Nanofilamentous Virus-Based Dynamic Hydrogels with Tunable Internal Structures, Injectability, Self-Healing, and Sugar Responsiveness at Physiological pH

Abstract

With expanding applications of hydrogels in diverse fields ranging from biomaterials to sensors, actuators, and soft robotics, there is an urgent need to endow one single gel with multiple physicochemical properties, such as stimuli-responsiveness, injectability, self-healing, and tunable internal structures. However, it is challenging to simultaneously incorporate these highly sought-after properties into one single gel. Herein, a conceptual hydrogel system with all of these properties is presented via combining bioconjugate chemistry, filamentous viruses, and dynamic covalent bonds. Nanofilamentous bioconjugates with diol affinity were prepared by coupling a tailor-synthesized low-pK a phenylboronic acid (PBA) derivative to a well-defined green nanofiber the M13 virus with a high aspect ratio (PBA-M13). Dynamic hydrogels with tunable mechanical strength were prepared by using multiple diol-containing agents such as poly­(vinyl alcohol) to cross-link such PBA-M13 via the classic boronic–diol dynamic bonds. The as-prepared hydrogels exhibit excellent injectability and self-healing behaviors as well as easy chemical accessibility of the PBA moieties on the virus backbone inside the gel matrix. Ordered internal structures were imparted into virus-based hydrogels by simple shear-induced alignment of the virus nanofibers. Furthermore, unique hydrogels with chiral internal structures were fabricated through in situ gelation induced by diffusion of diol-containing molecules to fix the chiral liquid crystal phase of the PBA-M13 virus. Sugar responsiveness of this gel leads to a glucose-regulated release behavior of payloads such as insulin. All of these properties have been implemented at physiological pH, which will facilitate future applications of these hydrogels as biomaterials.

Advances in Synthesis and Applications of Self-Healing Hydrogels

“…The stability of the boronate-diol bond mainly depends on the pH of the solution (Yan et al, 2004). Some researchers (Zhi et al, 2018) combined this kind of bond FIGURE 2 | The process of self-healing of (A) Two pieces or (B) Four pieces of hydrogels prepared by Zhang et al (2018) (reproduced with permission from Zhang et al (2018). Copyright 2018 American Chemical Society).…”

“…Being glucose-responsive and injectable at a physiological pH, the hydrogel based on poly(vinyl alcohol), M13 virus, and PBA developed by Zhi et al (2018) was suitable for controlled insulin delivery. A tumor responsive self-healing prodrug hydrogel was developed by Balakrishnan et al (2019).…”

“…Artificial tissue Deng Z. et al, 2018;Ghanian et al, 2018;Lee et al, 2018;Chen et al, 2019b;Guo Z. et al, 2019;Shao et al, 2019;Sun C. et al, 2019 Drug/cell delivery Qu et al, 2017;Yang et al, 2017;Deng Z. et al, 2018;Khan et al, 2018;Sharma et al, 2018;Wei and Gerecht, 2018;Zhi et al, 2018;Balakrishnan et al, 2019;Chen et al, 2019e;Guo B. et al, 2019;Jiang F. et al, 2019;Li Q. et al, 2019;Liu P. et al, 2019;Qian et al, 2019;Shen et al, 2019;Sun C. et al, 2019;Xu H. et al, 2019 Electrical devices Liao et al, 2017;Ding et al, 2018;Jing et al, 2018;Li R. et al, 2019;Pan et al, 2018;Shao et al, 2018;Wang S. et al, 2018;Becher et al, 2019;Chen et al, 2019c;Deng et al, 2019;Han et al, 2019;Hu et al, 2019;Lin et al, 2019;Peng et al, 2019;Qiao et al, 2019;Qin et al, 2019;Rao et al, 2019;Shin et al, 2019;…”

“…The stability of the boronate-diol bond mainly depends on the pH of the solution ( Yan et al, 2004 ). Some researchers ( Zhi et al, 2018 ) combined this kind of bond with bioconjugate chemistry and filamentous viruses to prepare a hydrogel system, which was shown to be stimuli-responsive, injectable, and self-healing. The researchers first conjugated PBA derivative with the M13 virus, and then poly(vinyl alcohol) was used to make cross-linkage with the PBA-M13 via boronate-diol complexation.…”

“…Those networks can be mainly divided into two cross-linking types: (1) dynamic chemical covalent bonds and (2) physical non-covalent interactions. Dynamic covalent bonds include imine bond ( Qu et al, 2017 ; Yan et al, 2017 ; Chen H. et al, 2018 ; Chen et al, 2019e ; Khan et al, 2018 ; Wei and Gerecht, 2018 ; Zhang et al, 2018 ; Guo B. et al, 2019 ; Jiang F. et al, 2019 ; Li Q. et al, 2019 ; Qian et al, 2019 ; Wang et al, 2019b ; Wang W. et al, 2019 ; Zhou et al, 2019 ), Diels–Alder (DA) reaction ( Oehlenschlaeger et al, 2014 ), boronate-diol complexation ( Hong et al, 2018 ; Pan et al, 2018 ; Smithmyer et al, 2018 ; Zhi et al, 2018 ; Han et al, 2019 ), acylhydrazone bond ( Yang et al, 2017 ; Shen et al, 2019 ; Sun C. et al, 2019 ), dynamic disulfide bond ( Song L. et al, 2019 ), and dynamic metal oordination ( Shao et al, 2018 ; Chen et al, 2019a ; Qin et al, 2019 ). Physical non-covalent interactions include hydrogen bonding ( Fan et al, 2018 ; Uzumcu et al, 2018 ; Cao et al, 2019 ; Chen et al, 2019c ; Hu et al, 2019 ; Huang et al, 2019 ; Kuddushi et al, 2019 ; Li R. et al, 2019 ; Liao et al, 2019 ; Su et al, 2019 ; Wang L. et al, 2019 ), hydrophobic interaction ( Liu P. et al, 2019 ), host-guest interaction ( Deng Z. et al, 2018 ; Li Q. et al, 2018 ; Liu L. et al, 2019 ; Wang W. et al, 2019 ), and ionic interaction ( Ma et al, 2018 ; Wang Y. et al, 2018 ; Becher et al, 2019 ).…”