Antimicrobial hydrogels: promising materials for medical application

Figures & data

Figure 1 The different applications of hydrogels.

Figure 2 Transmission electron microscope image of Escherichia coli cells treated with silver nanoparticles in liquid Luria-Bertani medium: (A) membrane of E. coli; (B) nanoparticles accumulated in the membrane and penetrated the cell (arrows).

Note: Reprinted from Adv Drug Deliv Rev. 65(13–14). Pelgrift RY, Friedman AJ, Nanotechnology as a therapeutic tool to combat microbial resistance1803–1815, Copyright (2013), with permission from Elsevier.³¹

Table 1 Information of hydrogels with Ag NPs

Species of hydrogels	Synthesis of hydrogels	Highlights of hydrogels	Antimicrobial agents delivered	Content of antimicrobial agents	Rate of release	Diameter of nanoparticles	Antimicrobial capability	Application	References	Year
Alginate hydrogel	Electrochemical synthesis	Uniform hydrogel microbeads	Ag NPs	0.5–3.9 mM/mL	–	10–30 nm	~32 µg/mL Staphylococcus aureus (95.8%)	Biocompatible carriers	^Citation43	2012
Alginate-based nanocomposite hydrogel	Synthesis by aggregative mechanism and Ostwald ripening, then grown in alginate solutions	Colloid solutions can be stable for 30 days	Ag NPs	0.2–4.5 mM/mL	–	~30 nm	~112 µg/mL Escherichia coli 97.5% for 1 h and 99.9% over 24 h	Biomimetic bioreactor	^Citation45	2012
Alginate nanocomposite hydrogels	Electrochemical synthesis and rehydration	Composition and mechanical properties of Ag/hydrogel disks based on alginate, PVA and PVP can be adjusted	Ag NPs	0.3–5 mM/mL	35%–53% silver released for 48 h	10–30 nm	~10 µg/mL S. aureus (99.8% 24 h) and E. coli (over 99.99% 24 h)	Potential wound dressings	^Citation44	2014
Alginate/PVA silver nanocomposite hydrogel	Free radical polymerization and green process	Appropriate rate parameter for swelling	Ag NPs	1–15 mM/mL	–	4–10 nm	MBC/MIC ratio of E. coli and S. aureus both achieved 4	Wound dressings, catalysis and water purification	^Citation46	2014
Sodium alginate- based semi-IPN hydrogels	Cross-linked via radical redox polymerization	Well dispersed Ag NPs, cytocompatible and biodegradable hydrogel networks	Ag NPs	1 mM/mL	–	~5 nm	E. coli and S. aureus. E. coli is better than S. aureus	Drug delivery applications	^Citation47	2013
PAM hydrogels and its mixtures	Facile synthetic strategy of cross- linking	Hydrogels as templates to obtain metal nanostructures of different sizes and morphologies	Ag NPs	–	–	1–10 nm	Clear inhibition in growth of E. coli and Bacillus on solid agar medium	Desired nanoproduct tailor made for particular applications	^Citation48	2010
Hydrogel fibers loaded with Ag NPs	Wet spinning in a CaCl2 precipitation bath and chemical cross-linking	Mechanically robust and biodegradable	Ag NPs	0.383 wt% in 0.05 mM AgNO3 solution and 0.033 wt% in 0.005 mM AgNO3 solution	–	11 nm	–	Wound dressings for improving the overall quality and speed of healing	^Citation49	2012
Semi-IPN hydrogel of PVP and PAM	Free radical polymerization	Excellent nanoreactors for producing and stabilizing metal nanoparticles	Ag NPs	3.71 wt%	–	3–5 nm	Significant inhibition of E. coli on solid agar medium	Preliminary antibacterial applications	^Citation50	2008
Thermosensitive CS/2-glycerophosphate/nanosilver hydrogels	Synthesized in low temperature	Similar antibacterial activity, lower MW CS, lower concentration of Ag NPs and lower cytotoxicity	Ag NPs	DD80 and DD88 CS hydrogels were 3.82 kg/cm^2 (14.8%) and 4.99 kg/cm^2 (19.4%)	–	21.8 nm and 20.22 ppm	Inhibition of Pseudomonas aeruginosa and S. aureus on solid agar medium	Thermosensitive in situ formed wound dressings	^Citation51	2013
Iota-carrageenan- based Ag NP hydrogels	Green process using acrylamide with iota- carrageenan	Biodegradable, reducing AgNO ^Citation3 with leaf extracts of Azadirachta indica	Ag NPs	100.07 mM (5.1 g/300 mL)	Only weight loss of the composite hydrogels	3 ± 2 nm	Inhibition of Bacillus and E. coli on solid agar medium	Inactivation of bacteria	^Citation53	2013
Ag NP-loaded PVA/GA hydrogel	One-pot method by gamma radiation-induced cross-linking	GA improves the biocompatibility and swelling properties of the hydrogel	Ag NPs	1 mM	Increase with content of GA fraction	10–40 nm	Inhibition of E. coli on solid agar medium	–	^Citation54	2012
CMC-based hydrogels	Prepared using epichlorohydrin in alkaline medium, silver nitrate	Ag NPs prepared using two different processes: in situ process and postloaded technique	Ag NPs	18.99 wt% for in situ process and 9.51 wt% for postloaded method	Only TEM about distribution of Ag NPs using two processes	10–38 nm	Inhibition of E. coli, P. aeruginosa, S. aureus and Bacillus subtilis on solid agar medium	Potential candidates for medical field with high antibacterial activity	^Citation55	2013
Semi-hydrogel networks of PAM and carbohydrates	An optimized rapid redox solution polymerization	Highly stable and uniformly distributed Ag NPs	Ag NPs	–	–	2–5 nm	Mild inhibition of E. coli on solid agar medium	Preliminary antibacterial activity	^Citation56	2009
Gelatin-based inorganic nanocomposite hydrogels	Incorporating Ag^+ and treatment with sodium borohydride	Using acrylamide and biodegradable gelatin	Ag NPs	9.38%	–	~15 nm	Inhibition in growth of Bacillus on solid agar medium	Useful in medical applications, as antibacterial agents	^Citation57	2013
Hydrogels composed of acrylamide, ionic monomer and CS	Ag NPs were synthesized and stabilized using the hydrogel template method	Template nanoreactors	Ag NPs	12.5 µg for spherical nanoparticles, 50–100 µg for rod-shaped particles	–	70 nm	Inhibition zone Bacteria: Bacillus cereus B. subtilis S. aureus E. coli Yeast: Candida albicans Candida pseudotropicalis and the other five fungi	An antimicrobial agent	^Citation58	2011
Hydrogels composed of pluronic and PAM	Free radical polymerization with a redox initiator system	Semi-interpenetrating network to produce highly stable and uniformly distributed Ag NPs	Ag NPs	35%	–	5–10 nm	Inhibition of E. coli on solid agar medium	–	^Citation59	2011
PAM/poly(vinyl alcohol) hydrogel	An aqueous redox copolymerization	PVA acts as an highly efficient stabilizer for Ag NPs in the hydrogels	Ag NPs	–	–	2–3 nm	Inhibition of E. coli on solid agar medium	Antibacterial and wound dressing applications	^Citation60	2010
PAM/itaconic acid–Ag NP hydrogels	Gamma irradiation	Different sizes and morphologies depend on different irradiation doses	Ag NPs	100 µL/mL	–	10–100 nm	Promising activity against P. aeruginosa and slightly active against E. coli, MRSA and Klebsiella pneumoniae	Antibacterial coatings on different material surfaces for various biomedical applications	^Citation61	2013
Silver/starch/PAM nanocomposite hydrogels	By grafting/cross- linking reaction	Starch components are capable of arresting the agglomerated Ag NPs	Ag NPs	Changed from 0 to 50 ppm	–	60% 10 nm 40% 13–30 nm	Inhibition zone began from 5 ppm Fungi: Aspergillus flavus and C. albicans Bacteria: S. aureus and E. coli	–	^Citation62	2014
NIPAM-based nanogels	Free radical polymerization	Thermoresponsive nanogels which have an LCST close to the human body temperature	Ag NPs	–	–	5–100 nm	Inhibition of Staphylococcus epidermidis and E. coli on solid agar medium	Biomedical applications such as wound dressings	^Citation65	2014
