ISSN: 0970-020 X

ORIENTAL JOURNAL OF CHEMISTRY CODEN: OJCHEG

An International Open Free Access, Peer Reviewed Research Journal
2013, Vol. 29, No. (3):
Pg. 861-870
Est. 1984
www.orientjchem.org

Hydrogels: Smart Materials for Drug Delivery

ARTI VASHIST and SHARIF AHMAD*

Department of Chemistry, Jamia Millia Islamia, New Delhi - 110 025 India.
*Corresponding author E-mail: [email protected]

DOI: http://dx.doi.org/10.13005/ojc/290303

(Received: July 12, 2013; Accepted: August 04, 2013)

ABSTRACT

The limitations associated with the conventional therapeutics have intended the use of
controlled drug delivery systems. In recent years, the hydrogel technology has been an integral
part of human health care. The pharmaceutical industry has been developing hydrogel based drug
delivery system in an advanced manner by tuning the structure, shape and surface modifications
of the biopolymers. The present review highlights the role of hydrogels in drug delivery. It also
highlights the use of important polymers and their applications in drug delivery. In addition, the use
of nanocomposite hydrogels with reference to the inorganic and magnetic nanoparticles is also
discussed.

Key words: Hydrogels, Drug delivery, Biomaterials, Starch, Nanocomposite.

INTRODUCTION a highly water swollen, soft and elastic gel. This led
to the keen interest in hydrogels as a class of
The term hydrogels was originally biomaterials and their application as drug delivery
introduced by Wichterle and Lim in 1960s and its systems. The natural and synthetic polymer in
biological application was put forward.1 Since then, demand for the synthesis of DDS is tabulated below.
hydrogel technology has evolved at a huge scale The emphasis in this review is to highlight the few
in pharmaceutical industry. The term hydrogel is special biopolymers like hydroxyethylcellulose
self explanatory for their existence, since the (HEC), Poly (lactic –glycolic acid) (PLGA), starch,
evolution of life on earth. The structure of plants, the NIPAAm (N-isopropylacrylamide). Hydrogels are
components of extracellular matrix, the bio-films of defined as a three dimensional biopolymeric
microorganisms are everywhere, all the swollen networks, which have the tendency to absorb large
moieties in nature are the proofs of their occurrence. quantity of water and they themselves are not
The first paper sighted was by DuPont scientist in soluble in water. A three dimensional network
1936 for medical applications, which introduced formation occurs by the cross linking of the
the spark that was enlightened in 1960 by Wichlerte polymeric chains. This cross linking can occur via
and Lim who worked on poly (2- physical interactions, covalent bonding, hydrogen
hydroxyethylmethacrylate) poly(HEMA). 1 It bonding and by van der walls interactions.2 The
highlighted the properties of this brittle polymer as chemistry behind the interpenetrating hydrogel
862 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013)

networks (IPN) can be best understood in terms of ´ Hydrogen bonded or complexation

the presence of the specific functional groups viz., - structures (the three dimensional network
OH, -CONH2, -SO3H, -CONH,-COOR which have a formed due to Hydrogen bond)10
hydrophilic tendency and thus absorb water and
biological fluids. The soft and rubbery surface, Emergence of hydrogels as drug delivery system
structure and physico-chemical properties of The word smart polymers originated from
hydrogels mimic to that of human tissue. These the ability of hydrogels to imitate the non-linear
characteristic features make them potential response of DNA and Proteins. 11 Above all the
candidate for drug delivery systems. Recently, characteristic features of hydrogels, their behaviour
biopolymers have emerged as a smart candidate to adapt structural changes in response to various
for the synthesis of hydrogels for drug delivery. physical or chemical trigger (Figure 3) and make
them intelligent candidates for drug delivery system.
Classification of hydrogels The current drug delivery systems are grievous,
The important parameters opted for the ineffective and meddlesome. The discovery of Micro/
classification of hydrogels is the structure of Nano Hydrogels provided perspicacious means of
hydrogels, route of synthesis, types of crosslink’s. sustained drug delivery systems that unfold the
The differences in the properties are the above obstacles. Furthermore, the drug release
consequences of the variation in any of the defined kinetics may be reconciled by modifying the shape,
characteristics. Firstly, on the basis of route of their size and drug distribution of the hydrogels during
synthesis can be classified as:3 assembling process. The smart hydrogels loaded
´ Homopolymer hydrogels (made up of only with cancer drugs resulted in sustained release of
one type of hydrophilic monomer) the drugs until they reach the target cancer cells.
´ Copolymer hydrogels or network gels These types of systems provide great potential for a
(composed of two types of monomers) safe and effective vehicle for the future drugs with
´ Mutipolymer hydrogels (made up of three improved mechanisms.12 The hydrogels from natural
types of monomers or inter penetrating resources have become an integral part of human
polymeric network) health care system.13

