Surface-enhanced Raman spectroscopy (SERS) inherits the rich chemical fingerprint information on Raman spectroscopy and gains sensitivity by plasmon-enhanced excitation and scattering. In particular, most Raman peaks have a narrow width suitable for multiplex analysis, and the measurements can be conveniently made under ambient and aqueous conditions. These merits make SERS a very promising technique for studying complex biological systems, and SERS has attracted increasing interest in biorelated analysis. However, there are still great challenges that need to be addressed until it can be widely accepted by the biorelated communities, answer interesting biological questions, and solve fatal clinical problems. SERS applications in bioanalysis involve the complex interactions of plasmonic nanomaterials with biological systems and their environments. The reliability becomes the key issue of bioanalytical SERS in order to extract meaningful information from SERS data. This review provides a comprehensive overview of bioanalytical SERS with the main focus on the reliability issue. We first introduce the mechanism of SERS to guide the design of reliable SERS experiments with high detection sensitivity. We then introduce the current understanding of the interaction of nanomaterials with biological systems, mainly living cells, to guide the design of functionalized SERS nanoparticles for target detection. We further introduce the current status of label-free (direct) and labeled (indirect) SERS detections, for systems from biomolecules, to pathogens, to living cells, and we discuss the potential interferences from experimental design, measurement conditions, and data analysis. In the end, we give an outlook of the key challenges in bioanalytical SERS, including reproducibility, sensitivity, and spatial and time resolution.

The attachment and subsequent colonization of bacteria on the surfaces of synthetic materials and devices lead to serious problems in both human healthcare and industrial applications. Therefore, antibacterial surfaces that can prevent bacterial attachment and biofilm formation have been a long-standing focus of considerable interest and research efforts. Recently, a promising "kill-release" strategy has been proposed and applied to construct so-called smart antibacterial surfaces, which can kill bacteria attached to their surface and then undergo on-demand release of the dead bacteria and other debris to reveal a clean surface under an appropriate stimulus, thereby maintaining effective long-term antibacterial activity. This Review focuses on the recent progress (particularly over the past 5 years) on such smart antibacterial surfaces. According to the different design strategies, these surfaces can be divided into three categories: (i) "K + R"-type surfaces, which have both a killing unit and a releasing unit; (ii) "K → R"-type surfaces, which have a surface-immobilized killing unit that can be switched to perform a releasing function; and (iii) "K + (R)"-type surfaces, which have only a killing unit but can release dead bacteria upon the addition of a release solution. In the end, a brief perspective on future research directions and the major challenges in this promising field is also presented.

Antibacterial coatings that eliminate initial bacterial attachment and prevent subsequent biofilm formation are essential in a number of applications, especially implanted medical devices. Although various approaches, including bacteria‐repelling and bacteria‐killing mechanisms, have been developed, none of them have been entirely successful due to their inherent drawbacks. In recent years, antibacterial coatings that are responsive to the bacterial microenvironment, that possess two or more killing mechanisms, or that have triggered‐cleaning capability have emerged as promising solutions for bacterial infection and contamination problems. This review focuses on recent progress on three types of such responsive and synergistic antibacterial coatings, including i) self‐defensive antibacterial coatings, which can “turn on” biocidal activity in response to a bacteria‐containing microenvironment; ii) synergistic antibacterial coatings, which possess two or more killing mechanisms that interact synergistically to reinforce each other; and iii) smart “kill‐and‐release” antibacterial coatings, which can switch functionality between bacteria killing and bacteria releasing under a proper stimulus. The design principles and potential applications of these coatings are discussed and a brief perspective on remaining challenges and future research directions is presented.

For various human healthcare and industrial applications, endowing surfaces with the capability to not only efficiently kill bacteria but also release dead bacteria in a rapid and repeatable fashion is a promising but challenging effort. In this work, the synergistic effects of combining stimuli-responsive polymers and nanomaterials with unique topographies to achieve smart antibacterial surfaces with on-demand switchable functionalities are explored. Silicon nanowire arrays are modified with a pH-responsive polymer, poly(methacrylic acid), which serves as both a dynamic reservoir for the controllable loading and release of a natural antimicrobial lysozyme and a self-cleaning platform for the release of dead bacteria and the reloading of new lysozyme for repeatable applications. The functionality of the surface can be simply switched via step-wise modification of the environmental pH and can be effectively maintained after several kill-release cycles. These results offer a new methodology for the engineering of surfaces with switchable functionalities for a variety of practical applications in the biomedical and biotechnology fields.

