Highly Efficient Self‐Healable and Dual Responsive Cellulose‐Based Hydrogels for Controlled Release and 3D Cell Culture

Abstract

To face the increasing demand of self-healing hydrogels with biocompatibility and high performances, a new class of cellulose-based self-healing hydrogels are constructed through dynamic covalent acylhydrazone linkages. The carboxyethyl cellulose-graft-dithiodipropionate dihydrazide and dibenzaldehyde-terminated poly(ethylene glycol) are synthesized, and then the hydrogels are formed from their mixed solutions under 4-amino-DL-phenylalanine (4a-Phe) catalysis. The chemical structure, as well as microscopic morphologies, gelation times, mechanical and self-healing performances of the hydrogels are investigated with 1 H NMR, Fourier transform infrared spectroscopy, atomic force microscopy, rheological and compression measurements. Their gelation times can be controlled by varying the total polymer concentration or 4a-Phe content. The resulted hydrogels exhibit excellent self-healing ability with a high healing efficiency (≈96%) and good mechanical properties. Moreover, the hydrogels display pH/redox dual responsive sol-gel transition behaviors, and are applied successfully to the controlled release of doxorubicin. Importantly, benefitting from the excellent biocompatibility and the reversibly cross-linked networks, the hydrogels can function as suitable 3D culture scaffolds for L929 cells, leading to the encapsulated cells maintaining a high viability and proliferative capacity. Therefore, the cellulose-based self-healing hydrogels show potential applications in drug delivery and 3D cell culture for tissue engineering.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm.201703174.For this purpose, intensive efforts have been made so far to design and fabricate self-healing hydrogels by incorporating dynamic covalent and noncovalent bonds into the hydrogel networks. [2] Since dynamic covalent bonds, such as Schiff bases, [3] disulfide bonds, [4] Diels-Alder reactions, [5] and phenylboronate complexations, [6] can integrate both the stability of covalent bonds and the reversibility of noncovalent bonds, [2a] they have been employed to prepare the self-healing hydrogels with diverse functions. In particular, chitosan-based self-healing hydrogels constructed via Schiff bases have been widely explored as biomaterials for hemostasis, [7] drug delivery, [8] cell therapy, and 3D cell culture, [3a,9] due to their good biocompatibility and automatic repair ability under physiological conditions. [3b] However, the relatively fast hydrolytic degradation rate, [2a] poor structural integrity, and weak mechanical properties [3b] of those hydrogels impede their biomedical applications for achieving longer-lasting functions. Acylhydrazone bonds, which formed via the condensation of hydrazides with carbonyl groups, are very close relatives to Schiff bases, but are much more stable. Thus, the acylhydrazone bonds have been utilized to construct the selfhealing hydrogels with robust mechanical properties. [4b,10] For instance, a strong self-healing hydrogel that...

Enhancing the Stability of Hydrogels by Doubling the Schiff Base Linkages

“…Subsequently, the stabilities of hydrogels were further investigated by rheological measurements. As shown in Figure C,D, gelation was observed when the value of storage modulus (G′) exceeded that of loss modulus (G′′), and the gelation time decreased with the increase in gel concentration (Table S1, Supporting Information), which was consistent with the previous report . After gelation, the G′′ would gradually increase with time, indicating further formation of Schiff base linkages in the hydrogels.…”

Transiently malleable multi-healable hydrogel nanocomposites based on responsive boronic acid copolymers

“…It has been reported that hydrogels containing dynamic reversible crosslinks may promote the exchange of nutrients and metabolites between the cells and the external environment, and allow the cells to engage in complex cellular functions, which can represent an advantage in 3D cell culture compared with permanently crosslinked networks. 95,111,112 Therefore we believe that our proposed materials could constitute a robust remotely healable platform to encapsulate and release cells with applications in cell delivery technologies.…”

Injectable Self‐Healing Antibacterial Bioactive Polypeptide‐Based Hybrid Nanosystems for Efficiently Treating Multidrug Resistant Infection, Skin‐Tumor Therapy, and Enhancing Wound Healing

“…The disappearance of skeletal vibration of aromatic and presence of –NH– stretching band of EPL (3247 cm −1 ) suggested the formation of FEPL. In the FTIR spectrum of the FCE hydrogels, the disappearance of bands at 1687 cm −1 (aldehyde) and the new peak at 1662 cm −1 (CN), suggesting the Schiff base reaction between –CHO groups of F127‐Phe‐CHO and –NH 2 of FEPL …”

“…Fabrication and Characterizations of FCB Hydrogel : Dibenzaldehy determinated F127 (F127‐Phe‐CHO) and F127‐EPL (FEPL) copolymer was prepared in a similar method as described previously, as shown in Supporting Information . The FCB hydrogel was prepared through a facile mixing method.…”