Secondly the other mode of classification Biodegradable and pH responsive hydrogels

is on the basis of type of ionic charges present on The advancement in the polymer science
polymer networks: has led to the development of effective and smart
´ Anionic hydrogels (anionic biodegradable polymeric hydrogels that have the
thermoassociative carboxymethylpullulan ability to self regulate the drug delivery in response
hydrogels 4 to a specific stimulus. The degradability can be
´ Cationic hydrogels (new thermosensitive, broadly classified in two terms (i) the physical
cationic hydrogels of N-isopropylacrylamide damage also termed as erosion of the polymers,
(NIPAM) and (3-acrylamidopropyl) which is dependent on the dissolution and diffusion
trimethylammonium chloride (AAPTAC) 5 process, (ii) the chemical degradation. 14 The
´ Neutral hydrogels (miscible blends from biodegradability of the polymers can be modified
water-insoluble polymers like poly(2,4,4- by introducing various labile groups such as ester,
trimethylhexamethylene terephthalamide) 6 orthoester, anhydride, carbonate, amide, urea and
· Ampholytic hydrogels (acrylamide based urethane in their backbone.14 The most valuable
ampholytic hydrogels) 7 characteristics of hydrogel, which make them
suitable candidate to be used in drug delivery
Thirdly, on the basis of physical structures system is their ability to respond to external stimuli
hydrogels can be classified as: specifically to pH variation. The mechanism behind
´ Amorphous hydrogels (chains are randomly it can be understood in simple terms. As it is known
arranged)8 that the hydrogels are the swollen ionic network
´ Semi crystalline hydrogels (Dense regions containing either acid or basic pendant groups,
of ordered macromolecular arrangement)9 which can ionize and develop fixed charge on the
 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013) 863

