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Switchable Dual-Function and Bioresponsive Materials to Control Bacterial

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DOI: 10.1021/acsami.9b05901

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Switchable Dual-Function and Bioresponsive Materials to Control

Bacterial Infections
Mehran Ghasemlou,† Fugen Daver,‡ Elena P. Ivanova,§ Jong-Whan Rhim,# and Benu Adhikari*,†
†
School of Science and ‡School of Engineering, RMIT University, Melbourne, VIC 3083, Australia
§
School of Science, RMIT University, Melbourne VIC 3000, Australia
#
Center for Humanities and Sciences, Department of Food and Nutrition, Bionanocomposite Research Center, Kyung Hee
University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea

ABSTRACT: The colonization of undesired bacteria on the surface of devices used in

biomedical and clinical applications has become a persistent problem. Different types of
single-function (cell resistance or bactericidal) bioresponsive materials have been
developed to cope with this problem. Even though these materials meet the basic
requirements of many biomedical and clinical applications, dual-function (cell resistance
Downloaded by RMIT UNIV at 00:51:14:741 on July 03, 2019

and biocidal) bioresponsive materials with superior design and function could be better
suited for these applications. The past few years have witnessed the emergence of a new
from https://pubs.acs.org/doi/10.1021/acsami.9b05901.

class of dual-function materials that can reversibly switch between cell-resistance and
biocidal functions in response to external stimuli. These materials are finding increased
applications in biomedical devices, tissue engineering, and drug-delivery systems. This
review highlights the recent advances in design, structure, and fabrication of dual-
function bioresponsive materials and discusses translational challenges and future
prospects for research involving these materials.
KEYWORDS: dual-function materials, stimuli-responsive surfaces, regenerable materials, bioresponsive materials,
antibacterial surfaces

1. INTRODUCTION million patients each year.6 Earlier antibiotics were effective

Bacterial proliferation on the surface of medical devices and
processing equipment is a persistent and ubiquitous problem
even in developed countries. Bacterial proliferation begins with
the adhesion of the bacterial cells to the surface and the
formation of biofilm containing large bacterial colonies.1 The
biofilm shelters the bacterial cells and provides necessary
ground for proliferation and infection. The transition from a
free-living to an aggregated biofilm lifestyle can be devastating,
because bacterial cells present in biofilms can survive in a wide
range of hostile environments. This behavior can be problem-
atic when infectious materials are treated to remove these
complex structures because of the extreme resistance of
bacterial cells inside the biofilms against most antimicrobial
mechanisms.2 It is now commonly accepted that accumulation
of biofilm on medical devices adversely affects their function,
shortens their durability, and in many instances renders them
unusable. For example, the infections associated with medical
implants are one of the most frequent and complex infection-
related problems that do not yet have a clear solution.3
Bacterial contamination of implantable materials often leads to
postsurgical complications to remove and replace the infected
implant and causes immense healthcare costs to both patients
and hospitals.4 In 2011, ∼722 000 people in the United States
were estimated to be infected with medical-device-related
infections each year while residing in a U.S. hospital; of these,
∼75 000 patients died due to these infections.5 In Europe,
bacterial infections acquired in hospitals affect more than 4.2
against such infections; however, their overuse has led to the
evolution of resistant bacterial species, rendering them far less
effective than before. Currently available knowledge on
bacterial behavior cannot provide a precise solution to
completely eradicate biofilm formation; nevertheless, a number
of strategies have been proposed to minimize the adhesion and
growth of bacteria on the surface of medical equipment and
devices. The underlying operational mechanisms in these
strategies are based on preventing bacteria from adhering to
the surface, killing the bacteria that manage to attach on the
surface, or sometimes a combination of cell-resistance and
biocidal approaches. Single-function materials are found to
satisfy primary requirements of many clinical applications.
However, the design and engineering of dual-function
materials that can readily detect the biological signals produced
during biofilm formation and subsequently trigger the killing
response are expected to better suit complex, real-world clinical
applications. New classes of dual-function bioresponsive
materials have rapidly emerged in recent years.7,8 These
materials are not only able to resist and kill microbial cells
upon contact but also able to reversibly switch between these
functions in response to a change in environmental stimuli.7
Over the past decade, several comprehensive review articles
Received: April 3, 2019
Accepted: June 10, 2019
Published: June 10, 2019

© 2019 American Chemical Society 22897 DOI: 10.1021/acsami.9b05901

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ACS Applied Materials & Interfaces Review

Figure 1. Schematic illustration of major stages involved in biofilm formation.

Figure 2. Schematic illustration of the formation of a hydration layer in two different bacteria-resistant materials fabricated with (a) zwitterion-
based and (b) PEG brushes. The chemical structures of three commonly used zwitterion-based polymers and PEG are also provided.
Abbreviations: PSBMA (poly(sulfobetaine methyl acrylate)), PCBMA (poly(carboxybetaine methacrylate)), PMPC (poly(2-methacryloyloxyethyl
phosphorylcholine), and poly(ethylene glycol) (PEG).

have documented various aspects of biomaterials with single
functionality;8−10 however, there is no systematic review that
covers the recent developments in switchable bioresponsive
materials. Hence, this review outlines the most notable
developments for two main categories of single-function
(bacteria-resistant and biocidal) materials and highlights recent
advances on the design and implementation of switchable dual-
22898
function bioresponsive materials. Given the practical impor-
tance and increasing research interest in these smart materials,
greater emphasis is placed on reviewing the most recent
advances in their structure−function aspects. Finally, this
review also presents translational challenges and an outlook for
future research.
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Table 1. A Summary of Some Recent Publications that Deal with the Development of Bacteria-Resistant Superhydrophobic
Materials
water contact
substratea specific method angle targeted microorganism(s)b reduction ratec ref
carbon steel electrodeposition 158° P. aeruginosa 32
polypropylene thermal annealing 158° S. aureus and E. coli ∼95% and ∼53% 33
Teflon micro/nano patterning 158° E. coli and S. typhimurium ∼99.2% and ∼95.6% 34
stainless steel sol−gel method 154° E. coli ∼80% 35
PDMS chemical etching 169° E. coli >5 logs 36
polypropylene electrodeposition 152° S. aureus and P. aeruginosa inhibition: ∼65% 37
film
killing: ∼90%
silicon wafer deposition a thin layer of Ag and Cu on nanostructured 168° E. coli ∼97% 38
surface
aluminum anodizing and chemical etching S. aureus and E. coli >99% 39
PHB/PCL electrospinning 151° E. coli and S. aureus ∼99.95% and 40
∼99.91%
titanium anodizing and chemical etching 166° S. aureus and P. aeruginosa 41
stainless steel electrodeposition 163° P. aeruginosa and L. 42
monocytogenes
copper chemical etching 158° S. aureus 43
polycarbonate sol−gel method 154° P. aeruginosa 44
polypropylene chemical etching 155° E. coli ∼99.6% 45
film
a
Abbreviation: poly(dimethylsiloxane), PDMS; poly(hydroxybutyrate), PHB; poly(ε-caprolactone), PCL. bBacterial strains: Escherichia coli, E. coli;
Staphylococcus aureus, S. aureus; Salmonella typhimurium, S. typhimurium; and Pseudomonas aeruginosa, P. aeruginosa. cThe reduction rate (%) is
calculated as [(A − B)/A] × 100, where A and B are number of viable bacterial cells in unmodified and modified surfaces, respectively, after
incubation for 24 h.

