Advanced Drug Delivery Reviews 107 (2016) 192–205

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Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Poly(lactic acid) based hydrogels☆

Arijit Basu a,⁎, Konda Reddy Kunduru a, Sindhu Doppalapudi b, Abraham J. Domb a,⁎, Wahid Khan b
a
School of Pharmacy-Faculty of Medicine, The Hebrew University of Jerusalem, and Jerusalem College of Engineering (JCE), Jerusalem 91120, Israel
b
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India

a r t i c l e i n f o a b s t r a c t

Article history: Polylactide (PLA) and its copolymers are hydrophobic polyesters used for biomedical applications. Hydrogel me-
Received 5 May 2016 dicinal implants have been used as drug delivery vehicles and scaffolds for tissue engineering, tissue augmenta-
Received in revised form 28 June 2016 tion and more. Since lactides are non-functional, they are copolymerized with hydrophilic monomers or
Accepted 8 July 2016
conjugated to a hydrophilic moiety to form hydrogels. Copolymers of lactic and glycolic acids with poly(ethylene
Available online 16 July 2016
glycol) (PEG) provide thermo-responsive hydrogels. Physical crosslinking mechanisms of PEG–PLA or PLA-
Keywords:
polysaccharides include: lactic acid segment hydrophobic interactions, stereocomplexation of D and L-lactic
PLA acid segments, ionic interactions, and chemical bond formation by radical or photo crosslinking. These hydrogels
PLA–PEG may also be tailored as stimulus responsive (pH, photo, or redox). PLA and its copolymers have also been poly-
Hydrogel merized to include urethane bonds to fabricate shape memory hydrogels. This review focuses on the synthesis,
Thermo-responsive characterization, and applications of PLA containing hydrogels.
In situ hydrogel © 2016 Elsevier B.V. All rights reserved.
Responsive polymer

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
192
2. PLA–PEG hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2.1. PLA–PEG hydrogels through hydrophobic entanglement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2.2. Stereocomplex driven PLA–PEG hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2.3. Hydrogels from armed-PEG–PLA copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
2.4. Dual responsive and miscellaneous PLA–PEG hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
3. PLGA–PEG hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
4. PCLA–PEG hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
5. PLA–polyurethane hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
6. PLA–polysaccharide hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
7. POSS-lactide hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
8. PLA-based organogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
9. PLA-peptide hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
10. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Abbreviations: PLA, poly(lactic acid); PDLA, poly(D-lactic acid); PLLA, poly(L-lactic acid); PLGA, poly(lactide-co-glycolide) or poly(D,L-lactide-co-glycolide); PEG, poly(eth-
ylene glycol); DCC, dicyclohexylcarbodiimide; PEOz, poly (2-ethyl-2-oxazoline); EPR, enhanced permeability and retention; Tgf-β1, transforming growth factor beta 1; PCLA,
poly(ε-caprolactone-co-lactide); RGD, arginine–glycine–aspartate; PCL, polycaprolactone; PUs, polyurethanes; PLAUs, PLA based PUs; PEO, poly(ethylene oxide); PDLLA,
poly(DL-lactic acid); PEGMA, PEG-methacrylate; HPMC, hydroxypropyl methylcellulose; POSS, polyhedral oligomeric silsesquioxane; PTMC, poly(trimethylene carbonate);
KRGDKK, Lys-Arg-Gly-Asp-Lys-Lys.
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “PLA biodegradable polymers”.
⁎ Corresponding authors.
E-mail addresses: [email protected] (A. Basu), [email protected] (A.J. Domb).

http://dx.doi.org/10.1016/j.addr.2016.07.004
0169-409X/© 2016 Elsevier B.V. All rights reserved.
 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205 193