PNIPAM-co- allylamine nanogels	Nanogels were synthesized and grafted onto non-woven polypropylene	Thermally responsive	Ag NPs	50 mmol dm^−3 silver nitrate solution	–	220 ± 10 nm below 34 s and 72 ± 12 nm at 37°C	Bacteria: S. aureus and P. aeruginosa below the LCST, bacteria grew, above the LCST bacterial growth was prevented or retarded	Utility in designing infection responsive wound dressings	^Citation63	2011
Hydrogels composed of gelatin and NIPAM	Green process Ag NPs reduced with neem leaf (A. indica) extracts	Gelatin, biodegradable hydrogels	Ag NPs	–	9.83%	5–10 nm	Inhibition of Bacillus on solid agar medium	Applications in wound and burn dressings	^Citation64	2014
Hydrogels composed of 2-acrylamido-2- methylpropane sulfonic acid sodium salt	Gamma irradiation at 25 kGy to form Ag NP-infused hydrogels	Comparison to two common silver burn wound dressings: Acticoat and PolyMem Silver	Ag NPs	–	5 mM initial concentration	2.1–15.6 nm	Burn wound pathogens (P. aeruginosa, MSSA, Acinetobacter baumannii and C. albicans) and antibiotic-resistant strains (MRSA and VRE) has 94%–99% viability after 24 h exposure	A novel burn wound hydrogel dressing	^Citation66	2014
2-Acrylamido-2- methylpropane sulfonic acid sodium salt hydrogels	Ultraviolet radiation	No cytotoxicity	Ag NPs	70%–82% of silver was released within 72 h and 88.0%–94.5% after 10 days of immersion	1, 2.5 and 5 mM	2–16 nm	5 mM silver hydrogel had the greatest inhibitory activity against MRSA and P. aeruginosa, S. aureus	A potential burn wound dressing	^Citation67	2014
Hydrogels prepared from acrylic acid, PEG methyl ether acrylate	In situ polymerization by UV irradiation	A good electrical conductivity	Ag NPs	–	56–139 ppm	233 nm	A perfect antibacterial efficiency against E. coli	Promising bioadhesive patch or wound dressing material or electrical massage patch	^Citation70	2009
Hydrogel composed of multiblock PEG-POSS polyurethanes	A one-step method synthesized and electrospun into nanofibrous webs	Thermoplastic and unusual shrinkage during water uptake	Ag NPs	–	1.0 wt% AgNO3	Nanofiber (diameter ~150 nm)	No E. coli cells on the surface of electrospun nanofibrous mat for 10 days incubation	Wound dressings	^Citation71	2009
Hydrogels of PVA/PVP	Gamma irradiation	Highly stable and uniformly distributed	Ag NPs	–	0.01 g of polymer powder contain 12 mmol AgNO3	Mean size 23 nm by TEM	–	A good candidate as wound dressing	^Citation72	2012
PMAA hydrogel	Novel approach involving equilibration of PMAAc hydrogels and reduction with borohydride	In situ formation of Ag NPs	Ag NPs	–	50 mg AgNO3 per 50 mL water	Average size is 10–20 nm	Fair antibacterial action against E. coli	Wound dressing	^Citation73	2013
Poly(2- hydroxyethyl methacrylate/itaconic acid) nanocomposite hydrogels	In situ reduction of silver nitrate and gamma radiolysis method	IA used as a carrier and a stabilizing agent	Ag NPs	–	0.68 wt% Ag in Ag(c1)/P(HEMA/IA3.5), 1.27 wt% Ag in Ag(c2)/P(HEMA/IA3.5) and 6.3 wt% Ag in Ag(c3)/P(HEMA/IA3.5)	<30 nm	Inhibition of S. aureus, E. coli and C. albicans was proved by measuring the colony-forming unit	Wound dressing	^Citation74	2013
P(MMA-co- MAA)/silver nanocomposite hydrogels	Free radical cross-linking polymerization and follow-up reduction of silver nitrate	pH-responsive	Ag NPs	–	13.7 wt%	–	Significant antibacterial properties against both S. aureus and B. subtilis by inhibition zone	A potentially smart material in the range of applications of antibacterial activity	^Citation75	2014
Hydrogel synthesized with PEG containing reactive catechol moieties	Utilizing silver nitrate to oxidize polymer catechols, leading to covalent cross-linking and hydrogel formation with simultaneous reduction of Ag(I)	No significantly affecting mammalian cell viability	Ag NPs	Sustained for at least 2 weeks in PBS solution with total amount 1 µg	100 µg in one hydrogel disk	~50 nm	Inhibition zones of S. epidermidis and P. aeruginosa	Antibacterial biomaterial coatings and tissue adhesives	^Citation78	2012
An agar hydrogel model with Ag NPs immobilized	Produced ligand- free Ag NPs laser ablation in water	A significant reduction of antibacterial activity in the presence of BSA	Ag NPs	–	Ag NP concentrations is 0.5–7.1 wt%	10–60 nm	All P. aeruginosa, E. coli, Streptococcus salivarius and S. aureus should be inhibited completely by any of the applied Ag NP concentrations in the presence of BSA except S. aureus	The presence of a major blood serum protein significantly decreases the antimicrobial effects of Ag NPs	^Citation80	2012
TMV as a biomediator	TMV as a biomediator	Simple, robust and size-tunable synthesis of Ag NPs with TMV as a biomediator under mild aqueous conditions	Ag NPs	–	1, 5, 10 and 20 mM initial concentration	Average diameter of 2, 4 and 9 nm	MIC of 2.3 and 2.5 ppm for 2 and 9 nm Ag NPs, respectively, against E. coli	Improved functionalities such as high catalytic and antibacterial activity	^Citation82	2014
CS hydrogel beads	Physically cross- linked in sodium tripolyphosphate as the cross-linker	CS chains easily bind to the Ag^+ cations. Not requiring heat or any other tools for nanoparticle in situ synthesis	Ag NPs	1 g of CS and desired amount of AgNO3 (0.5, 1.0 and 1.5 mmol)	In vitro drug release was performed in pH 7.4 PBS for 24 h	–	They showed antibacterial activity toward S. aureus and E. coli for >1 week	Potential drug delivery carrier	^Citation296	2015
FA cross-linked CMC hydrogel	NaCMC was dissolved in distilled water. FA was added to solution and stirred until FA was dissolved	Silver ions were dispersed in hydrogel coating on cotton fabric which can sustain antimicrobial ability after being washed	Ag NPs	5 × 10^−4, 1 × 10^−3 and 2 × 10^−3 mol/L	–	–	Showed 99.999% reduction for S. aureus and K. pneumonia	A green method which can apply to cotton fabric	^Citation68	2015
Cross-linking copolymers of acrylic acid (acrylic acid, methyl acrylate and a silicone nish)	The wet spray- coated fibers were exposed to UV irradiation	Silver antibacterial coating was deposited for the first time on hydrogel fibers through an in situ photochemical reaction	Ag NPs	4 g of Ag solution per each gram of hydrogel fibers	After 168 h (7 days), silver release calculated per gram was 6 ppm (g/mL)	100–600 nm<100 nm	They exhibited an excellent capability in inhibiting the growth of S. aureus and E. coli	A novel silver antibacterial coating hydrogel fibers	^Citation69	2015
QPVA hydrogel	Freeze–thaw method	The effect of QAS- grafted PVA hydrogel on selected microbes and its synergetic effect in combination with Ag NPs	Ag NPs	Solubilizing 10 g QPVA in 100 mL Ag NPs solution (7.8 µg/mL)	Major release mechanism of Ag NPs release follows Fickian diffusion	1.3–1.9 nm	They showed promising antimicrobial property after 96 h against E. coli, S. aureus and P. aeruginosa	A promising antimicrobial dressing	^Citation76	2016
RGO-based composite hydrogel	In situ reduction of GO using vitamin C in the presence of heat (90°C)	The facile preparation and dye degradation capacity of RGO/PEI/Ag hydrogels	Ag NPs	50 µL of aqueous solution of CH3 COOAg (8 mg/mL) added to 1.2 mL mixture	The amount of released silver ions was 4.696 × 10^−5 and 2.348 × 10^−4 g/L/g after 20 days	60–70 nm	–	Highly efficient catalyst for wastewater treatment	^Citation79	2015