2. SINGLE-FUNCTION BIORESPONSIVE MATERIALS
2.1. Bacteria-Resistant Materials. The formation of biofilm
typically starts with the interaction of bacterial cells with a material
that paves the way for propagation and multiplication on its surface
(Figure 1).11
The success of antimicrobial biomaterials lies in their ability to
prevent the bacteria from interacting with the surface, because the
behavior of bacteria changes quite significantly once a biofilm is
formed. The idea behind this strategy is that bacteria may not have a
chance to grow on a surface if they are simply prevented from
attaching to it.12 The prevention mechanism is associated with the
presence of an unfavorable hurdle that can limit the attachment of
bacteria primarily due to an unattractive surface chemistry.13 The
mechanism by which bacterial cells attach to a material’s surface is not
adequately understood; however, it is recognized as being greatly
influenced by environmental factors, the characteristics of the
bacteria, and the surface characteristics of the material involved.14
From the perspective of material science, it is possible to design a
material through physical or chemical modification to significantly
reduce bacterial adhesion and biofilm formation. For instance,
because many bacteria are inherently hydrophobic, it is generally
accepted that increasing the hydrophilicity of a surface can result in
increased resistance to bacterial adhesion.15 Hydrophilic surfaces
typically have high surface tension and can readily form hydrogen
bonds with surrounding water molecules.16 This hydration layer
ultimately helps prevent or reduce bacterial adhesion. On the basis of
this phenomenon, many studies have proposed immobilizing the
surface with nonfouling hydrophilic materials including poly(ethylene
glycol) (PEG) and zwitterionic polymers (carboxybetaine, phospho-
betaine, and sulfobetaine) on different substrates to increase
resistance to cell adhesion.17,18 The antiadhesion properties of PEG
are attributed to the ability of PEG to form a hydration layer through
hydrogen bonding with water molecules, which gives rise to repulsive
forces and subsequent resistance to bacterial adhesion (Figure
2b).17,19 Zwitterionic materials, having both positively and negatively
charged functional groups, have received increased attention in recent
years due to their ability to strongly bind with water molecules
through electrostatically induced hydration (Figure 2a). Zwitterionic
materials can bind water more strongly than PEG-based materials, and
they are promising candidates in the design of surfaces that resist the
attachment of bacterial cells.17,20 Another defensive strategy is
creating or inducing surface charge to tune the interaction between
the desired material and bacterial cells. Most bacterial cells are
negatively charged, because ionized carboxylate and phosphate
substituents are present in their outer cell wall.21 Thus, a surface
with similar charge is expected to exhibit an electrostatic repulsion,
while one with the opposite charge is expected to exert an
electrostatic attraction.21,22
On the basis of this, cell adhesion can be prevented when a
polyanion is deposited on the material’s surface. Zhu et al.23 reported
that a negatively charged surface could electrostatically interact with
other oppositely charged extracellular polymers produced by bacteria,
such as proteins (below their isoelectric point). Protein adsorption on
the surface can further promote bacterial adhesion. Thus, a control of
surface charge alone may not be an effective strategy to prevent
bacterial adhesion over a long period.21 For this reason, no study has
indicated that controlling the surface charge alone can significantly
alter cell adhesion. However, there are some studies that report the
effect of surface charge when it is combined with other factors. For
example, Guo et al.24 combined the layer-by-layer (LBL) technique to
assemble anionic PEG and cationic poly(ethylenimine) (PEI) on
poly(isobutylene-alt-maleic anhydride) (PIAMAn) and investigated
the integral effect of surface charge and hydrophobicity on protein
adsorption and cell adhesion. To modulate the surface charge, they
created the (deposited) surface layer to be alternately polyanionic or
polycationic by adjusting the pH and to modulating the surface
hydrophobicity. They showed that, when the positively charged
surface layer was deposited on a hydrophilic polymer, it resulted in
the highest cell adhesion. On the contrary, when the negatively
charged surface layer was deposited on a hydrophobic polymer, it led
to the lowest cell adhesion.
Alteration of surface topography is another important strategy that
can effectively stop biofilm formation by inhibiting the attachment of
bacteria.25 Recent advances in material and surface engineering enable
the manufacture of a material with controlled roughness and a well-
defined topography. 26 In this context, Perera-Costa et al.25
demonstrated that modifying the topographical properties of a