1. Introduction 2. PLA–PEG hydrogels

Hydrogels are hydrophilic, chemically or physically crosslinked 2.1. PLA–PEG hydrogels through hydrophobic entanglement
polymeric networks that absorb water. They may be designed to
degrade and eventually be eliminated. The physical and mechanical Polyethylene glycol (PEG) is a widely used hydrophilic polymer for
properties of hydrogels may be tailor-made by using combinations of preparing PLA-based hydrogels. PEGs are biocompatible, elicit tempera-
cross-linkers and copolymers. Crosslinking may be reversible by ture responsiveness, and are non-ionic yet water soluble [48]. The first
molecular entanglements, ionic forces, hydrogen bonding, hydrophobic PLA–PEG hydrogel (PEG–PLLA–PEG) was prepared in 1997 by Jeong
interactions, or irreversible by chemical bonds [1,2]. Various hydrogels et al. [23]. In this report, the authors prepared PEG–PLLA–PEG, a
for biomedical research have been reviewed elsewhere [3–8]. thermo-gelling copolymer. The hydrogel obtained was used to release
In this review, we focus on hydrogels containing polylactides (PLA) fluorescein isothiocyanate labeled dextran as a model drug for bioactive
and its copolymers. Their physical properties are transformed when macromolecules. Since then many such thermo-responsive hydrogels
copolymerized with hydrophilic polymers like polyethylene glycol were prepared, keeping PEG as a hydrophilic segment and PLA or its
(PEG). The biphasic copolymer forms micelles that are tunable by co-polymers as hydrophobic segments.
changing the molecular weight of both PLA and PEG [9,10]. Synthesis PEG–PLA–PEG was also synthesized by reacting mono hydroxylated
of tri- and multi-block copolymers of PEG and PLA opens the door for PEG–PLA di-blocks with adipoyl chloride in the presence of
PLA as a material for hydrogel synthesis [11]. Their incorporation with dimethylaminopyridine as a catalyst. The aqueous solution of the
hydrophilic polymers like PEG and polysaccharides elicits a series of synthesized polymers showed gel to solution transition as temperature
special properties. The copolymer ratio may be tuned for stimulus increased [49]. Multiblock copolymers were prepared from succinic acid
responsive hydrogels with numerous possibilities. terminated PLLA and PEG using dicyclohexylcarbodiimide (DCC)
The most attractive feature of some PEG–PLA hydrogels is their mediated esterification. Different copolymers were prepared, varying
thermo-responsive nature. The copolymer solution remains soluble at the molecular weights of PLLA and PEG. The formation of thermo-gels
room temperature and gels at body temperature ~ 37 °C (Fig. 1). PLA– is dependent on the molecular weight of both the PEG and PLA
PEG based thermo-responsive polymers started as PLA based thermo- segments [50].
responsive gels [12], synthesized as PLA–PEG-polyurethane copolymers Recently, the effect of chain length on thermo-gelling behavior of
that remained soluble at 45 °C and gelled when cooled to 37 °C — in PEG-poly(L-lactic acid) (PLLA) diblock copolymers has been studied in
essence, a gel injection rather than a solution to gel transition. detail. The current authors have observed that longer PLLA segments
Later, Jeong and coworkers synthesized the copolymer system that show thermo-gelling effects at lower polymer concentration. Converse-
resulted in a copolymer that is soluble in water at room temperature ly, a higher concentration of polymer is needed as the PEG block length
and gels at body temperature. In a series of studies, they demonstrated increases [51]. Other factors such as the molecular weight and block
that PEG–PLGA–PEG triblock copolymers form a free-flowing solution at segment lengths also have to be considered for designing
room temperature and become a gel at body temperature. Upon thermo-gelling polymers. Further, both triblock (PEG–PLA–PEG or
implantation the copolymer aggregates to form an in situ implant that PLA–PEG–PLA) copolymers exhibit thermo-liquefying transitions. In
remains for a month [13]. This unique property of a PLA based system 2001 Mason et al., build models to predict the controlled release behav-
led to exploration of other ampiphilic systems like PLA-polysaccharides. ior from such systems. They synthesized acrylate terminated triblock
Stereoregular D and L-PLA, have been used as crosslinking moieties copolymers (PLA–PEG–PLA) as the hydrogel model system. The Authors
by forming stereocomplexes (Fig. 1) [14]. This stereocomplexation has demonstrated the release of high molecular weight proteins from PLA–
also been used as a driving force for making in situ forming hydrogels. PEG–PLA hydrogels [52]. They described building a predictive model for
Jong et al., first demonstrated using stereocomplexation to form a release kinetics of protein drugs. The study provided a statistical model
crosslinked network. Grafted dextran with D and L lactide forms for future use by other scientists who attempts to use PLA–PEG–PLA
hydrogel in solutions [15]. This concept has been applied to form (acrylate terminated) hydrogels for macromolecular delivery.
stereocomplex driven hydrogels [16–21]. Recently, Ding and coworkers investigated the effect of molecular
In the following sections, hydrogels based on PLA polymers are weight distribution of PEG chains on thermo-gelling behavior [53,54].
discussed. Table 1 summarizes different PLA-based hydrogel systems The authors proposed a thermodynamic explanation for the phenome-
together with their biomedical applications. na as follows. Water and PEG interact through a network of hydrogen

Fig. 1. Chain exchange mechanism of triblock copolymer micelles, (a) single enantiomeric micelles, (b) equimolar mixture of both enantiomeric micelles. Micelles containing either PLLA
or PDLA cores are designated as blue or yellow, respectively. However, micelles containing both PLLA and PDLA within a single core are designated by the color green to emphasize the co-
crystallization and formation of a new stereocomplexed crystal. These systems undergo sol–gel transformation at 37 °C. This thermoresponsive gelling may form due to hydrophobic
interactions (above) or stereocomplex driven (below). These two remain the most widely used in situ gelling procedures, but chemical, photo, ionic cross linking methods have also
been applied. Reproduced from Ref. [22], with permission.
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Table 1
Polylactide based hydrogels and their applications.

Category Polymer Hydrogel formation Delivery/application References

1. PLA–PEG hydrogels PEG–PLLA–PEG Thermosensitive FITC-labeled dextran [23]

PLLA–PEG–PLLA and PDLA–PEG–PDLA Thymopentin [24]
stereocomplex
PLA stereocomplex silica coated pH/thermoresponsive Doxorubicin [25]
magnetite
2. PLGA–PEG hydrogels PEG–PLGA–PEG Thermosensitive Ketoprofen and spironolactone [26]
Delivery of plasmid DNA [27]
Delivery of plasmid TGF-β1 [28]
Delivery of FITC [29]
PLGA–PEG–PLGA Thermosensitive Insulin [30]
GLP-1 [31]
Testosterone [32]
Indomethacin, 5-flurouracil [33]
Ganciclovir [34]
Levonorgestrel, [35]
Interleukin-2 [36]
Paclitaxel [37]
Cisplatin, Doxorubicin, Methotrexate [38]
3. PLA–polyurethane hydrogels Poly(β-aminoester urethane)– pH/Thermoresponsive Human growth hormone [39]
PCLA–PEG–PCLA
4. PCLA–PEG hydrogels OSM–PCLA–PEG–PCLA–OSM pH/Thermosensitive Paclitaxel [40]
5. PLA–polysaccharide hydrogels PLA-dextran Lysozyme and IgG [41]
Pullulan-g-PLA Thermosensitive Doxorubicin [42]
Chitosan-g-PLGA Thermosensitive Vancomycin hydrochloride, Betamethasone [43]
sodium phosphate
PLA-hyaluronic acid Vascular endothelial growth factor [44]
β-CD PLLA-benzimadazole modified PEG pH sensitive Doxorubicin [45]
Dextrin-g-PLA Ciprofloxacin, Ornidazole [46]
6. PLA–peptide hydrogels Peptide–PCLA–PEG–PCLA–peptide Thermosensitive Paclitaxel [47]

