Hydrogels do not dissolve in water[1,2]. In recent

Hydrogels are three-dimensional, cross-linked
networks of water-soluble polymers that have the ability to
swell but do not dissolve in water1,2.
In recent years, hydrogels have emerged as a promising biomaterial for tissue
engineering and regenerative medicine, diagnostics, cellular immobilization,
therapeutic delivery of cells and bioactive molecules, barrier materials to
regulate biological adhesions and medicine1,3. Based on networks,
hydrogels are divided into natural or synthetic polymeric. Natural hydrogel constructs are often made of polysaccharide or
protein chains. Some polysaccharide-based hydrogels are hydrogels which
consisted of alginate, cellulose, chitin, chitosan, and hyaluronic acid 4.
Hyaluronic acid (HA), or hyaluronan, is a linear polysaccharide that contains of intermittent units of a disaccharide
repetition, ?-1,4- D-glucuronic acid–?-1,3-N-acetyl- D-glucosamine. This
hydrogel is found throughout the body, from the vitreous of the eye to the
extracellular matrix (ECM) of cartilage tissues 5. During the years,
HA has been obtained from rooster combs or, extracted via microbial
fermentation. Nowadays, the manufacturing and purification of HA have turned into an industry. At present,
highly pure HA is producing and accessible in an extensive range of molecular
weights at relatively low costs6. By reason of
biocompatibility and chemical-physical and biological properties of HA, this
hydrogel has developed increasing interest among researchers and it is already
applied in several biomedical applications such
as regenerative medicine, and drug delivery 7. However, HA
hydrogels have short turnover rate and poor mechanical properties that restrict
their applications in tissue engineering. In fact, biodegradable polymers have
to be crosslinked in order to adjust their general properties and to degrade at a desired time for delivering drugs. Therefore, several methods have been used to attain
an optimal injectable hydrogel including ionic interaction,
photopolymerization, thermal gelation, physical self-assembly and chemical
crosslinking with agents 6,8–10. Moreover, the Schiff-base reaction has been used
for rapid gelation, that resulted to injectable hydrogels. In this method, the
gelation is related to the chemical reaction between amino and aldehyde groups
of polysaccharide derivatives10. Chemical
crosslinking of pure HA polymers modified its properties, as the resistance
against mechanical stress under applied living tissues was increased and
biodegradation time decreased comparing to unmodified HA polymers. These two
factors are very important required properties in biomaterials 11.
Different reagents such as glutaraldehyde (GTA), adipic dihydrazide (ADH), 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide (EDC), poly(ethylene glycol)
diglycidyl ether (EX 810), divinyl
sulfone (DVS), butanediol diglycidyl
ether (BDDE)  and genipin have been used for HA as crosslinkers in previous studies 5–8,11–14.
Genipin (GP), a crystalline and well defined chemical compound, is a
cross-linker that can be isolated from the fruits of Gardenia jasminoides
Ellis. Because of its low cytotoxicity of GP in compare with glutaraldehyde and
other crosslinkers, Genipin has gained increasing interest in the field of
biomaterial processing technology and can be widely used for various biomedical
applications 15–17. According
to previous studies, optimized amount of GP to crosslink natural biocompatible
polymers, such as chitosan and gelatin is between 0.5 and 3.5 wt%9. Polymeric
microparticulate and nanoparticulate systems have a long history of use for
drug delivery 18. Amongst
all the biomaterials, application of the biodegradable polymer polylactide-co-glycolide (PLGA) has presented tremendous
potential as a drug delivery carrier 19. PLGA
can be synthesized by the ring opening polymerization (ROP) and
polycondensation. The advantages of ROP over polycondensation are its milder
reaction conditions, shorter reaction time and the absence of reaction
by-products. The ring-opening copolymerization of lactide with other cyclic
monomers is commonly carried out using stannous compounds as initiators 20,21. Stannous
octoate, Sn(Oct)2, is the most commonly used initiator in the
polymerization of cyclic esters due to its non-toxicity and high efficiency22. Oil-water
or water-oil-water emulsion is a method can be used for preparation to
encapsulate hydrophobic and hydrophilic drugs in micro- or nano-scale form of
PLGA23. Dexamethasone
(DEX) has potent anti-inflammatory activities by inhibiting activated
macrophages and have been widely used to treat chronic and severe inflammatory
diseases. It is a synthetic, poorly soluble and crystalline corticosteroid 24,25. However, their
systemic or repeated applications are restricted due to high incidences of
systemic harmful effects such as weight gain, cardiovascular diseases,
cataracts and osteoporosis. To overcome these restrictions, targeted drug
delivery to activated macrophages has been used to reduce systemic adverse
effects as well as to increase drug efficacy 24.