Available online at www.sciencedirect.

com

ScienceDirect
Procedia Manufacturing 12 (2017) 263 – 279

International Conference on Sustainable and Intelligent Manufacturing, RESIM 2016, 14-17

December 2016, Leiria, Portugal

Smart Biopolymers and Their Biomedical Applications

Nandini A. Pattanashetti, Geetha B. Heggannavar, Mahadevappa Y. Kariduraganavar*
Department of Chemistry, Karnatak University, Dharwad 580 003

Abstract

It is a well known fact that polymers have gained an important place in day-to-day life for their specific properties which make
them applicable in wide range of applications. Specifically, biopolymers are gaining particular attention in view of their
biodegradability, biocompatibility, renewability and inexpensiveness. In addition to these properties, smart biopolymers exhibit a
characteristic feature of being sensitive to some of the factors like temperature, humidity, pH, intensity of light and electrical or
magnetic fields. Consequently, this review briefly explains about smart biopolymers and their classifications with examples
including their biomedical applications. Some of these smart biopolymers are also shape memory polymers (SMPs) in view of
their ability to regain their original shape on exposure to a specific stimulus. The shape memory effect of these polymers is
explained by quoting some examples. Special emphasis is given on the applications of smart biopolymers in the field of drug
delivery and tissue engineering, which clearly indicate the advancement and employment of the smart biopolymers in recent
biomedical applications.
© 2017
© 2017Published
The Authors. Published
by Elsevier B.V.byThis
Elsevier B.V. access article under the CC BY-NC-ND license
is an open
Peer-review under responsibility of the scientific committee of the International Conference on Sustainable and Intelligent
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer-review
Manufacturing.under responsibility of the scientific committee of the International Conference on Sustainable and Intelligent
Manufacturing
Keywords: Biopolymers; Biodegradability; Biocompatibility; Shape Memory Polymers.

1. Introduction

Biopolymers are defined as biologically degradable polymers which are produced by living organisms. In simple
words, they are polymeric biomolecules. They contain monomeric units that are covalently bonded to form larger
structures. Biopolymers are generally sustainable and renewable materials, as they are made from living (plant)
materials which can be grown indefinitely. Biopolymers have a surprising number of responsibilities in our body;

* Corresponding author. Tel.: +0-000-000-0000 ; fax: +0-000-000-0000 .

E-mail address: author@institute.xxx

2351-9789 © 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer-review under responsibility of the scientific committee of the International Conference on Sustainable and Intelligent Manufacturing
doi:10.1016/j.promfg.2017.08.030
264 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

they hold cells together to form tissues, they provide subtle chemical signals to the cells to guide their behaviour,
they contribute to the skin’s hydration and elasticity, they lubricate our joints and gastrointestinal tracts, and protect
us against pathogens by assembling into the mucus gel that covers our eyes and respiratory tract. Basically these
biopolymers exhibit important properties such as biodegradability, biocompatibility and antibacterial activity. The
degradation of biopolymers results from the action of naturally occurring micro-organisms such as bacteria, fungi
and algae. Consequently, biopolymers can be produced from natural raw materials like starch, sugar and cellulose as
well as fossil oil [1-3]. The chemical structures and compositions of biopolymers are very similar to the
macromolecules of the native extracellular environment. The advantages of biopolymers over traditional plastics are
unprecedented, provided that they are used in situations in which they raise the functionality and generate extra
benefits. Utilization of these materials in living systems would possibly reduce the simulation of chronic
inflammation or immunological reactions and toxicity which occur frequently when a synthetic polymer device is
implanted into the host [4]. In addition, chemically modified biopolymers can provide the mechanical and electrical
properties required for particular applications [5,6].

There are three main classes of biopolymers classified according to the monomeric units used and the structure of
the biopolymer formed.
i. Polynucleotides (RNA and DNA) - these are long polymers composed of 13 or more nucleotide monomers.
ii. Polypeptides - these are short polymers of amino acids.
iii. Polysaccharides – these are linear bonded polymeric carbohydrate structures.

Materials constructed from these molecules are classified as soft, stretchy and gel-like, and have the properties in
between solids and liquids. Biopolymers are said to be smart and adaptable materials in living things, because their
structures are constantly manipulated either by enzymes throughout different stages of an organism’s lifecycle, or in
response to environmental changes [7].

Smart polymeric materials have the characteristic property to respond by large changes due to small changes in
environment. These polymers are referred as smart polymers or stimuli-responsive polymers or environmentally
sensitive polymers. Smart polymers undergo fast and reversible changes in the microstructure triggered by small
stimuli in the environment. The stimuli that have been demonstrated to induce these changes in physical properties
of the polymers are diverse in nature, and include temperature, pH, solvent or ionic composition, electric field, light
intensity, and introduction of specific ions [8-12]. The changes are apparent at the macroscopic level either as
precipitate formation or as phase separation or as magnitude changes in case of hydrogels. These phenomena are
reversible in nature, i.e., the system can return to its initial state when the trigger is removed. The driving force
behind these transitions varies with common stimuli including neutralization of charged groups by either pH shift or
the addition of an oppositely charged polymer, changes in the efficiency of hydrogen bonding with an increase in
temperature or ionic strength and collapse of hydrogels and interpenetrating polymer networks. Polymers of such
responsive features are being developed for uses in various bulk engineering and microscale medicine, specifically
as microfluidic devices [13], pulsatile drug release systems [14-17], bioadhesion mediators [18-20] and
motors/actuators [21,22]. The changes in the property of smart polymers have shown various applications in
biological system [23].

2. Classification of smart biopolymers

The use of functional polymers has been growing rapidly in the last two decades. These polymers respond in some
desired way to a change in temperature, pH, electric or magnetic fields or some other parameters. Recent
developments have shown an exponential growth in the subject where smart polymeric materials are being tailor
made for application in biotechnology and medicine. Different types of smart biopolymers have been developed for
a wide range of applications. These are classified based on the type of stimuli and functionality of polymers:
i. pH-sensitive smart polymers
ii. Thermosensitive smart polymers
iii. Stimuli responsive smart polymers
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 265

2.1 pH-sensitive smart polymers

Polymers containing ionizable functional groups that respond to change in pH are called pH-sensitive polymers.
These polymers are able to accept or release protons in response to pH changes as they contain acidic groups
(carboxylic or sulphonic) or basic groups (amino salts) in their structure [24]. In other words, the polymers with acid
functional groups are polyanions and the polymers with basic functional groups are polycations. The carboxylic
groups of polyanions accept protons at low pH values and release protons at high pH values. Therefore, when a pH
increased, the polymer swells due to the electrostatic repulsion of the negatively charged groups. Examples of
polyanions are poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA). On the other hand, polybases or
polycations are protonated at high pH values and ionized at neutral or low pH values. Examples are: poly(4-vinyl
pyridine), poly(2-vinyl pyridine) (PVP) and poly(vinyl amine) (PVAm), poly(2-diethyl aminoethyl methacrylate)
(PDEAEMA), with amino groups in their structure gain the proton in acid environment and releases the protons in
basic environment [25]. This type of smart polymers have the transition between soluble and insoluble state that is
created by decreasing the net charge of the polymer molecule [26]. By generating the charge along the polymer
backbone, the electrostatic repulsion results in an increase in the hydrodynamic volume of the polymer [27].

