Hydrogels: Biomaterials for Sustained and Localized Drug Delivery
219
2.2 Based on Crosslinking Methods
Different crosslinking strategies are employed for hydrophilic monomeric units in
hydrogel fabrication to form stable polymeric networks [118, 54, 71]. Different
physical and chemical crosslinking methods are listed in Fig. 2. Physical crosslinking
include charge ion interactions, hydrogen bonding, crystallization/stereo-complex
formation mechanisms, while synthetic strategies involve radical polymerization
[64–102], photo-polymerization [11, 127], high energy irradiation, enzyme induced
crosslink reaction, addition reaction of the polymeric units [184], Diels-Alder “click
reaction,” and Schiff-base formation. Depending upon the structure and desirable
mechanical properties, nature of polymers, the crosslinking strategy is preferred for
fabrication.
2.2.1 Physical Crosslinking
The physically cross-linked hydrogel, also known as a reversible hydrogel, is usually
created by inter-molecular bonding through ionic interactions, polymerized entanglements, hydrophobic/hydrophilic bonding, etc. This reversible property is exploited
in designing stimuli-responsive hydrogel with self-healing and injectable features for
efficient drug delivery purposes. They are also referred to as the ‘smart drug delivery
systems’ (SDDS).
i. Ionic/electrostatic interactions
Molecules with opposite charges tend to attract each other influencing formation of a hydrogel. Alginate a natural source of polysaccharide with mannuronic
and glucuronic acid units, are cross-linked to achieve gel formation by divalent
cations such as magnesium (Mg
2+ ), calcium (Ca
2+ ) and barium (Ba
2+ ) [22, 107]. It
is widely employed in wound healing, drug delivery, tissue engineering. A similar
mechanism occurs in macromolecules with opposite charges through electrostatic
interactions to give polyelectrolyte complexes (PECs) [141]. For example, chitosan
forms PECs by the electrostatic interactions between its amino group (cationic) and
from other natural polyelectrolytes such as pectin, alginate, chondroitin sulphate or
artificial polymers like polylactic acid (PLA), polyacrylic acid, and polyphosphoric
acid (anionic) [9, 63]. These hydrogels fabrication using PECscan be modulated
using the charge density of the polymer, amount of the polymer, the mix ratio,
and the surrounding microenvironment of the polymer [210, 114]. When the net
charge of the polymer is zero, the hydrogel complex precipitates in its microenvironment. The significant advantage of the preparation of the hydrogel through the
ionic/electrostatic interactions is their deformability under high stress and ability to
reform once the pressure is removed, making it a candidate for SDDS. However,
limitations of ionic/electrostatic interaction-based hydrogel include the decreased
mechanical strength due to the bonding involved [9, 107, 63, 114].
219
2.2 Based on Crosslinking Methods
Different crosslinking strategies are employed for hydrophilic monomeric units in
hydrogel fabrication to form stable polymeric networks [118, 54, 71]. Different
physical and chemical crosslinking methods are listed in Fig. 2. Physical crosslinking
include charge ion interactions, hydrogen bonding, crystallization/stereo-complex
formation mechanisms, while synthetic strategies involve radical polymerization
[64–102], photo-polymerization [11, 127], high energy irradiation, enzyme induced
crosslink reaction, addition reaction of the polymeric units [184], Diels-Alder “click
reaction,” and Schiff-base formation. Depending upon the structure and desirable
mechanical properties, nature of polymers, the crosslinking strategy is preferred for
fabrication.
2.2.1 Physical Crosslinking
The physically cross-linked hydrogel, also known as a reversible hydrogel, is usually
created by inter-molecular bonding through ionic interactions, polymerized entanglements, hydrophobic/hydrophilic bonding, etc. This reversible property is exploited
in designing stimuli-responsive hydrogel with self-healing and injectable features for
efficient drug delivery purposes. They are also referred to as the ‘smart drug delivery
systems’ (SDDS).
i. Ionic/electrostatic interactions
Molecules with opposite charges tend to attract each other influencing formation of a hydrogel. Alginate a natural source of polysaccharide with mannuronic
and glucuronic acid units, are cross-linked to achieve gel formation by divalent
cations such as magnesium (Mg
2+ ), calcium (Ca
2+ ) and barium (Ba
2+ ) [22, 107]. It
is widely employed in wound healing, drug delivery, tissue engineering. A similar
mechanism occurs in macromolecules with opposite charges through electrostatic
interactions to give polyelectrolyte complexes (PECs) [141]. For example, chitosan
forms PECs by the electrostatic interactions between its amino group (cationic) and
from other natural polyelectrolytes such as pectin, alginate, chondroitin sulphate or
artificial polymers like polylactic acid (PLA), polyacrylic acid, and polyphosphoric
acid (anionic) [9, 63]. These hydrogels fabrication using PECscan be modulated
using the charge density of the polymer, amount of the polymer, the mix ratio,
and the surrounding microenvironment of the polymer [210, 114]. When the net
charge of the polymer is zero, the hydrogel complex precipitates in its microenvironment. The significant advantage of the preparation of the hydrogel through the
ionic/electrostatic interactions is their deformability under high stress and ability to
reform once the pressure is removed, making it a candidate for SDDS. However,
limitations of ionic/electrostatic interaction-based hydrogel include the decreased
mechanical strength due to the bonding involved [9, 107, 63, 114].