bonding. The local ordering of water molecules surrounding a PEG chain gel storage modulus [60]. The hydrogels have been used to deliver re-
leads to a significant entropy loss of water. Such an entropy effect in- combinant human IL-2 protein [62].
creases at higher temperatures, leading to increased hydrophobicity of Mao et al., recently reported on stereocomplex driven hydrogels
PEG (shrinkage or aggregation in water) upon heating. At high temper- made from diblock and triblock copolymers of PLA (D and L configura-
ature the micelles start to aggregate upon heating, and an entropic effect tions) and PEG. The gelation is quick (~10 s) and mixing of these diblock
leads to enhanced hydrophobic interaction of PLA (or polylactide-co- ‘star’ and triblock ‘flower’ micelles with opposite PLA configuration ex-
glycolide) portions. This leads to physical gelation and loss of solubility. change chains to form cross linking network. However, as described
They provided a mechanistic overview on the gelation mechanism of with other PLA–PEG block copolymers the gelation is influenced by
PEG–PLA based hydrogel systems. Fig. 1 illustrates the phenomenon of PEG block length, especially in triblock copolymers for this di/tri block
hydrogel formation through hydrophobic entanglement. enantiomeric mixture. If PEG block in the triblock copolymer is smaller
than the distances between micellar cores, the PLA of triblock copoly-
2.2. Stereocomplex driven PLA–PEG hydrogels mer will enter into the same micelle and forms a stereocomplexed solu-
tion rather than a gel. When the PEG length is relatively larger, the
Stereocomplexation has also been used to synthesize crosslinked triblock copolymer PLA's can enter the cores of the micelle and triblock
hydrogels [55]. PLLA–PEG–PLLA and PDLA–PEG–PDLA forms gel in the copolymer acts as connective bridge between diblock ‘star’ micelles. If
presence of water at body temperature (37 °C) [27,56]. Triblock PEG– PEG block length is too large, the PEG bridging chains between micelles
PLLA–PEG and PEG–PDLA–PEG also form a gel due to helical transition will be too long and forms loosely crosslinked gels. These gels may have
of PEG chains [57]. The mechanical properties of these hydrogels were low critical gelation temperatures. (Fig. 1) [63].
later improved by varying the molecular weights of the lactide [58]. PEG–PLA hydrogels were also prepared by dual mode —
Triblock PLLA–PEG–PLLA and PDLA–PEG–PDLA form sol-to-gel transi- stereocomplexation followed by photo crosslinking where hydrogel for-
tion at body temperature, but they have weaker storage modulus mation was quick. Methacrylate (MA) functionalized copolymers were
(~1000 Pa), which is insufficient to be used as an injectable implant bio- synthesized (PEG–PLA–MA and PLA–PEG–MA). The acrylate crosslinking
material. Abebe et al., reported similar stereo block copolymers with dif- shows longer degradation and improves the gel strength. [64]. Fan et al.,
ferent sizes of PEG blocks. The size of PEG block showed influence on recently reported similar dual mode crosslinking via radical polymeriza-
both thermo-responsiveness and mechanical properties of the hydro- tion of stereocomplexed acrylate–PEG–PLLA and acrylate–PEG–PDLA
gel. The stereomixture of these triblock co-micelles showed sol-to-gel with acrylate–PEG. Stereocomplexation made from PLLA–PDLA co-
transition at a wide range of temperatures with varying copolymer ra- network is stronger compared to a non-stereocomplex system. It was ob-
tios and also exhibited very high storage modulus (~6000 Pa). served that both storage and loss moduli of this co-network increased
Star block copolymers PEG–(PLLA)8 and tri block copolymers of with the increasing amount of PLA stereocomplex in the crosslinked
PDLA–PEG–PDLA were also demonstrated to form hydrogels through co-network, which is due to increase of physical cross-linking. The elas-
stereocomplexation [59,60]. The 8-armed star triblock copolymers of tic modulus of co-networks increased from 1200 Pa to 4200 Pa by in-
PEG–PLLA–PEG form an irreversible hydrogel that has very high storage creasing the stereocomplex concentration from 2% to 10%. The
modulus of 9.8 kPa at body temperature. These properties enable these swelling capacity of the hydrogels was decreased with the increasing
polymers to be used in drug delivery and tissue engineering [61]. amount of PLA. This is due to increased crosslinking with the increasing
Thermosensitive hydrogels of PEG–PLLA and PEG–PDLA di-block co- amount of PLA stereocomplex in the co-networks (Fig. 2) [65].
polymers have also been reported. Compared to triblock copolymers, Injectable tissue engineering scaffolds are attractive biomaterials.
their gelation is faster, lower critical gelation concentration, and higher Stereocomplex driven hydrogels are ideal for this application due to
 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205 195

Fig. 2. Synthesis of co-networks and gels via stereocomplexation of PLA. Reproduced from Ref. [65], with permission.