In human body, we can see remarkable changes in pH that can be used to direct therapeutic agents to a specific body
area, tissue or cell compartment. When we consider the pH variation in our body, the gastrointestinal tract is an
important site for the application of pH-sensitive polymers. The gastric pH is ~2 whereas intestinal pH is ~7.4 or
7.8. Polyethylene glycol (PEG) and PMAA form complexes at low pH by hydrogen bonding of ether groups from
PEG and carboxylic acid moieties from PMAA. A graft PMAA–g–PEG copolymer was evaluated for calcitonin
delivery to the intestine [28]. In this system, the release of calcitonin followed a relaxation-controlled mechanism.
This polypeptide is a therapeutic agent for bone diseases like Paget’s disease, hypercalcemia, and osteoporesis. As
the pH increased during the passage from the stomach to upper small intestine, the ionized pendant carboxyl groups
caused electrostatic repulsion, which results in swelling of the network and release of hormone. These conditions
make the pH sensitive polymers ideal for pharmaceutical systems to deliver the specific therapeutic agents. The
applications of various pH-sensitive polymeric employed for drug delivery systems are shown in Table 1[29].

Table 1. Various applications of pH-sensitive polymers in drug delivery systems

Drug Polymer Application
Paclitaxel and dauxorubicin Poly(ethylene glycol)-block- Prolongation of survival
poly(propylene glycol)-poly(ethylene time in comparison
glycol) with single drug
therapy

Fibroblast growth factor Poly(n-isopropylacrylamide-co- To improve

propylacrylicacid-co-butylacrylate) angiogenesis in
infracted
myocardium

Ketoprofen Poly(acrylamide)-g-carrageenan For colon-targeted

and sodium alginate delivery

Dexamethasone Poly(methoxyl ethylene glycol- For oral drug delivery

caprolactoneco-
methacrylic acid-co-poly(ethylene
glycol)methylethylenemethacrylate)

Protein drug Alginate and chemically modified For oral delivery

carboxymethyl chitosan
266 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

Recently, pH-sensitive polymers have been gaining attention for applications in gene delivery and gene therapy
research. Transport of naked DNA into a cell is a difficult process because of negative charges and the large size of
DNA molecules at physiological conditions [30]. Therefore, positively charged polymers are used to balance the
charge and condense the DNA to nanoparticles of ~100 nm in size.

The transport mechanism of DNA–polymer nanoparticles is considered to be receptor-mediated endocytosis. During

the course of endocytosis, the pH of an endosome drops to ~5 or 6. The endosome is then fused with a pre-lysosome
secreted from a Golgi body, forming a lysosome, containing many digestive enzymes like nucleases. To maximize
the DNA transport to the nucleus, DNA should escape from the endosome before the lysosomal fusion [31]. From
this concept, several membrane fusion polymers were designed and investigated for DNA delivery.

2.2. Thermo-sensitive smart polymers

These smart polymers are sensitive to temperature and change their microstructural features in response to change in
temperature. These are the most studied, most used and most safe polymers in drug administration systems and
biomaterials [32,33]. This type of polymer system exhibits a critical solution temperature at which the phase of the
polymer and the solution is changed in accordance with their composition. Basically, there are two types of thermo-
responsive polymers, i.e., the first present a lower critical solution temperature (LCST) while the second present an
upper critical solution temperature (UCST). LCST and UCST are the respective critical temperature points below
and above which the polymer and solvent are completely miscible as shown in Fig. 1 [34].

Fig.1. Schematic illustration of temperature vs. polymer volume fraction phase diagrams for polymer solution:(a)
lower critical solution temperature (LCST) behaviour and
(b) upper critical solution temperature (UCST) behaviour [34].

Particularly, the LCST can be defined as the critical temperature in which the polymeric solution shows a phase
separation, going from one phase (isotropic state) to two phases (anisotropic state). Below the LCST, the enthalpy
term related to the hydrogen bonding between the polymer and the water molecules, is responsible for the polymer
dissolution. When raising the temperature above the LCST, the entropy term (hydrophobic interactions) dominates
leading to polymer precipitation. The LCST of polymers in water solutions can be modulated by incorporating
hydrophilic or hydrophobic moieties [35]. The polymers with LCST are the most widely used in drug delivery
systems. The therapeutic agents as drugs, cells or proteins can be mixed with the polymer which could be injected in
the human body in the subcutaneous layer or at the damaged area. This forms a gel deposit at the area of injection
after increasing the temperature [30]. The most commonly used thermo-sensitive polymers with lower critical
solution temperature include poly(N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide), poly(N-
vinyl alkylamide), poly(N-vinyl caprolactam), phosphazene derivatives, pluronics, tetronics, polysaccharide
derivatives, chitosan and triblock copolymer based on hydrophilic poly(ethylene glycol) and hydrophobic
copolymer poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers [24,36]. Other examples of
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 267

thermo-responsive polymers are: copolymers blocks of poly(ethylene glycol)/poly(lactide-co-glicolide)

(PEG/PLGA, Regel®), poly(oxyethylene)-poly(oxypropylene) (PEO/PPO), triple blocks of copolymers
poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) (PEO-PPO-PEO) and poly(ethylene glycol)-poly(lactic
acid)-poly(ethylene glycol) (PEG-PLA-PEG) [35]. Among these, poly(N substituted acrylamide) are widely used in
drug delivery applications. PNIPAAm is the most investigated synthetic thermo-sensitive polymer exhibiting a
LCST close to body temperature. It also exhibits phase transition at 32 0C in water, and for the purpose of drug
targeting, its phase-transition temperature can be easily adjusted to the temperature around 40 0C by the introduction
of a hydrophilic co-monomer such as N,N-dimethylacrylamide (DMAAm) [37,38].

The advantages of temperature sensitive polymeric systems includes: ability to deliver hydrophilic and lipophilic
drugs, site-specific drug delivery, avoidance of toxic organic solvents, and sustained release properties with reduced
side effects. On the other hand, these also exhibits several disadvantages, like, high-burst drug release, lack of
biocompatibility of the polymeric system and gradual lowering of pH of the system due to acidic degradation
[39,26]. Table 2 represents the list of various applications of thermo-sensitive polymers for drug delivery systems
[29].

