen–antibody interactions, enzymes, and glucose are becoming more and more popular. The polymers which are sensible to light, electric-field, magnetic-field, sonic-field are also being explored. Oral delivery has been most popular way of drug administration for its ease of administration and patient compliance. Hence a lot of research is going on in this area. The other areas where the increasing trend is seen are bio-sensing (due to increasing health concern and expenditure) and improvement of durability of polymer products( due to decrease in average of people getting organ & skin transplant) for organ and bone implantation.

4.1.2.1] DRUG DELIVERY

Drug delivery systems target to deliver medicine at specific target without any leak in the way, hence an efficient system is required to identify the right spot and deliver the medicine by means of either a physiological or chemical trigger. More sophisticated delivery systems are required to design an oral delivery system which could tolerate the harsh acidic environment and tight layer of endothelial cells present in the gastro-intestinal tract and deliver the medicine at desired spot. Some specialized systems are required for ophthalmology, cardiovascular and dermatology products. Smart polymers, specific to particular target, offer promising means in these areas but also pose a challenge of meeting biodegradability and non-toxicity requirement.

Among the most deeply explored tactics to stimulate the activation and release of drugs is to exploit the endogenous mechanism within or near the targeted cell. The self-directed nature of such machinery for activation makes this approach particularly attractive for treatment of diseases that are not easily localized, isolated, or tracked in the body. The use of endogenous natural enzymes and acidic environment within the endosomes or lysosomes of cells to trigger the release of drugs is also being explored as potential option. The polymers which are sensitive to redox- microenvironments within the cell are being developed to design an autonomous natural stimulus drugs delivery system.

4.1.2.2] OPHTHALMOLOGY

Conventional drug delivery system for ophthalmology require frequent installation of drugs, it is seen that only 1-2% of the Pilocarpine hydrochloride, drug used for treatment of glaucoma reaches to target tissues of eye. Hence for ophthalmological drug delivery systems, special polymers are being developed which can offer long retention time even in tear flow environment and form a personalized film that can cover a large surface area in the physiological environment of cornea and sub-conjunctiva after phase transition. These drug delivery systems must not have very large Interference with vision and must have ability to retain medicine even if eyes are rubbed.

4.1.2.3] DERMATOLOGY

The skin is considered to be a complex organ for drug delivery purpose because of its complicated structure. Drug delivery systems are developed so as to perform a controlled release of the drug via the skin into the system’s circulation, thereby maintaining effectiveness and reducing the related side effects. Hence selection of drug delivery vehicle is the most important. A lot of polymers have been developed till date but still a lot of research is still going on to develop more efficient polymers as current polymers, alone, are not sufficient to meet varied demands of pharmaceutical industry. The current trend is in development of polymers which can regulate release of drug dependent of time elapsed from injection (e.g. the insulin requirement for a diabetes patient varies during whole day cycle). Further the polymers have to identify regional variability in the skin barrier and assess the response of the underlying viable tissues to the absorption.

4.1.2.4] CARDIOVASCULAR PRODUCTS

Cardiovascular (CV) disease is the most widespread life-threatening clinical problem and is a major cause of disability and economic burden worldwide. CV gene therapy offers the advantage of controlled expression of desired proteins in cell types, which makes it more valuable in providing durable clinical benefits. Success of gene therapy depends on the choice of the vector and the delivery approach. Smart polymers offer a non-viral transport means for these gene material but these have to be adequate enough to overcome multiple extracellular and intracellular barriers. These barriers include binding to the cell surface, escaping lysosomal degradation, traversing the plasma membrane and overcoming the nuclear envelope.