polymer matrix. All the ionic materials possess a which is in solution form at room temperature and
pH and ionic strength sensitivity. The swelling force gets converted into a gel on instillation into the
actually dominates over the non-ionic materials, human body and give a suitable mode of
which are the aftermath of the localization of fixed administration and help in release of the drug. A
charges present on the pendant groups. The result triblock copolymer Polyethylene glycol-polylactic
is that the total mesh size of the network changes to acid, glycolic acid-polyethylene glycerol (PEG-
a large extent with a small variation of pH in the PLGA-PEG), properties of this copolymer can be
environment.15 Figure 1 demonstrates the swelling altered by varying the ratio of hydrophilic and
and deswelling behaviour of hydrogel networks hydrophobic segments, block length and
with the change in temperature and pH. pH polydispersity. Lee et al. 19 used this triblock as a
responsive nature of hydrogels is studied wound dressing and scaffold. It was observed that
extensively for drug delivery applications. The thermo sensitive hydrogel increased the
structure of the polymeric matrix plays an important engraftment of muscle derived stem cell (MDSCs)
role in deciding its pH responsive characteristics. by 20 to 30- fold unit till 20 days. The increased
The pendant acidic carboxylic and sulphonic acids engraftment resulted in enhanced wound healing,
or basic functional groups like ammonium salts acts which was shown by the wound closure rate,
as proton acceptor or donor with the change in pH. epithelium migration and collagen deposition. Thus
Figure 2 shows the structures of the polymers it was hypothesized that postnatal (MDSC) in the
,which are used in synthesizing the hydrogels for appropriate environment could regenerate tissue
drug delievery systems. in diabetic wound as well as this system is quite
biocompatible with diabetic skin wound and
Smart polymers used for hydrogel based drug prompted engraftment of stem cells. Similar efforts
delivery systems for the release behaviour for two moral drugs
Poly (lactic –glycolic acid) ketoprofen and spironolatone, was studied by
The anionic polymerization of this cyclic Jeong et al. 20 ,which have different hydrophobicities,
lactide monomer was performed in early 1960’s. from the PEG–PLGA–PEG triblockcopolymer
Kulkarni et al. 16 was the first to use this polymer in hydrogel formed in situ by injecting the solutions
medicine. The team found that there was no side into a 37°C aqueous environment. Ketoprofen (a
effect of the implantation of these polymers in model hydrophilic drug) was released over 2 weeks
guinea pigs and rats and there was a subsequent with a first-order release profile, while
degradation of the polymer hydrogel matrix. Thus spironolactone (a model hydrophobic drug) was
the copolymer of lactic and glycolic acid s widely released over 2 months with an S-shaped release
opted for the controlled release of the profile. The release profiles were simulated by
pharmaceuticals excepients. Langer and Vacant models considering degradation and diffusion, and
1993 were the pioneers who developed these were better described by a model gel. In an
polymers in the form of porous scaffolds in tissue evaluation the use of PLGA copolymers and it’s
engineering.17 This emerging copolymer, which is composite with carbon fibers or hydroxyapatite in
being exposed exclusively to be used in the the regeneration of bone tissue has been seen the
synthesis of various drug delivery systems (DDS), mechanical properties of the composite to have
owing to its biocompatibility and biodegradability great endurance-elasticity relationship in relation
has been approved by food and drug administration to their density. They provide fibrous three
(FDA) for use in biomedical applications. The dimensional bases and other applications like bone
important parameter for this copolymer is that it defect restoration in tissue engineering.21 Akdemir
shows a glass transition temperature in the range et al. 22 also prepared biocompatible and UV cured
of 40-60 ºC unlike to the homopolymers of lactic fumarated poly (ether-ester)-based tissue
acid (polylactide) and glycolic acid (polyglycolide), engineering hydrogels. The modification of the poly
which show poor solubility. Thus this makes it a (lactide-co-glycolide) (PLGA) copolymer was done
suitable candidate to be used in the synthesis of using stannous octoate as a catalyst. These
various thermo responsive hydrogels.18 Basically hydrogels were found to be biocompatible
thermo responsive hydrogels are a dispersion, confirmed by MTT cytotoxicity assay.
864 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013)

Hydroxyethylcellulose hydrogel formed showed a swelling profile of knitted

Hydroxyethyl cellulose is an important cotton fabricated with a thin surface layer of
derivative of cellulose, which finds application in modifying hydrogels was also investigated. In an
drug delivery. The highlighting properties of HEC important investigation by Hoemann et al . 24
such as, water solubility, non-ionic form , thickening prepared cytocompatible chitosan hydrogels
agent, and can form suspension and emulsion crosslinked by HEC-Glyoxal, which were employed
adhesion, film formation, and dispersion, water for cartilage repair applications. Cell viability and
retention, providing protection make this a suitable metabolic MTT assay were perfomed and
candidate to be used in synthesis of hydrogels used hypothesized that the trace glyoxal present in
for drug delivery. Of all these characteristics HEC commercially available HEC is responsible for
has water retention is twice of methyl cellulose and solidification of Chitosan-GP/HEC hydrogels and
hydroxypropyl cellulose, and the protection power these gels can be used as a cytocompatible
for collide is the strongest. This section addresses adhesive delivery vehicle for articular cartilage
the new progress in hydroxyethyl cellulose based repair applications. Thus it is seen that HEC can be
hydrogels fabrication. The glucose repeat unit is used for in situ delivery of cells and other factors for
replaced with hydroxyethyl ether. These are the a therapeutic effects. The effect of incorporation of
favourable groups that do not allow the polymer to nanofillers in HEC matrix was studied by Dai et al.
25
crystallize and when this is added in solution it studied the effect of nanofillers like oxidized
becomes soluble. Firstly, the nanocomposite cellulose nanocrystals and montmorillonite
hydrogels prepared by using HEC in conjugation nanoclay on CMC/HEC hydrogels system. Efforts
with other polymers through physical or chemical have been made to develop hydrogel membranes
blending and the formation of temperature using HEC for wounds. Researchers are working
responsive hydrogels based on it and its derivatives on the development of membranes, which is
and their application is discussed. Gorgieva et al. 23 transparent and the wounds can be visualized
synthesized a unique hydrogel with dual responsive during the course of dressings without disrupting
absorption properties using HEC and the healing process. This invention developed
carboxymethyl cellulose in an aqueous solution and hydrogels that can be made from fabrics made from
using citric acid (CA) as a cross-linker. The resulted woven or non woven gel forming fibers. These