Table 2. Various applications of temperature-sensitive polymers for drug delivery systems.

Drug Polymer Application
Docetaxel Conjugated linoleic acid Peritoneal
coupled with pluronic dissemination of
F-127 gastric cancer
Exenatide PLGA–PEG–PLGA Treatment of type II
diabetes

Ethosuximide Chitosan with Injectable gels for

glycerophosphate depot therapy
disodium salt and glycerol
Human mesenchymal stem cells Chitosan-beta For the treatment of
and desferroxamine Glycerophosphate critical limbic
ischemia
Leuprolide Polybenzofulvene For treatment of
tumours

2.3. Stimuli-responsive smart polymers

These polymers are further divided into light sensitive polymers, electrical sensitive polymers, magnetic sensitive
polymers and multi stimuli-responsive polymers.

2.3.1. Light sensitive polymers

Polymers which are sensitive to visible light are called as light-sensitive polymers. A light-sensitive polymer
undergoes a phase transition on exposure to light. Light is one of the clean stimuli that allows remote control
without physical contact or any mechanical apparatus. The light-sensitive polymers are water soluble, biocompatible
and biodegradable in nature. They are widely used in the field of engineering and biomedical applications. Light-
responsive polymers are very attractive for triggering drug release for their ability to control the spatial and temporal
triggering of the release.

Light-responsive polymers may be either UV or visible light-sensitive. However, visible light-responsive polymers
are more beneficial since they are safe, inexpensive, readily available, clean and easily manipulated [24]. Light-
268 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

sensitive drug carriers are fabricated from polymers that contain different photo-sensitizers such as azobenzene,
stilbene and triphenylmethane.

Visible light-responsive hydrogels can be prepared by the introduction of light-sensitive chromophores like,
trisodium salt of copper chlorophyllin to poly(N-isopropylacrylamide) hydrogels. The chromophore absorbs the
light when exposed and is then dissipated locally as heat by radiation less transitions, which increases the ‘local’
temperature of the hydrogel. This results in an increase in temperature and thus alters the swelling behaviour of the
hydrogel [40]. Light-sensitive polymers exhibit some of the limitations that include inconsistent response due to the
leaching of non-covalently bound chromophores during swelling or contraction of the system, and a slow response
of hydrogel towards the stimulus.

Polymers that form two phase systems have the potential to be used in industrial bioseparation techniques. Many of
the problems of two phase systems (which cannot be recycled, require purification processes etc.) have been
overcome using light sensitive smart polymers. As one such example, a light-sensitive polymer was synthesized by
using N-isopropylacrylamide, n-butyl acrylate and chlorophyllin sodium copper salt as monomers. The synthesis
mechanism of this polymer is shown in Fig. 2 [41].

Fig. 2. Synthesis of light-sensitive polymer [41].

The polymer was applied to form aqueous two-phase systems with Dextran 20000; the polymer containing
chlorophyllin sodium copper salt sensitive to visible light. It was observed that the polymer could be recycled after
irradiation with visible light at 488 nm or by increasing the temperature to levels above 28 oC; the polymer could be
recovered at levels above 95 %. Thus, this light-sensitive copolymer would precipitate from solution under light
irradiation (488 nm) and could be reused [41].
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 269

Chemical modification of a hydrogel with photoresponsive moieties is the most straight forward method to obtain a
photoresponsive hydrogel. For example, a hydrogel composed of poly(2-hydroxyethyl methacrylate) functionalized
with pendant azobenzene groups was obtained. This hydrogel upon irradiation with ultraviolet light deswelled, while
the reversal process could be induced with visible light. These photoresponsive swelling-deswelling hydrogels have
been engineered to fabricate photoactive microcantilevers [29].

2.3.2. Electro-sensitive smart polymers

The polymers which change their physical properties in response to a small change in electric current are known as
Electro-sensitive polymers. Electro-responsive polymers transform electric energy into mechanical energy and have
wide application in the field of controlled drug delivery, artificial muscle actuations, energy transductions and sound
dampening. These polymers contain a relatively large concentration of ionisable groups in their back bone chain. In
most of the cases, electro-responsive polymers also exhibit a pH-responsiveness. The small change in electric
current causes a change in pH which leads to disruption of hydrogen bonding between polymer chains, causing the
degradation or bending of the polymer chain and thereby leading to drug release. Under the influence of an electric
field, electro-responsive hydrogels generally shrink or swell and this property has allowed its application in drug
delivery systems, artificial muscle or biomimetic actuators [42]. The electro-responsive concept is depicted in Fig. 3
[27].

Fig. 3. Schematic representation of the electro-responsive effect in a polymer gel [27].

The very important fact that has to be considered in this type of drug delivery system is the critical selection of
electric current which can cause drug release without stimulating the nerve endings in the surrounding tissue [43].
Electrically controlled delivery systems include technologies such as sonophoresis, iontophoresis and infusion
pumps [44].

Electro-responsive polymers have been typically investigated in the form of polyelectrolyte hydrogels. These gels
deform under the influence of an electric field due to anisotropic swelling/deswelling when the charged ions are
directed toward the anode or cathode side of the gel [45]. For example, in case of hydrolyzed polyacrylamide gels
under the influence of electric field, H+ ions migrate towards the cathode whereas the negatively charged acrylate
groups are attracted towards the anode thereby creating a uniaxial stress within the gel. The greatest stress was
experienced at the region surrounding the anode while the area in the vicinity of the cathode exhibits the smallest
stress. This stress gradient contributes to the anisotropic gel deformation under an electric field [46].
Although most polymers that exhibit electro-sensitive behavior are polyelectrolytes, a few neutral polymers have
also demonstrated electric field sensitivity in non-conducting media. For instance, a lightly crosslinked
poly(dimethyl siloxane) (PDMS) gel containing electro-sensitive colloidal TiO 2 particles was synthesized. A
significant and rapid bending of the gel in silicon oil was observed. Since the TiO2 particles were not able to exit the
matrix, the force acting on these particles was transferred to the polymer, which resulted in gel deformation (Fig. 4)
[45].
270 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

Fig. 4. Electro-response of PDMS gel loaded with 10% TiO2 as a function of uniform field strength [45].

2.3.3. Magnetic- sensitive polymers

Magnetic targeting is based on the attraction of magnetic micro- and nanoparticles to an external magnetic field
source. When designing a magnetic-responsive delivery system several factors need to be considered such as the
magnetic properties of the carrier particles, field strength and field geometry. The principle says that in the presence
of a magnetic field gradient, a translational force will be exerted on the particle/drug complex. This effectively traps
the complex in the field at the target site and thus pulls it towards the magnet [27,47]. Magnetic drug carriers like
magnetite, cobalt, ferrite and carbonyl iron are mainly used and they are biocompatible, non-toxic and non-
immunogenic [48].