4.1.2.5] BIO-SENSING/ DIAGNOSTICS

As the smart polymers are sensible to their environment and their physical and chemical properties can be manipulated over wide ranges of characteristics, the use of these polymers is finding increasing use in development of sophisticated bio-sensors. They are, in current period, extensively being used in measuring gene expression, monitoring metabolic disorder and detect the presence of disease. There is lot of scope of development of new polymers to improve sensitivity, selectivity and decrease reaction scale. The broad utility of polymer stems for their flexibility to incorporate various chemical functional groups into single molecule has triggered the development of macromolecules which will be sensible to nano-molar concentration and sensible to very weak stimuli. The reliability on polymers is increasing in order to move forward from centralized laboratories and develop the diagnostic medicines which will be able to identify the presence of decease. The use of fluorescent particles, semiconductor quantum dots and surface-enhanced Raman spectroscopy has prompted new research toward the development of polymers which can be used as medium/vehicle for these practices. Solid-state polymer sensor devices are being developed which will be based on electrical response to their chemical environment.  Such a variation in electrical properties of polymer is utilized to detect the disease.

4.1.2.6] ORGAN IMPLANTATION

There is growing need of developing polymers for making the supporting blocks and/or response systems for development artificial organs. These polymers have to be environment sensible, quick responsive, sufficiently sensible to very small stimuli and strong of course. People are trying to develop organs in the laboratory with the help of smart polymers. For example researchers at Wake forest University in North Carolina at trying to develop artificial livers and kidneys while labs in Netherlands and China are involved in development of blood vessels. The future research will be more oriented towards development of artificial heart and brain. Tissue engineers are developing artificial morphological organs with the help of smart polymers which can respond similar to original organs and patient feel like normal. They are involved in developing more responsive and cheaper polymers for plastic surgery. The research in stem-cell friendly polymers is on boom. The new technology of developing the polymers to make scaffold which can support the formation of organs in-vivo is being explored. There is new trend among the athletes and players to replace their critical muscles and organs so as to achieve higher strength. Clinical engineers are investing a lot more time in development of organs which will have higher performance and strength than natural organs. Similarly in a number of cases, athletes have got extra muscles implanted to provide them more strength.

4.2] STIMULI RESPONSIVE POLYMERS IN SENSOR APPLICATIONS

4.2.1] KEY CHALLENGES

Amidst various advantages of polymer sensors over conventional sensors, it has its own set of limitations. The performance of the sensors is greatly affected by characteristics of transducer materials. A very limited size-dependence towards physical properties is shown Conducting-polymer. But very little research has been done in this area to be able to develop sensors readily. During manufacturing, control over the characteristics of polymer is a big challenge to maintain decent sensitivity and to achieve suitable sensing capability. Polymeric materials are susceptible to degradation by harsh environmental conditions such as heat, moisture, and light thus much attention must has to be paid to enriching their long term stability and reliability which is considered to be the most important factor in commercial operations.

4.2.2] CURRENT AND FUTURE TRENDS

Due to better usability and wide scale applications smart polymers are getting more and more recognition in recent years. Better measurement standard and high selectivity can be achieved by the use of stimuli responsive polymers. The polymers which are sensible toward the change of ion-concentration, pH, humidity, specific gases or physical stimuli are extensively being explored for manufacturing of sophisticated miniature chemical, physical and biological sensors

The recent legislations in environment policies, the monitoring of environment and effluent materials has become very important from the point of view of industries as well as monitoring agencies. The amount of nitrogen oxides, sulfur dioxide, and other toxic gases has to be monitored very carefully. Henceforth research in development of polymers which are sensible to these gases is on fire. The readymade sensors of these gases promise an inexpensive and safe solution to monitoring of leakage of hazard gases in environment.

Polymers for optical fibre sensor transducers are being developed which show reversible changes in optical properties in presence of some solvents, hence they can be deployed to detect volatile organic compounds (VOCs). 

In the area of control the dielectric elastomers are being developed to generate deformations by transforming electrical energy directly into mechanical work. They are categorized under the name of electro-active polymers (EAP). Many other applications of these actuator polymers are visualized such as mini- micropumps, micro air vehicles, micro robots, micro valves, disk drives, flat panel loudspeakers and prosthetic devices.

