Nano Today
Safety and effectiveness evaluation of flexible electronic materials for next generation wearable and implantable medical devices
Graphical abstract
Introduction
Traditionally, electronic materials and biomaterials are viewed as separate and incompatible entities [1]. Electronic materials are often hard materials based on electrons. Such materials are prepared by a top-down process according to the Maxwell equation and operate in an anhydrous state [2,3]. On the contrary, biomaterials are usually soft materials based on ions. Biomaterials are always assembled from the bottom up, following the central dogma of molecular biology. They exist usually in an aqueous environment [4,5]. These differences present a great challenge to analytical bioscience: how can one achieve instantaneous, localized biological measurements when human body is “soft and curved”, while electronic materials are “hard and flat” [6]? It is expected that the future development of electronics will transfer from solid-state electronics to flexible materials [7]. Complex and precise flexible electronics will eventually bring to fruition bio-integrated electronics in the forms of wearable/implanted biological diagnostics and eventually humanoid robots [5].
Nowadays, with the improvements in the standard of living, extended life expectancy, the expansion of an aging society, and the development of medical technology, health management has increasingly become a research hotspot in the field of medicine [8]. The concept of "active health" has been put forward in response to this change [9]. Thus, the health management gateway is transitioning to a pre-disease and pre-hospital stage, such that healthy people monitor and manage their physiological parameters throughout their daily life. This approach to health management enables early warning of life-threatening chronic diseases, such as cardiovascular and cerebrovascular diseases, tumors, and diabetes, reducing the pain and burden on patients. Similarly, such advancements will improve the quality of life, reduce the pressure on public health resources. The latest developments in the field of flexible electronic technology have brought us closer to the realization of wearable, active health data collection products [10]. Novel materials, machinery, and manufacturing provide the basis for high-performance electronic and microfluidic technologies with physical properties that precisely match human tissue. Such devices can be integrated into the skin in a physically imperceptible manner and provide continuous physiological information with clinical precision [11,12] (Fig. 1).
Several different research groups have developed a variety of procedures to manufacture flexible electronic materials in combination with organic electronic materials, conductive hydrogels, or metal nanowires (Fig. 2).
From electrodes to transistors, from tactile sensors to biochemical sensors, flexible electronic technology has been widely used in various fields. As early as 2012, Lee et al. proposed to develop long silver nanowires for use as high tensile and high conductivity metal electrodes [16]. Xu et al. reported a synthetic functionalized graphene hydrogel [17], which can be used directly as the electrode in a supercapacitor without the addition of any other adhesive or conductive additives. The highly flexible and transparent MoS2 FET, based on hBN dielectric and graphene gate electrodes, was reported by Lee et al. [18], while Jheng et al. reported a novel conductive film with a three-layer sandwich structure, based on carbon nanotubes (CNT) and silver nanowires (NWs), and encapsulated in silicone rubber, with high tensile and negligible piezo resistance, suitable for use as stretchable interconnectors [19]. Wang et al. developed a type of internally stretchable transistor array, generating a 10 × 10 tactile sensor array using the CNT-based stretchable electrode, which can be used as electronic skin [10]. Zhao et al. prepared and applied an all gold, fiber-based stretchable three electrode electrochemical biosensor platform based on wearable enzymatic glucose detection, which can realize high sensitivity glucose detection under tension to monitor with high selectivity the glucose level in artificial sweat [20]. According to the work of Lee et al., graphene doped with gold and combined with gold mesh has a higher electrochemical activity than bare graphene, enabling the generation of a wearable patch for sweat based diabetes monitoring and feedback therapy [21].
The application of flexible electronic technology in the human body also includes consumer electronics products and sports health products. The increasing maturity of these uses buttresses the development of flexible electronic technology in medical devices to meet the growing clinical needs. However, all jurisdictions strictly regulate medical devices, especially those using innovative technology. Most newly synthesized flexible electronic materials have no history of use in the human body. For use as medical devices, the safety and efficacy in the intended clinical application must be rigorously demonstrated. Furthermore, reliability and accessibility must also be considered when novel medical devices based on flexible electronic technology are conceived.