Generally, inorganic magnetic nano-particles are physically entrapped within or covalently immobilized to a three-
dimensional crosslinked network and leading to materials with shape and size distortion that occurs reversibly and
instantaneously in the presence of a non-uniform magnetic field [49,50]. In such cases, the magnetophoretic
force conferred to the polymeric material as a result of the magnetic susceptibility of the particles obtained wide
applications in soft biomimetic actuators, sensors, cancer therapy agents, artificial muscles, switches, separation
media, membranes, and drug delivery systems [51-53].

Magnetic micro and nanoparticles were explored as possible drug carriers for site-specific drug targeting in the late
1970s [54]. Drugs were attached to these carriers and injected into the subject either via intravenous or intra-arterial
injection. High-gradient, external magnetic fields generated by rare earth permanent magnets were then used to
guide and concentrate the drugs at the tumor sites [27].

By casting nanoparticle dispersions from organic media onto surfaces, a diverse range of mesoscale morphologies
have been observed. For example, a film was cast under an applied magnetic field to obtain a dispersion of
poly(acrylonitrile)-stabilized ferromagnetic cobalt (Co) nanoparticles, after the ligand exchange. Stabilization and
pyrolysis of the resulting nanoparticle chains led to 1D carbon nanoparticle chains with cobalt inclusions as shown
in Fig. 5 [55].
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 271

Fig.5. 1D
1D carbon
caarr bo
car
ca bon
bon
on nanostructures
nnaanos
noosstru
no ttrru
ru cct
ctu
ttu
urre
res
eess formed
ffo
orme
meed via
m via
ia functionalization
ffun
fu
un
u nncti
ctttiio
ccti on
ona
naal
n alliz
liiz
izaati
atti
tio on
nooff fe
fferromagnetic
fer
eerrrom
rro
om
o magn
a etic nanoparticles

Fig. 5. 1D carbon nanostructures formed via functionalization of ferromagnetic nanoparticles [55].

2.3.4. Dual/multi stimuli-responsive polymers

Dual/multi stimuli-responsive polymers are the polymers sensitive to more than one/two stimuli simultaneously. For
example, the polymeric structures sensitive to both temperature and pH, obtained by the simple combination of
ionization and hydrophobic functional groups. This can be achieved by the copolymerization of monomers bearing
the required functional groups, combining temperature sensitive polymers with polyelectrolytes or by the
development of new monomers that respond simultaneously to both the stimuli [56].

In order to obtain a temperature and pH sensitive polymer, it is necessary to combine both temperature sensitive and
pH-sensitive monomers, for example, poly(N-isopropylacrylamide-co-methacrylic acid). Combining PNIPAm and
PMAA with different ratios, nanoparticles containing vitamin B-12 were prepared. The increase in temperature from
37 to 43ºC and decrease of the pH from 6 to 4 increased the permeability, causing the release of vitamin B-12 [57].
The copolymer constituted by 2-dimethylaminoethyl methacrylate (DMAEM) and the acrylic acid obtained by
ultraviolet radiation can also respond to both of these impulses, i.e., pH and temperature. The polymer poly(N,N-
dimethylaminoethyl methacrylate) (PDMAEMA) exhibits multistimuli responsiveness. It presents a temperature
sensibility between 38 and 40ºC and it is sensitive to a pH of 2.5, presenting also sensitivity to electrical fields with
a voltage near 3.0 volts [58].

In case of glucose oxidase (GOD) responsive insulin delivery, the enzyme is usually immobilized on the pH
sensitive polymer surface/membrane with insulin. After glucose diffuses inside the gel, it is enzymatically converted
into gluconic acid, leading to decrease in its pH, and the polymer becomes charged due to amino group protonation.
The hydrogel swells, facilitating the release of insulin by the diffusion mediated process [59].
272 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

The selected examples of polymers responsive to two stimuli demonstrate very well the strength of combining
several stimuli within one polymer. However, the addition of one more stimulus is particularly advantageous
because it can improve the degree of precision, enlarge the switching window or even change the switching
conditions due to the higher level of complexity of the polymer. Sumaru et al. [60] functionalized PNIPAM with
spirobenzopyran. The obtained polymer acted as a logic gate due to the responsive behaviour towards temperature,
light and pH. While the PNIPAM polymer provided the general thermo-responsive behaviour, the spiropyran acted
in dual sense as a pH- and light-responsive unit. In another system, with a serial impact as well, a statistical
copolymer (shown in Fig. 6) was prepared from N-hydroxymethylacrylamide (NHMA), NIPAm and 2-diazo-1,2-
naphthoquinone-5-sulfonylmethylacrylamide (DNQ), which exhibits irreversible triple responsive behaviour [61].

Fig. 6. Triple responsive system, bearing thermo-, pH- and photosensitive moieties [61].

One example of a pH and thermo-responsive block copolymer is PNIPAM-b-PMAA. This dual-responsive polymer
was grafted onto mesoporous silica to moderate the flow of loaded drugs in and out of the mesopores (Fig. 7). The
polymer controlled the diffusion of drug molecules through the pores. In contrast to the 9.5% release of model drug
Fluorescein at 30oC (pH 7.4), the release profile reached nearly 40% at 45oC (pH 7.4) and about 80% at pH 3.5 (45
o
C) (Fig. 7 b to 7 d). This silica-polymer hybrid showed pH-induced thermo-responsive drug release due to lowering
of the LCST of PNIPAM with decreasing g ppH [[62].
]
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 273

[MPS- methacryloxypropyl-trimethoxysilane, NIPAM- N-Isopropylacrylamide, MA- methacrylic acid, MBA- N,N0-methylenebisacrylamide,

SDS- sodium dodecyl sulphate, KPS- Potassium persulfate, EDC- 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, NHS- N-
Hydroxysuccinimide]

Fig. 7. Preparation of the temperature/pH-responsive drug-release system. Release profiles of FL-loaded MSN@PNIPAM-co-PMA)-FA (FA-
folic acid) in response to temperatures in Phosphate Buffer Saline: b) pH 7.4, c) pH 5.5 and d) pH 3.5 [62].