their enhanced mechanical strength [66,67]. Electroactive scaffolds are temperature. The micelles are surface grafted with folic acid for
widely studied for cardiac tissue engineering and developing artificial targeting the tumor cells. The nanoparticles reach the tumor environ-
muscles. Cui et al., reported one such carboxyl-capped tetraniline linked ment through an enhanced permeability and retention (EPR) effect.
to PLA–PEG–PLA electro active hydrogels [17]. The terminated aniline These surface grafted nanoparticles are recognized by the folate recep-
oligomers have different oxidation states and responsive to voltage tors on the cell membrane. Thereafter they were internalized, once in-
stimulation. Further the nonbonding interactions (π–π stacking side the cells they experience a pH change from neutral to as low as
between the aniline oligomers), and hydrogen bonding between the 5.5–6.5 in endosomes and 4.5–5.0 in lysosomes. The drug (doxorubicin
two stereoregular lactides enhanced their electroactive and mechanical in this case) is released as the chain of PEOz ionizes at acidic pH, leading
properties. These hydrogels carrying the signaling molecule (electroactive to electrostatic repulsion between PEOz chains. As a result the PEOz
tetraaniline) showed accelerated tissue repairing ability and regeneration moieties swell and interfere with the micellar structures, finally
of the fibroblast cells with electrical stimuli. resulting in release of the drug near the tumor environment (Fig. 3)
[72].
2.3. Hydrogels from armed-PEG–PLA copolymers Buwalda et al., recently report PEG–PLA in situ, forming hydrogels
with a pendant carboxylic acid group. The carboxylic acid renders an
Star or armed PEG and PLA block copolymers have also been used to ionic crosslinking especially sensitive to divalent cations like Ca2 +
synthesize hydrogels. Their properties and gelation behavior are (Scheme 1) [73]. Shi et al., recently report thermosensitive gelation
different from the hydrogels made from linear block copolymers [68, using PDLA–PEG–PDLA triblock copolymers, unlike the most commonly
69]. Nagahama et al., report an 8-arm PEG–PLA–cholesterol copolymer used PLLA–PEG systems [20]. The in situ forming hydrogel is used as a
that gels at 34 °C in water, but the 8-armed PEG–PLA does not form post-operative adhesion barrier. The authors observed significant anti-
gel at the same temperature. This cholesterol substituted hydrogels adhesion property compared to commercially available hyaluronic
promotes cell proliferation, and might be used as tissue engineering acid hydrogel.
scaffolds [70]. Zeng et al., report a redox sensitive hydrogel based on PLA–PEG.
The aggregation behavior and dynamics of star PEG–PLA block These bio reducible polymers are promising drug carriers for tumor
copolymers were studied in water at different concentrations and therapy. They are stable in extracellular circulation and rapid drug
temperatures. NMR experiments (1H and 2H relaxation experiments) release in an intracellular reducing environment. They fabricate the
and dynamic light scattering measurements reveal self-aggregated hydrogel system using di-selenide crosslinking. The amphiphilic PLLA–
systems made of rigid hydrophobic PLA and highly flexible hydrophilic PEG di-selenide polymer has been used to deliver docetaxel. The
PEG domains. At low concentrations the PLA domains cannot entangle, authors observed that the hydrogels are responsive to glutathione.
giving rise to molecular micelles. At intermediate concentrations above Approximately 40% of docetaxel was burst-released in the reducing
the critical association concentration (but below the critical gel concen- environment of tumor [74].
tration), nanogels are formed by the interconnection of several PLA Shen and colleagues describe an in situ-forming hydrogel with a
domains. Above critical gel concentration, the network extends to the PEG–PLA-platinum (IV) conjugate. The conjugate was synthesized by
entire system, giving rise to macroscopic gels [71]. covalently linking of Pt(IV) complex with two methoxy poly(ethylene
Stereo complex driven star-block copolymer hydrogels have already glycol)-poly(D,L-lactide) (mPEG–PLA). It resulted in the formation of a
been discussed in the earlier section for the following: star block Bis(mPEG–PLA)–Pt(IV) complex. The conjugate self-assemble into
copolymers PEG–(PLLA)8 and tri block copolymers of PDLA–PEG– micelles, and exhibited a thermo-reversible sol–gel transition at higher
PDLA [59,60], 8-armed star triblock copolymers of PEG–PLLA–PEG concentrations. In vitro release experiments reveal that platinum got
[61], and PEG–PLLA and PEG–PDLA di-block copolymers [60]. released for two months (Fig. 4) [75].
A recent example of a PLA–PEG based hydrogel system involves
2.4. Dual responsive and miscellaneous PLA–PEG hydrogels injectable in situ forming hydrogels containing radiopaque substances.
The authors used mPEG–PLA diblock and PLA–PEG–PLA triblock copol-
Recently Zhao et al., report a pH sensitive hydrogel for tumor sensi- ymers end-capped with triiodo benzoic acid derivatives as a radiopaque
tive drug delivery. Poly(2-ethyl-2-oxazoline) (PEOz) is a pH sensitive thermo-gel. These hydrogels show significant radiopacity both in vivo
polymer. The protonated amide induces hydrogen bonding networks and in vitro [76].
at lower pH (found in tumor environment). The authors fabricated a hy- Other examples involving PLA–PEG system involves hydrogels syn-
brid system using PEOz–PLA and phospholipid–PEG–folate. The system thesized from amine functionalized PEG and PLLA. These copolymers
self-assembles and forms a thermosensitive hydrogel at body show gel–sol transition with increase in the temperature [77]. Graft
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Fig. 3. Hybrid thermo-pH responsive in situ forming hydrogels. The nanoparticles were also surface modified by folate to target folate receptors overexpressed in cancer cells. (A) Schematic
illustration of multifunctional polymeric micelles modified with folate and the acid-triggered drug release from the pH-sensitive micelles. (B) Schematic illustration of multifunctional
polymeric micelles for targeted and controlled drug delivery. Poly (2-ethyl-2-oxazoline) (PEOz) D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), 1,2-distearoyl-sn-glycero-
3-phosphoethanolamine-N-[amino(polyethylene glycol). Reproduced from Ref. [72], with permission.

copolymers based on poly(depsipeptide–lactide) and PEG side chains used. This problem also limits the use of high molecular weight PLA
have also been reported. This copolymer forms a gel at 33 °C and the for fabricating hydrogels. In order to overcome this problem of crys-
transition temperature may be controlled by varying the copolymer tallization and solubility poly(D,L-lactic acid-co-glycolic acid)
and PEG molecular weight [78]. (PLGA) is often the hydrophobic segment of choice, as outlined in
In general, PLA–PEG based hydrogels are advantageous over the next section.
pluronics or acrylamide based thermoresponsive systems. Not only
because they are biodegradable, but also their critical gel concentra- 3. PLGA–PEG hydrogels
tion is lower. Moreover, these hydrogels show superior controlled
release properties. They can be tuned for macromolecule and drug As mentioned in the earlier section PLGA–PEG system solves the
release for over a month. However, one of the main drawbacks of problem of crystallization and solubility significantly. PLGA–PEG copol-
using PLAs in thermogelling polymers is crystallization and subse- ymers are liquid at room temperature and form instantaneous hydrogel
quent precipitation in solution. Moreover, it is often difficult to solu- at body temperature. Moreover, the mechanical properties are also
bilize these block copolymers in water when short chain PEGs are superior compared to PLA–PEG hydrogels. The properties of these

Scheme 1. PEG–PLA hydrogels with pendant carboxylic acid side chains were synthesized. The carboxylic acid group was protected with benzyl ester, later deprotected after
polymerization. The resulting polymer can form thermosensitive/ionic hydrogel in situ. Reproduced from Ref. [73], with permission.
 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205 197

Fig. 4. In situ forming PEG- PLA polymer–platinum (IV) hydrogels were reported for sustained slow release of platinum based chemotherapeutic agents. The resultant conjugates can self-
assemble into micelles in water. The solution (sol) is micellar suspension at room temperature, spontaneously turns into a semisolid gel upon heating. Reproduced from Ref. [75], with
permission.