Fig. 1: Swelling and deswelling behaviour of interpenetrating

hydrogel network with the variation in temperature and pH
 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013) 865

reinforcing materials results into transparent or reports the use of nimesulide topical gels using
translucent on adsorption of exudates, which makes this natural bioadhesive polymer HEC and it was
easy for the visualization of the wound. The sheet is found that effect of polymer on bioadhesive strength
made up of hydrogel polymer. The removal of the was extremely significant. The drug studied in the
dressing is exempted by this invention. In particular, present work is a second generation non-steroidal
derivatives of cellulose, which are gel forming fibres anti-inflammatory drug used for long term therapy
with absorbency of between 10g/g of sodium / of rheumatoid arthritis, in alleviating pain and
calcium chloride, are used. Formulations of many inflammation. The half life of 3 to 4 h requires multiple
vaginal microbicides constitute HEC as an inactive dosing for the maintenance of the therapeutic effect
ingredient. These microbicides are designed to in a day, which results in more fluctuation. Thus this
prevent the transmission of sexually transmitted gel prevents these side effects in a day, which
diseases, including HIV. This polymer has been results in more fluctuation. Thus this provides
studied for use as a placebo gel in clinical trials of advantage of delivering the drug into site of action.
HIV microbicides. Its use as a universal placebo for The reduction in the cost of the therapy and patient
HIV microbicide trials has been adopted and the compliance are the valuable benefits of this mode
safety of this product is being evaluated.26 A study of drug delivery.

Fig. 2: Polymers used for the synthesis of interpenetrating

hydrogel network used for drug delivery systems
866 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013)

Fig. 3: Physical (a) and chemical (b) strategies for enhancing the interactions between
a loaded drug and a polymeric gel to slow drug release. “Reprinted from reference 1,
Copyright (2008), with permission from Elsevier