Abbreviations: Ag⁺, silver ions; Ag NPs, silver nanoparticles; CMC, carboxymethyl cellulose; CS, chitosan; FA, fumaric acid; GA, gum acacia; HEMA, 2-hydroxyethyl methacrylate; IA, itaconic acid; IPN, interpenetrating polymer network; LCST, lower critical solution temperature; MIC, minimal inhibition concentration; MRSA, methicillin-resistant S. aureus; MW, molecular weight; NaCMC, CMC sodium salt; NIPAM, N-isopropylacrylamide; PAM, poly(acrylamide); PBS, phosphate buffered saline; PEG, poly(ethylene glycol); PMAA, Poly(methacrylic acid); PNIPAM, poly(N-isopropylacrylamide); POSS, polyhedral oligosilsesquioxane; PVA, poly(vinyl alcohol); PVP, poly(N-vinylpyrrolidone); QPVA, quaternized PVA; RGO, reduced graphene oxide; TEM, transmission electron microscope; TMV, tobacco mosaic virus; UV, ultraviolet; VRE, vancomycin-resistant Enterococcus.

Figure 3 Gao et al synthesized hydrogel containing Au NP-stabilized liposomes for antimicrobial application (A) illustrations of hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery; (B) bacteria incubated with AuC–liposome hydrogel (PEGDMA 0.8 vol%) at pH = 4.5; (C) a zoomed-in image of (B).

Note: The scale bars in (B and C) represent 1 µm. Reproduced from Gao W, Vecchio D, Li J, et al. Hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery. ACS Nano. 2014;8(3):2900–2907.⁸⁹

Table 2 Information of hydrogels with other metal nanoparticles

Species of hydrogels	Synthesis of hydrogels	Highlights of hydrogels	Antimicrobial agents delivered	Content of antimicrobial agents	Rate of release	Diameter of nanoparticles	Antimicrobial capability	Application	References	Year
Alginate hydrogel	CS pellet was mixed with alginate solution as a cross-linker to strengthen the alginate hydrogel through freeze–dry process	Alginate hydrogel/nano-zinc oxide composite showed controlled degradation profile, faster blood clotting ability and excellent cytocompatibility	ZnO NPs	The suspension of ZnO NPs was added into the alginate hydrogel at different concentrations (0.05%–1% w/w)	–	70–120 nm	Excellent antimicrobial activity against Escherichia coli, Staphylococcus aureus, Candida albicans and MRSA	Alginate hydrogel/nano-zinc oxide composite bandages for infected wounds	^Citation101	2015
HT CS–metal composite hydrogel	Copper sulfate and/or zinc nitrate at room temperature mixed with HT CS	Hydrothermal treatment of CS results in increased functional groups availability for loading high amounts of antimicrobial copper and similar metals	Cu/CuO NPs Zn/ZnO NPs	Copper sulfate (10 mg/mL) and zinc nitrate (100 mg/mL) were added to the CS dissolved in 1% HCl at 10 mg/mL	–	< 5 nm	Growth inhibitory effect on both the “fermenters” group of gastric flora and the “opportunistic pathogen” group	Animal feed in industrial scale livestock farms	^Citation116	2015
SF/nano-HA hydrogel	Incorporated nanosized HA particles (nanoHA) into porous SF hydrogels	Hydrogels showed promising physicochemical performance with improved osteoblastic induction characteristics	Ag NPs Au NPs	Solutions were mixed with the SF solution with Au NP/Ag NP concentrations of 0%, 0.1%, 0.5% and 1%	–	12.7–69.1 nm 9.3–54.7 nm	Hydrogels with Ag NPs/Au NPs presented antimicrobial activity against MRSA, MSSA and E. coli (not effective against Staphylococcus epidermidis and Pseudomonas aeruginosa)	Bone tissue engineering with antimicrobial properties	^Citation90	2017
AG with IPN structure	IPN hydrogel nanocomposites based on ZnO- PEGMA and AG-N3 were prepared under UV irradiation	The IPN hydrogels exhibited excellent mechanical strength, light transmittance, bactericidal activity and negligible cytotoxicity	ZnO NPs	–	–	–	IPN hydrogel has shown antibacterial activity against Gram-positive and Gram-negative bactericides	A potential material for wound dressing	^Citation103	2016
CMC/ZnO nanocomposite hydrogels	Cross-linked with Fe^3+ in solution of CMC and ZnO NPs	pH sensitive, allow controlling and adjusting of the final release properties of the formulation	ZnO NPs	–	–	< 70 nm	–	An oral drug delivery system for the controlled delivery of drugs	^Citation104	2016
CMCh hydrogel	CMCh solution cross-linked with epichlorohydrin at 80°C	CMCh has several advantages over CS, such as increased water solubility, better biocompatibility, high moisture retention ability, etc	ZnO NPs	0.6 g of dry CMCh hydrogel was immersed in different concentrations of Zn(NO3)2 solutions (0.005, 0.010, 0.020, 0.030 and 0.050 M) for 24 h	–	190–600 nm	The CMCh/ZnO nanocomposite hydrogel has shown antibacterial activity against Gram- positive and Gram- negative bactericides	Applications in biomedical fields	^Citation106	2016
CS hydrogel	CS hydrogel beads were physically cross-linked using sodium tripolyphosphate as the cross-linker	Prolonged and controlled drug releases were observed for ZnO NPs containing CS beads	ZnO NPs	Zn(NO3)2·6H2O (0.5, 1.0 and 1.5 mmol) was added to 437.5 mL mixture system	–	10–25 nm	–	Hopeful candidates for the controlled delivery of drugs	^Citation105	2016
CMC/ZnO nanocomposite hydrogels	CMC solution cross-linked with epichlorohydrin at 80°C	Novel CMC/ZnO nanocomposite hydrogels were synthesized by in situ oxidation of the Zn^2+ ions in the CMC hydrogel matrix	ZnO NPs	0.6 g of dried CMC hydrogel was immersed in zinc nitrate solutions with different concentrations (0.005, 0.010, 0.020 and 0.030 M) for 24 h	–	30–40 nm	The CMC/ZnO nanocomposite hydrogel has shown antibacterial activity against Gram- positive and Gram- negative bactericides	Applications in biomedical fields	^Citation102	2015
Modified κC hydrogel	κC was blended with NaCMC dissolved in distillated water	The release ability of carrageenan hydrogels was increased under pH of gastrointestinal conditions	MgO NPs	0.1, 0.15 and 0.2 g in the 30 mL system with 0.48 g κC and 0.12 g NaCMC	–	< 50 nm	–	A potential strategy to develop controlled drug delivery especially in gastrointestinal tract studies	^Citation120	2012
Agarose hydrogels	An agarose gel is loaded with Au salt by immersion for 24 h	Approximate size of the particles increases with increasing Au loading	Au NPs	–	20 mM	0.5–4 nm	–	–	^Citation83	2009
Gelatin hydrogels	Genipin cross- linked	Thermoresponsive	Au NPs	–	52, 104 and 156 ppm	10 ± 2 nm	–	Application of these nanocomposites as carriers in remotely controlled light- triggered drug release	^Citation84	2013
Hydrogel PMAA capsules	PMAA/PVPON multilayer precursors through cross- linking with EDA	pH-responsive layered hydrogel	Au NPs	–	–	(PMAA) 10 average size of 16 ± 3 nm	–	Potential use for fabrication of hybrid organic- Au NPs for biochemical sensing and delivery applications	^Citation88	2009
AuC–liposome hydrogel	Au NPs through sodium borohydride reduction method and liposomes through the standard extrusion method	pH-responsive Au NP-stabilized liposomes and no observable skin toxicity	Au NPs	0.7 and 0.8 vol%, within the first 24 h, only 25% and 17% liposomes were released	Mixing with AuC at a liposome-to-AuC molar ratio of 1:200	AuC liposomes 97.1 ± 1.0 nm, Au NPs 4 nm	Inhibition zone against S. aureus on solid agar medium	Hold great promise for topical applications against various microbial infections	^Citation89	2014
AM and 2-acrylamido- 2-methyl-1- propanesulfonic acid-based hydrogels	Free radical polymerization of AM monomer with the addition of hydrophilic vinyl monomer	Bimetallic (Ag, Au) hydrogel nanocomposites	Au NPs and Ag NPs	–	–	–	Inhibition zone against Bacillus on solid agar medium	Promising antibacterial materials in biomedical field	^Citation92	2012
Hydrogels of Carbopol^® 980 NF and AM	A green process by the nucleation of silver and gold salts with mint leaf extract to form a hydrogel network	Bimetallic (Ag, Au) hydrogel nanocomposites	Au NPs and Ag NPs	3.41 wt%	–	5 ± 3 nm	Inhibition zone against Bacillus and E. coli on solid agar medium	Effective pharmaceutical formulations for wound dressing	^Citation93	2014
Hydrogel of acrylic acid Zn(Bipy- (MMOES)2)	Free radical polymerization to give a new cross- linked polymer system	pH responsive	Zn(Bipy- (MMOES)2)	4%–10%	From 3.47 ± 0.43 to 5.78 ± 0.45 ppm/h according to different pH values	–	Inhibition zone against both MSSA 476 and P. aeruginosa (PA01) and MIC	–	^Citation97	2011
CS hydrogel	Incorporation of ZnO NPs into CS hydrogel	Flexible and microporous	Nano ZnO composite	0.005%–0.01% ZnO NPs	–	70–120 nm	Antibacterial ability exhibited by evaluation of P. aeruginosa, Streptococcus intermedius, Staphylococcus hyicus isolated from the rat wound	Bandages for burn wounds, chronic wounds, and diabetic foot ulcers	^Citation98	2012
Poly(N- isopropylacrylamide) hydrogel	Spin coating and photocross-linking	Quite a uniform distribution	ZnO NPs	0.58–2.5 mmol cm^−3 for the thin and 0.63–3.36 mmol cm^−3 for the thick films	–	23 ± 6 nm	Efficient antimicrobial activity against E. coli at very low ZnO loadings	Promising candidates for novel biomedical device coatings	^Citation100	2012
Chitin nanogels	Nickel nanoparti- cles prepared by hydrothermal method	Cytocompatibility	Nickel nanoparticles	800 µg/mL support both cytocompatibility and antibacterial activity	–	120–150 nm	Antibacterial activity against S. aureus	Various applications in biomedical field	^Citation110	2013
Zeolite/poly(vinyl alcohol) hydrogel	Physically cross- linked by the freezing–thawing method	Natural zeolite powder loaded with cobalt(II) ions	Co-zeolite content	Co-zeolite content higher than 0.48–4.77 wt%	, 0.02 mg after 24 h immersion	–	Co-zeolite content higher than 0.48 wt% has antibacterial activity against E. coli by the disk-diffusion method	–	^Citation111	2013