As discussed earlier, macromolecules containing azobenzene as a chromophore are the most widely studied photo-
responsive polymers. The incorporation of azobenzene into a polymer network of a thermo-responsive polymer
generates light- and temperature- dual-responsive polymers. For example, thermo- and photo-dual-responsive
micelles in water was prepared by using amphiphilic block copolymers that included a hydrophilic poly(ethylene
oxide) block and a hydrophobic block prepared by copolymerizing azobenzene-containing methacrylate and
PNIPAM. The size of the micelles was dependent on the temperature and the controlled release of encapsulated Nile
Red was achieved through heating and cooling the system [63].Thus, multiple-stimuli responsive polymers have
found applications in a wide range of fields, some abandoned in the past due to lack of suitable polymer systems.
The majority of reports focus on the delivery of drugs and genes. Their applications are also observed in the field
other than biomedicine, such as catalysis, separation, coating and sensing [62].

3. Applications of smart biopolymers

Smart biopolymers that can respond to different features/stimuli as mentioned in the preceding sections have a wide
range of biomedical applications that include drug delivery, gene delivery and tissue engineering. The versatility and
untapped potentials of smart polymeric materials make biopolymers a particularly exciting interface of chemistry
and biology. Since their stimulus-responsive behaviour occurs in aqueous solution, such polymers and hydrogels are
becoming increasingly attractive in biotechnology and medicine.

As discussed earlier, smart polymers are biocompatible, non-thrombogenic, strong, resilient, flexible, easy shaping
and colouring. These properties of smart biopolymers play a very major role in drug delivery. They maintain the
stability of the drug and are easy to manufacture, good nutrient carriers to the cells, easily changed using cell
adhesion ligands. Moreover, it is possible to inject them in vitro as liquid to create a gel at the body temperature. For
instance, thermo-sensitive polymers were used to solubilise some hydrophobic drugs, like paclitaxel to produce
excellent formulations with low solubility drugs as a carrier for drug delivery.

The application of smart polymers for drug delivery shows great promise due to the observed modulated or pulsatile
drug release pattern which mimics biological demand. Stimuli occurring externally or internally include
temperature, photo-irradiation, electric current, pH and metabolic chemicals. To explain with an example, when an
enzyme is immobilized in smart hydrogels, the products of enzymatic reaction have the capacity to trigger the gel’s
phase transition. Then the chemical signal is translated into the environmental signal and then into the mechanical
signal, resulting into shrinking or swelling of smart gel. This phenomenon can be used to control drug release,
because diffusion of the drug out of the beads depends on the gel state. When a smart polymer is integrated into a
microcapsule wall or a liposomal lipid bilayer, the conformational transition of the polymer affects the integrity of
the microcapsule or liposome and thus allows the regulated release of the drug loaded into the microcapsule or
liposome. By using such drug formulations incorporated into the hydrogels, pharmaceutical companies are able to
increase the efficiency, cost-effectiveness and range of applications. One example of an insulin delivery system is a
hydrogel comprising an insulin-containing reservoir within a poly(methacrylic acid-g-ethylene glycol) copolymer in
which glucose oxidase was immobilised [64]. The surface of the polymer contained a series of molecular ‘entrances’
which opened and released insulin dependent on glucose concentration. Ingress of glucose through the polymer
274 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

layer to the entrapped glucose oxidase resulted in a drop of pH as glucose was oxidised to gluconic acid, and the
released protons caused the pendent PMAA chains of the hydrogel to contract, thus opening the gates to allow
insulin transport (see Fig. 8). An additional feature of this system was the cross linked polyethylene glycol graft
component, in which the expanded state of the gel was able to adhere to the specific regions of upper intestine. In
this way, deliveryy of insulin could be targeted
g to ppreferred locations in the bodyy [65].
[ ]

Fig. 8.
Fi 8 Poly(methacrylic
P l ( th li acid-g-ethylene
id th l glycol)
l l) responsive
i hydrogel
h d l system
t for
f controlled
t ll d iinsulin
li release
l [65].

The application of smart biopolymers has also been observed in gene delivery that aims at the treatment of many
genetic diseases. DNA (therapeutic gene) is a negatively charged hydrophilic molecule and its delivery into the
nucleus of the cell by passing through negatively charged and hydrophobic cell membrane is not feasible.
Consequently, gene delivery carriers (also called vectors or vehicles) have been developed. Viruses were the
nature’s first carriers used for gene delivery. To avoid the immune response caused by the viruses, non-viral
polymers were employed as the carriers. It is interesting to note that thermo-responsive polymers have been used to
enhance the transfection (gene delivery) efficiency by changing the temperature either during the complexation
and/or during the incubation or transfection period. Anionic polymers can also be used to increase the delivery
efficiency of DNA molecules overcoming the endosome membrane through a different mechanism of cationic
polymers [31]. Nanoparticles composed by some of these anionic polymers like poly(ethyl acrylic acid) (PEAA) or
by poly(propyl acrylic acid) (PPAA) promotes the stability of the formulation, increasing the efficiency of the DNA
transfection [35].

In addition to the above applications, smart biopolymers have also been used in the field of tissue engineering.
Tissue engineering has evolved as an emerging field to repair organs and tissues damaged by disease or injury. It
aims to regenerate or replace biologically damaged or diseased tissue or generate replacement organs for a wide
range of medical conditions such as heart diseases, diabetes, cirrohosis, osteoarthritis, spinal cord injury and
disfiguration [34]. The concept of tissue engineering embodies the creation of a scaffold structure that has the
appropriate physical, chemical and mechanical properties to enable cell penetration and tissue formation in three
dimensions. The main aim is the growth of new tissue in the scaffold to integrate with the host tissue. On the other
hand, the scaffold provides a temporary pathway for the regeneration and will degrade either during or after healing,
thereby obviating the need to remove the material later and thus eliminating possible side effects associated with
leaving materials in the body. This indicates the role in tissue regeneration and repair. Scaffolds are therefore
defined as three-dimensional porous solid biomaterials designed to perform some or all of the following functions:
(i) promote cell-biomaterial interactions, cell adhesion and extracellular matrix (ECM) deposition; (ii) permit
sufficient transport of gases, nutrients and regulatory factors to allow cell survival, proliferation, and differentiation;
(iii) biodegrade at a controllable rate that approximates the rate of tissue regeneration under the culture conditions of
interest; and (iv) provoke a minimal degree of inflammation or toxicity in vivo [66].

In the field of tissue engineering, thermo-responsive polymers are commonly used in two cases, i.e., as substrates
enabling the cell growth and proliferation and as injectable gels, for in situ of the scaffold. In the first case, the
ability of the thermo-responsive polymers is used to regulate the cells’ attachment and detachment on its surface.
Whereas, second involves the encapsulation of cells within a 3D structures of a body [67-69]. The in situ formation
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 275

of cell/scaffold construct allows the delivery of encapsulated cells, nutrients and growth factors to defects of any
shape using minimally invasive techniques when compared to that of in vitro formation of the construct. The basic
concept is as shown in Fig. 9 [34].

Fig. 9. In situ formation of a scaffold [34].

