The preparation and characterization of self-healing hydrogels based on polypeptides with a dual response to light and hydrogen peroxide.

Injectable self-healing hydrogels are being widely used in drug delivery, tissue engineering, and other fields. Because of their excellent biocompatibility and biodegradability, polypeptides are an ideal candidate for preparing injectable self-healing hydrogels. In this study, a polypeptide-based hydrogel with dual response to hydrogen peroxide and light was obtained by copolymerizing 4-arm PEG-amine, N-(p-nitrophenoxycarbonyl)-l-methionine, and N-(p-nitrophenoxycarbonyl)-γ-o-nitrobenzyl-l-glutamate. The hydrogel exhibits injectable self-healing behavior due to the hydrophobic interactions among peptide blocks, which also act as the reservoir of hydrophobic drug molecules. In the presence of hydrogen peroxide or under light irradiation, the thioether bond in methionine was oxidized to sulfoxide, whereas the o-nitro benzyl ester bond was broken to form glutamic acid. As a result, the corresponding hydrophobic blocks of polypeptide become hydrophilic, accelerating the release of drug molecules loaded in the polypeptide hydrophobic blocks. Using this technique, the controlled release of hydrophobic drug molecules was achieved. Our efforts could provide a new strategy for the preparation of self-healing hydrogels based on polypeptides with a dual response to hydrogen peroxide and light. In this view, the practical application of polypeptides in drug delivery, tissue engineering, and other fields, could be expanded and advanced.

Thermal- and salt-activated shape memory hydrogels based on a gelatin/polyacrylamide double network.

Shape memory hydrogels have been extensively studied in the past decades owing to their exceptionally promising potential in a wide range of applications. Here, we present a gelatin/polyacrylamide double network hydrogel with thermal- and salt-activated shape memory effect. The thermally activated behavior is attributed to the reversible triple helix transformation of gelatin, and the salt-activated performance can be ascribed to the formation of hydrophobic interaction domains under the Hofmeister effect. The hydrogel can memorize a temporary shape successfully through soaking with (NH4)2SO4 solution or decreasing temperature, and recovers its permanent shape by extracting ions with deionized water or increasing temperature. In particular, the hydrogel exhibits excellent shape fixity and recovery ratio. The presented strategy may enrich the construction as well as application of biopolymer based shape memory hydrogels.

A pH-responsive self-healing hydrogel based on multivalent coordination of Ni2+ with polyhistidine-terminated PEG and IDA-modified oligochitosan.

Metal coordination hydrogels have drawn intensive attention in controlled drug release due to their facile incorporation of stimuli and dynamic self-healing properties. However, many metal coordination hydrogels which are responsive to mild physiologically relevant stimuli are restricted by their poor stability in non-triggering environments. Here, we reported a new strategy for enhancing the neutral stability of a pH-responsive self-healing hydrogel based on multivalent metal coordination without loss of its responsiveness. The hydrogel was formed by multivalent coordination of Ni2+ with polyhistidine (PHis) and multiple iminodiacetic acid (IDA) ligands which were modified on the terminal groups of polyethylene glycol (PEG) and the side groups of oligochitosan (OChi), respectively. By incorporating multivalent coordination, the hydrogel maintains its self-healing character and weak acid responsiveness; it can also be used as an injectable hydrogel by injecting it into a neutral environment. Through varying the PHis : IDA ratio, the mechanical strength and dynamic relaxation of the hydrogel can be regulated conveniently. More importantly, the hydrogels with multivalent coordination can remain stable and integral in neutral buffer (pH 7.4); meanwhile, they dissolve quickly in a weak acid environment (pH 5.5), which is similar to some tissue disease conditions. In contrast, the control hydrogel without multivalent coordination disintegrated within 4 hours in the neutral non-triggering buffer. Because the hydrogel consists of large amounts of coordinative Ni2+ ions, it naturally possesses relatively high affinity to molecules containing polyhistidine motifs. Thus, pH-tuned controlled release of a model molecule, rhodamine-modified polyhistidine, was accomplished, with limited neutral leakage and quick release in weak acid. These results indicate potential applications for this multivalent coordination hydrogel in the controlled release field.

A photo-degradable injectable self-healing hydrogel based on star poly(ethylene glycol)-b-polypeptide as a potential pharmaceuticals delivery carrier.

As one of the most promising biomaterials, injectable self-healing hydrogels have found broad applications in a number of fields such as local drug delivery. However, controlled release of drugs in hydrogels is still difficult to realize up to now. Here, we report a novel photo-degradable injectable self-healing hydrogel based on the hydrophobic interaction of a biocompatible four-arms star polymer, poly(ethylene glycol)-b-poly(γ-o-nitrobenzyl-l-glutamate). The hydrophobic interaction between poly(γ-o-nitrobenzyl-l-glutamate) not only connects poly(ethylene glycol)-b-poly(γ-o-nitrobenzyl-l-glutamate) together with a crosslink but also provides a hydrophobic domain to encapsulate hydrophobic pharmaceuticals such as doxorubicin (DOX). Due to the dynamic character of the hydrophobic interaction, the hydrogel exhibits excellent injectable and self-healing ability. In particular, the photolabile o-nitribenzyl ester group is cleaved under UV irradiation. As a result, the hydrophobic domain transforms into the hydrophilic one and the embedded DOX is released effectively. An increasing release ratio of DOX dramatically enhances the apoptosis ratio of HeLa cells. We expect these attractive properties may be beneficial to practical applications of the hydrogel as an effective local drug delivery means in a truly physiological environment.

Polyhistidine-Based Metal Coordination Hydrogels with Physiologically Relevant pH Responsiveness and Enhanced Stability through a Novel Synthesis.

Utilizing the abnormal physiological conditions of disease tissues can result in a site-specific functionality with high control and efficiency of stimuli-responsive hydrogels. Here, a physiologically relevant pH-responsive and self-healing hydrogel is reported based on coordination between Ni2+ and four-arm poly(ethylene glycol)-b-polyhistidine (4PEG-PHis) that is synthesized by a novel and facile PHis preparation method using amino-terminalized four-arm PEG as the macroinitiator. Reversible PHisNi coordination bonds endow the hydrogel with multistimuli-triggered sol-gel transition (physiologically relevant pH, EDTA) and self-healing properties. It is also demonstrated that 4PEG-PHis could be used as an injectable hydrogel in phosphate buffer (pH 7.4), and excellent stability in neutral buffer via multivalent coordination is shown, thus indicating its potential applications in controlled drug release systems.