Abbreviations: AG, agarose; Ag NPs, silver nanoparticles; AG-N3, 4-azidobenzoic agarose; AG-N3, 4-azidobenzoic agarose; AM, acrylamide; Au NPs, gold nanoparticles; CMC, carboxymethyl cellulose; CMCh, carboxymethyl chitosan; CS, chitosan; CuO/Cu NPs, copper-containing NPs; EDA, ethylenediamine; HA, hydroxyapatite; HT, hydrothermally treated; IPN, interpenetrating polymer network; κC, κ-carrageenan; MgO NPs, magnesium oxide-containing nanoparticles; MRSA, methicillin-resistant S. aureus; NaCMC, CMC sodium salt; PMAA, poly(methacrylic acid); SF, silk fibroin; UV, ultraviolet; ZnO NPs, zinc oxide nanoparticles; ZnO-PEGMA, poly(ethylene glycol) methyl ether methacrylate-modified ZnO.

Figure 4 Multiple mechanisms of antimicrobial action of Ag NPs, ZnO NPs, copper-containing nanoparticles and Mg NPs are separately exhibited.

Note: Reprinted from Adv Colloid Interface Sci. 166(1–2). Dallas P, Sharma VK, Zboril R, Silver polymeric nanocomposites as advanced antimicrobial agents: classification, synthetic paths, appli cations, and perspectives, 119–135, Copyright 2011, with permission from Elsevier.³⁷

Abbreviations: Ag NPs, silver nanoparticles; Mg NPs, magnesium-containing nanoparticles; NP, nanoparticle; ROS, reactive oxygen species; UV, ultraviolet; ZnO NPs, zinc oxide nanoparticles.

Table 3 Antimicrobial mechanism of nanoparticles

Nanoparticles	Antimicrobial mechanisms	References
Ag NPs	1. Ag^+ dissolved from Ag NPs interact with sulfur-containing and phosphorus-containing groups of proteins of the cell wall and plasma membrane of bacteria. Binding to negatively charged parts of the membrane creates holes in the membrane, allowing plasma contents (including K^+) to flow out of the cell, dissipating the H^+ gradient across the membrane.	^Citation34, ^Citation36, ^Citation39^–^Citation42
	2. Inside the microbial cell, Ag NPs exert several antimicrobial effects: 1) inhibiting cytochromes of the electron transport chain of microbes; 2) causing damage to DNA and RNA of microbes; 3) inducing formation of ROS, which are also toxic to host cells; and 4) inhibiting cell wall synthesis in Gram-positive bacteria.
	3. After the Ag NPs are leaked from the dead microbes, Ag NPs could go on to kill other microbial cells.
Au NPs	Au NPs can be attached to bacterial membrane, which leads to leakage of bacterial contents or penetration of the outer membrane and peptidoglycan layer, resulting in bacterial death.	^Citation85
Au NP-Amp	First, the presence of multiple Amp molecules on the surface of Au NP allows the Au NP-Amp to overwhelm high concentrations of beta-lactamase expressed by these bacteria. Second, Au NP-Amp inhibits the transmembrane pump that catalyzes drug efflux from the bacterial cell.	^Citation86
ZnO NPs	1. ZnO NPs bind to bacterial cell membranes and destroy the lipids and proteins on them.	^Citation31, ^Citation33, ^Citation35, ^Citation95, ^Citation98
	2. ZnO NPs could cause formation of Zn^2+ ions and ROS, which damage the bacterial cell.
	3. When coated with PVA, ZnO NPs increase membrane permeability and enter the cytoplasm of the bacterial cell.
CuO/Cu NPs	1. Cu interacts with amine and carboxyl groups on the surfaces of microbial cells. Therefore, microbes with higher density of the two groups have higher sensitivity to CuO/Cu NPs.	^Citation112^–^Citation114
	2. Cu++ ions induce formation of ROS.
MgO/MgX2 NPs	1. MgO/MgX2 NPs inhibit certain enzymes of microbial cells.	^Citation117^–^Citation120
	2. MgX2 NPs may induce formation of ROS.
	3. MgX2 NPs inhibit growth and biofilm formation.
	4. Unlike any other metal, the antimicrobial activity of MgO works by adsorbing halogen molecules onto the surface of the MgO.

Abbreviations: Ag NPs, silver nanoparticles; Amp, ampicillin; Au NPs, gold nanoparticles; CuO/Cu NPs, copper-containing NPs; MgO NPs, magnesium oxide-containing nanoparticles; MgX₂ NPs, magnesium halogen-containing nanoparticles; PVA, polyvinyl alcohol; ROS, reactive oxygen species; ZnO NPs, zinc oxide nanoparticles.

Figure 5 Development of antibiotics and appearance of drug resistance are summarized chronologically referring to Huh and Kwon,³⁵ Andersson and Hughes,¹³² Rodriguez- Rojas et al,¹³³ van Hoek et al,¹³⁴ Molton et al.¹³⁵

Abbreviations: E. coli, Escherichia coli; K. pneumoniae, Klebsiella pneumoniae; MRSA, methicillin resistant S. aureus; S. aureus, Staphylococcus aureus; VISA, vancomycin intermedicate resistant S. auereus; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistant S. aureus.