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Figure 3. Schematic illustration of an LBL assembly used in four major technological categories (a) immersive, (b) spin, (c) spray, and (d)
electrodeposition.
surface, regardless of the material’s hydrophobicity or hydrophilicity,
is a promising approach in controlling and inhibiting bacterial
adhesion. One class of recently developed materials that take
advantage of surface topography is superwettable materials. These
unique, nature-inspired materials have been found to be effective in
suppressing the adhesion between bacteria and solid materials and
preventing bacteria from forming biofilms.27,28 These topology-tuned
materials have received increased attention in the past few years. For
example, Shirtcliffe et al.29 reviewed the methods that could be used
to create superhydrophobic surfaces, and Celia et al.30 reviewed
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Review
progress made on designs of a number of superhydrophobic surfaces.
Similarly, Darmanin et al.31 and Das et al.27 reported more recent
developments and applications of biomimetic superhydrophobic
materials in various fields. Table 1 summarizes some of the latest
studies that have successfully implemented the concept of super-
hydrophobic materials and achieved good efficiency against photo-
genic bacteria.
2.2. Bactericidal Materials. Despite noteworthy progress made
in developing bacteria-resistant materials for preventing bacterial
adhesion, these materials do not kill bacteria. For this reason, once the
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bacterial cells manage to attach to these surfaces, they can still grow
and produce biofilms. Thus, it is essential to develop bactericidal
materials that can attach to the substrate. In this context, research
efforts are underway to develop a strategy that can effectively destroy
biofilms that have established themselves on materials.46 An overview
of this aspect revealed that two common bactericidal materials are
commonly used to kill bacteria that would otherwise proliferate on the
substrate. The first approach is to permanently immobilize or graft a
nonleaching bactericidal layer onto a material surface to kill bacteria
when they come in contact.47 The materials belonging to this group
are often called “contact kill”, as they can kill bacteria upon contact.9
The second approach involves developing materials that can gradually
release (leach) the bactericidal agent from the material surface in
response to environmental stimuli and kill the bacteria near as well as
on the surface.48
2.2.1. Contact-Kill Bactericidal Materials. Over the past decade,
developing contact-kill materials made through covalent bonding has
received particular attention. This strategy usually involves a two-step
approach in which the surface is initially treated using an appropriate
surface modification technique to create the functional group (e.g.,
carboxyl groups from the biocide that react with amine groups on the
surface) required for the next step.10 These surface modification
methods either modify existing functional groups or introduce new
functional groups on the surface.49 In the second step, the covalent
bond is created through a chemical reaction between the functional
groups on the material surface and the functional groups of the
bactericidal agent. The covalent bonds formed between the surface
and the biocide make the leaching of biocide from the surface quite
unlikely, thus enabling a long-term use of the material. The bonding
between the bactericide and the surface can be achieved either
through the direct attachment of the participating components or the
use of a binding molecule called a “spacer” or “linker”. Thus,
intermediate steps are often performed to create a spacer between the
bactericide and the surface.10 In some cases, this bonding is achieved
in a single step by attaching a polymer brush (a long-chain polymer)
with a terminal functional group to the material’s surface. This
reaction between the polymer brush and tethered functional groups
on the surface can typically be performed either through a “grafting-
to” or a “grafting-from” approach. In the grafting-to approach, a
functionalized polymer brush is directly grafted onto the surface
through covalent bonds. In grafting-from approach, a high-density
polymer brush grows on the surface by immobilizing initiating sites on
the surface.50
2.2.2. Layer-By-Layer Self-Assembly. Among the physical (non-
covalent) immobilization methods, the LBL self-assembly approach
has shown greater promise in developing more effective materials
through surface manipulation. The promise of the LBL technique lies
in its simplicity, flexibility, and ease of application to almost any
surface, regardless of size.51 Moreover, the LBL technique can be used
to fabricate bactericidal materials under mild conditions (e.g., aqueous
solution, absence of organic solvents, neutral pH, and ambient
temperature).51
LBL assembly is generally performed via a step-by-step deposition
of oppositely charged polyelectrolytes onto the surface of a charged
substrate (e.g., metal, silicone, or glass). It is essential for the substrate
surface to carry a charge by itself or readily undergo pretreatments to
acquire a desired charge.52 Four distinct types of treatment
immersive, spin, spray, and electrodepositioncan be used to make
LBL materials. Immersive LBL assembly, sometimes referred to as
“dip assembly”, is the most commonly used method. To properly
assemble a thin coating using this method, the charged substrate is
first immersed into a polyelectrolyte solution carrying the opposite
charge to the desired final charge.53
Next, the substrate surface is washed with deionized water to
detach the loosely adsorbed molecules from the surface and to
prevent cross-contamination of the polyelectrolyte solution.54 The
entire procedure is repeated as many times as required to deposit a
multilayered polyelectrolyte coating of the desired thickness (Figure
3a).52 In spin coating, a small amount of liquid is deposited on the
surface and spread across a planar surface through rapid spinning
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Review
(Figure 3b). In spray assembly, two layers are set down by pumping
the polymer solution through an atomizer and sequentially spraying it
onto the substrate (Figure 3c). Electrodeposition uses an applied
voltage in an electrolytic cell to produce a multilayered surface. In a
typical electrodeposition setup, an electric current is applied to two
electrodes immersed in the desired polymer solution. The electrodes
are then washed and placed into an oppositely charged polymer
solution, the polarities are reversed, and the cycle is repeated (Figure
3d). Depending on the characteristics of top terminating layer, the
resultant material can function as either bacteria-resistant or
bactericidal. If the terminating top layer is positively charged, the
material can be used as a platform to kill bacteria; if it is negatively
charged, the material will serve as a bacteria-resistant platform.
2.2.3. Triggered-Release Bioresponsive Materials. Another
effective biocidal strategy to overcome infections is to load or
embed biocidal agents onto the material’s surface in a way that
enables their release over time. These bioresponsive materials are
capable of killing bacteria on the surface as well as in the surrounding
area.55 There are four challenges that can potentially limit the
performance of these materials: (i) slow rate of release from the
material surface; (ii) lack of complete and sustained killing of bacteria;
(iii) effectiveness only for a short time and decreasing effectiveness
over time; and (iv) development of bacterial resistance because of
biocide release. To achieve the highest level of performance, the rate
of biocide release should not be too fast to avoid rapid loss of the
biocide. At the same time, the rate of release should not be too slow,
because the concentration may be insufficient to effectively protect
against bacterial growth. Despite the effectiveness of nonsustained,
release-based materials in bacterial removal, the continuous-release
strategy faces several challenges. A major challenge regarding
widespread application of these release-based systems is their inability
to effectively protect the surface for longer duration, as the biocidal
cargo on the surface continuously elutes and ultimately become
exhausted.56 Moreover, the intensive use of these leaching materials
can add more complexity to the unsolved problems associated with
the emergence of bacterial resistance. Therefore, a triggered-release
bioresponsive material that can store biocide agents for longer
durations and, more importantly, release the load on demand only in
the presence of bacteria are currently receiving increased research
interest.57 These materials are shown to be capable of providing the
required concentrations of a biocide at the right time and place, thus
preventing unwanted release in the absence of bacteria and reducing
the risk associated with the development of resistant bacterial
strains.58
The proliferation of bacteria on a material’s surface often leads to
an increase in temperature and/or a drop in the pH of the surface. On
the basis of this phenomenon, current research trends have focused
on designing bioresponsive materials that can easily sense changes in
environmental factors (e.g., temperature and/or pH) as a result of
microbial metabolism.59 In recent years, many reports have shown
that pH and temperature are two important stimuli that can trigger
the release of biocide agents from different surfaces that can switch
their water affinity in response to an external stimulus, opening or
closing their internal channels and releasing their cargo on
demand.60,61 Novel bioresponsive materials can be synthesized by
grafting a polymer that can respond to these environmental changes
to the desired substrate (either physically or chemically). The
following sections will specifically review the recent strategies and
achievements on the synthesis and application of materials and
systems that intelligently release biocidal agents when triggered by
temperature and pH as two external stimuli.
pH-Triggered Release Materials. pH-triggered release materials
are gaining significant attention owing to their great potential in
biomedical applications. As mentioned earlier, most bacterial
infections are often associated with the production of some acidic
substances such as lactic and acetic acids.59 The production of acids
and acidic substances immediately decreases the pH of the substrate.
Such changes in pH can be used in the design of smart materials that
can respond promptly and release a biocide specifically at the
contamination areas.62 Generally, pH-responsive polymers have
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Figure 4. Schematic illustration of triggered-release bioresponsive materials: (a) pH-triggered release systems and (b) temperature-triggered release
systems.