Specifically, the thermo-responsive polymer is mixed at room temperature with the cells and then injected into the
body. Upon injection due to the temperature increase (to 37 °C) that is above the polymer’s LCST, the polymer
forms a physical gel. The cells are encapsulated within the 3D structure of the gel. For example, when PNIPAAm
due to its LCST being very close to body temperature, is crosslinked into hydrogels, the coil to globule transition
causes a rapid decrease in the volume of the gel resulting in a fast release of entrapped drug and solvent followed by
a more linear, diffusion controlled release [11].

For tissue engineering, it is important to be able to grow cells at a surface and then to detach the cells at an
appropriate stage to be harvested, ideally without a biochemical or chemical reagent step. PNIPAm grafted surfaces
were shown to support growth of cells as diverse as bovine endothelia and rat hepatocytes when PNIPAm-grafted
tissue culture surfaces were above polymer LCST and to allow recovery of the cells when the temperature was
reduced below the phase transition temperature. In addition, human skin fibroblasts have been shown to attach and
proliferate at the surface of thermo-responsive hydrogels of ethylene glycol vinyl ether and butyl vinyl ether
copolymers.

In addition to the various applications studied about smart polymers, it is also an important point to note that some
of the smart polymers exhibits a shape memory effect. The shape-memory effect is the ability of a material to
change its dimension in a pre-defined way in response to an external stimulus [70]. The shape-memory phenomenon
in polymers arises from a dual-segment system, in which one segment is highly elastic and the other is able to
remarkably reduce its stiffness in the presence of a particular stimulus mentioned in the above sections. These SMPs
are able to respond by means of significantly changing their shape. Thus, the SMPs can be activated under the
influence of light, heat, magnetism and also by moisture and even a change of pH value similar to smart polymers
[71].

Biocompatible and degradable SMPs with appropriate mechanical properties could be developed for novel medical
devices. In case of animal testing, large bulky devices could be introduced potentially into the body in a compressed
temporary shape by means of minimally invasive surgery and then expanded to their permanent shape to fit as
required. Tying of a knot with instruments and sutures to close an incision or open lumen is one of the challenges in
endoscopic surgery. It is observed to be difficult in order to manipulate the suture to press the wound lips under the
276 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

right stress. A possible solution for this is to design a smart surgical suture, whose temporary shape will be obtained
by elongating the fiber under a controlled stress. This suture can be applied loosely in its temporary shape; when the
temperature is raised above its transition temperature (T trans ), the suture will shrink and tighten the knot thus
applying the optimum force. Fig. 10 shows a fiber of thermoplastic shape-memory polymer which was programmed
by stretching about 200% at 40 °C. After forming a loose knot, both the ends of the suture were fixed. It is observed
that the knot gets tightened in 20 s when heated to 40 °C. This procedure is currently being tested on animals [71].

Fig. 10. A fiber of thermoplastic shape-memory polymer [71].

The SMPs have found various applications in the field of tissue engineering. Bioactive porous scaffold based on
shape memory polymer has been developed with simultaneous capacities of minimally invasive surgery and fast
regeneration of new bone. For instance, bioactive multifunctional porous scaffolds were developed with capacities
of minimally invasive implantation, self-fitting and drug delivery for prompting the repairing of irregular bone tissue
via the one-step creation of interconnected pores and loading with BMP-2 protein inside the pores. BMP-2 loaded
calcium alginate (CA) hydrogel microspheres were fabricated using electro-spraying technology. Poly(ethylene
glycol)-SRO\İ-caprolactone)-based polyurethane (PEG-PCL-PU) with excellent shape memory function was used as
the scaffold matrix. In this case, CA hydrogel microspheres were also employed as pore-forming agent and also as a
drug carrier. The produced scaffold possessed an excellent shape memory function in response to a temperature of
41o C, being able to undergo compression like a sponge for convenient implanting via a minimally invasive surgery
and later return to its original porous structure upon a temperature stimulus for self-fitting into the irregular cavity of
a maxillary sinus. Also, the loaded BMP-2 induced a fast osteogenetic capability in the maxillary sinus area [72].

Thus, considering these wide properties and advantages of smart polymeric biomaterials and shape memory
polymers, they can be efficiently applied in controlled drug delivery systems, implants, wound covers and tissue
engineering. Here, the smart behaviour as a novel functionality of polymers could potentially play an important role
and thus these polymers have attracted substantial scientific and technological interest, especially for biomedical
applications, which is reflected in the rapidly increasing number of publications on smart polymers during the last
few decades. In this review, the general principle of different stimuli responsive smart polymers was investigated
with brief explanation on suitable examples. Although there are various other applications of smart polymers as
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 277

biosensors, bioactuators and in other electronic and optical fields, but this review is confined only to the biomedical
applications.

Acknowledgments

The authors sincerely acknowledge the financial supports of UGC, New Delhi under UPE-FAR-I Program [F. No.
14-3/2012 (NS/PE)] and DST, New Delhi under DST-PURSE-Phase-II Program [F. No. SR/PURSE Phase
2/13(G)].

