Switchable Dual-Function and Bioresponsive Materials to Control

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Cite This: ACS Appl. Mater. Interfaces 2019, 11, 22897−22914

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 Downloaded via GUILFORD COLG on July 21, 2019 at 12:44:50 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

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 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 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 dualfunction 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 million patients each year.6 Earlier antibiotics were effective 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

1. INTRODUCTION 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 problematic 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 infectionrelated 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 © 2019 American Chemical Society

Received: April 3, 2019 Accepted: June 10, 2019 Published: June 10, 2019 22897

DOI: 10.1021/acsami.9b05901 ACS Appl. Mater. Interfaces 2019, 11, 22897−22914

Review

ACS Applied Materials & Interfaces

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) zwitterionbased 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-

function bioresponsive materials. Given the practical importance 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. 22898


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Table 1. A Summary of Some Recent Publications that Deal with the Development of Bacteria-Resistant Superhydrophobic Materials substratea

specific method

water contact angle

targeted microorganism(s)b

reduction ratec

ref

carbon steel polypropylene Teflon stainless steel PDMS polypropylene film

electrodeposition thermal annealing micro/nano patterning sol−gel method chemical etching electrodeposition

158° 158° 158° 154° 169° 152°

P. aeruginosa S. aureus and E. coli E. coli and S. typhimurium E. coli E. coli S. aureus and P. aeruginosa

∼95% and ∼53% ∼99.2% and ∼95.6% ∼80% >5 logs inhibition: ∼65%

32 33 34 35 36 37

silicon wafer

168°

E. coli

killing: ∼90% ∼97%

38

aluminum PHB/PCL

deposition a thin layer of Ag and Cu on nanostructured surface anodizing and chemical etching electrospinning

151°

S. aureus and E. coli E. coli and S. aureus

titanium stainless steel

anodizing and chemical etching electrodeposition

166° 163°

copper polycarbonate polypropylene film

chemical etching sol−gel method chemical etching

158° 154° 155°

S. aureus and P. aeruginosa P. aeruginosa and L. monocytogenes S. aureus P. aeruginosa E. coli

>99% ∼99.95% and ∼99.91%

39 40 41 42

∼99.6%

43 44 45

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. 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 welldefined topography. 26 In this context, Perera-Costa et al.25 demonstrated that modifying the topographical properties of a

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, phosphobetaine, 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 22899


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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. 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 superhydrophobic materials and achieved good efficiency against photogenic 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

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 22900


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(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

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 “graftingto” 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 (noncovalent) 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 22901


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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 stimulus

biocide/drug agent

nominal amount of biocide/drug

bioresponsive polymera

target microorganism(s)b

pH pH pH pH

Vancomycin ZnO nanoparticles Amoxicillin silver nanoparticles

500 μg/mL 0.03 mol/L 100 mg/mL 0.05 mol/L

PDMAEMA CMC CMC CMC

S. aureus S. aureus and E. coli S. aureus and E. coli E. coli and S. aureus

pH

Ciprofloxacin

0.015 mg/mL

PMAA

pH

Gentamicin and polymyxin triclosan crystal violet silver nanoparticles curcumin Oxacillin

0.1 mg/mL

PMAA

S. aureus, E. coli, and P. aeruginosa S. aureus and E. coli

20 mg/mL 1% (w/w) 16 mg/mL 300 μg/mL 8.03 mg/mL

PVCL PNIPAAm PNIPAAm PNIPAAm PNIPAAm

S. aureus and E. coli S. epidermidis and E. coli E. coli and S. epidermidis S. aureus and E. coli S. aureus and P. aeruginosa

pH temp temp temp temp

reduction ratec >92% ∼95% ∼98.36 and 99.98%

∼40% and ∼52% >83% ∼90%

potential application delivery delivery delivery delivery

ref

systems systems systems systems

69 70 71 72

delivery systems

73

delivery systems

74

delivery systems delivery systems delivery systems delivery systems tissue engineering

65 58 75 76 77

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 > 22902


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Table 3. Summary of Some of Recent Studies That Adopted Resist-Kill to Develop Dual-Function Bioresponsive Materials substrate

bacteria-resistant unit

bactericidal unit

nominal amount of biocide/drug

target microorganism(s)

reduction ratec

potential application

ref

15 mg/mL

E. coli and S. aureus

∼93% and ∼95%

medical devices

82

PEGMA

chitosan-geugenol QACs

20% (v/v)


>99%

78

silicone rubber glass

APEG polyglycerol

PHMB glucose oxidase

38.0% (w/w) 2.5% (w/w)

∼5 logs >99.99%

thin-film composite PDMS

PSBMA PEG

QACs QACs

72.6 mg/mL 1.83 mg/mL

E. coli P. putida and S. aureus E. coli E. coli and S. aureus

tissue engineering medical devices medical devices medical devices medical devices

87 88

PDMS

PEG

antimicrobial peptide

16 mg/mL

tissue engineering

89

polycarbonate

PEG

28.8 mg/mL

∼99.9%

medical devices

90

thin film composite

PSBMA

5 mmol/15 mL

P. aeruginosa

∼95%

medical devices

91

polyurethane film surface silicon wafer cotton fabrics

PEG/lysine

antibacterial cations silver nanoparticles QACs

S. aureus, P. aeruginosa, and E. coli E. coli and S. aureus

∼72% ∼96.9% and ∼99.4% >99%

4.96% (w/w)