Table 4 Information of hydrogels with antibiotic agents

Species of hydrogels	Synthesis of hydrogels	Highlights of hydrogels	Antimicrobial agents delivered	Content of antimicrobial agents	Rate of release	Antimicrobial capability	Application		References	Year
Amphiphilic mono-mPEG-PLGA copolymers	Ring-opening polymerization of monomers and mPEG in the presence of stannous 2-ethyl hexanoate	Easy preparation, 100% encapsulated rate, near-linear sustained release of drugs, injectable design and in situ gelling at the target tissue	Teicoplanin	840 mg/mL	At day 31, teicoplanin releases 73%, 70% and 60%, respectively (in different groups)	Antimicrobial activity against Staphylococcus aureus	A therapeutic strategy for infected diseases, such as osteomyelitis		^Citation202	2010
Gentamicin-loaded thermosetting composite hydrogels	Combined CS with bovine bone substitutes (Orthoss^® granules), beta- glycerophosphate as cross-linker and lyophilized	Porosity (80%–86%), scaffold water uptake and retention capability	Gentamicin	4 mg in 1 mL thermosetting composite hydrogel starting solution	Release was completed in 4 h	Antimicrobial effect on Escherichia coli	Drug delivery for reducing infection risk during bone open surgeries		^Citation155	2017
OPF/SMA charged	UV cross-linking	Negatively charged, non-toxic and is able to be cross- linked into several known copolymer formulations	Vancomycin	500 µg/mg	33.7% in the first 6 h <80% in the first 24 h	Antimicrobial activity against MRSA	Appropriate candidates to deliver local antibiotic therapy for prophylaxis of surgical site infection		^Citation164	2016
Micrometer-sized β-cyclodextrin-based hydrogel (bCD-Jef-MPs)	Introduced Jeffamine segments in the polymeric network	1) Appropriate stiffness, 2) adaptability to the pocket geometrical structure and 3) ease of application by minimally invasive approach	CHX-dg	–	CHX-dg was released in a time-dependent fashion and by following a quasi- constant rate of 10%/day	–	Effectively treating periodontitis lesions		^Citation177	2017
O-CMCS hydrogels	O-CMCS hydrogel was prepared by CS, monochloroacetic acid EDC and NHS	The hydrogels performed good swelling capacities and obvious pH-sensitive properties	Lincomycin	–	–	Significant antibacterial activities against Gram-negative E. coli and Gram- positive S. aureus	Antibacterial material		^Citation197	2016
CS/G/β-Gp hydrogel	Added gelatin molecules to the thermosensitive CS/β-Gp hydrogels to form CS/G/β-Gp hydrogels	The gel strength increased at body temperature over the results from the CS/β-Gp hydrogel	MTZ vancomycin hydrochloride	–	The initial burst and total in vitro drug release for MTZ was 13% and 67%, while vancomycin hydrochloride 3% and 23%	Inhibition of anaerobic Gram- positive Clostridium sporogenes	Drug carrier with no cytotoxic effects		^Citation163	2016
PBAE hydrogel	Through the free radical polymerization of PBAE macromers using redox initiators	May reduce the potential for bacterial colonization of this biomaterial as antibiotic was found to be released until the hydrogel loses structural integrity	Vancomycin	1.5 wt%	One group finished vancomycin release after 11 days The other 21 days	Against S. aureus	An important step in degradative- based drug delivery for local antibiotic treatment		^Citation165	2014
Calcium–alginate–gelatin hydrogels with CS/poly-γ-glutamic acid nanoparticles	Dropping aqueous alginate–gelatin into an aqueous solution of calcium chloride	Hydrogels are pH- sensitive, leading to protection of the nanoparticles from destruction by gastric acid	Amoxicillin	–	At pH 6.0, only a very small amount of amoxicillin was released, whereas, at pH 7.0, the amoxicillin was released rapidly	Effective for Helicobacter pylori	An efficient carrier for antibiotic drug (amoxicillin) delivery		^Citation188	2010
c-Dxt/PAA hydrogel	The c-Dxt/pAA hydrogel was synthesized via free radical polymerization in the presence of KPS initiator	Non-cytotoxic toward human mesenchymal stem cells, degradable in nature	Ornidazole and ciprofloxacin	–	Controlled release behavior remains stable in the tablet formulations for up to 3 months	–	Open a new platform as matrix for controlled release of ornidazole and ciprofloxacin		^Citation144	2015
Cross-linked hydrogel derived from Dxt, N-isopropylacrylamide and N,N′-methylene bis(acrylamide) (c-Dxt/pNIPAm)	Dxt as biopolymer, NIPAm as monomer, MBA as cross-linker and KPS as initiator	The pH and temperature responsiveness, non-cytotoxicity, biodegradability and good compatibility between the drugs and the matrix along with the controlled release behavior	Ornidazole and ciprofloxacin	–	Controlled release behavior ~97% ornidazole and ~98% ciprofloxacin remain stable in the tablet formulations for up to 3 months	–	An excellent alternative for controlled release of ornidazole and ciprofloxacin		^Citation170	2015
P (NIPAM-AA-HEM) hydrogel	Poly(NIPAM-AA- HEM) was cross- linked by free radical copolymerization of monomers in 1,4-dioxane under N2 atmosphere with TEGDM (0.1 wt%) as a cross-linking agent	The hydrogel enhanced drug concentration at the topical site than powder amoxicillin, thus reducing the adverse effects	Amoxicillin	1%, 2% and 5%	88.5% of amoxicillin in the hydrogels was released in 4 h in the pH 1.0 medium, whereas at pH 7.4 not >45% at 37°C	Effective for H. pylori	A novel therapeutic modality for the treatment of H. pylori-mediated infections	^Citation189		2011
Floating pH-sensitive CS hydrogels	Cross-linking high molecular weight CS in lyophilized solutions containing MTZ using either citrate or tripolyphosphate salts at 1% or 2% concentration	Hydrogel formula was retained in environment of stomach for at least 48 h	MTZ	Ranged from 246 ± 4.24 to 249.5 ± 10.60 mg/500 mg formula	More than 70% of the loaded drug was released in SGF (pH 1.2) within 24 h, while none of the prepared formulas released >70% within the 24 h in phosphate buffer (pH 7.4)	More effective against H. pylori than the commercially available oral MTZ tablets	A promising site-specific delivery system for the treatment of peptic ulcer caused by H. pylori	^Citation173		2016
PVA hydrogel	Glutaraldehyde was used as the cross- linking agent for PVA hydrogels	The drug size, matrix pore size, drug–matrix interaction, electrode polarity and an applied electric field were shown to be important controlling factors for drug release	Sulfanilamide	–	Drug release was effected by different factors	–	Drug delivery system	^Citation180		2012
CG injectable hydrogels	Solution of 2% (w/v) CS, 4% (w/v) gelatin, 2% (w/v) powdered low glucose DMEM and 0.003% (w/v) transglutaminase were prepared in 0.1 N HCl	Controlled release of DOX and improved mechanical stability	DOX	–	90% of DOX released from cross-linked CG hydrogels after 4 days	–	Significant potential as a carrier for cell delivery	^Citation199		2015
PNDJ	Free radical polymerization in a blend of dioxane/tetrahydrofuran	Gentamicin is delivered from PNDJ hydrogel with low systemic exposure and decreased treatment failure for orthopedic infection	Gentamicin	1.61% 3.14%	96% of the contained gentamicin load was recovered by 72 h for the lower- dose formulation, whereas the higher dose delivered 75% and took 7 days to release 100%	Sustained antimicrobial activity against S. aureus	Resorbable viscous hydrogels for local antimi- crobial delivery may improve outcomes for one-stage management of implant infections	^Citation153		2015
mPEG-PLCPHA thermosensitive hydrogels	mPEG-PLCPHA was synthesized by polymerization of aromatic polyanhydrides, mPEG and polyesters	mPEG-PLCPHA copolymer could form gel at body temperature with excellent biocompatibility and a stable release for 30 days	Cefazolin	20 mg/mL	The steady release of cefazolin lasted up to 4 weeks and no significant burst effect was shown in the release profiles	Sustained antimicrobial activity against E. coli	Injectable depot gel for drug delivery	^Citation194		2014
PVA	The scaffolds of PVA were fabricated by quenching in liquid nitrogen and freezing–drying and resoaking method from different original concentration aqueous solutions	Excellent release capability of ciprofloxacin, non- cytotoxicity and induction of cell growth	Ciprofloxacin	10 wt% of corresponding PVA weight	86.0%, 76.6% and 54.5% for 10 wt%, 14 wt% and 18 wt% scaffolds, respectively, at 128 h	Completely inhibited the growth of E. coli	A good potential application in tissue engineering, demanding high strength and well drug release capability	^Citation143		2016
PMAA nanogels	Ethylene glycol dimethacrylate is used as the cross- linker of PMAA nanogels	MTZ/PMAA nanogels sustained the release of MTZ in the simulated gastrointestinal medium and exhibited less cytotoxicity than MTZ alone	MTZ	23.2–69.1 g/mg	<12.7% (pH =1.2), 33.3% (pH =6.8) and 58.9% (pH =7.2)	Excellent antibacterial activity against Bacteroides fragilis	MTZ/PMAA nanogel would be a more useful dosage form than MTZ for mild- to-moderate Clostridium difficile infections	^Citation171		2014
Dxt and poly (2-hydroxyethyl methacrylate)-based cross-linked hydrogel (c-Dxt/pHEMA)	c-Dxt/pHEMA was synthesized by free radical polymerization technique, with MBA and KPS as cross- linker and initiator, respectively, in nitrogen atmosphere	Non-toxic against HaCaT cells, excellent drug stability and released ciprofloxacin hydrochloride in more sustained way than that of other hydrogels	Ciprofloxacin	1 wt%	Sustainable release of ciprofloxacin (33.75% release after 18 h)	–	A potential candidate for ciprofloxacin carrier	^Citation145		2015
CS with PEG pH- sensitive hydrogels	CS and PEG cross-linked with tetraethyl orthosilicate as cross-linker	The pH sensitivity and non- cytotoxicity made these hydrogels an appropriate candidate for injectable drug delivery	CFX	CFX (25 mg/25 mL of methanol) was loaded into blend of CS (0.75 g) and PEG (0.1 g, MW = 6,000)	Sustained amount of drug (CFX) is released (85%) during 80 min	Hydrogels exhibited antibacterial activity against Gram-negative bacteria E. coli and Gram-positive bacteria S. aureus	An attractive biomaterial for injectable drug delivery with physiological pH and other biomedical applications	^Citation192		2015