Starch and chemical interactions. The inclusion of

Starch is high value natural polymeric nanoparticles in the hydrogel matrix add on to the
material extracted from seeds, tubers or roots and unique physico-chemical characteristic properties
is a chain of glucose molecules by glycocidic to hydrogels like mechanical, optical, thermal,
linkages. The two forms are amylase (linear) and barrier, sound, electric simulations etc. 29
other is amylopectins (branched). Hydrogels based
on starch as base or modifying material represent a Nanocomposite based on inorganic and magnetic
great choice in tissue engineering, drug delivery, nanoparticles
and other biomedical applications. Recently, Lima The property of aggregation is shown by
et al.27 developed a stimuli responsive injectable nanoparticles, which are neither charged nor
hydrogels of chitosan – starch. The research group stabilized. Exfoliation in water may occur for
encapsulated the chitosan –starch based gels charged nanoparticles such as silicates due to the
derived stromal cells for the regeneration of articular colloidal interactions that stabilize the gel formed.
cartilage. The incorporation of the starch gave a firm For the formation of stabilized hydrogel
textured gels and thus providing the desirable nanocomposite the dispersion of these nanopaticles
mechanical strength. The degradation profile of the should be uniform and the formation of large scales
gels was also improved. The influence of the structure need to be controlled. Thus, the addition
inclusion of starch in the chondrogenesis of of silicates to poly (ethylene oxide) and poly (acryl
encapsulated adipose stromal (ADSC) cells was amide) matrices function as cross-linking agents
studied. Thus it was found that these chitosan ²- and to improve network strength. Researchers found
glycerophosphate-starch hydrogels can be used for that hydrogen bonding, ionic, dipole, and other
chondrogenic differentiation of ADSC for cartilage interactions such as polymer entanglements must
regeneration. Starch hydrogels have found their use play a role in typical cross linking.
in wound dressing. Pal et al. 28 attempted to prepare
transparent starch based hydrogel membranes by A large body of literature and some recent
cross linking of polyvinylalcohol with heat treated reviews covers the synthesis, characterization, and
corn starch suspension. The diffusion coefficient of applications of polymer nanocomposite hydrogels
a fourth generation fluoroquinolone-gatifloxacin containing inorganic and magnetic nanoparticles.30,
31
was determined to be 3.24 × 10 6 cm2/s techniques Takahashi et al. 32 has shown that a modified PEO–
with biocompatibility towards L929 fibroblast cell. Laponite system can be developed into a drug
delivery system at physiological conditions. A
Nanocomposite hydrogels broader variety of applications is mentioned for
Nanocomposite hydrogel are defined as colloidal dispersions (attractive gels) made from
cross linked three dimensional water swollen nanoparticulate bentonites (natural layered silicate)
networks in the presence of nanoparticles. The and PEO polymer. Inclusion of metal nanoparticles
formation of the network occurs by both physical (i.e., Ag, Au) dispersed within polymer hydrogels
 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013) 867

can improve electrical conductance and anti- properties of PVA was studied.38 The nanocomposite
microbial properties 33, 34. Nanoparticles can also formed from the inclusion of kaolinite in PVA matrix
function as cross-linking (physical and chemical) resulted in a composite of high tensile strength and
agents. Polymer–magnetic nanocomposites, with tensile modulus. The DMTA test was performed in
particles in the polymer matrix (dispersed within the compression mode, using disc-shaped samples
and/or cross linking polymer chains), can be used with a diameter of 11 mm and a thickness of 5 mm.
for the remote release of drugs.35, 36 Negatively The storage modulus of PVA hydrogel increases
charged silica nanoparticles are immobilized within by increasing the kaolinite content. The storage
a PAM matrix. An applied electric field causes modulus of nanocomposite hydrogel containing 15
electro-osmotic flow of silica particles, and viscous wt.% of kaolinite in the regions below and above
drag within the fluid results in the mass transport of 0ºC were on average 210 and 140 % higher than
neutral solutes (drugs, proteins, etc.) smaller than of pure PVA hydrogel, respectively. The results also
the gel pore size. 29 F Templated block-copolymer showed that the hardness is directly depended to
gel with nanoparticles residing in the interstitial the quantity of kaolinite added to the nanocomposite
space between neighbouring micelles.37 Recently, hydrogel. 38 Nanocomposite hydrogels for
the significance of kaolinite on the mechanical biomedical applications have been studied. A