References

[1] S. Gopi, A. Amalraj, S. Thomas, Effective drug delivery system of biopolymers based on nanomaterials and hydrogels - A review, Drug
Designing. 5 (2016) 1-7.
[2] R.P. Babu, K. O’Connor, R. Seeram, Current progress on bio-based polymers and their future trends, Progress in Biomaterials. 2 (2013) 1-16.
[3] A. Salerno, C.D. Pascual, Bio-based polymers, supercritical fluids and tissue engineering, Process Biochemistry. 50 (2015) 826-838.
[4] M. R. Yates, C. Y. Barlow, Life cycle assessments of biodegradable, commercial biopolymers— A critical review, Resources, Conservation
and Recycling. 78 (2013) 54– 66.
[5] K. V.Velde, P. Kiekens, Biopolymers: overview of several properties and consequences on their applications, Polymer Testing. 21 (2002)
433–442.
[6] B.S. Kim, C. E. Baez, A. Atala, Biomaterials for tissue engineering, World J. Urol. 18 (2000) 2-9.
[7] I. Y. Galaev, B. Mattiasson, ‘Smart’ polymers and what they could do in biotechnology and medicine, Trends Biotechnol. 17 (1999) 335–
340.
[8] K. Dusek, D. Patterson, Transition in swollen polymer networks induced by intramolecular condensation, J Polym Sci A-2. 6 (1968) 1209-
1216.
[9] K. Dusek, W. Prins, Structure and elasticity of nanocrystalline polymer networks, Adv Polym Sci. 6 (1969) 1-102
[10] A.S. Hoffman, Intelligent polymers in medicine and biotechnology, Macromol Symp. 98 (1995) 645-664.
[11] Y. Osada, S.B. Ross-Murphy, Intelligent Gels, Scientific American. 268 (1993) 82–87.
[12] D.E. Rossi, K. Kawana, Y. Osada, A. Yamauchi, Polymer gels, fundamentals and biomedical applications, Plenum, New York, 1991.
[13] S.L.R. Barker, D.Ross, M.J.Tarlov, M.Gaitan, L.E.Locascio, Control of flow direction in microfluidic devices with polyelectrolyte
multilayers, Anal. Chem. 72 (2000) 5925–5929.
[14] A.Kikuchi, T.Okano, Pulsatile drug release control using hydrogels, Adv. Drug Delivery Rev. 54 (2002) 53–77.
[15] S.K. Li, A. D’Emanuele, On-off transport through a thermoresponsive hydrogel composite membrane, J. Controlled Release. 75 (2001) 55–
67.
[16] J. Kost, R. Langer, Responsive polymeric delivery systems, Adv. Drug Delivery Rev. 46 (2001) 125–148.
[17] N. Peppas, Hydrogels and drug delivery, Curr. Opin. Colloid Interface Sci. 2 (1997) 531–537.
[18] L.K. Ista, G.P. Lopez, Lower critical solubility temperature materials as biofouling release agents, J. Ind. Microbiol. Biotechnol. 20 (1998)
121–125.
[19] D. Cunliffe, C.L.H Alarcon, V. Peters, J.R. Smith, C. Alexander, Thermoresponsive surface-grafted poly(N-isopropyl acrylamide)
copolymers: effect of phase transitions on protein and bacterial attachment, Langmuir. 19 (2003) 2888–2899.
[20] M. Yamato, C. Konno, M. Utsumi, A. Kikuchi, T. Okano, Thermally responsive polymer grafted surfaces facilitate patterened cell seeding
and co-culture, Biomaterials. 23 (2002) 561–567.
[21] J. Hoffmann, M. Plotner, D. Kuckling, W. J. Fischer, Photopatterning of thermally sensitive hydrogels useful for microactuators, Sens.
Actuators A. 77 (1999) 139–144.
[22] D. W. Urry, Five axioms for the functional design of peptide-based polymers as molecular machines and materials: Principle for
macromolecular assemblies, Biopolymers. 47 (1998) 167–178.
[23] A. Kumar, A. Srivastava, I. Y. Galaev, B. Mattiasson, Smart polymers: physical forms and bioengineering applications, Prog. Polym. Sci. 32
(2007) 1205–37.
[24] Y. Qiu, K. Park, Environment-sensitive hydrogels for drug delivery, Adv. Drug. Deliv. Rev. 53 (2001) 321–339.
[25] R. Ghizal, G. Roohi, F.S. Srivastava, Smart polymers and their applications, International Journal of Engineering Technology, Management
and Applied Sciences. 2 (2014) 104-115.
[26] D. Schmaljohann, Thermo- and pH-responsive polymers in drug delivery, Adv. Drug. Deliv. Rev. 58 (2006) 1655–1670.
[27] P. Bawa, V. Pillay, Y.E. Choonara, L.C du Toit, Stimuli-responsive polymers and their applications in drug delivery, Biomedical materials.
4 (2009) 1-15.
[28] I. Roy, M.N Gupta, Smart polymeric materials: emerging biochemical applications, Chemistry & Biology. 10 (2003) 1161–1171.
[29] H.P. James, R. John, A. Alex, K..R. Anoop, Smart polymers for the controlled delivery of drugs – a concise overview, Acta Pharmaceutica
Sinica B. 4 (2014) 120–127.
[30] B. Jeong, A.Gutowska, Lessons from nature: stimuli-responsive polymers and their biomedical applications, Trends Biotechnol. 20 (2002)
305-310.
[31] S.T. Grainger, M.E.H. El-Sayed, Stimuli-sensitive particles for drug delivery. biologically-responsive hybrid biomaterials: a reference for
material scientists and bioengineers. World Scientific Publishing Co. Pte. Ltd., Danvers (2010) 171-189.
[32] M. Nakayama, T. Okano, T. Miyazaki, F. Kohori, K. Sakai, M. Yokoyama, Molecular design of biodegradable polymeric micelles for
temperature-responsive drug release, J. Control Rel. 115 (2006) 46–56.
[33] L.E. Bromberg, E.S. Ron, Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery, Adv. Drug
278 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279

Deliv. Rev. 31 (1998) 197–221.