Hyaluronic acid nanohydrogels	Self-assembling of the hyaluronic acid-cholesterol amphiphilic chains in aqueous environment	Polysaccharide nanohydrogel	Levofloxacin	5.0% ± 0.5% w/w	–	Mean MIC values of S. aureus is 0.104 ± 0.058 mg/L and Pseudomonas aeruginosa is 0.557 ± 0.078 mg/L	Promising method for intracellular infection treatment	^Citation127		2014
Polysaccharide hydrogel	In situ cross-linking and Michael addition reaction	Closely mimic the nature extracellular matrix glycosaminoglycans	Vancomycin	0.9 mg/mL	6%, 30% and 48% in the initial 48 h	Inhibition against E. coli and S. aureus	A promising carrier have potential application for wound healing	^Citation162		2014
Hydrogelator containing an l-lysine	Synthesized by linking with amino acid or carboxylic acid derivatives	(−)-Menthol- based thixotropic hydrogels	Zn^2+ or lincomycin	Zn^2+ 0.01 M lincomycin 0.001 M	–	Oxford cups inhibition zone against Staphylococcus epidermidis and E. coli	A universal carrier for antibacterial agent	^Citation196		2014
CS-based composite hydrogels	Free radical cross-link copolymerization	wt% of CS and MBA and pH of the medium strongly influence the drug release	Tinidazole	15–20 wt%	Close to Korsmeyer–Peppas model	–	Optimum swelling, drug entrapment and drug release profiles at pH 7.5	^Citation172		2014
Bacterial nanocellulose hydrogels	Octenidine was incorporated in bacterial nanocellulose with the intension	Biocompatible, stable, releasable and biologically active over a period of 6 months	Octenidine	0.1 mg/mL	Rapid release in the first 8 h, followed by a slower release rate up to 96 h	Freshly prepared and 6 months both act effectively on S. aureus	Ready-to-use system for wound treatment	^Citation178		2014
PVA hydrogels	Prepared from PVA in a saline solution by γ-irradiation	Easy and inexpensive synthesis, suppressed release	Cetylpyridinium chloride	0.08%–0.24%	<1.08 mg/mL for 0.08% CPC, <1.35 mg/mL for 0.16% CPC and <2.44 mg/mL for 0.24% CPC	Inhibition zone against E. coli	Achieving the suppressed release of antibacterial agents	^Citation181		2014
Nanostructured hydrogel containing self- assembly of ciprofloxacin and a tripeptide	Modified morphology and rheological properties	Self-assembly of ciprofloxacin and a hydrophobic tripeptide	Ciprofloxacin	30 µg/mL for 0.1% w/v CIP, and 51 µg/mL for 0.2% w/v CIP	0.1% w/v or 0.2% w/v 2 mg/mL^−1	Inhibition zones of S. aureus, E. coli, Klebsilla pneumoniae	Cost-effective wound dressings and novel antimicrobial formulations	^Citation129		2013
Hydrogel based on Dxt grafted with poly(2-hydroxyethyl methacrylate)	Synthesized via free radical polymerization technique	Good biocompatibility and drug release in a controlled and sustained way	Ornidazole	0.36992–1.8496 × 10^−6 mol	Ornidazole release follows first-order kinetics and non- Fickian diffusion mechanism	–	Colon-specific delivery of ornidazole	^Citation130		2013
Gelatin/genipin hydrogel	Gelatin/genipin solution firstly absorbed by TCP cements via vacuum treatment, then cross-linked	Gentamicin-doped beta-TCP scaffold reinforced with a gelatin/genipin hydrogel	Gentamicin	–	17% initial release on the first day and 2–4 µg after that	Antimicrobial ability against S. aureus by spread plate method	Promising gentamicin releasing bone scaffolds in treating osteomyelitis	^Citation146		2013
Acacia gum and carbopol hydrogels	Solution casting method	Blood compatibility, antioxidant activity, mucoadhesion, oxygen/water vapor permeability, microbial penetration	Gentamicin	Diffusion coefficients 3.095 × 104 mm^2/min	Fickian diffusion mechanism	Inhibition zones against Gram-negative bacteria than Gram- positive	Wound dressings	^Citation150		2013
Hydrogels of Poloxamer 407 and polyacrylic acids (Carbopols 971P and 974P)	Commercial acquired	Comparison of three transdermal microgels	Gentamicin	P90H-based C971P gave the best drug content of 95.66%	Fast antimicrobial activity	P90H-based microgels of P407 had the highest IZD value against E. coli	Transdermal system	^Citation152		2013
Hydrogels based on dextran and poly(l-glutamic acid)	Photo cross-linking	Higher swelling ratio and quicker degradation	Vancomycin	Higher vancomycin loading content	Sustained release up to 72 h	Efficient MRSA inhibition to 7 days	Scaffolds or coatings for local antibacterial drug release in tissue engineering	^Citation166		2013
PVA–alginate hydrogel	Physically cross- linked and freezing–thawing method	No riskiness of chemical reagents and cross-linkers	Sodium ampicillin	0.2–0.8 mg in 50 mL	38%–45% burst release of ampicillin and no significant distinctions after 6 h of release	Inhibition zones against Streptococcus pyogenes, S. aureus, P. aeruginosa and Proteus vulgaris	Wound dressing applications	^Citation190		2013
Hydrogel tablets of carbopol and sodium alginate	Direct compression of the tablets	Successful gastroretentive effect	Cefditoren and pivoxil	94.25%–97.88%	Release of 95.012% at 24th hour	–	Achieve gastroretentive effect	^Citation193		2013
Hydrogel of polycarbonate and PEG triblock copolymers	Incorporating polycarbonates with vitamin E moiety into physically cross-linked network	Biodegradable and excellent compatibility, vitamin E-functionalized polycarbonates	Fluconazole	4 mg/L	Most drug molecules at 2 h	MBC observed in S. aureus, E. coli, Candida albicans	Prevention and treatment of skin infections	^Citation224		2013
β-cyclodextrin hydrogels	Directly cross-linked hydroxypropyl- cyclodextrin	Superhydrophilic	Thiosemicarbazones	Up to 4,000 µg/g dry hydrogel	A controlled TSC release for at least 2 weeks	Against P. aeruginosa and S. aureus	Treatment of ocular infections	^Citation179		2013
Poly(N- hydroxyethylacrylamide)/SA hydrogels	Prepared by adding “monomer solution” and MBAA as cross-linker	High surface resistance to protein adsorption, cell adhesion and bacteria attachment	SA	SA was increased from 3.4% to 34% (w/v), the loading efficiency of SA incorporation was 20% and ~80% (w/w)	82% SA rapidly released within 15–20 min, reached a limit (98%) after 240 min	E. coli and S. epidermidis	Antifouling and antimicrobial properties	^Citation184		2013
Alginate hydrogel sphere	Two-step approach	Improved alkali and heat resistances	Isothiazolinones	Drug loading is 12.8 mg/g	Released MCI/MI in a sustained manner	Long-term antibacterial activity	Easily added antibacterial hydrogel sphere for a wide range of products	^Citation185		2013
PVA and PVA- poly(AAm) hydrogel	Solution casting method	Permeable for oxygen and water vapor, blood compatibility	Gentamicin	–	Non-Fickian and Case II diffusion mechanism	Completely impermeable of microorganism and inhibition zone against microorganisms	Wound dressings for the slow release of antibiotic drug to the wound	^Citation149		2012
Pluronic-α-cyclodextrin supramolecular gels	Cold method	A cyclodextrin concentration acts on the tuning of the rheological features and drug release	Vancomycin	5.5 mg/mL	The higher the cyclodextrin proportion, the slower the release was	Inhibition zones against S. aureus	Sustained delivery of vancomycin	^Citation161		2012
CS hydrogel	Conventional film method for liposomes	Liposomes-in- hydrogel and prolonged retention time of this delivery system on the skin surface	Mupirocin	10%, w/w	505 µg/mL	S. aureus and Bacillus subtilis	Burn therapy	^Citation200		2012
Alginate hydrogel	By three- dimensional plotting system	Changes in fiber size and porosity altered the performance of the dressings	Tetracycline	–	65%–75% of TCH for the fibrous samples after 6 h and 94%–99% for films after 6 h	Inhibition zone against E. coli	Wound dressings	^Citation208		2012
Hydrogel of carboxymethyl CS	Prepared from CS, cross-linked with glutaraldehyde	Excellent pH- sensitivity	Ornidazole	>74% drug loading	Where 0.5 <n<1.0 non-Fickian transport and for n approaches 1 zero order, release is approaching zero order	–	Colon-targeted drug delivery	^Citation169		2012
Hydrogels of poly(2-hydroxyethyl methacrylate) or poly(ethylene–glycol diacrylate) or acrylic acid	Electrosynthesized directly on titanium substrates and loaded with ciprofloxacin	In situ sustained release system	Ciprofloxacin	100 µg/mL	0.45 ± 0.05, 1.25 ± 0.02, 3.38 ± 0.16 µg/mL^−1 after 48 h	Inhibition zones of MRSA	Prevention of titanium implant- associated infections	^Citation128		2011
Polysaccharide hydrogels	Chemical cross- linking	Superabsorbent	Gentamicin	400,000 U/mL	60%–90% release according to different cross-linking hydrogels after 72 h	Inhibition zones against both S. aureus and E. coli	New ideal wound-dressing materials	^Citation151		2011
Poloxamer hydrogels	Dox by a mechanism involving poloxamer corrosion	Chemically and physically stable formulation and thermal sensitive	DOX	0.1 wt%–0.3 wt%	Release follows a zero-order equation	–	Ophthalmic delivery	^Citation198		2011
Liposomal hydrogels	Reverse-phase evaporation for the preparation of liposomes	Prolonged-release liposomal hydrogel formulation	Ciprofloxacin	0.3% ciprofloxacin aqueous solution	75% release of ciprofloxacin for 10 h	–	Maximum in vitro ocular availability	^Citation136		2010
Hydrogel of PVA and polyaminophenyl boronic acid	Generated by polymerizing aminophenylboronic acid in PVA	Extended swelling	Ciprofloxacin	–	95% was diffused out of the system in 5 h	Inhibition zone against S. aureus, E. coli, K. pneumoniae, Acinetobacter calcoaceticus anitratus and Klebsiella sap	Tuning a new dressing for wounds particularly in diabetic patients	^Citation141		2010
Hydrogels of PVA and poly(acrylamide)	Free radical polymerization	Containing laxative psyllium	Ciprofloxacin	–	Fickian diffusion mechanism in pH 2.2 and pH 7.4 buffer non-Fickian diffusion mechanism in distilled water	–	Constipation caused by diverticulitis	^Citation142		2010
CS hydrogel	Free radical polymerization	Thermosensitive and injectable	Chlorhexidine	0.1%	68% release of CSHTCC/GP and 85% release from CS/GP at 18 h	Inhibition zones and MIC of Porphyromonas gingivalis, Prevotella intermedia and Aggregatibacter actinomycetemcomitans	A local drug delivery system for periodontal treatment	^Citation175		2010
PVA/PVP/glycerin hydrogels	γ-Irradiation and freezing–thawing	Excellent swelling capacity	Silver sulfadiazine, silver nitrate and sulfadiazine sodium salt	1 wt%	–	Inhibition zone against E. coli, S. aureus and S. aeruginosa	A wound dressing	^Citation182		2009