Fig. 4: Transparent PEG–silicate nanocomposite hydrogels. (a) A precursor solution was prepared
by mixing silicate nanoparticles (x = 0%, 1%, 2.5%, and 5%) and PEG– diacrylate (15% or 20%) in
solutions containing 0.2% initiator and 0.5% pyrophosphate. A covalently cross-linked PEG
network is formed upon exposure to UV irradiation. Interactions between silicate and PEG lead to
formation of a physically cross-linked network within the same hydrogel. (b) Injectability of the
precursor solutions was determined by ûow experiments (measuring viscosity as a function of
shear rate). Neat polymer solutions show Newtonian behavior and nanocomposite solutions show
thixotropic behavior. Due to low viscosities over the wide range of shear rates, the solutions can
be easily injected using a syringe. (c) Photo-cross-linked nanocomposite hydrogels showing high
toughness and resistance to fracture when compressed with a sharp blade. Cross-
linked hydrogels are highly transparent and hydrate quickly in physiological conditions. (d)
Images display elasticity of nanocomposite hydrogels containing 20% PEG and 5% LRD. A thin
hydrogel strip can be easily stretched to five times its initial length without visible and permanent
deformation. (e) All the hydrogels readily saturate in PBS within 4–6 h. The saturated hydration
degree (compared to as- prepared hydrogels) directly depends on the composition of the
nanocomposites. “Reprinted from Reference 2 Copyright (2011), with permission from Elsevier.
868 VASHIST & AHMAD, Orient. J. Chem., Vol. 29(3), 861-870 (2013)

research group prepared poly(hydroxyethyl applications. The effects of monodisperse

acrylate), PHEA/silica nanocomposites by sol-gel polystyrene nanoparticle fillers on the network
techniques as potential scaffold materials for tissue formation, rheological properties and adhesion
engineering.39 performance of hydrogel nanocomposites based
on polyacrylamide and poly(acrylamide-
In an interesting study carried out by hydroxyethyl methacrylate) is investigated.42
Gaharwar et al.40 hydrogels composed of PEG and
silicate nanoparticles (Laponite RD) were Organ clay is an organically tailored
investigated. This study demonstrated the potential phyllosilicate, derived from a naturally occurring clay
of silicate –PEG nanocomposite hydrogels in mineral. The incorporation of these organo-clays in
orthopaedic, craniofacial sand dental applications. Polydimethyl siloxane (PDMS) results in formation
Figure. 4 (a-b) showed viscosity measurements as of pressure sensitive adhesives. Shaikh et al. 43
a function of shear rates. The results showed the obtained the partially exfoliated nanocomposites
potential of the synthesized nanocomposite to retain of PDMS. It was shown that by varying the
the shape of the mold containing them (Fig. 4) and concentration of the organoisilicate additive to the
were capable to sustain the extreme mechanical polymer matrix, a major control over the drug
deformation. Moreover, the amount of silicate release kinetics and the adhesive properties of the
nanoparticles affected the swelling characteristics matrix can be enhanced. Now days the emphasis is
of the nanocomposites. to develop transdermal formulations, which are
based on natural polymer matrix and for better
Several other aspects of polymer release technologies in, which the dispersion of the
nanocomposites are currently being intensively drug is uniform within the transdermal layer.44, 45
investigated, such as the effects of nanofiller on
chain dynamics, and the dependence of the final Future prospectives and conclusion
properties on the degree and mode of dispersion The innovation behind the successful
Novel hydrogels have been prepared using direct application of hydrogel based drug delievery system
dissolution of chitin at low temperature. The is the development of new polymeric materials and
dissolution problem is common for chitin in various advancement in nanotechnology. The key to improve
solvents. Clear transparent solution in a mixture of the hydrogel technology is to direct the research on
8wt%NaOH/ 4wt% urea aqueous solution by freeze the design of efficient drug delievery systems with
/thawing method to prepare transparent.41 minimal limitations and easy route of
administrations. The use of biodegradable synthetic
Furthermore, the results of a 293T cell polymers have shown prominent results in drug
viability assay on this system indicated their delievery. Self assembled hydrogel and hydrogels
excellent biocompatibility and safety. Thus resulted for tumor targeting and imaging are to be explored
chitin hydrogels showed more stable structure and at a greater pace. The valuable addition of an
better biocompatibility. The chitin hydrogels may efficient drug delievery systems in comparision to
find wide use in bio-applications, as a result of the the development of newly found drug can benefit
more stable structure and better compatibility of both ecnomically as well as drastically reduce the
chitin than that of its derivatives, such as chitosan.41 duration of time taken to develop a new drug in the
Hydrogel nanocomposites are also being studied pharmaceutical world.
as pressure-sensitive adhesives for skin contact

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