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

Abstract

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 Ni 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.

Behavior control of membrane-less protein liquid condensates with metal ion-induced phase separation

“…Previous studies with model poly-His peptides suggested a stable complex formation between two 6His peptides and two Ni 2+ (refs. 40,47 ). PRM-SH3-6His dimers might be the most dominant form upon Ni 2+ -induced clustering.…”

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

“…Tang e t al . utilized the coordination between Ni 2+ and four‐arm PEG to endow the hydrogel with multi‐stimuli (pH, EDTA) triggered sol–gel transition (Figure ) . Because of the exchangeable property of the coordination, Ni‐coordinated hydrogels demonstrated shear‐thinning and self‐healing properties, characterized by a decrease in viscosity upon increase in shear and near‐complete recovery between dynamic strain steps during rheological studies.…”

“…(b) Photographs for pH (left) and EDTA (right) triggered gel–sol transition for 4PEG‐PHis6 gel. Adapted with permission from . Copyright, 2018 Wiley.…”

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

“…These monovalent systems were not designed for tissue engineering, and as such their biocompatibility has not been fully evaluated and their stability in vivo is likely low, making them less useful for longer‐term applications . Recently, an injectable hydrogel that uses reversible poly‐histidine‐Ni coordination bonds has been used to make a multivalent biomaterial stable enough for use in sustained drug delivery systems but its in vivo suitability is yet to be proven …”