The design, fabrication, and applications of flexible biosensing devices

Abstract

Flexible biosensors form part of a rapidly growing research field that take advantage of a multidisciplinary approach involving materials, fabrication and design strategies to be able to function at biological interfaces that may be soft, intrinsically curvy, irregular, or elastic. Numerous exciting advancements are being proposed and developed each year towards applications in healthcare, fundamental biomedical research, food safety and environmental monitoring. In order to place these developments in perspective, this review is intended to present an overview on field of flexible biosensor development. We endeavor to show how this subset of the broader field of flexible and wearable devices presents unique characteristics inherent in their design. Initially, a discussion on the structure of flexible biosensors is presented to address the critical issues specific to their design. We then summarize the different materials as substrates that can resist mechanical deformation while retaining their function of the bioreceptors and active elements. Several examples of flexible biosensors are presented based on the different environments in which they may be deployed or on the basis of targeted biological analytes. Challenges and future perspectives pertinent to the current and future stages of development are presented. Through these summaries and discussion, this review is expected to provide insights towards a systematic and fundamental understanding for the fabrication and utilization of flexible biosensors, as well as inspire and improve designs for smart and effective devices in the future.

Keywords: Biosensor; Epidermal sensor; Flexible; Implantable sensor.

Figure 1 –

Schematic showing the essential elements of biosensors in flexible configurations.

Figure 2 –

Examples of locations where flexible biosensors may be or are already being used. Clockwise from top: a) soft tissue such as the brain Adapted with permission from ref.(Kim et al. 2010). Copyright 2010 Nature Publishing Group. b) nerve fibers Adapted with permission from ref. (Seo et al. 2016). Copyright 2016 Cell Press. c) eyes/cornea (as optical implants or soft contact lenses) Adapted with permission from ref. (Kim et al. 2017). Copyright 2017 Nature Publishing Group. d, e) skin and other flexible environments, Adapted with permission from ref.(Liao et al. 2015a). Copyright 2014 Wiley. Adapted with permission from ref. (Lee et al. 2016a) Copyright 2016 Nature Publishing Group. f) surfaces of fruits and agricultural products Adapted with permission from ref. (Tao et al. 2012). Copyright 2012 Wiley. g) Enamel, h) muscle tissue. Adapted with permission from ref. (Mannoor et al. 2012). Copyright 2012 Nature Publishing Group.

Figure 3.. Representative mechanical challenges in the design of flexible biosensors.

The top row reflects the idea of mechanical stress/strain (e.g. bending, stretching, rolling, twisting, curling, crumpling or even sharp indentation). a) Adapted with permission from ref. (Zhong et al. 2015). Copyright 2012 American Chemical Society. b) Adapted with permission from ref.(Yang et al. 2017b). Copyright 2012 Wiley. c) Adapted with permission from ref.(Vandeparre et al. 2013). Copyright 2013 AIP Publishing. The bottom row represents ideas of conformability and compatibility to a very delicate environment (e.g. a lesion or wound) and skin. d) Adapted with permission from ref.(Dagdeviren et al. 2015). Copyright 2015 Nature Publishing Group. e) Adapted with permission from ref.(Chen et al. 2017). Open Access.

Figure 4.. Representative strategies for the immobilization of biomolecules for flexible biosensing applications a)

Lens-less imaging detection and counting of CD4⁺ T lymphocytes on polyester film-based platform with microchannels. Biotinylated anti-CD4 antibodies immobilized using NeutrAvidin on chemically activated surface. Adapted with permission from ref. (Shafiee et al. 2015). Copyright 2015 Nature Publishing Group. b) Conductive copolymer coated and avidin bound flexible electron-spun mats. Adapted with permission from ref. (Bhattacharyya et al. 2011). Copyright 2011 Wiley. c) AMP, Magainin I (GIGKFLHSAGKFGKAFVGEIMKS) covalently functionalized on hRGO, yielding a gram-negative specific biosensor Adapted with permission from ref.(Chen et al. 2014). Copyright 2014 American Chemical Society. d) biotinylated C-reactive protein (CRP) antigen and the bound analyte (anti-CRP antibody) grown on biotinylated self-assembly monolayer-covered printed gold electrodes on a paper substrate. Adapted with permission from ref. (Ihalainen et al. 2013). Copyright 2013 MDPI. e) Glucose oxidase enzyme immobilized within a PEDOT:PSS-silk sericin conducting ink, photolithographically patterned on a fibroin substrate. Adapted with permission from ref. (Pal et al. 2016a). Copyright 2016 Wiley. f) modifying silver electrode with lactate oxidase immobilized by bovine serum albumin on a PET substrate. Adapted with permission from ref. (Abrar et al. 2016). Copyright 2015 Nature Publishing Group. g) Graphene nanomesh FETs GNM FET biosensor. 1-pyrenebutanoic acid succinimidyl ester linker conjugated with the amino modified HER2-specific aptamer through the formation of an amide bond integrated on the PDMS film and attached on the human skin. Adapted with permission from ref.(Yang et al. 2017b) Copyright 2017 Wiley