hydrogels depend on hydrophilic-hydrophobic balance, molecular micellization and further physical gelation in water. Their study high-
weight of the copolymers, and crystallinity [79,80]. PLGA–PEG based co- lights the importance of polymerization conditions including synthesis
polymers are also more haemo-compatible and suitable for biomedical temperature in “random” copolymerization of two monomers with
use as compared to PLA–PEG based copolymers [81]. In 1999 by Jeong different reactivity [87].
et al., reported injectable PEG–PLGA–PEG triblock copolymer for the PLGA–PEG based hydrogels have been used as sustained release
first time. It forms a gel depot for the sustained release after injection vehicles for different hydrophilic and lipophilic drugs [80]. The release
[82,83]. profile of PEG–PLGA–PEG polymers was studied for two model drugs
The gelation mechanism of PLGA–PEG–PLGA was different from (hydrophobic-ketoprofen and hydrophilic-spironolactone). The
PEG–PLGA–PEG copolymers. The copolymers with end PLGA blocks first-order release profile was observed for the drug ketoprofen, which
form micelle and also inter-micellar bridges between different micelles. was released in 2 weeks. An S-shape release profile was observed for
On the other hand, copolymers with middle PLGA blocks form lipophilic spironolactone, which was released for two months [26]. Sustained
core and hydrophilic shell. Therefore, copolymers with end PLGA blocks release of fluorescein isothiocyanate was observed after instilling of
form a gel at lower temperatures compared to copolymers with middle these polymer hydrogels into rats [29]. These triblock copolymer
PLGA blocks [84,85]. hydrogels were also used for the delivery of plasmid DNA [27], Tgf-β1
PLGA-PEG-PLGA copolymers with different alkyl end capped groups for skin wounds of diabetic mice [28], and for sustained release of
have been reported. These end capped copolymers show reversible sol– dexamethasone in the prevention of temporomandibular joint
gel transition. The authors show both the PLGA segment length and end ankyloses [88]. PLGA–PEG–PLGA triblock copolymer is also available
capped alkyl groups influence gelation [86]. At a later stage, the effect of commercially (ReGel® technology) [89].
varied lactic acid and glycolic acid blocks on the thermo-sensitive gela- Ma et al., recently report localized co-delivery of three chemothera-
tion was studied for this tri-block copolymer. peutic agents (doxorubicin, cisplatin, and methotrexate) by using
The gelation and degradation behaviors of thermogelling PEG/PLGA PLGA–PEG–PLGA copolymers [38] for treating osteosarcoma. The
block copolymers can be controlled by many internal factors such as authors observed that multi-drug co-loaded hydrogels exhibit
molecular weight (MW) of polymers, block ratio, concentration, and synergistic effects of those drugs in treating osteosarcoma in cell lines
end group. Their gelation behavior can also be affected by external (Saos-2 and MG-63 cells). Single peri-tumoral injection of the drug-
additives such as PEG homopolymers or salts. loaded hydrogels in mice with osteosarcoma shows significant tumor
PLGA block in PLGA–PEG copolymer is thought to result in “random” suppression efficacy up to 16 days.
distribution of the comonomer units along the polymer chains. Nanocomposites improve the property and drug release profile of
However, different reaction conditions results in different PLGA block hydrogels [90]. Recently PLGA–PEG delivery vehicles with clay nano-
sequences. Yu et al., reported the influence of the extent of randomness composite (clay nanodisks) were reported for sustained delivery of
and sequence structures on thermogelling behaviors of PEG–PLGA doxorubicin. Doxorubicin release was sustained, and no burst release
copolymers. These triblock copolymers having similar chemical compo- was observed. A single dose provides sustained in vivo antitumor
sitions and block lengths differ in sequences of units of LA and GA in the activity against human xenograft tumors in mice [91]. Another unique
PLGA block. Their study revealed that the macromolecular sequence finding from this study is that the loaded doxorubicin molecules in the
structure influences the hydrophobic/hydrophilic balance of this kind gel act as cross-linker to recruit new gel networks. They further
of amphiphilic copolymers. The sequence alteration affects mesoscopic observed doxorubicin controls its own release profile by modulating
198 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205

crosslinking density and mesh size in gel. This is the first report on used in the clinics successfully. PLGA–PEG–PLGA triblock copolymer
PLGA–PEG based injectable gel, which provides a ‘self-controlled drug has been commercialized as ReGel® technology; it has been used to
release’ system. deliver both hydrophobic and hydrophilic drugs. However, for medical
Significant gel strength is needed for using the hydrogels for medical devices and tissue engineering applications a hydrogel with greater me-
implants and tissue engineering purposes. PEG based hydrogels are nor- chanical strength and prolonged biodegradability is required.
mally softer, and often inadequate for these purposes. In order to en-
hance their mechanical strength Peak et al., recently synthesized an 4. PCLA–PEG hydrogels
elastomeric PLGA–PEG interpenetrating collagen network. The elasto-
meric hydrogels show enhanced gel strength. The hydrogel system PEG-poly(ε-caprolactone-co-lactide)(PCLA) based triblock systems
was synthesized using PEG modified with lactide and acrylate end can also be applied as thermo-responsive hydrogels, similar to those ob-
groups. These copolymers were photo cross-linked in the presence of served for PEG–PLA and PLGA [94]. Caprolactone with longer alkyl
type I collagen (Fig. 5) [92]. The hydrogels showed significant compress- group has been shown to increase the gelation range. They tend to over-
ibility of ~50% with their elastic modulus ~135 kPa. The Authors obtain- come two limitations of PLA or PLGA based triblock thermogels: i) in situ
ed PLGA–PEG based hydrogel with significant mechanical properties. forming hydrogels tend to form gels immediately at 37 °C. When
However, these gels are neither injectable nor thermoresponsive. injected, they form gels at the tip of the needle. Caprolactone with
Recently Li et al., report pH and thermosensitive PLGA–PEG based longer chains are softer and offers a larger gelation window. ii)
systems. The pH sensitive groups are grafted onto a PEG–PLGA system Compared to PLA/PLGA, they degrade slowly. The fast degradation to
by radical polymerization (acrylate side chain) [93]. Later the polymer lactic and glycolic acid for PLA/PLGA system results in accumulation of
was coated with a magnetic iron nanoparticle (silica-coated magnetite), these acids. These acids interfere with the bio-macromolecules, some-
making a hybrid responsive system (magnetic, thermo, and pH). They times denaturing them. Moreover, this leads to rapid degradation of
further demonstrate the release of doxycycline from these polymeric the hydrogels. PCLA degrades much more slowly which results in
systems (Scheme 2) [25]. much less accumulation. The following section reviews the PCLA
Overall PLGA–PEG based hydrogels overcomes the disadvantages of based hydrogel systems.
PLA–PEG based hydrogels. PLGA–PEG based system is more easily Lee and coworkers reported dual temperature and pH sensitive
soluble, having lesser critical gel concentration, and can be tuned to hydrogels based on PCLA and PEG by coupling with oligomeric sulfa-
form gel precisely at 37 °C. These systems are ideal for injectable in methazine. These sulfamethazines containing copolymers show gela-
situ gel forming applications especially as delivery vehicles and depots. tion in a neutral/acidic environment at body temperature. Similar to
The PLGA–PEG injectable hydrogel is a validated technology, and is PLA and PLGA systems, the gelation can be controlled by adjusting the