5.0] MARKET ANALYSIS OF CURRENT MATERIALS

The stimuli-responsive polymers are subjected to a wide variety of applications. These materials can be introduced into many products at comparatively low costs because generally only thin layer of coating of these materials is required. Once introduced, these materials provide added functionality which increases the value of the product very significantly.

[Fig 10: US market share for smart material applications][37]

Below we discuss some of the market trends and economics in which the stimuli-responsive polymers play a significant role.

5.1] MICROFLUIDS

Microfluidic technologies are a vastly expanding field in the market of commercial instruments due to their numerous applications in various fields such as biotechnology, pharmaceutics, diagnostics, agriculture and analytical devices.

[Fig 11: The market trends in micro fluidic devices] [36]

The estimated world market for the micro fluidic technologies in the year 2014 is about 3 billion dollars which is about six times greater than the market value in 2006, showing the growing market strength of these materials. The market of micro fluidics in the life sciences is considered to have the greatest potential in products and commercial devices. Accordingly, most efforts by both research groups and several companies have been focused on the development of micro fluidic devices for point-of-care (POC) diagnostics, biosensors and cell biology.

5.2] SMART FABRICS

Smart polymers, when integrated into textiles; provide a range of interactive properties such as electrical conductivity, ballistic resistance and biological protection. This area has been undergoing extensive research because in the future, there will be a need for even more materials whose properties change in response to external stimuli like temperature, humidity, biological hazards, etc.

According to the market survey conducted in the year 2004, the global market for electrically enabled smart fabrics and interactive textile (SFIT) technologies was worth US$248 million. By 2008 it is has grown into a US$485.6 million business, representing a compound annual growth rate of 18%. The global market for smart fabrics and interactive textiles is projected to reach US$1.31 billion by 2013.

In future, the smart fabrics find considerable applications in the military, consumer, medical and industrial markets. The use of smart polymers in creating very consistent integration between electronics and fabrics will be the driving force in the adoption of electro-active smart fabrics.

5.3] ELECTO-ACTIVE POLYMER

The global market for electro-active polymer (EAP) actuators and sensors reached US$15 million in 2008 and has grown to US$247 million by 2012. 

[Fig 12: Pie chart describing the breakdown of revenue of different segments of electro active polymers in the market] [36]

The overall international electro-active polymers market is expected to be of worth $3.4 billion by 2017 and is expected to grow by a compound annual growth rate of 7.7% from 2012–2017. The share of the conductive plastics segment was approximately 84% of the whole electro active polymer market in 2011, mostly because of the reason that it has an extensive application in the electromagnetic interference and electrostatic discharge segment.

The international electro-active polymers application market was also divided with respect to different geographical domains i.e. North America, Europe, Asia, and Rest of world. The study analysed the market capitalisation for each of these regions and gives the market share value for the different applications. Of all the markets that have been studied, North America ranks as the largest market for such kind of electro-active polymers with an estimated share of 65% of the global market revenue share in 2011 and is even projected to reach $2.2 billion by the end of 2017.

[Fig 13: Pie chart describing the breakdown of revenue based on the geographical locations] [36]

6.0] CONCLUSION

This report presents a general overview of the field of stimuli responsive or smart polymers. We first started with the definition of what such a polymer is and what are their basic types. Categories such as pH sensitive, thermo sensitive, electro active etc. were then discussed in detail with an emphasis on how exactly they work. Methods of processing and characterization were then looked at so as to get an understanding of how these polymers are manufactured on a lab or an industrial scale. Wide range of applications ranging from drug delivery to smart surfaces to bio separations and catalysis were then discussed to look at the enormous potential in these materials. We then concluded by looking at the various challenges that are involved in creating such a polymer and in what direction the research is progressing in today’s world. A market analysis was also performed to in order to look at the major players present, the major products required and also the scope for a new group looking for a start up in this area.