Multifunctional Composite Hydrogels for Bacterial Capture, Growth/Elimination, and Sensing Applications

Abstract

Hydrogels are cross-linked networks of hydrophilic polymer chains with a three-dimensional structure. Owing to their unique features, the application of hydrogels for bacterial/antibacterial studies and bacterial infection management has grown in importance in recent years. This trend is likely to continue due to the rise in bacterial infections and antimicrobial resistance. By exploiting their physicochemical characteristics and inherent nature, hydrogels have been developed to achieve bacterial capture and detection, bacterial growth or elimination, antibiotic delivery, or bacterial sensing. Traditionally, the development of hydrogels for bacterial/antibacterial studies has focused on achieving a single function such as antibiotic delivery, antibacterial activity, bacterial growth, or bacterial detection. However, recent studies demonstrate the fabrication of multifunctional hydrogels, where a single hydrogel is capable of performing more than one bacterial/antibacterial function, or composite hydrogels consisting of a number of single functionalized hydrogels, which exhibit bacterial/antibacterial function synergistically. In this review, we first highlight the hydrogel features critical for bacterial studies and infection management. Then, we specifically address unique hydrogel properties, their surface/network functionalization, and their mode of action for bacterial capture, adhesion/growth, antibacterial activity, and bacterial sensing, respectively. Finally, we provide insights into different strategies for developing multifunctional hydrogels and how such systems can help tackle, manage, and understand bacterial infections and antimicrobial resistance. We also note that the strategies highlighted in this review can be adapted to other cell types and are therefore likely to find applications beyond the field of microbiology.

Keywords: active hydrogels; bacterial adhesion; bacterial capture elements; bioactive elements; functionalized hydrogels; hydrogel-embedded carriers; interfaced sensors; multifunctional hydrogels; therapeutic hydrogels.

Figure 1

Hydrogel properties and mechanisms/functionalization for developing bacterial/antibacterial hydrogel platforms. Hydrogel properties and their respective bacterial/antibacterial applications are discussed in the text, in the corresponding sections indicated.

Figure 2

Surface functionalization strategies to attach BCEs to hydrogels. (a) Schematic illustrating BCE immobilization via EDC-NHS chemistry. EDC reacts with the carboxyl groups of the hydrogel, forming an unstable intermediate for interaction with BCEs. Addition of NHS improves the cross-linking efficiency by the formation of stable intermediates for interaction with BCEs. (b, c) Schematic representation of aptamer decorated PEG-hydrogel barcodes for specific bacterial capture: E. coli and S. aureus from complex biofluid. (a–c) Reprinted with permission from ref (30). Copyright 2018 Elsevier Ltd. (d) GA activation of hydrogel surfaces to produce carbonyl interface for BCE immobilization. (e) From left to right: GA activated hydrogel for tethering monosaccharides, followed by NH₂-PEG blocking to occupy unreacted sites. Con A immobilizes on hydrogels via monosaccharides, facilitating bacterial capture. Reprinted with permission from ref (45). Copyright 2014 Elsevier Ltd. (f) BMOE modification of protein hydrogel to immobilize lectins for bacterial capture. From ref (25). CC BY 4.0. (g) Thiol modification of PSiO₂/PAAm hydrogels for biotin/streptavidin conjugation on hydrogel surface to immobilize antibodies for bacterial capture. Reprinted with permission from ref (35). Copyright from 2010 John Wiley & Sons.

Figure 3

Studies indicating the effect of hydrogel stiffness and thickness on bacterial adhesion/growth. Increased growth of E. coli (a) and S. aureus (b) on agar and PEGDMA hydrogels with increased stiffness. Stiff agar hydrogels were not included as agar solubility limited its preparation. (a, b) Reprinted from ref (69). Copyright 2015 American Chemical Society. Increased growth of S. aureus (c) and E. coli (d) on thick poly(ethylene glycol) hydrogels with increased stiffness. (c, d) Reprinted from ref (65). Copyright 2018 American Chemical Society. Increased adhesion of S. aureus on the surface of ultrasoft PAAm hydrogels (500S and 700S) (e) and increased colonization of S. aureus in bulk of PAAm hydrogels (500B and 700B) (f). Increased growth of P. aeruginosa, P. mirabilis, and M. xanthus on PAAm hydrogels with increased stiffness (g). (e–g) Reprinted with permission from ref (72). Copyright 2016 Elsevier.