Fig. 5. The hydrogel was synthesized by mixing acrylate terminated PEG–PLA with a type I collagen to create a precursor solution. The precursor solution is then photo polymerized into
hydrogels. Bottom right: Schematic representation of a hydrogel network structure made from covalently cross-linked PEG (red) and semi-interpenetrating collagen PEG–PLGA
thermogelling system was prepared with terminal acrylates. Reproduced from Ref. [92], with permission.
 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205 199

Scheme 2. PLGA–PEG based hybrid pH responsive hydrogel systems. Reproduced from Ref. [93], with permission.

balance in lipophilic–hydrophilic blocks, molecular weight, segment system was further evaluated in higher mammals (horse joints). Two
length, etc. The hydrogels showed dual responsive properties. They doses of 50 mg/g and 250 mg/g of celecoxib via intra-articular injection
remained in solution at pH ~8.0 and at 25 °C. One of the advantages of show significant sustained effect. The animal showed discomfort initial-
PCLA–PEG based systems over PLGA–PEG or PLA–PEG based systems ly, but this was completely alleviated after the third day of injection
is the ease of injectability without clogging the needle. The authors [105].
also demonstrated delivering the materials using longer catheters PCLA–PEG hydrogel systems show longer degradation time and en-
[95–97]. Later, the same group (Lee et al.,) incorporated paclitaxel into hanced injectability compared to PLA–PEG or PLGA–PEG systems. How-
this hydrogel. They reported a sustained release of drug for a period of ever, drug release period from these depots cannot be significantly
one month. The drug loaded hydrogels released the drug for more enhanced compared to PLGA–PEG systems (both systems show an aver-
than two weeks in mice [40]. These hydrogels have also been used as age release period of 8–12 weeks). The real potential for PCLA–PEG
scaffolds to encapsulate stem cells and proteins for tissue engineering thermosensitive hydrogels are in tissue engineering and medical de-
applications [98]. vices where a longer enhanced degradation period is warranted.
Zang et al., synthesized block copolymer PCLA–PEG–PCLA [99]. They
functionalized these triblock copolymers with integrin targeting 5. PLA–polyurethane hydrogels
arginine-glycine-aspartate (RGD) peptides. They demonstrated unique
functionalization strategy on both PCLA and the PEG fragments. The Polyurethanes (PUs) have been extensively investigated for various
end group functionalization on PCLA system was afforded by carboxylic drug delivery applications owing to their biocompatibility, chemical
acid functionalization with succinic anhydride followed by N-(3- versatility, and superior mechanical properties [106,107]. Polyure-
dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) chemistry. The thanes (or poly urethane-esters) are used to synthesize shape memory
surface grafting on PEG was afforded by photochemical grafting biodegradable materials. The use of PLA and PCL diols with PEG and PUs
technique using an azido linker, according to Matsuda et al., [100]. give rise to newer hydrogels. Due to the high glass transition of PLA, this
This copolymer–peptide system can self-assemble and form a hydrogel is not suitable to be used alone in medical devices. PLA based PUs
at body temperature. These RGD ligands are exposed on the micellar (PLAUs) offer shape memory materials with enough mechanical
surface in water. Later the hydrogels loaded with RGD peptide was strength and shape recovery temperature [108].
repurposed as in situ gelling post operation peritoneal adhesion barrier PLAUs, the ampiphilic block copolymers are being explored as useful
[101,102]. This system is unique because a surface grafting and biomaterials for tissue engineering and drug delivery [109]. A series of
functionalization has been demonstrated on a triblock ampiphilic PLAUs can be prepared with starting materials like PLA diols,
biodegradable copolymer for the first time. We believe these studies hexamethylene diisocyanate, and 1,4-butane diol. The ratio of soft seg-
opened up ways for targeted delivery of thermoresponsive injectable ment to hard segment and average molecular weight distribution of
hydrogels. these copolymers determine their glass-transition temperature. PLAUs
Acetyl capped or 2-(2′,3,5′ triiodobenzoyl) capped PCLA–PEG–PCLA show better shape memory behavior and more rapid response to thermal
hydrogels was prepared. In rats this hydrogel has an enhanced degrada- stimuli compared to polycaprolactone (PCL) based PUs (PCLUs) designed
tion over a period of 12 weeks. The materials were cytocompatible on by Lendlein and Langer. The values of Fmax (frequency of maximum loss)
erythrocytes, chondrocytes, and in the cartilage [103]. Later the evaluated for PLAUs are higher than that of PCLUs, which is the reason for
hydrogel was investigated for releasing celecoxib in rats [104]. This rapid shape memory behavior in case of PLAUs [108].
200 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205