Abbreviations: c-Dxt/PAA, dextrin and poly(acrylic acid); CFX, cefixime; CG, chitosan–gelatin; CHX-dg, chlorhexidine digluconate; CS, chitosan; CS/G/β-Gp, chitosan/gelatin/β-glycerol phosphate; DOX, doxycycline; Dxt, dextrin; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; KPS, potassium persulfate; mPEG, methoxy poly(ethylene glycol); mPEG-PLGA, methoxypoly(ethylene glycol)-co-poly(lactic-co-glycolic acid); mPEG-PLCPHA, methoxy polyethylene glycol-co-poly(lactic acid-co-aromatic anhydride); MIC, minimal inhibition concentration; MRSA, methicillin-resistant S. aureus; MTZ, metronidazole; NHS, N-hydroxysuccinimide; O-CMCS, O-carboxymethyl CS; OPF/SMA, oligo(poly(ethylene glycol)fumarate)/sodium methacrylate; PBAE, poly(β-amino ester); PNDJ, poly(N-isopropylacrylamide-co-dimethyl-c-butyrolactone acrylate-co-Jeffamine^® M-1000 acrylamide); PEG, poly(ethylene glycol); P (NIPAM-AA- HEM), N-Isopropylacrylamide-acrylic acid-hydroxyethyl methacrylate; PMAA, poly(methacrylic acid); PVA, poly(vinyl alcohol); SA, salicylate; TCP, tricalcium phosphate; UV, ultraviolet; GP, glycerophosphate; IZD, inhibition zone diameter.

Figure 6 Mode of action for intracellular antimicrobial peptide activity. In this figure Escherichia coli was shown as the target microorganism from Brogden.

Note: Reprinted by permission from Springer Nature, Nat Rev Microbiol, Brogden KA, Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? 2005;3(3): 238–250, Copyright 2005.²³⁵

Figure 7 Morphological observation of various microorganisms seeded on hydrogels by scanning electron microscope. Left columns (control), right columns (antimicrobial hydrogels).

Note: Reprinted from Biomaterials. 32(11). Zhou C, Li P, Qi X, et al, A photopolymerized antimicrobial hydrogel coating derived from epsilon-poly-l-lysine, 2704–2712, Copyright 2011, with permission from Elsevier.²⁴²

Abbreviations: C. albicans, Candida albicans; E. coli, Escherichia coli; F. solani, Fusarium solani; P. aeruginosa, Pseudomonas aeruginosa; S.aureus, Staphylococcus aureus; S. marcescens, Serratia marcescens.