Table 2. Summary of Some of the Recent Studies that Deal with the Development of Triggered-Release Materials Capable of
Responding to Changes in Temperature or pH
nominal amount of bioresponsive potential
stimulus biocide/drug agent biocide/drug polymera target microorganism(s)b reduction ratec application ref
pH Vancomycin 500 μg/mL PDMAEMA S. aureus >92% delivery systems 69
pH ZnO nanoparticles 0.03 mol/L CMC S. aureus and E. coli delivery systems 70
pH Amoxicillin 100 mg/mL CMC S. aureus and E. coli ∼95% delivery systems 71
pH silver nanoparticles 0.05 mol/L CMC E. coli and S. aureus ∼98.36 and delivery systems 72
99.98%
pH Ciprofloxacin 0.015 mg/mL PMAA S. aureus, E. coli, and P. delivery systems 73
aeruginosa
pH Gentamicin and 0.1 mg/mL PMAA S. aureus and E. coli delivery systems 74
polymyxin
pH triclosan 20 mg/mL PVCL S. aureus and E. coli ∼40% and ∼52% delivery systems 65
temp crystal violet 1% (w/w) PNIPAAm S. epidermidis and E. coli delivery systems 58
temp silver nanoparticles 16 mg/mL PNIPAAm E. coli and S. epidermidis >83% delivery systems 75
temp curcumin 300 μg/mL PNIPAAm S. aureus and E. coli ∼90% delivery systems 76
temp Oxacillin 8.03 mg/mL PNIPAAm S. aureus and P. aeruginosa tissue 77
engineering
a
Abbreviations: poly(N-isopropylacrylamide), PNIPAAm; p(2-(dimethylamino)ethyl methacrylate), PDMAEMA; carboxymethylcellulose, CMC;
zinc oxide, ZnO; poly(methacrylic acid), PMAA; poly(N-vinylcaprolactam), PVCL. bBacterial strains: Escherichia coli, E. coli; Staphylococcus aureus,
S. aureus; Pseudomonas aeruginosa, P. aeruginosa; and Staphylococcus epidermidis, S. epidermidis. cThe reduction rate (%) is calculated as [(A − B)/A]
× 100, where A and B are number of viable bacterial cells in unmodified and modified surfaces, respectively, after incubation for 24 h.

ionizable chemical groups such as carboxyl, pyridine, sulfonic, or
phosphate that can accept or release protons in response to changes in
the environmental pH.63 They remain deprotonated or deionized
depending on polymer structure under normal pH conditions;
however, under acidic conditions they are protonated, causing
structural transformation or changes in solubility to specifically
release a preloaded biocide to the surface.64
Several pH-responsive polymers have been investigated over the
past few years to assess their suitability as carriers of biocidal
compounds. Among these polymers, the pH responsiveness of
chitosan has attracted considerable attention.65 This interest stems
primarily from the presence of amine groups in chitosan’s structure
that become protonated under mild acidic conditions (pH < 6.5) and
thus confer hydrophilic properties. However, in alkaline media (pH >

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Table 3. Summary of Some of Recent Studies That Adopted Resist-Kill to Develop Dual-Function Bioresponsive Materials
bacteria-resistant nominal amount of target potential
substrate unit bactericidal unit biocide/drug microorganism(s) reduction ratec application ref
PCU PSBMA chitosan-g- 15 mg/mL E. coli and S. aureus ∼93% and ∼95% medical devices 82
eugenol
silicon wafer PEGMA QACs 20% (v/v) E. coli and S. aureus >99% tissue 78
engineering
silicone rubber APEG PHMB 38.0% (w/w) E. coli ∼5 logs medical devices 79
glass polyglycerol glucose oxidase 2.5% (w/w) P. putida and >99.99% medical devices 86
S. aureus
thin-film composite PSBMA QACs 72.6 mg/mL E. coli ∼72% medical devices 87
PDMS PEG QACs 1.83 mg/mL E. coli and S. aureus ∼96.9% and medical devices 88
∼99.4%
PDMS PEG antimicrobial 16 mg/mL S. aureus, P. aeruginosa, >99% tissue 89
peptide and engineering
E. coli
polycarbonate PEG antibacterial 28.8 mg/mL E. coli and S. aureus ∼99.9% medical devices 90
cations
thin film composite PSBMA silver 5 mmol/15 mL P. aeruginosa ∼95% medical devices 91
nanoparticles
polyurethane film PEG/lysine QACs 4.96% (w/w) E. coli and S. aureus >99.99% medical devices 92
surface
silicon wafer PEG QACs 10 mg/mL S. aureus ∼60% medical devices 93
cotton fabrics PSBMA QACs 2 % (w/w) E. coli and S. aureus >99.99% medical devices 94
a
Abbreviations: poly(sulfobetaine methyl acrylate), PSBMA; polycarbonate urethane, PCU; poly(ethylene glycol), PEG; quaternary ammonium
compound salts, QACs; poly(hexamethylene biguanide), PHMB; poly(dimethylsiloxane), PDMS; poly(ethylene glycol) methyl ether methacrylate,
PEGMA; allyloxy poly(ethylene glycol), APEG. bBacterial strains: Escherichia coli, E. coli; Staphylococcus aureus, S. aureus; Pseudomonas aeruginosa,
P. aeruginosa; and Pseudomonas putida, P. putida. cThe reduction rate (%) is calculated as [(A − B)/A] × 100, where A and B are number of viable
bacterial cells in unmodified and modified surfaces, respectively, after incubation for 24 h.

6.5) these amine groups are deprotonated, displaying the hydro-
phobicity of chitosan (Figure 4a).66
Temperature-Triggered Release Materials. Bioresponsive materi-
als that provide on-demand release in response to a change in
temperature are also of practical significance. A careful examination of
the current literature revealed that most in vitro studies in the field of
smart materials with switchable biocide/drug release have been
devoted to those responding to changes in pH values; only a handful
of studies have focused on the synthesis and characterization of
bioresponsive materials using temperature-responsive polymers
(Table 2).
There are generally two types of polymers in this category, based
on how a polymer responds to changes in temperature. The first is
polymers with a low critical solution temperature (LCST) that exhibit
a hydrophilic-to-hydrophobic transition and become insoluble upon
heating. The second is polymers with an upper critical solution
temperature (UCST) that undergo an opposite transition and become
soluble as the temperature increases.67 To prepare temperature-
responsive materials using UCST polymers, it is necessary to perform
experiments at relatively high temperatures to facilitate mixing the
UCST polymers and biocides. Since most drugs or biomolecules are
unstable at high temperatures, the application of UCST polymers as a
temperature-triggering release platform is quite limited.68 Typical
LCST polymeric materials include poly(N-isopropylacrylamide)
(PNIPAAm), poly(N-vinylcaprolactam) (PVCL), and poly(2-hydrox-
yethylmethacrylate) (PHEMA); of these, PNIPAAm is the most
studied. PNIPAAm undergoes a hydrophilic/hydrophobic phase
transition once exposed to temperatures above or below its LCST
of ∼32 °C. At temperatures below the LCST, PNIPAAm is water-
soluble and hydrophilic and forms intermolecular and intramolecular
hydrogen bonds between the polymer chains and water molecules to
maintain coil integrity. This makes them ideal carrier materials for
biocide/drug molecules. However, when the temperature is increased
to above LCST, a morphological change from a coil to a globular state
occurs, causing the PNIPAAm chain to become hydrophobic due to
the breakdown of hydrogen bonds between the PNIPAAm and the
adsorbed water molecules. This leads to volumetric shrinkage, as the
water molecules from the matrix are squeezed out. This transition
eventually removes the biocide imbedded in the polymer (Figure
4b).58,61
3. DUAL-FUNCTION BIORESPONSIVE MATERIALS
Each of the single-function bioresponsive materials described above
has shown remarkable efficiency in the short term. The long-term
efficacy of these single-function systems is limited, since each suffers
from its inherent limitations. For example, on the one hand, bacteria-
resistant materials may prevent the initial attachment of bacteria to
the material’s surface for a certain period, but once the surface is
contaminated, these materials are no longer effective in preventing the
bacterial growth and subsequent biofilm formation.78 On the other
hand, the materials that leach out bactericidal agents are more likely
to give rise to bacterial resistance and cause environmental
contamination due to nonuniformity and excessive release of
bactericides. Moreover, the unleached bactericidal materials become
ineffective, as they can easily become fouled with a layer of proteins,
lipids, or even the dead bacterial cells. All of these factors prevent the
invading live bacteria from being exposed to the surface-tethered
biocidal groups and fail to prevent their growth and proliferation.79,80
Considering these limitations, single-function bioresponsive materials
are not sufficiently effective in controlling complex microbial
contamination on various surfaces.81 Thus, dual-function materials
are being developed to integrate the advantages of various single-
function materials into a single system.82 To more effectively prevent
the formation of biofilm, an ideal bioresponsive material should
perform the following functions: (i) resist initial bacterial attachment;
(ii) kill bacterial cells that crossed the antiadhesion barrier; and (iii)
release dead bacteria or other debris from the material’s surface.83 To
achieve these goals, researchers have attempted to develop
bioresponsive materials by combining two or more functions. In
particular, two types of dual-function bioresponsive materialsresist-
kill and kill-releasehave been the major focus of recent research.
The important characteristic features of these two types of dual-
responsive materials and the methods used for their design and
production are critically reviewed in the following sections.
3.1. Resist-Kill Bioresponsive Materials. The resist-kill
bioresponsive materials combine bacteria-resistance and bactericidal