PLAUs have been used for preparation of thermo-responsive solvents, and other cross-linking agents making the system suitable for
hydrogels for novel biomedical applications such as controlled release macromolecular delivery [119].
of loaded moieties and tissue engineering. In one study, poly(isopropyl Das et al., prepared a hydrogel based on dextrin and PLA with N,N′-
lactate diol) [PLA based diol], poly(ethylene oxide)–poly(propylene methylenebisacrylamide as crosslinker. Introduction of PLA into dextrin
oxide)–poly(ethylene oxide) triblock copolymer [soft segment of PUs] enhances the porous and rough morphology of the hydrogels and swell-
and various aliphatic diisocyanates [hard segment of PUs] were used ing capacity. The balance of hydrophilic–hydrophobic segments along
in the preparation of thermo-responsive hydrogel. The architecture of with a crosslinker controls the swelling capacity of the hydrogels. This
diisocyanate used in PU synthesis determines the hydrophilic- hydro- is important in the controlled release of the drugs. This hydrogel has
phobic balance of the polymer surface, sol–gel–sol transition behavior, been used for the sustained delivery of ciprofloxacin and ornidazole
viscoelastic parameters and the gelation time of the hydrogels. PLAUs following first order kinetics and non-Fickian diffusion (Scheme 3) [46].
based hydrogels exhibit gelation temperature near body temperature Similar to dextran or cellulose, PLA–pullulan graft copolymers have
(37 °C) and short gelation time (seconds) [106]. Hydrogels prepared also been reported to be thermo-responsive [120]. Nanogel prepared
from PUs composed of poly(ethylene glycol)-block-poly(propylene gly- from pullulan-g-PLA copolymers has been used for delivery of anti-
col)-block-poly(ethylene glycol) triblock copolymers [PEG–PPG–PEG] cancer agents like doxorubicin [42]. The pH responsive chitosan D,L-lac-
exhibit poor biodegradability and burst effect when releasing bioactive tic acid hydrogel system has also been reported where the hydrogel was
agents. The introduction of PLA into the polymer backbone enhances prepared based on chitosan-g-(L-lactic-co-citric acid). The hydrogel
hydrolytic degradability. Lower critical solution temperature (LCST) be- matrix supports the growth of fibroblast cells more effectively than on
havior of these thermo-gelling copolymers depends on the content of chitosan membrane alone [121]. Thermosensitive hydrogels of chito-
PLA in the copolymer. Research results show critical gelation at a con- san–PLGA has also been reported by graft copolymerization of chitosan
centration of 7 to 9 wt.% of the copolymer with about 1.3 to 6.8 wt.% and PLGA. The authors demonstrated the entrapment and release of
of PLA in the total copolymer composition [110]. vancomycin hydrochloride and betamethasone sodium phosphate as
In another study, thermo-responsive gel based on PU with soft seg- model drugs [43]. PLA–hyaluronic acid based hydrogels were synthe-
ments composed of PCL and/or 10 mol% of PLLA–PEO diblock or PDLLA– sized from hydroxyethyl methacrylate, lactic acid and hyaluronic acid.
PEO diblock or 20 mol% of PDLLA–PEO–PLLA triblock and a diisocyanate The resultant hydrogel was explored for delivery of vascular endothelial
as hard segment show low viscosity at room temperature and rapid ge- growth factor. Substituting lactic acid with caprolactone influences deg-
lation at body temperature. This thermo-responsive hydrogel has a radation. Caprolactone segments degrade slowly compared to PLA seg-
novel application as a cell printing material near body temperature ments [44].
[111]. Poly(ester urethane)s consisting of PLA and poly (ethyl succi- β-Cyclodextrin is a cyclic oligosaccharide that is often involved in in-
nate) segments exhibit excellent tensile properties. They may have ap- tramolecular ‘host–guest’ type interactions (where no covalent bonds
plication as biomaterials [112]. Thermo-gelling PLGA–PU triblock co- are formed between interacting molecules). Such interactions have
polymers have also been widely reported. They show PLGA-PEG like been used to drive crosslinking and hydrogel formation. Zhang et al., re-
properties — solution at room temperature, but gel at body tempera- port pH-responsive hydrogels based on host-guest interaction between
ture. One of the early reports was gene (TGF-β) delivery using such a benzimidazole and β-cyclodextrin. The system consists of terminated
system [28]. Later they were also used as scaffolds for tissue engineering poly(ethylene glycol) and β-cyclodextrin-modified poly(L-lactide).
[113,114]. Overall, these segmented lactide/glycolide based polyure- The hydrogel dissociates in acidic environments. The authors demon-
thanes form in situ gels on contact with an aqueous environment [115]. strate this pH sensitive behavior using doxorubicin as a model drug. Re-
Lactide based hydrogels have also been used recently for labile pro- lease of doxorubicin was triggered by reducing the pH from 7.4 to 5.5
tein based delivery (human growth hormone). The negatively charged (Fig. 6) [45].
peptide is self-assembled into a thermo- and pH sensitive hydrogel sys- A similar host–guest induced crosslinking system has been reported
tem. The authors reported an interesting copolymer system made from for PEG–methacrylate (PEGMA) and α-cyclodextrin to fabricate ther-
triblock poly(ε-caprolactonelactide)–poly(ethylene glycol)–poly-(ε- mo/pH responsive hydrogels. The thermo-responsive system consti-
caprolactone-lactide) (PCLA–PEG–PCLA). They further modified this co- tutes PLLA–PEGMA. The copolymers PLLA–PEGMA and PLLA-α-
polymer system with hexamethylene diisocyanate mediated polyure- cyclodextrin were synthesized separately. In solution, they self-
thane polymers [39]. assemble and form hydrogels. Lower pH triggers the dissociation of
the host-guest hydrogel linkage [122].
6. PLA–polysaccharide hydrogels Recently Langer and co-workers report hydrogels based on PEG–PLA
nanoparticles and organo-modified hydroxypropyl methylcellulose
Hydrogels of PLA (or PLGA, or PCLA) with most commonly used (HPMC). They self-assemble and form hydrogel by nanoparticle-
polysaccharides (dextran, pullulan, hyaluronic acid, chitosan) have polymer interaction. This transient interaction allows flow of the formu-
been reported. There are few advantages of using polysaccharide in lation under shear. Such system also allows entrapment of hydrophobic
hydrogels i) large swelling capacity compared to PEG, ii) all reactions molecules in the nanoparticle core and hydrophilic molecules in the
are carried out in aqueous solutions iii) polysaccharide have functional HPMC core (Fig. 7) [123].
groups (−COOH, −NH2, − OH, etc.) and easier for chemical conjuga- Overall, polysaccharide PLA based hydrogels are promising with nu-
tion and crosslinking. merous opportunities and innovations. They can be tailored and func-
Copolymers of polysaccharides and PLA have been reported for vari- tionalized as required especially for responsive or targeted delivery
ous biomedical applications [116]. PLA has been grafted with polysaccha- system and also as tissue engineering scaffolds. However, fabricating
rides like cellulose, cellulose derivatives, pullulan, amylose, dextran, etc. an injectable in situ forming hydrogel is still a challenge for polysaccha-
[109]. Polysaccharide and PLA (or its copolymers) block copolymers are ride based systems.
also capable of undergoing thermoresponsive behaviors like any other
ampiphilic block copolymers [117]. However, thermoresponsive systems 7. POSS-lactide hydrogels
using polysaccharides are less reported compared to PEG based systems.
Similar to PEG–PLA stereocomplex driven hydrogel De Jong et al., report- Chemically modified polyhedral oligomeric silsesquioxane (POSS) is
ed L-and D-lactic acid are grafted onto dextran. These PLA-dextran based widely used in nano-structured hybrid materials. POSS improves
hydrogels were further used to deliver lysozyme and IgG as model thermal and mechanical properties which has been exploited as a hy-
proteins [118]. One of the advantages of using polysaccharide based drophobic unit to develop ampiphilic polymers for drug/gene delivery
ampiphilic systems in the hydrogel synthesis is devoid of organic and formation of hydrogels [124]. The POSS center was modified by
 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205 201