Methicillin-resistant Staphylococcus aureus (MRSA) has been one of the major nosocomial pathogens to cause frequent and serious infections that are associated with various biomedical surfaces. This study demonstrated that surface modified with host defense peptide-mimicking β-peptide polymer, has surprisingly high bactericidal activities against Escherichia coli ( E. coli) and MRSA. As surface-tethered β-peptide polymers cannot move freely to adopt the collaborative interactions with bacterial membrane and are too short to penetrate the cell envelop, we proposed a mode of action by diffusing away the cell membrane-stabilizing divalent ions, Ca and Mg. This hypothesis was supported by our study that Ca and Mg supplementation in the assay medium causes up to 80% loss of bacterial killing efficacy and that the addition of divalent ion chelating ethylenediaminetetraacetic acid into the above assay medium leads to significant recovery of the bacterial killing efficacy. In addition to its potent bacterial killing efficacy, the surface-tethered β-peptide polymer also demonstrated excellent biocompatibility by displaying no hemolysis and supporting mammalian cell adhesion and growth. In conclusion, this study demonstrated the potential of β-peptide polymer-modified surface in addressing nosocomial infections that are associated with various surfaces in biomedical applications.

Smart biointerfaces with capability to regulate cell-surface interactions in response to external stimuli are of great interest for both fundamental research and practical applications. Smart surfaces with "ON/OFF" switchability for a single function such as cell attachment/detachment are well-known and useful, but the ability to switch between two different functions may be seen as the next level of "smart". In this work reported, a smart supramolecular surface capable of switching functions reversibly between bactericidal activity and bacteria-releasing ability in response to UV-visible light is developed. This platform is composed of surface-containing azobenzene (Azo) groups and a biocidal β-cyclodextrin derivative conjugated with seven quaternary ammonium salt groups (CD-QAS). The surface-immobilized Azo groups in trans form can specially incorporate CD-QAS to achieve a strongly bactericidal surface that kill more than 90% attached bacteria. On irradiation with UV light, the Azo groups switch to cis form, resulting in the dissociation of the Azo/CD-QAS inclusion complex and release of dead bacteria from the surface. After the kill-and-release cycle, the surface can be easily regenerated for reuse by irradiation with visible light and reincorporation of fresh CD-QAS. The use of supramolecular chemistry represents a promising approach to the realization of smart, multifunctional surfaces, and has the potential to be applied to diverse materials and devices in the biomedical field.

Development of a versatile strategy for antibacterial surfaces is of great scientific interest and practical significance. However, few methods can be used to fabricate antibacterial surfaces on substrates of different chemistries and structures. In addition, traditional antibacterial surfaces may suffer problems related to the attached dead bacteria. Herein, antibacterial surfaces with multifunctionality and regenerability are fabricated by a universal strategy. Various substrates are first deposited with multilayered films containing guest moieties, which can be further used to incorporate biocidal host molecules, β-cyclodextrin (β-CD) derivatives modified with quaternary ammonium salt groups (CD-QAS). The resulting surfaces exhibit strong biocidal activity to kill more than 95% of attached pathogenic bacteria. Notably, almost all the dead bacteria can be easily removed from the surfaces by simple immersion in sodium dodecyl sulfate, and the regenerated surfaces can be treated with new CD-QAS for continued use. Moreover, when another functional β-CD derivative molecule is co-incorporated together with CD-QAS, the surfaces exhibit both functions simultaneously, and neither specific biofunction and antibacterial activity is compromised by the presence of the other. These results thus present a promising way to fabricate multifunctional and regenerable antibacterial surfaces on diverse materials and devices in the biomedical fields.

The development of effective antibacterial surfaces to prevent the attachment of pathogenic bacteria and subsequent bacterial colonization and biofilm formation is critically important for medical devices and public hygiene products. In the work reported herein, a smart antibacterial hybrid film based on tannic acid/Fe3+ ion (TA/Fe) complex and poly­(N-isopropylacrylamide) (PNIPAAm) is deposited on diverse substrates. This surface is shown to have bacteria-killing and bacteria-releasing properties based on, respectively, near-infrared photothermal activation and subsequent cooling. The TA/Fe complex has three roles in this system: (i) as a universal adhesive “anchor” for surface modification, (ii) as a high-efficiency photothermal agent for ablation of attached bacteria (including multidrug resistant bacteria), and (iii) as a robust linker for immobilization of NH2-terminated PNIPAAm via either Michael addition or Schiff base formation. Moreover, because of the thermoresponsive properties of the immobilized PNIPAAm, almost all of the killed bacteria and other debris can be removed from the surface simply by lowering the temperature. It is shown that this hybrid film can maintain good antibacterial performance after being used for multiple “kill-and-release” cycles and can be applied to various substrates regardless of surface chemistry or topography, thus providing a broadly applicable, simple, and reliable solution to the problems associated with surface-attached bacteria in various healthcare applications.