Table 5 Information of hydrogels with inherent antibacterial activity

Species of hydrogels	Synthesis of hydrogels	Highlights of hydrogels	Antimicrobial mechanism or agents	Antimicrobial capability	Applications	References	Year
Poly(2-hydroxyethyl methacrylate/itaconic acid) hydrogels	Prepared by γ-irradiation	pH and temperature sensitive	A good barrier against the microbes	Microbe penetration test: neither Staphylococcus aureus nor Escherichia coli passed through the hydrogel dressing	Great potential for biomedical applications, especially for skin treatment and wound dressings	^Citation230	2010
Hydrogels of PEGDA and containing ammonium salt (RNH3Cl)	Photopolymerization	Extremely high water uptake and permeability	Containing quaternary ammonium moieties	Excellent anti-fouling efficiency in cross- flow filtration test and antibacterial activity against E. coli	Coatings for water purification membrane	^Citation231	2011
Anionic hydrogel copolymers	Binding a cationic porphyrin through electrostatic interactions as a thin surface layer	Photodynamic	Anionic	Staphylococcus epidermidis adherence reduced by up to 99.02% ± 0.42%	Prevention of intraocular lens-associated infectious endophthalmitis	^Citation232	2009
Hydrogels of self- assembling β-hairpin peptides	Designed to self- assemble into a mechanically rigid antibacterial hydrogel	Arginine content largely influences the antibacterial activity	Arginine-rich self- assembling peptides	Extremely effective to Gram- positive, Gram-negative bacteria and multi-drug resistant Pseudomonas aeruginosa	Directly treat accessible wounds to prevent or kill existing infection	^Citation238	2012
A novel designed peptide for hydrogels	Electrostatic repulsion and hydrophobic attraction determines the molecular state	Stimuli-responsive self-assembling	Peptide sequences (KIGAKI)3-NH2	Antibacterial assay against E. coli	Applications in drug delivery, tissue engineering and regenerative medicine	^Citation239	2013
Hydrogels of epsilon- poly-L-lysine-graft- methacrylamide	Photopolymerization	Conveniently ultraviolet- immobilized onto plasma-treated plastic surfaces	Epsilon-poly-l-lysine	Wide spectrum antimicrobial activity against bacteria (E. coli, P. aeruginosa, Serratia marcescens, S. aureus, Candida albicans, Fusarium solani)	Hydrogel coatings for medical devices and implants	^Citation242	2011
Poly(2-hydroxyethyl methacrylate) hydrogels	Matrix loaded and immersion loaded	Antiadherent properties	Ultrashort peptide H-Orn-Orn-Trp-Trp- NH2 and lipopeptide C12-Orn-Orn-Trp-Trp-NH2	Antibacterial activity against S. epidermidis	Serve as an important weapon against biomaterial associated infections	^Citation244	2012
Polypeptide and poly(ethylene glycol) hydrogel	Metal-free ring-opening polymerization	Cell-adhesive	Poly(Lys)x(Ala)y	Significant antibacterial activity against E. coli and S. aureus	A potential scaffold for cutaneous wound healing	^Citation250	2012
Poly(ethylene glycol) diacrylate hydrogel	GST to anchor melittin to the surface of hydrogel microspheres	The anchored protein is enzymatically released	Bactericidal peptide, melittin	Efficiently inhibits growth of Streptococcus pyogenes	Novel way to load therapeutic proteins into a hydrogel-microsphere- based drug delivery system	^Citation251	2013
Polycarbonate and poly(ethylene glycol) hydrogels	Antimicrobial polycarbonate chemically incorporated into PEG hydrogel networks via Michael addition chemistry	No significant hemolytic activity or skin toxicity	Polycarbonate	>99.9% killing efficiency against multidrug-resistant Gram-positive, Gram- negative bacteria and fungi	A wide range of biomedical applications including catheter coating and wound dressing to prevent multidrug- resistant infections	^Citation266	2012
Polyampholytic hydrogels	Synthesized by inverse suspension polymerization	Can be separated by filtration after contacting with bacterial suspensions	Polyampholytic	Antibacterial activity against E. coli and Staphylococcus hyicus	–	^Citation267	2009
Hydrogelators of Fmoc amino acid/peptide- functionalized cationic amphiphiles	Incorporation of a pyridinium moiety and self-assembly of functionalized amphiphiles	Cell membrane penetration	Fmoc-peptide functionalized cationic amphiphiles	Efficient antibacterial activity against both Gram-positive and Gram-negative bacteria	Immense importance in the materials science	^Citation268	2010
Zwitterionic hydrogel	Conjugated with an antimicrobial agent as a leaving group	Switchable polymer and one-salicylate-per- monomer drug loading	Salicylate anion	Inhibition of growth against S. epidermidis	Open a door to the design and development of stealth materials and coatings with built-in biological functions	^Citation265	2012
Cholesterol-based hydrogelators	Synthesized in situ within the hydrogels using sunlight	Better water gelation efficiency	Amphiphile Ag NPs soft nanocomposite	Notable bactericidal property against both Gram- positive and Gram-negative bacteria	An effective step for designing smart biomaterials in future	^Citation269	2013
Supramolecular hydrogels	Synthetically modify antimycobacterial 4-alkoxyanilines by amidation with diglycolic acid anhydride yielding amphiphilic hydrogelators	Thermoreversible	Antimycobacterial amphiphiles	Mycobacterium leprae Mycobacterium bovis and Mycobacterium tuberculosis	–	^Citation270	2012
Boron/starch/polyvinyl alcohol hydrogels	Synthesized using glutaraldehyde as a cross-linking agent	Moderate antibacterial activity and antifungal activity	Boron complexes	Antibacterial activity against five different bacterial cultures and one fungus proved by disk diffusion susceptibility tests	–	^Citation271	2011
Hydrogel coating of chitosan/alkynyl chitosan	Electrophoretic co-deposition	Alkynyl chitosan derived from chitosan	Chitosan/alkynyl chitosan	MIC against E. coli and S. aureus were tested	Better antibacterial activities than pure chitosan hydrogel	^Citation275	2013
Poly(N- isopropylacrylamide)/polyurethane copolymer hydrogel	Synthesized by using ammonium persulfate as initiator and N,N,N^0,N^0- tetramethyl-ethane-1,2- diamine as accelerator	Temperature sensitive	Chitosan	Antibacterial efficiency against S. aureus and E. coli iŝ80%	Smart non-woven fabric potentially applicable in medical and cosmetics fields	^Citation278	2009
Chitosan-grafted mica-containing nanocomposite hydrogels	Radical copolymerization	Mica provides a rougher surface	Chitosan	Antiproliferative activity against S. aureus	–	^Citation279	2013

Abbreviations: Ag NPs, silver nanoparticles; Fmoc, N-fluorenyl-9-methoxycarbonyl; GST, glutathione S-transferase; PEG, poly(ethylene glycol); PEGDA, polyethylene glycol diacrylate; MIC, minimal inhibition concentration.

Figure 8 A new strategy that uses catecholic chemistry to synthesize antimicrobial silver nanoparticles impregnated into antifouling zwitterionic hydrogels.

Notes: On the top is the schematic illustration of the combination of AgNPs and antifouling hydrogel. In the middle, Photographs show the changes in color of hydrogels by changing the pH because of reaction that converts the Ag+ into solid AgNPs. The bottom section shows the surface structure and the morphology of hydrogel via scanning electron microscopy. Reprinted with permission from GhavamiNejad A, Park CH, Kim CS. In situ synthesis of antimicrobial silver nanoparticles within antifouling zwitterionic hydrogels by catecholic redox chemistry for wound healing application. Biomacromolecules. 2016;17(3):1213–1223. Copyright (2016), American Chemical Society.²⁸⁷

Figure 9 Graphical representation of MICs obtained after growing S. aureus and P. aeruginosa in the presence of different concentrations of gentamicin and ZnO/gentamicin–chitosan.

Note: Reprinted from Int J Pharm. 463(2). Vasile BS, Oprea O, Voicu G, et al, Synthesis and characterization of a novel controlled release zinc oxide/gentamicin-chitosan composite with potential applications in wounds care, 161–169, Copyright 2014, with permission from Elsevier.²⁹⁰

Abbreviations: MICs, minimal inhibition concentrations; S. aureus, Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa.

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