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Table 4. Summary of Some of Recent Studies That Followed the Kill-Release Strategy to Develop Switchable Dual-Function
Bioresponsive Materials
nominal amount of target
stimulus biocidal unit biocide bacteria-resistant unita microorganism(s)b biocidal rate release rate ref
temp QACs 1% (w/w) PNIPAAm E. coli ∼90% ∼67% 99
temp QACs 5 mg/mL PNIPAAm E. coli and S. ∼80% ∼66% and ∼60% 100
epidermidis
and ∼85%
temp QACs 10 mg/mL PNIPAAm S. aureus ∼3 logs >90% 101
temp OPE PNIPAAm E. coli and S. ∼70% and ∼78% ∼64% 102
epidermidis
temp PMT 4% (w/w) PNIPAAm S. aureus ∼90% ∼85% 103
temp Vancomycin 1 mg/mL PSBMA and S. aureus ∼88.6% ∼72.5% 104
PNIPAAm
temp PDMAEMA 10 mg/mL PNIPAAm S. aureus >80% ∼58.5% 59
temp PPE 10 mM PNIPAAm E. coli and S. aureus ∼70% and 65% ∼80% 105
temp QACs 6 mmol/mL PNIPAAm E. coli and S. aureus 106
temp AgNPs 0.02 m M PNIPAAm E. coli and S. aureus 107
pH PCBOH (cationic PCBOH E. coli >99% >99% 108
form)
pH antimicrobial peptide 1 mg/mL PMAA S. aureus ∼4.88 log 109
pH lysozyme PMAA E. coli >95%. >90% 110
photo CD-QACs 1 mM azo group E. coli ∼93% ∼91% 111
photo CD-QACs 1 mM azo group E. coli ∼81% 112
photo PDMAEMA 50 mg/mL azo group E. coli 71.40% 113
salt (NaCl) triclosan 0.1 M PDVBAPS E. coli and S. aureus ∼97% and ∼95% ∼97% 114
salt (NaCl) lysozyme 3,6-O-sulfated E. coli 115
chitosan
salt (NaCl) silver nanoparticles 0.01 M PDVBAPS E. coli and S. aureus ∼99% >96% 116
salt (NaCl) PMETAC 1.7 mmol/mL PDVBAPS E. coli and S. aureus >93% ∼90% 117
salt (NaCl) Q4VP 150 mM P(Q4VP-co-AA) E. coli and S. aureus >90% 118
salt (NaCl) PTA 4.93 mmol/mL PDVBAPS E. coli and S. aureus ∼94.7% and ∼94.9% and 119
∼93.4% ∼93.3%
anionic LiTf2N 0.2 M PIL(Br) E. coli ∼90% 120
counterion
anionic PTMAEMA 1.5 M hexametaphosphate E. coli and S. ∼94.3% ∼96.2% and 97
counterion anions epidermidis ∼93.7%
sugar CD-QAS 1 mM PBA E. coli >99% ∼80% 121
a
Abbreviations: quaternary ammonium salts, QACs; poly(N-isopropylacrylamide), PNIPAAm; oligo (p-phenylene-ethynylene), OPE; poly[2-
(methacryloyloxy)ethyl]trimethylammonium chloride, PMT; poly(N,N-dimethylaminoethyl methacrylate), PDMAEMA; poly(methacrylic acid),
PMAA; poly(sulfobetaine methacrylate, PSBMA; poly(methacrylic acid), PMAA; poly(2-((2-hydroxyethyl)(2-(methacryloyloxy)ethyl)(methyl)
ammonio) acetate), PCBOH;azobenzene, azo; β-cyclodextrin derivative, CD; poly(p-phenylene ethynylene, PPE; silver nanparticles, AgNPs;
lithium bis(trifluoromethanesulfonyl) amide, LiTf2N; poly(2-(tert-butylamino)ethyl methacrylate), PMETAC; poly(3-(dimethyl(4-vinylbenzyl)-
ammonio) propyl sulfonate, PDVBAPS; poly(1-(2-methacryloyloxyhexyl)-3-methylimidazolium bromide), PIL (Br); poly [2-(tert-butylamino)
ethyl methacrylate], PTA; poly((trimethylamino)ethyl methacrylate chloride, PTMAEMA; phenylboronic acid, PBA; poly(quarternized-4-
vinylpyridine-co-acrylic acid), P(Q4VP-co-AA). bBacterial strain: Escherichia coli, E. coli; Staphylococcus aureus, S. aureus; and Staphylococcus
epidermidis, S. epidermidis.