Scheme 3. Synthesis of dextrin–acrylamide–PLA hydrogel. The authors demonstrated controlled release of a few drugs from this matrix.

PLA–PEG–acrylate followed by photo/radical crosslinking. POSS incor- 8. PLA-based organogels

poration significantly slows the degradation rate [125]. A similar
POSS–PLA based hydrogel has been suggested to be used as a porous tis- Organogels are thermo-reversible semi-solid systems composed of a
sue engineering scaffold [126]. Xie et al., recently report their tunable liquid phase, which can be either an organic solvent or oil, and a cross
mechanical properties (5.8 ± 0.2–130 ± 23 MPa in tensile modulus, linked network formed by self-assembled polymeric molecules. The liq-
30 ± 6%–144 ± 13% in elongation, beyond 90% recovery), biodegrada- uid phase of organogels becomes entrapped in three dimensional poly-
tion, bio-mineralization activity, and osteoblast compatibility [127]. meric networks. These polymer based organogels can act as a depot
Gu et al., recently report POSS–PLA–PU based shape memory following parenteral administration. They have the ability to retain
hydrogels. This star-shaped POSS–PLA was synthesized by ring opening low molecular weight polar compounds in their matrix [129]. The equi-
polymerization of D,L-lactide followed by cross-linking with librium water content of organogels is about 35%, which leads to a rela-
hexamethylene diisocyanate. All POSS–PLA–PUs have shape memory tively short release duration for hydrophilic drugs. Although in situ
properties with high shape fixity ratios above 99%, and shape recovery solidifying organogels have gained significant interest in the recent
ratios around 84% for the first cycle and above 89% for the second years, only a few organogels are being studied as drug delivery vehicles.
cycle. POSS–PLA–PUs with the shorter arm length show faster recovery The presence of pharmaceutically unacceptable organic liquids and/or
speed due to the higher content of POSS cores (Scheme 4) [128]. unacceptable/untested gelators in most of the existing organogels may

Fig. 6. pH responsive host–guest (cyclodextrin–benzimidazole) interaction based hydrogels were synthesized based on PLA–cyclodextrin conjugate. Redrawn from Ref. [45], with
permission.
202 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205

Fig. 7. (a) Synthesis of polymer–nanoparticle hydrogels through non-covalent interactions between core-shell nanoparticles; (b) hydrophobically modified hydroxypropylmethylcellulose.
(c) The NPs are composed of poly(ethylene glycol)-block-poly(lactic acid) (PEG–PLA) copolymers. (d) Cryogenic scanning electron microscopy images of the hydrogels. The polymer–
nanoparticle interactions are illustrated in the right bottom box, polymer chains are in gray, the nanoparticle is in orange.
Reproduced from Ref. [123], with permission.

be a reason behind this. Microemulsion-based gels, lecithin gels, (PTMC) is necessary to introduce cross linking points while preparing
sorbitan monostearate organogels, amphiphilogels, alanine derivative PLA based oil gels [132].
based gels, and eudragit organogels are various classes studied in this Testosterone encapsulated oil gel composed of PLA, PTMC,
category [130]. oligo(ethylene glycol) has been developed, in which dimethyl sulphoxide
Poloxamer based organogels have been investigated recently due to or dimethyl carbonate were used as organic solvents. Since testosterone
their thermo-responsive nature and potential to form in situ gels. The is a lipophilic drug, it is difficult to deliver through normal hydrogels be-
replacement of polypropylene oxide blocks of poloxamer by biodegrad- cause of its lipophilicity. This strategy implies that PLA based oil gels may
able ester group containing PLA and poly(DL-lactic acid-co-glycolic serve as promising carriers for lipophilic drugs [133]. The possibility of
acid) (PLGA) results in the formation of durable and biocompatible stereocomplexation between enantiomers of lactic acid occurring in the
block copolymers that undergo micelle aggregation [131]. PLA has a network may lead to shrinkage of oil gel. This property of gel shrinkage
strong affinity for organic solvents, making it quite suitable for prepar- caused by stereocomplexation plays an important role in stimuli-
ing oil gels. However, PLA does not have cross linking points due to responsive materials and also determines the degradation of the polymer
which an additional compound such as poly(trimethylene carbonate) network [132]. Injectable implants based on in situ precipitation of PLGA

Scheme 4. POSS–PLA based star copolymer crosslinked by diisocyantes. These hydrogels show shape memory effect.
Reproduced from Ref. [128], with permission.
 A. Basu et al. / Advanced Drug Delivery Reviews 107 (2016) 192–205 203

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