[34] M.A. Ward, T. K. Georgiou, Thermoresponsive polymers for biomedical applications, Polymers. 3 (2011) 1215-1242.
[35] H. Almeida, M.H. Amaral, P. Lobão, Temperature and pH stimuli-responsive polymers and their applications in controlled and
selfregulated drug delivery, Journal of Applied Pharmaceutical Science. 02 (2012) 01-10.
[36] S. Choi, M. Baudys, S.W. Kim, Control of blood glucose by novel GLP- 1 delivery using biodegradable triblock copolymer of PLGA–PEG–
PLGA in type 2 diabetic rats, Pharm Res. 21 (2004) 827–831.
[37] L. H. Gan, Y.Y. Gan, G.R. Deen, Poly(N-acryloyl-N-propylpiperazine): a new stimuli-responsive polymer, Macromolecules. 33 (20007)
893-897.
[38] L.H. Gan, D.G. Roshan, X.J. Loh, Y.Y. Gan, New stimuli responsive copolymers of N-acryloyl-N-alkyl piperazine and methyl methacrylate
and their hydrogels, Polyme. 42 (2001) 65–69.
[39] E. Ruel-Gariépy, J.C. Leroux, In situ-forming hydrogels-review of temperature-sensitive systems, Eur. J. Pharm. Biopharm. 58 (2004) 409–
426.
[40] A. Suzuki, T. Tanaka, Phase transition in polymer gels induced by visible light, Nature. 346 (1990) 345–347.
[41] K. F. Qi, C. Xuejun, X. Jinan, B.K. Hur, Synthesis and application of a light-sensitive polymer forming aqueous two-phase systems, J. Ind.
Eng. Chem. 13 (2007) 424-428.
[42] T. Shiga, Deformation and viscoelastic behavior of polymer gels in electric fields, Adv. Polym. Sci. 134 (1997) 131–163.
[43] S. Murdan, Electro-responsive drug delivery from hydrogels, J Control Release. 92 (2003) 1–17.
[44] T. Aoki, M. Muramatsu, A. Nishina, K. Sanui, N. Ogata, Thermosensitivity of optically active hydrogels constructed with N-(l)-(1-
hydroxymethyl) propylmethacrylamide, Macromol. Biosci. 4 (2004) 943–949.
[45] G. Filipcsei, J. Feher, M. Zrinyi, Electric field sensitive neutral polymer gels, J. Mol. Struct. 554 (2000) 109–117.
[46] A. Bajpai, S. Shulka, S. Bhanu, S. Kankane, Responsive polymers in controlled drug delivery. Prog. Polym. Sci. 33 (2008) 1088–1118.
[47] A. D. Grief, G. Richardson, Mathematical modelling of magnetically targeted drug delivery, J. Magn. Mater. 293 (2005) 455–463.
[48] J.L. Arias, L.H. Reddy, P. Couvreur, Magnetoresponsive squalenoyl gemcitabine composite nanoparticles for cancer active targeting,
Langmuir. 24 (2008) 7512-7519.
[49] M. Zrinyi, L. Barsi, D. Szabo, H.G. Kilian, Direct observation of abrupt shape transition in ferrogels induced by nonuniform magnetic field,
J Chem Phys. 106 (1997) 5685–5692.
[50] G. Wang, W.J. Tian, J.P. Huang, Response of ferrogels subjected to an ac magnetic field, J. Phys. Chem. B. 110 (2006) 10738–45.
[51] M. Babincova, D. Leszczynska, P. Sourivong, P. Cicmanec, P. Babinec, Superparamagnetic gel as a novel material for electromagnetically
induced hyperthermia, J. Magn. Magn. Mater. 225 (2001)109–112.
[52] S.G. Starodoubtsev, E.V. Saenko, A.R. Khokhlov, V.V. Volkov, K.A. Dembo, V.V. Klechkovskaya, Poly(acrylamide) gels with embedded
magnetite nanoparticles, Microelectron Eng. 69 (2003) 324–329.
[53] M.K. Sewell, K.D. Fugit, I. Ankareddi, C. Zhang, M.L. Hampel, D-H Kim, Magnetothermally-triggered drug delivery using hydrogels with
imbedded cobalt ferrite, iron platinum or manganese ferrite nanoparticles, PMSE Prepr. 98 (2008) 694–695.
[54] A. Senyei, K. Widder, C. Czerlinski, Magnetic guidance of drug carrying microspheres, J. Appl. Phys. 49 (1978) 3578–3583.
[55] S.E. Bowles, W. Wu, T. Kowalewski, M.C. Schalnat, R.J. Davis, J.E. Pemberton, Magnetic assembly and pyrolysis of functional
ferromagnetic colloids into one-dimensional carbon nanostructures, J. Am. Chem. Soc. 129 (2007) 8694–8695.
[56] E.S. Gil, S.M. Hudson, Stimuli-responsive polymers and their bioconjugates, Prog. Polym. Sci. 29 (2004) 1173-1222.
[57] J. You, D. Almeda, G.J.C. Ye, D.T. Auguste, Bioresponsive matrices in drug delivery, J. Biol. Eng. 4 (2010) 1-12.
[58] M.R. Aguilar, C. Elvira, A. Gallardo, B. Vázquez. J.S. Román, Smart polymers and their applications as biomaterials, in: N. Ashammakhi,
R. Reis, E. Chiellini (Eds.), Topics in Tissue Engineering, University of Oulu, Finland, 2007, pp. 1-27 .
[59] M. Oak, R. Mandke, J. Singh, Smart polymers for peptide and protein parenteral sustained delivery, Drug Discovery Today: Technologies. 9
(2012) 131-140.
[60] K. Sumaru, M. Kameda, T. Kanamori, T. Shinbo, Chracteristic phase transition of aqueous solutions of poly(N-isopropylacrylamide)
functionalized with sphirobenzopyran, Macromolecules. 37 (2004) 4949–4955.
[61] Y.-Y. Yu, F. Tian, C. Wei, C.C. Wang, )DFLOH V\QWKHVLV RI WULSOHဨVWLPXOL SKRWRS+WKHUPR UHVSRQVLYH FRSRO\PHUV RI ဨGLD]Rဨ
ဨQDSKWKRTXLQRQHဨPHGLDWHG SRO\ 1ဨLVRSURS\ODFU\ODPLGHဨFRဨ1ဨK\GUR[\PHWK\ODFU\ODPLGH, J. Polym. Sci. Part A: Polym. Chem. 47 (2009)
2763–2773.
[62] S. Guragain, B.P. Bastakoti, V. Malgras, K.Nakashima, Y. Yamauchi, Multi-stimuli-responsive polymeric materials, Chem. Eur. J. 21
(2015) 13164 – 13174.
[63] Z. Feng, L. Lin, Z. Yan, Y. Yu, Dual responsive block copolymer micelles functionalized by NIPAM and azobenzene, Macromol. Rapid
Commun. 31 (2010) 640-644.
[64] N. A. Peppas, K. B. Keys, M. TorresLugo, A. M. Lowman, Poly(ethylene glycol)-containing hydrogels in drug delivery, J. Controlled
Release. 62 (1999) 81–87.
[65] C.L.H. Alarco´n, S. Pennadam, C. Alexander, Stimuli responsive polymers for biomedical applications, Chem. Soc. Rev. 34 (2005) 276–
285.
[66] B. Dhandayuthapani, Y. Yoshida, T. Maekawa, D. S. Kumar, Polymeric scaffolds in tissue engineering application: A Review, International
Journal of Polymer Science. 2011 (2011) 1-19.
[67] D. Cunliffe, C.D. Alarcon, V. Peters,; J.R. Smith, C. Alexander, Thermoresponsive surface-grafted poly(N-isopropylacrylamide)
copolymers: Effect of phase transitions on protein and bacterial attachment, Langmuir. 19 (2003) 2888-2899.
[68] Y. Kumashiro, M. Yamato, T. Okano, Cell attachment-detachment control on temperature-responsive thin surfaces for novel tissue
engineering, Ann. Biomed. Eng. 38 (2010) 1977-1988.
[69] M.A. Ward, T.K. Georgiou, Thermoresponsive terpolymers based on methacrylate monomers: Effect of architecture and composition, J.
Polym. Sci. Part A. 48 (2010) 775-783.
[70] J. Leng, H. Lu, Y. Liu, W.M. Huang, S. Du, Shape-memory polymers—A Class of novel smart materials, MRS Bulletin. 34 (2009) 848-855.
[71] A. Lendlein, R. Langer, Biodegradable, Elastic shape-memory polymers for potential biomedical applications, Science. 296 (2002) 1673-
1676.
 Nandini A. Pattanashetti et al. / Procedia Manufacturing 12 (2017) 263 – 279 279

[72] S. Di, X. Liu, D. Liu, T. Gong, L. Lu , S. Zhou, A multifunctional porous scaffold with capacities of minimally invasive implantation, self-
fitting and drug delivery, Materials Today Chemistry. 1-2 (2016) 52-62.