capabilities. They can be prepared by introducing a nonfouling
hydrophilic polymer onto a substrate and then incorporating a
contact-active/releasable biocide agent onto the nonfouling hydro-
philic polymer, either by chemically grafting or by noncovalent
deposition using an LBL technique.83,84 These materials have been
intensively studied over recent years (Table 3).
For example, Yan et al.78 developed a new bioresponsive material
composed of a covalently bonded PEG top layer and a quaternary
ammonium compounds (QACs) bottom layer using the resist-kill
strategy. They showed that their dual-function surfaces reduced the
growth of Staphylococcus aureus and Escherichia coli during the 7 d of
the experimental test. Similarly, Gaw et al.85 produced a dual-function
bioresponsive material using an electrochemical approach. The
resultant material showed a high degree of bacteria-resisting activity
by preventing ∼99.5% of E. coli from attaching to the surface and
biocidal activity by reducing the bacterial count by ∼95%. Zhi et al.79
prepared yet another dual-function bioresponsive material by
tethering polyhexanide (PHMB) and allyloxy poly(ethylene glycol)
(APEG) onto a silicon rubber. This surface effectively reduced the E.
coli cells by approximately a 5-log cycle. More recently, Li et al.82
produced a dual-function bioresponsive material using poly-
(sulfobetaine methyl acrylate) (PSBMA) as a bacteria-resistant unit
and chitosan cross-linked eugenol as a bactericidal unit; this material
showed an inhibition of ∼93% and ∼95% against E. coli and S. aureus,
respectively. In many instances, the resist-kill dual-functional materials
performing both bacteria-resisting and bactericidal functions are
incapable of preventing bacterial growth. A major problem associated
with these materials is the interference between the two functions and
subsequent lowering of efficiency even below that of single-function
materials.95 The bactericidal function usually attracts the bacteria to
the surface to kill them, while the bacteria-resisting function works in
the opposite direction and repels the approaching bacteria. Moreover,
the accumulation of dead bacterial cells and other debris can block the
biocidal functional groups, rendering them ineffective.96,97 To achieve
the best performance, these two functions should work in such a way
that the surface performs only one function at a time to avoid
interference. The resist-kill bioresponsive materials are found to meet
the primary requirements of most biomedical applications.