Figure 4

Bacterial sensing hydrogel platforms. (a) Arrangement of chitosan-PDMS plastic films and functionalization of chitosan hydrogels with metabolic substrates to enable enzyme-mediated bacterial detection. (b) Detection of specific bacteria via their unique secreted enzymes that convert the metabolic substrates within chitosan hydrogels to produce end products with distinct colors. (a, b) From ref (163). CC BY-NC-ND 4.0. (c) Schematic representing the fabrication of functionalized chitosan hydrogel film for enzyme-mediated E. coli detection. Reprinted with permission from ref (161). Copyright 2018 Wiley. (d) Schematic representing the formation of carbon dot hydrogel, collapse of hydrogel network due to bacterial esterases, and fluorescence transformation of hydrogels before and after bacterial treatment. (e) Degrees of fluorescence quenching: i, hydrogel without bacteria; ii, P. aeruginosa; iii, B. subtilis; iv, S. aureus; v, B. cereus. (d, e) From ref (164). CC BY 3.0. (f) Schematic representing the DNase secretion by the host during wound infection and (g) sensing mechanism of DNA gel which is degraded upon exposure to DNases causing alterations in capacitance of the sensor. (f, g) Reprinted with permission from ref (165). Copyright 2021 American Association for the Advancement of Science.

Figure 5

Multifunctional bacterial “capture and respond” hydrogels. (a) Schematic illustrating strategic “capture and kill” multifunctional hydrogel platform. The top layer constitutes serum albumin based hydrogel modified with BMOE cross-linker to immobilize lectin B for enabling bacterial capture. The bottom layer constitutes a fibrillary hydrogel encapsulated with AMPs for their release during bacterial contact resulting in bacterial killing. Increased capture of E. coli (b) and P. aeruginosa (c) with increasing concentration of lectin B. Effect of time and concentration of AMP encapsulated within hydrogels: after 24 h no E. coli cells (d) and P. aeruginosa cells (e) were viable. (a–e) From ref (25). CC BY 4.0. (f) Schematic representing functionalization of hydrogel with MoS₂, antibacterial activity, and treatment of wound infections. (g) E. coli cell viability after treatment with and without MoS₂ functionalized hydrogels in the presence and absence of NIR. (h) Evaluation of wound disinfection and healing upon treatment with MoS₂ functionalized hydrogels with and without NIR. (f–h) Reprinted with permission from ref (33). Copyright 2019 Wiley.

Figure 6

Multifunctional bacterial “sense and treat” hydrogels. (a) Schematic illustrating the application of multifunctional GelDerm wound dressing functionalized with pH-sensitive and drug-eluting compounds. pH variations for P. aeruginosa (b) and S. aureus (c) on hydrogels in comparison with commercial pH strips. (d) Colorimetric detection of bacterial infection in pig skins by multifunctional hydrogels indicating increased color intensity with increasing bacterial concentration. (a–d) Reprinted with permission from ref (135). Copyright 2017 Wiley. (e) Schematic illustration of multifunctional bromothymol blue (BTB)/near-infrared-absorbing conjugated polymer (PTDBD)/thermosensitive chitosan (CS) hydrogel for visual detection and diagnosis of bacterial infections. (f) pH-based colorimetric detection of bacterial growth via multifunctional BTB/PTDBD/CS hydrogel due to change in color from green BTB to yellow. (g) Images indicating multifunctional BTB/PTDBD/CS hydrogel mediated diagnosis of bacteria-infected wounds in mice. (e–g) Reprinted from ref (171). Copyright 2020 American Chemical Society. Schematic representing (h) the preparation of vancomycin-loaded “sense and treat” hydrogel and their mechanism of action for bacterial elimination. (i) pH- and polymer-dependent release kinetics of vancomycin from the “sense and treat” hydrogel. (j) Percentage survival of bacteria over time upon hydrogel treatment. (k) Percentage survival of bacteria over time upon treatment with hydrogels containing varying concentration of nanoparticles. (h–k) Reprinted with permission from ref (133). Copyright 2015 Wiley.