>99.99%

medical devices

92

PEG PSBMA

QACs QACs

10 mg/mL 2 % (w/w)

S. aureus E. coli and S. aureus

∼60% >99.99%

medical devices medical devices

93 94

PCU

PSBMA

silicon wafer

79 86

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 hydrophobicity of chitosan (Figure 4a).66 Temperature-Triggered Release Materials. Bioresponsive materials 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 temperatureresponsive 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-hydroxyethylmethacrylate) (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 watersoluble 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, bacteriaresistant 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 singlefunction 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resistkill and kill-releasehave been the major focus of recent research. The important characteristic features of these two types of dualresponsive 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 22903


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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 stimulus

biocidal unit

nominal amount of biocide

bacteria-resistant unita

target microorganism(s)b

release rate

ref

∼90% ∼80%

∼67% ∼66% and ∼60%

99 100

and ∼85% ∼3 logs ∼70% and ∼78%

>90% ∼64%

101 102

∼90% ∼88.6%

∼85% ∼72.5%

103 104

S. aureus E. coli and S. aureus E. coli and S. aureus E. coli and S. aureus E. coli

>80% ∼70% and 65%

∼58.5% ∼80%

>99%

>99%

59 105 106 107 108

S. aureus E. coli E. coli E. coli E. coli E. coli and S. aureus E. coli

∼4.88 log >95%. ∼93%

0.01 M 1.7 mmol/mL 150 mM 4.93 mmol/mL

PMAA PMAA azo group azo group azo group PDVBAPS 3,6-O-sulfated chitosan PDVBAPS PDVBAPS P(Q4VP-co-AA) PDVBAPS

E. E. E. E.

>96% ∼90%

LiTf2N

0.2 M

PIL(Br)

E. coli

∼99% >93% >90% ∼94.7% and ∼93.4% ∼90%

PTMAEMA

1.5 M 1 mM

E. coli and S. epidermidis E. coli

∼94.3%

CD-QAS

hexametaphosphate anions PBA

∼96.2% and ∼93.7% ∼80%

temp temp

QACs QACs

1% (w/w) 5 mg/mL

PNIPAAm PNIPAAm

E. coli E. coli and S. epidermidis

temp temp

QACs OPE

10 mg/mL

PNIPAAm PNIPAAm

temp temp

PMT Vancomycin

4% (w/w) 1 mg/mL

temp temp temp temp pH

10 mg/mL 10 mM 6 mmol/mL 0.02 m M

pH pH photo photo photo salt (NaCl) salt (NaCl)

PDMAEMA PPE QACs AgNPs PCBOH (cationic form) antimicrobial peptide lysozyme CD-QACs CD-QACs PDMAEMA triclosan lysozyme

PNIPAAm PSBMA and PNIPAAm PNIPAAm PNIPAAm PNIPAAm PNIPAAm PCBOH

S. aureus E. coli and S. epidermidis S. aureus S. aureus

salt salt salt salt

silver nanoparticles PMETAC Q4VP PTA

(NaCl) (NaCl) (NaCl) (NaCl)

anionic counterion anionic counterion sugar

1 mg/mL 1 mM 1 mM 50 mg/mL 0.1 M

coli coli coli coli

and and and and

S. S. S. S.

aureus aureus aureus aureus

biocidal rate

∼97% and ∼95%

>99%

>90% ∼91% ∼81% 71.40% ∼97%

∼94.9% and ∼93.3%

109 110 111 112 113 114 115 116 117 118 119 120 97 121

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-4vinylpyridine-co-acrylic acid), P(Q4VP-co-AA). bBacterial strain: Escherichia coli, E. coli; Staphylococcus aureus, S. aureus; and Staphylococcus epidermidis, S. epidermidis. 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.

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 hydrophilic 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. 22904


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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 killrelease 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 dualfunction 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 Natureinspired 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

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 antimicrobial enzymeinstead of QAC.126 The nanopatterned PNIPAAm/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(pphenylene-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 bacteriakilling 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 22905


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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 bacteriarepelling 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

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 22906


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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 lightresponsive 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 CDQACs 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 transto 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 transAzo 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

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 dualfunction 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(Nhydroxyethyl acrylamide) (PHEAA), and silver nanoparticles (AgNPs). Huang et al.97 developed a novel salt-bioresponsive material using a poly(trimethylamino)ethyl methacrylate) (PTMAEMA) 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 22907


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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. 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.

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-responsive 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 22908


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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

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 22909


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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.

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 environments. 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.

fabrication procedures that will potentially hinder future exploration beyond laboratory demonstration. Future technological innovations of these materials should be directed toward translational feasibility instead of decoration with sophisticated structures and/or developing newer yet inapplicable 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 disciplines such as surface science, materials science, and

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Elena P. Ivanova: 0000-0002-5509-8071 Benu Adhikari: 0000-0002-7571-7968 22910


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ACS Applied Materials & Interfaces Notes

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The authors declare no competing financial interest.

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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 PowerPoint 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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