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Figure 5. Schematic illustration of a kill-release switchable dual function material made of a nanopatterned PNIPAAm/biocide hybrid surface
fabricated through the combination of interferometric lithography (IL) and surface-initiated polymerization (SIP) techniques (top) and its kill-
release strategy in response to the change in temperature of the surface (bottom).
3.2. Kill-Release Bioresponsive Materials. To overcome the
limitations of resist-kill type of bioresponsive materials and to improve
their performance in complex, real-world situations, switchable dual-
function materials have been proposed. These materials not only
enable multiple functions under bacterial infections but also are able
to reversibly switch between the “resist” and “kill” functions when
triggered by environmental stimuli.98 Therefore, to develop the next
generation of dual-function bioresponsive materials, a number of
designs and polymeric materials have been proposed (Table 4). One
of these designs gives rise to kill-release bioresponsive materials. The
bactericidal function of this design starts to kill the attached bacterial
cells without being affected by the hidden antifouling function of the
material. A change in environmental conditions activates the
antifouling function to repel the dead bacteria from the material
surface.
Cheng et al.122 were among the first authors to recognize this
phenomenon and innovatively developed a polymer surface that could
intelligently switch between bactericidal and antifouling functions.
This strategy has since attracted the attention of many other
researchers and resulted in the development of a series of functionally
switchable bioresponsive materials that can kill and release bacteria.
Several types of materials triggered by different stimuli are reviewed
below.
3.2.1. Temperature-Responsive Materials. One of the basic
characteristics of a living entity is its ability to respond to changes
in its environment. For example, the leaves of the touch-me-not or shy
plant (Mimosa pudica) can quickly collapse upon contact as a
mechanism of fighting against invading agents and maintaining
integrity. Biological systems can respond to many different stimuli,
including temperature, pH, light, chemicals, and pressure.123 Nature-
inspired nanotechnology enables material surfaces to be modified at
the nanoscale level and efficient bioresponsive materials to be
designed to fight against bacterial biofilm formation. Several
intelligent bioresponsive designs have been proposed that can
respond more effectively to changes in a variety of environmental
stimuli. Thermoresponsive polymeric materials such as PNIPAAm
have been extensively studied, since they can undergo surface
transitions in response to changes in temperature.124 As mentioned in
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Section 2.2.3, the wettability and adhesion properties of surfaces
modified with PNIPAAm can reversibly change depending on
whether the temperature is above or below LCST.125
Yu and colleagues showed that an altered LCST changed the
wettability of the PNIPAAm chain, which facilitated reversible
switching between the adsorption and desorption of biomolecules.
In other words, at temperatures above the LCST (T > 32 °C), the
bacterial cells were attracted to the dehydrated nanopatterned
PNIPAAm/biocide surface, which facilitated their attachment. The
attached cells were subsequently killed when the biocide function was
triggered. A temperature below the LCST (T < 32 °C) triggered the
hydration of the PNIPAAm brush and promoted the release of dead
bacteria from the surface upon mild shearing (Figure 5).100,125 The
efficacy of these materials in both killing and releasing E. coli was
satisfactory given the complex environment. The same technique was
later applied using lysozymean environment-friendly and anti-
microbial enzymeinstead of QAC.126 The nanopatterned PNI-
PAAm/lysozyme surface showed a biocidal activity of ∼60% against
E. coli when the temperature was above the LCST. Also, this surface
released more than 70% of the dead bacteria when the temperature
was above the LCST of PNIPAAm. In another report,102 the same
authors proposed a simple and generic technique using resonant
infrared, matrix-assisted pulsed laser evaporation (RIR-MAPLE) to
deposit dual-function materials possessing biocidal and release
properties. They produced dual-function switchable bioresponsive
materials by depositing a hybrid matrix of PNIPAAm and oligo(p-
phenylene-ethynylene) (OPE) as a biocide on a solid surface.
Evaluating the bioresponsiveness of these materials against E. coli and
S. epidermidis showed that most bacterial cells were killed when the
temperature was above the LCST (∼37 °C). The dead cells were
easily removed when washed with water at a temperature below
LCST (∼25 °C). Shi et al.103 further demonstrated the effectiveness
of this technique by adopting the kill-release strategy and synthesizing
a temperature-dependent PNIPAAm that readily switched between
kill and release functions across its LCST. The efficiency of bacteria-
killing and detachment of dead cells from the surface was tested
against S. aureus. The authors reported that the transitional change in
molecular structure enabled a killing effectiveness of ∼90% and a
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Figure 6. Schematic illustration of a dual-function pH-responsive capable of loading biocide, killing bacteria, and releasing dead bacteria by change
in pH value. Under an acidic pH, the surface shows a high tendency to bind with biocide. Under a neutral pH value, the surface can release loaded
biocide to kill the bacteria that have approached or are near the surface. Under an alkaline pH, the surface shows a high tendency to release the
dead bacteria to regenerate the clean surface for the next cycle.
detachment efficiency of ∼85%. Wang et al.104 fabricated hierarchical
PNIPAAm bioresponsive materials that could effectively kill bacterial
cells at room temperature and automatically switch their bacteria-
repelling function to a removal function under physiological
temperatures, eventually removing the dead bacterial cells from the
surface. Poly(vinylcaprolactam) (PVCL) is a thermoresponsive
polymer with lower overall cytotoxicity than PNIPAAm. Wang et
al.59 made use of the nontoxic nature of PVCL and fabricated a new
switchable thermoresponsive material comprising PVCL, hydrophilic
2-methacryloyloxyethyl phosphorylcholine, and QACs; this material
could reversibly switch between kill and release functions across an
LCST of ∼35 °C.
3.2.2. pH-Responsive Materials. pH-responsive polymers have also
received interest in the development of bioresponsive materials
possessing a switchable kill-release function. Poly(methacrylic acid)
(PMAA) is a well-known pH-responsive polymer with several
carboxyl groups in its structure. Ionization of these groups to
carboxylate ions under acid conditions results in the accumulation of a
high number density of negative charge on the PMAA chains, which
ultimately leads to extensive swelling. When bacteria grow and
colonize on the surface, a rapid reduction of pH occurs at the location
where bacterial colonies form. The acidification triggers the swelling
and collapse of the PMAA chains and leads to the exposure and
activation of the bactericidal layer.95
Making use of this phenomena, Yan et al.109 constructed a
hierarchical polymer architecture with two layers. The outer layer was
composed of grafted negatively charged PMAA that served as an
actuator that adjusted the surface behavior. The inner layer was
composed of an immobilized, positively charged antimicrobial peptide
that served as a biocide to kill the bacteria attached to the surface. The
authors reported that, when the environmental pH was increased to
neutral, the PMAA surface hydrated and fully expanded, offering
strong resistance to bacterial attachment. This pH-dependent
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hydration-expansion of PMAA made it easier to remove dead bacteria
from the surface. The covalent grafting of the antimicrobial peptide
allowed this bioresponsive material to reversibly switch between kill
and release functions. It also helped avoid leaching or unnecessary
reloading of biocidal agents to the surface. Wei et al.110 used a
chemical-etching method to develop bioresponsive materials that
could easily switch between kill and release functions in response to
changes in environmental pH. They used a silicon substrate modified
with PMAA to perform as a pH-responsive material and lysozyme to
serve as a biocidal agent that would be released to kill bacteria. Under
acidic pH conditions (pH < 7.0), the collapse of the PMAA-grafted
chains enabled most of the lysozyme content to adsorb and bond onto
the silicon surface. Under neutral pH, the extension of some of grafted
PMAA chains led to the release and activation of the lysozyme’s
biocidal function. This PMMA-lysozyme dual-function system was
effective in that the released lysozyme killed bacteria attached to the
surface as well as in the bulk solution. Once the bacteria were killed,
with an additional increase in pH (pH ≈ 10), the grafted PMAA
chains extended further and became fully ionized, enabling them to
readily release the killed bacteria from the surface. This mechanism
regenerated a clean surface to reload lysozyme for the next cycle
(Figure 6).
To properly switch the kill and release functions of pH-responsive
materials, the pH of the surface must change over a large pH range
(between highly acidic and highly alkaline), which might not be
feasible in many biomedical applications. Similarly, the time required
for temperature-responsive materials to heat up or cool down may
also limit their biomedical applications.111,127
3.2.3. Light-Responsive Materials. The limitations of pH- and
temperature-responsive materials discussed above can be overcome by
using light as an external trigger. A stimulus of light can be delivered
easily using a remote source; it induces a fast response and avoids the
risk of unwanted side effects.95 Light is more attractive among the
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Figure 7. Schematic illustration of a light-responsive antibacterial surface capable of switching between kill and release functions of bacteria in
response to light.
external stimuli, because its wavelength and intensity (dose) can be
precisely controlled as required by medical devices.128 Surprisingly,
currently only a few publications have reported the development of
bioresponsive materials capable of switching between bactericidal and
bacteria-releasing functions in response to UV or visible light.111−113
A common strategy to synthesize a light-responsive bioresponsive
material is to attach a photoswitchable molecule onto a solid
substrate. For example, azobenzene (Azo) is a widely used light-
responsive molecule that can reversibly react to light of different
wavelengths. Using this functional group, Wei et al.111 fabricated a
light-responsive material composed of a compound containing an Azo
group and a derivative of biocidal β-cyclodextrin (CD) coupled to
seven QACs moieties (CD-QACs). The light-responsiveness of Azo/
CD-QACthat is, light-triggered switching between the kill and
release functionsbasically stems from the interactions between CD-
QACs and Azo. The authors found that the Azo/CD-QACs complex
had good biocidal activity, with a killing effectiveness of ∼90% under
visible-light conditions. Exposure of this material to UV light (365
nm) for 30 min caused an isomerization of the Azo group from trans-
to cis-form, due to which the CD-QACs/Azo complex was
dissociated, which ultimately led to the release of dead bacteria
from the surface (Figure 7).
This work also showed that the high efficiency of cis−trans
isomerization of Azo after a kill-release cycle could regenerate the
original surface for the next cycle. A simple irradiation of this material
with visible light (450 nm) was shown to convert the cis-Azo to trans-
Azo to make the surface ready for reloading with fresh CD-QACs.
3.2.4. Salt-Responsive Materials. The unique salt-responsiveness
of zwitterionic polymers makes them one of the most interesting areas
of scientific research. It has been reported that zwitterionic polymers
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can significantly reduce the adsorption of bacterial cells to the
surface.117,129 Zwitterionic polymers form strong and stable bonds
with water molecules through electrostatic interactions. Hydrophilic
polymers and coatings, in contrast, achieve surface hydration through
hydrogen bonds between the polymer and water molecules.16 Apart
from their high surface hydration, zwitterionic polymers have another
unique property, often referred to as the “anti-polyelectrolyte effect”.
The zwitterionic polymer chains can show two different behaviors in
water and in salt solutions: collapsed conformation in water and
stretched conformation in salt solutions.130 This behavior has opened
many research opportunities, including the development of dual-
function bioresponsive materials that can reversibly shift between kill
and release functions.97,114,116,117,120,131,132 Notably, Wu et al.114
developed a salt-responsive switchable material using a brush of
zwitterionic polymer, poly(3-(dimethyl(4-vinylbenzyl)ammonium)-
propyl sulfonate) (PDVBAPS), which was pregrafted with the biocide
triclosan. The material effectively killed up to ∼95% of the bacteria
attached on the surface and subsequently released most (∼97%) of
the dead bacteria after brief (10 min) washing with 1.0 M NaCl
(Figure 8).
Additionally, the surface of this material maintained its kill and
release efficiencies up to four cycles. More recently, Zhang et al.116
followed this approach to synthesize a reusable, salt-responsive
hydrogel composed of zwitterionic PDVBAPS, antibiofouling poly(N-
hydroxyethyl acrylamide) (PHEAA), and silver nanoparticles
(AgNPs). Huang et al.97 developed a novel salt-bioresponsive
material using a poly(trimethylamino)ethyl methacrylate) (PTMAE-
MA) brush that was immobilized using a chemical grafting strategy
through a surface-initiated polymerization (SIP) reaction. Under
neutral conditions, the PTMAEMA brush attracted bacterial cells to
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Figure 8. Schematic illustration of a salt-responsive dual-function material based on a zwitterion-based polymer brush (PDVBAPS). Triclosan
serves as a biocide.
the surface, where QAC moieties were abundant, and killed them on
contact. Subsequently, an electrolyte solution containing anionic ions
(e.g., chloride, sulfate, or citrate) was poured into the PTMAEMA
brush to adsorb the counteranions onto the PTMAEMA polymer.
The presence of counteranions promoted the hydration and collapse
of the PTMAEMA brush, making the surface highly negatively
charged. This process created a strong repulsive force on the surface
that led to the removal of dead bacterial cells from the surface and the
recovery of the killing function for the next cycle (Figure 9).
3.2.5. Sugar-Responsive Materials. Sugar-responsive materials are
a new class of bioresponsive materials with potential biological
applications. In a recent report, Zhan et al.121 developed a new
switchable bioresponsive material using phenylboronic acid (PBA)-
containing polymer and CD conjugated to QACs (CD-QACs) as a
biocidal agent. Both the PBA-containing polymer and the CD-QACs
were grafted onto a gold (Au) surface. The resultant material was
found to switch between kill and release functions in response to an
introduced sugar solution. In the absence of the sugar solution and at
room temperature, the kill function of Au-PBA/CD-QACs was
activated, and the killed bacterial cells appeared on the surface.
Addition of a sugar (e.g., fructose) solution dissociated the boronate
ester bonds between the secondary hydroxyls of the CD and PBA.
This dissociation led to the release of CD-QAS anchored to dead
bacterial cells from the surface (Figure 10). The authors further
indicated that ∼80% of killed bacterial cells could be detached from
the Au-PBA surface by simply adding fructose solution.
3.2.6. Dual-Stimulus-Responsive Materials. Single-stimulus-re-
sponsive materials can closely mimic the dynamic nature of living
systems. However, living systems can respond to two or more external
stimuli simultaneously, and new bioresponsive materials should be
able to better emulate them.133 Therefore, to develop the next
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generation of dual-function bioresponsive materials, a variety of
strategies is proposed to create a single switchable material capable of
being triggered by more than one environmental stimulus.134 Such
dual-stimulus-responsive materials will be able to better adapt to
different biological systems and applications. For example, Liu et al.133
synthesized dual-stimulus bioresponsive materials by grafting a
poly(acrylamidophenylboronic acid) (PAAPBA) brush to a silicon
surface. This material efficiently and quickly switched between cell
capture and release in response to a simultaneous change in both pH
and glucose concentration. At pH ≈ 6.8, the PAAPBA surface showed
a cell-capture efficiency of ∼60%, but when the pH was increased to
∼7.8, only a few cells adhered to the surface. At pH ≈ 7.8, the
PAAPBA surface showed glucose-responsive behavior that could
reversibly capture and release bacterial cells as a function of glucose
concentration. This work showed that a simultaneous change in pH
and glucose concentration resulted in a switch between cell capture
and release. In another study, Wang et al.135 constructed an enzyme
(bacterial hyaluronidase) and pH dual-stimulus-responsive materials
by sequential LBL assembly of (PEG-bis(succinimidyl succinate))
and PEI. This was then followed by sequential covalent attachment of
antibiotic vancomycin and electrostatic adsorption of hyaluronic acid
(HA) onto a multilayered surface. When bacteria attacked to the
surface, the hyaluronidase secreted by Gram-positive bacterial strains
hydrolyzed the HA upper layer and allowed the release of vancomycin
in response to the local acidification (pH reduction). On the basis of
this work, the surface was shown to respond to both bacterial
hyaluronidase and pH stimuli, which enabled accurate control of
antibiotic release profile.
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Figure 9. Schematic illustration of a dual-function material produced using a kill-release strategy. The contact-kill function is realized through
multiple QAC moieties on a PTMAEMA polycation brush. The release function is performed through the addition of an electrolyte solution (e.g.,
NaCl, MgSO4, or sodium citrate). The reversible switching between the kill and release actions of the PTMAEMA is realized through the
undocking and docking of counteranions.

