Composite Hydrogels Using Bioinspired Approach with in Situ Fast Gelation and Self-Healing Ability as Future Injectable Biomaterial

Abstract

Biopolymers are attractive candidates to fabricate biocompatible hydrogels, but the low water solubility of most of them at physiological pH has hindered their applications. To prepare a water-soluble derivative of chitosan (WSC) biopolymer, it was grafted with a small anionic amino acid, l-glutamic acid, using a single-step 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide coupling reaction. This resulted in a zwitterion-tethered structure onto the polymer backbone. The degree of substitution range was 13-16 ± 1.25%, which was controlled by varying the feeding reagent ratios. Differential scanning calorimetry- and X-ray diffraction-based analysis confirmed a transition from amorphous into a moderately amorphous/crystalline morphology after amino acid grafting, which made the derivative water-soluble at physiological pH. Composite hydrogels gelated within 60 s when using this WSC together with benzaldehyde-terminated 4-arm poly(ethylene glycol) as cross-linker. The compressive modulus of these hydrogels could be easily tuned between 4.0 ± 1.0 and 31 ± 2.5 kPa, either by changing the cross-linker concentration or total solid content in the final gel. The gels were injectable at the lowest cross-linker as well as total solid content, due to the enhanced elastic behavior. These hydrogels showed biodegradability during a 1 month incubation period in phosphate-buffered saline with weight remaining of 60 ± 1.5 and 44 ± 1.45% at pHs 7.4 and 6.5, respectively. The cytocompatibility of the gels was tested using the fibroblast cell line (i.e., WI-38), which showed good cell viability on the gel surface. Therefore, these hydrogels could be an important injectable biomaterial for delivery purpose in the future.

Hydrogels Based on Schiff Base Linkages for Biomedical Applications

“…Benzaldehyde-terminated PEO can also be facilely prepared in one step using carbodiimide condensation chemistry, similar to Figure 6B [37,72,73,74,75,76]. The very first work on the synthesis of benzaldehyde-terminated Pluronic L64 using carbodiimide chemistry was reported in 2010 [75].…”

Recent advances in shear‐thinning and self‐healing hydrogels for biomedical applications

“…Schiff base reactions between amine and aldehyde groups to form imine derivatives have been used extensively for cell encapsulation, tissue repair, drug delivery, and wound dressing applications. The dynamic Schiff base reactions are commonly formed between the amine groups on chitosan backbones and benzaldehyde groups at telechelic difunctional poly(ethylene glycol) (DF‐PEG) chain ends; however, HA, dextran, chondroitin sulfate, poly(vinyl alcohol), other chitosan derivatives, and recently vanillin (4‐hydroxy‐3‐methoxybenzaldehyde), have all been used for the preparation of hydrogels via Schiff base reaction. Toward 3D cell encapsulation, HeLA cells, bovine articular chondrocytes, murine neural stem cells, as well as zebrafish embryos have been encapsulated in Schiff base hydrogels and reported to maintain their normal morphology.…”

Click-cross-linked, doxorubicin-loaded hydrogels based on poly(styrene-alt-maleic anhydride)

“…The materials with marvelous biocompatibility would be necessary for a successful application of injectable hydrogels. Furthermore, fast gelation property is an important requirement in the in-situ injectable hydrogel formation because it prevents the gel precursors from spreading away from the injection site [19,20]. The advantages of injectable hydrogels make it suitable for cancer localization chemotherapy.…”