3.2.1 Temperature-Responsive Injectable Hydrogels
poly(N-isopropylacrylamide) (pnipaam) has received the most attention because of its sharp transition behavior. it shows a well-defined lower critical solution temperature (LCSt) around 32–34 °C, which is close to body tem- perature.5 recently, thermosensitive injectable hydrogels based on pnipaam and polyethylene glycol (peg) with different architectures have been devel- oped for tissue engineering applications due to their excellent properties including thermosensitivity, biodegradability, biocompatibility, and easily controlled characteristics.6
Wagner et al. synthesized types of thermosensitive injectable copolymers by using N-isopropylacrylamide (nipaaM), acrylic acid, N-acryloxysuccinimide, and polylactide–hydroxyethyl methacrylate. Collagen i could be further incorporated into this copolymer via covalent bonding, which results in enhanced cell adhesion on the hydrogels.7
the copolymer of poly(ethylene oxide) and poly(propylene oxide) (with the trade name pluronic®) in aqueous solutions is another well-known thermo- sensitive injectable material.8 it has also been frequently utilized to combine with other biodegradable polymers to provide thermal thermosensitivity.
pluronic has been chemically grafted onto chitosan to obtain a thermosensi- tive hydrogel, which could serve as an injectable vehicle for cell delivery, thus showing good potential for cartilage regeneration.9
in addition to the non-degradability, a major drawback associated with pluronic is low stability, and the gel persists for only one day after gelation. in order to resolve these problems, peo–pLLa–peo was synthesized, in which the central block ppo is replaced by a degradable poly(l-lactic acid) segment, and low-molecular-weight peo is also utilized (Figure 3.1).10 Moreover, mod- ification of the hydroxyl terminal group of the copolymer offers an opportu- nity to modulate the rheology and degradation of the hydrogels.11 Ding et al. systematically investigated the effect of end-groups on the physical gelation of pLga–peg–pLga aqueous solution, and further discussed the sol–gel mechanism of the thermosensitive derivatives.12
in general, the majority of temperature-responsive hydrogels do not solidify quickly around body temperature. to address this problem, Wang et al.
prepared a novel hydrogel by using an aBa block copolymer, poly(ethylene glycol)-co-poly(propanol serinate hexamethylene urethane)-co-poly(ethylene
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00067
glycol). it took less than a minute to form a gel, which demonstrates promise for internal injection applications.13
a thermosensitive hydrogel has also been prepared by combination of nat- ural polymer chitosan with glycerol phosphate (gp),14 that shows a sol–gel transition at physiological ph via electrostatic interactions, hydrogen bond- ing, and hydrophobic interactions.15
3.2.2 pH-Responsive Injectable Hydrogels
polyacrylic acid (paac) is an example of a ph-responsive polymer that responds to the ph of a medium due to the presence of carboxyl groups.
Besides, the ph sensitivity of various copolymers is imparted by incorporat- ing carboxylic acid-derived monomers, for example aac.16
Figure 3.1 gel–sol transitions of a peo–pLLa diblock copolymer (a) and peo–
pLLa–peo triblock copolymer (b). (reprinted by permission from Mac- millan publishers Ltd: [nature] (ref. 24), copyright (1997).)
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00067
Sulfamethazine oligomers (SMos) with ph sensitivity were coupled to the terminal groups of a thermosensitive poly(ε-caprolactone-co-lactide)–poly (ethylene glycol)–poly(ε-caprolactone-co-lactide) block copolymer to generate a thermo- and ph- dually sensitive SMo–pCLa–peg–pCLa–SMo copolymer.
Under physiological conditions (37 °C and ph 7.4), the copolymer formed a stable hydrogel rapidly, while it underwent a gel–sol transition at 37 °C and ph 8.0. the hydrogel thus formed holds optimal biocompatibility and demon- strates good promise in bone tissue engineering as an injectable scaffold.17
Stayton and co-workers synthesized a ph- and thermo-sensitive hydrogel based on a copolymer of N-isopropylacrylamide and propylacrylic acid. the hydrogel could form a hydrogel at acidic ph, which shows promise to deliver drugs to local acidosis environments, including tumors, ischemia, or wound sites.18
3.2.3 Enzyme-Responsive Injectable Hydrogels
an enzyme-responsive injectable hydrogel is a novel type of smart mate- rial that undergoes macroscopic transitions when triggered by the selective catalysis of certain enzymes.19 therefore, the functions of enzymes include catalyzing synthesis and hydrolysis, thus resulting in sol-to-gel and gel-to-sol phase transitions.
3.2.3.1 Sol-to-Gel Transition
gibson et al. synthesized a phosphorylated polymer based on poly(oligoeth- ylene glycol methacrylate), and isothermal transitions could be induced by dephosphorylation mediated by alkaline phosphatase.20
3.2.3.2 Gel-to-Sol Transition
over the past ten years, numerous studies have focused on the employment of matrix metalloproteinase (MMp)-sensitive peptides for the preparation of cell-invasive hydrogels, which could be hydrolyzed by MMp secreted from cells to provide space for cell migration.21 in addition, thrombin cleavage sites have also been utilized for the construction of enzyme-degradable hydrogels.22
CrDtege-argSViDrC, a peptide derived from the aggrecanase-degrad- able segment in aggrecan (a component of cartilage eCM), was introduced into peg hydrogel. this system enables the encapsulation and delivery of chondrocytes for cartilage repair and regeneration.23
Werner et al. designed a thrombin-responsive hydrogel to deliver heparin in a controlled manner. the release of heparin was triggered by the level of thrombins, which play an important role in the coagulation cascade and will become inactivated because of the released heparin (Figure 3.2).24
Similarly, Burdick et al. designed a novel MMp-sensitive polysaccha- ride-based hydrogel, in which crosslinks could be degraded by active MMps and encapsulated MMp inhibitors (rtiMp-3) were released locally.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00067
hence, on-demand delivery of rtiMp-3 effectively decreased the activity of MMp, and reduced ventricular remodeling of an infarcted heart in a porcine model.25