4. CONCLUSION AND PERSPECTIVE
The advances made in material science and associated
technologies have led to the development of a new class of
bioresponsive materials that perform better in preventing and
removing bacterial infections. These bioresponsive materials
can perform either resist-kill or kill-release dual functions, and
they can reversibly switch between these functions in response
to environmental stimuli. Innovations made in the structure
and function of bioresponsive materials are impressive;
however, most of these materials are still in the laboratory or
research stage. So far, only limited platforms have made their
way to industrial production and commercialization. Several
challenges need to be carefully considered to take the recently
developed bioresponsive materials from the laboratory to
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industrial production. One of the most important challenges of
a bioresponsive material to be successfully translated into
commercial outcomes is its ability to uphold its function for a
long time. Most of these materials are shown to be effective for
a period of up to several hours. Long-term stabilityvarying
between a few months and several yearsis required by most
industries, such as for clinical or marine applications. This
durability aspect is often ignored, and discussion over whether
materials can retain their functionality for commercially
feasible duration remains unknown. Commercial translation
of some bioresponsive materials may also be restricted due to
the complexity involved in their fabrication. As it stands, many
of these materials can only be prepared in certain lab-scale
conditions using sophisticated instruments and/or multistep
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Figure 10. Schematic illustration and chemical structure of a dual-function material with sugar-responsive capability based on PBA-containing
polymer and CD-QACs as an antibacterial agent. Both are grafted onto a Au surface. In aqueous solution, D-fructose can appear as mixtures of
pyranose and furanose isomers. These isomers are mostly β-D-fructopyranose (∼68%) and β-D-fructofuranose (∼22%). The chemical structures of
both isomers are also shown.
fabrication procedures that will potentially hinder future
exploration beyond laboratory demonstration. Future techno-
logical innovations of these materials should be directed
toward translational feasibility instead of decoration with
sophisticated structures and/or developing newer yet inappli-
cable fabrication procedures. In fact, efforts must be made to
design and fabricate these materials using simple, cost-effective,
reproducible, and scalable protocols.
The current approach of testing these materials using model
bacteria instead of real-life bacterial contamination could be
another reason for the lack of translational success. Most of the
currently developed bioresponsive materials cannot be
confidently applied to complex biological media for the
duration required for real-life applications. To be considered
for such applications, these materials should have effective
biocidal and self-regenerating performance in environments
where many strains of microbial populations coexist. To
overcome these challenges, researchers from different dis-
ciplines such as surface science, materials science, and
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biomedical engineering should work collaboratively and
carefully consider the scaling up of the newly developed
materials and processes. We are just at the advent of
developing dynamically interactive materials; further research
is required to create materials that can more realistically
emulate the complexity of highly dynamic natural environ-
ments. We anticipate that future generations of bioresponsive
materials will have superior properties in terms of durability,
versatility, reusability, and their applicability to real-life
environments to address current biological and medical needs.
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: benu.adhikari@rmit.edu.au.
ORCID
Elena P. Ivanova: 0000-0002-5509-8071
Benu Adhikari: 0000-0002-7571-7968
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Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The first author acknowledges the scholarship support
provided to him by RMIT Univ. Some elements of the
illustrations in this work were created with minimal use of free
and publicly available templates from Servier Medical Art
(https://smart.servier.com/); we acknowledge this Power-
Point image bank. We wish to thank Prof. Q. Yu of Soochow
Univ. for his valuable comments on an early draft of this
manuscript.
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