Section snippets
Current state of research of flexible electronic materials for next generation wearable and implantable medical devices
Wearable technology can achieve continuous, long-term monitoring and personalized medical treatment, maintain health and prevent the progression of initial disease into more serious health problems. In recent years, flexible biomedical sensors have attracted increasing attention. Newly developed flexible (stretchable) electronic materials are expected to usher in a series of new applications, from in vitro wearable electronic products for health monitoring and human-machine interfaces to in vivo
Flexible electronic material evaluation from the perspective of regulation
At present, most of the research work on flexible electronic materials has been fundamental and application research. There are a limited number of systematic evaluations of flexible electronic materials applied in wearable and implantable medical devices from the perspective of regulatory scientific research, especially with consideration of China's medical device regulatory regulations and guidance. Based on the methods to evaluate the safety and effectiveness of materials used in medical
Safety evaluation
It should be pointed out that safety evaluation and effectiveness evaluation cannot be completely separated. The development of flexible electronic materials requires a balance of different properties, mainly softness, extensibility, conductivity, durability, and biocompatibility. It is difficult to find a material with all the above characteristics. Therefore, the current challenge is to study the biocompatibility and optimize the performance of newly-developed flexible electronic materials
Electrical performance
Currently, the disadvantages of inorganic electronic materials are mainly their rigid, brittle, and opaque characteristics. In order to achieve wearability, the ideal requirements for device components are excellent mechanical properties, a carrier mobility of greater than 10 cm2/Vs, a high switch ratio (greater than 106), and uniform device characteristics. Therefore, flexible stretchable conductor materials are widely used in the fields of bioelectronics, sensors, wearable devices, and
Mechanical properties
Next generation electronic devices will not only be flexible, but also stretchable, which can realize applications the current rigid circuit board technologies cannot achieve. Stretchability requires new materials and new design principles. Among many materials available, gold has advantages over other semiconductor materials in biocompatibility, chemical inertness, and band gap matching. A research team of Monash University studied the electronic skin wearable technology platform using
Comfort
An important aspect of flexible electronic materials as wearable medical devices is comfort, which reduces the mechanical damage to the human body caused by the long-term use of traditional rigid materials. Therefore, comfort should also be a criterion in safety and effectiveness evaluations. For example, a wireless EEG monitoring system attached to the forehead provides a simple method for brain diagnosis, which will not bring discomfort due to the use of stretchable sensor patches [66]. The
Optical properties
In the area of optical properties, as early as 2008, Lee et al. developed a transparent electrode based on silver nanowires [69]. The electrode is flexible with a bending radius as low as 4 mm, which is not possible with conventional ITO-based transparent electrodes. These flexible and transparent electrodes can be used to obtain cortical electroencephalograms (ECoGs) and perform optogenetic operations on the nervous system [70]. The transparent electrode based on silver nanowires has a
Standardized evaluation systems and processes
Based on the characteristics of flexible electronic materials and their clinical applications, the current paper summarizes the overall evaluation system and evaluation process. As for safety evaluation, unlike the silicon-based electronic components used in traditional active medical devices, most of the newly developed flexible electronic materials have no history of application in humans as medical devices. Therefore, their biocompatibility has not been evaluated. According to the nature of
Conclusion and perspective
Flexible electronic material is a technology essential to the wearability of active medical devices. Flexible electronic material must fit to the human skin and not lose electronic function when being stretched, bent, and twisted. Furthermore, for implantable and wearable medical devices, flexible electronic materials, such as organic semiconductors, require high tensile strength and durability. Conventional polymer semiconductors do not have tensile properties—their mechanical and electronic
CRediT authorship contribution statement
Kuan Chen: Conceptualization, Methodology, Investigation, Writing - original draft, Writing - review & editing, Visualization. Jiayu Ren: Investigation, Writing - review & editing, Visualization. Chunying Chen: Visualization, Investigation, Supervision. Wei Xu: Supervision, Project administration, Funding acquisition. Song Zhang: Conceptualization, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was performed as part of sub-project “Research on Specifications of Safety and Effectiveness Evaluation for Active Health Data Collection Products”, Sub-project No.: 2018YFC2000801, National Key Research Project “Research on Systematic Safety and Effectiveness Evaluation and Standards for Active Health Products and Human Health Status”, Project No.: 2018YFC2000800, Major program from the Ministry of Science and Technology of China (2016YFA0201600) and the Research and Development
Dr. Kuan Chen is a reviewer and associate research fellow at Center for Medical Device Evaluation of National Medical Products Administration. He received his PhD degree (2010) in Photobiophysics from Humboldt University in Berlin, Germany. His research interests include the safety and effectiveness evaluation of nanomaterials used in medical device, biodegradable medical materials, and flexible electronic technology used in wearable and implantable medical device.
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Dr. Kuan Chen is a reviewer and associate research fellow at Center for Medical Device Evaluation of National Medical Products Administration. He received his PhD degree (2010) in Photobiophysics from Humboldt University in Berlin, Germany. His research interests include the safety and effectiveness evaluation of nanomaterials used in medical device, biodegradable medical materials, and flexible electronic technology used in wearable and implantable medical device.
Jiayu Ren received her BS degree in Chemistry from Sichuan University, P. R.China in 2016. She then joined Prof.Chunying Chen’s research group and is currently pursuing her PhD degree at the CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China. Her research interests are mainly focused on the understanding of biological effects of nanomaterials and nanosafety for nanobiomedical applications.
Prof. Chunying Chen is a principal investigator at CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China. She received her Bachelor's degree in Chemistry (1991) and PhD degree in Biomedical Engineering (1996) from Huazhong University of Science and Technology of China. Her research interests include the potential toxicity of nanoparticles, therapies for malignant tumors using theranostic nanomedicine systems and vaccine nanoadjuvants using nanomaterials.
Wei Xu is the deputy director and research fellow at Center for Medical Device Evaluation of National Medical Products Administration. She has over 18 years of experience in medical device registration and supervision, her research has contributed to the safety and effectiveness evaluation of medical device. Before joining Center for Medical Device Evaluation, she has been engaged in clinical work for 16 years, serving as the director and deputy chief physician of neurology department.
Song Zhang is the project manager, lead reviewer and associate research fellow at Center for Medical Device Evaluation of National Medical Products Administration, meanwhile, has the national inspector qualification of medical device quality system. He has over 10 years of experience in the safety and effectiveness evaluation of active medical devices, his research interest focuses on electrophysiology in critical medicine, emergency medicine, cardiology, endocrinology and metabolism. Before joining Center for Medical Device Evaluation, he has serving as the deputy chief engineer in aerospace engineering for over 5 years.