Future trends in the market for electrochemical biosensing

Accepted Manuscript Future trends in the market for electrochemical biosensing Marta Maria Pereira da Silva Neves , Marı́a Begoña González-Garcı́a , David Hernández-Santos , Pablo Fanjul-Bolado PII: DOI: Reference: S2451-9103(18)30062-0 10.1016/j.coelec.2018.05.002 COELEC 246 To appear in: Current Opinion in Electrochemistry Received date: Revised date: Accepted date: 1 March 2018 20 April 2018 3 May 2018 Please cite this article as: Marta Maria Pereira da Silva Neves , Marı́a Begoña González-Garcı́a , David Hernández-Santos , Pablo Fanjul-Bolado , Future trends in the market for electrochemical biosensing, Current Opinion in Electrochemistry (2018), doi: 10.1016/j.coelec.2018.05.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Highlights Research into electrochemical biosensors (EBs) has been continuously growing.  The development of new materials and fabrication techniques are playing a key role.  Important advances in wearable and self-powered devices are being accomplished.   Wireless real-time data acquisition is a relevant feature for EBs development. EBs are expected to occupy an important place in the market as analytical tools. AC CE PT ED M AN US CR IP T  ACCEPTED MANUSCRIPT Future trends in the market for electrochemical biosensing Marta Maria Pereira da Silva Neves, María Begoña González-García, David Hernández-Santos, IP T Pablo Fanjul-Bolado* AC CE PT ED M AN *Corresponding author e-mail: [email protected] US CR DropSens S.L, Ed. CEEI, Parque Tecnológico de Asturias, 33428 Llanera, Asturias, Spain ACCEPTED MANUSCRIPT Abstract In the past years, research into electrochemical sensors and biosensors has been continuously growing and has especially focused on new materials and strategies to improve miniaturization and portability as an answer to new analytical paradigms. Moreover, important breakthrough achievements in terms of wearable and wireless technology with friendly operating systems and applications are also being accomplished, improving tremendously the user’s experience. IP T In this review, we summarize the current outline of electrochemical biosensors market and discuss some of the most recent advances, as well as the remaining challenges and future prospects, for electrochemical biosensing development that could make an impact on the US CR future global market. Keywords: electrochemical biosensing; flexible substrates; wearable biosensors; wireless AN sensing; self-powered biosensors; market trends. 1. Introduction Electrochemical biosensors are devices capable of providing quantitative or semi-quantitative electrochemical transducer [1] M analytical information using a biological recognition element in contact with an . The development of electrochemical biosensors as innovative PT ED tools for the generation of decentralized analytical devices has been of interest for decades. The continuous improvement of electrochemical biosensor technology along the years has been possible due to combined interdisciplinary efforts of several fields such as (bio)chemistry, electrochemistry, bioengineering, materials science, electrical engineering, microelectronics, [2] . Electrochemical biosensors have been building their CE software engineering, among others path as trustworthy analytical devices that work as an alternative to the conventional, bulky and expensive analytical instruments [3]. Indeed, since the first glucose sensor describe by Clark AC and Lyons in the 60’s, electrochemical biosensors have generated great expectation regarding their introduction in the market. However, despite the interest and progresses in the field, corroborated by the intensive scientific production in terms of publications (Figure 1), the commercialization of electrochemical biosensor technology did not follow the same trend. The well-established hand-held glucometers are, until the moment, the most successful application of electrochemical biosensor technology with a tremendous commercialization volume and dominating the biggest portion of the biosensors market [4]. For this reason, fundamental and ACCEPTED MANUSCRIPT applied research is essential for transference of innovative biosensing technology from academia to industry. In this short review, we aimed to provide a clear and concise view of the main advances achieved within the electrochemical biosensors research field in the past 2 years. We intended to resume the state of the art of the most recent scientific accomplishments in the development of smarter, user-friendly and consumer oriented electrochemical biosensors IP T along with the current opportunity fields, future challenges and prospects for these devices and their introduction in the market. US CR 2. Electrochemical biosensing market overview The market for electrochemical biosensors is projected to grow at a compound annual growth rate of 9.7% during 2016 and 2022 $23707.2 million market value [5] [5] . For the same forecast period is expected to achieve a . Electrochemical biosensors market can be mainly divided into diagnosis and monitoring applications. Currently, in the clinical field, point-of-care (POC) predictable to worth around $33 billion estimated to occupy a 35% of that market AN testing dominates as end-user application. By the year 2027 the market for POC biosensors is [4] [4] . Additionally, electrochemical test strips are . The main areas of development are especially M focused towards POC of home monitoring of chronicle diseases, POC testing of infectious pathologies, among others [3]. Additionally, POC-based biomedical electrochemical sensors for PT ED the detection of priority diseases in resource-limited countries are also extremely necessary [6]. Quality monitoring and on-site detection of pollutants in water is also an important field as well the agri-food industry with front-line detection of plagues, pesticides, and quality control of foodstuff [7, 8] . Furthermore, electrochemical biosensors can be interesting players in [9] as well as daily-basis tools in research laboratories. Thus, there are CE biodefense scenarios urgent needs for sensors across all market sectors. In terms of segmenting the market by AC region, the increasing of health awareness and lifestyle-related disorders combined with important technological advances in healthcare applications, allow North America to lead the global market of electrochemical biosensors [5]. Europe appears in the second place, followed by Asia Pacific region which is estimated to increase its current percentage [5]. Middle East and Africa occupies the smallest market share [5] . Abbott Laboratories (US), Bayer Healthcare (Germany), LifeScan Inc. (US), Medtronic Inc. (US), Roche Diagnostics (Switzerland) and Siemens Healthcare (Germany) are some of the major leading companies offering electrochemical hand-held biosensors mainly directed for POC monitoring of glucose but also ACCEPTED MANUSCRIPT for other relevant analytes (e.g., lactate, cholesterol, uric acid, cardiac and cancer markers, among others). 3. Emergent technologies for electrochemical biosensors development In the last years, several advances were made in terms of microfabrication techniques, IP T materials and electronics. These developments facilitated the production of smaller, portable and cheaper sensors. The integration and miniaturization of electrochemical cells were fundamental for the development of portable sensing devices [10] , overcoming the limitations US CR of large-scale production. Furthermore, the interest in wearable sensors for the continuous electrochemical monitoring of relevant biomarkers, combined with automated wireless data communication systems, represented a considerable step forward in biosensing field towards new market possibilities [11]. AN 3.1. Smart substrates materials Paper-based substrates, as a platform to develop low-cost and portable diagnostic devices, have a prominent position in the development of commercial POC or ‘in-situ’ biosensors [12, 13]. M Paper, being a recyclable and renewable material that can be easily printed and coated with chemical reagents or biomolecules, stood out as substrate material for microfluidic paper- PT ED based sensors (µPADs) construction. µPADs have been able to move smoothly from academia to industry from their early begin to integrate different kinds of biosensors [13] . Additionally, µPADs electrochemical sensors facilitate multiplexed testing answering to the multi-analyte paradigm [14]. µPADs are estimated to have also particular relevance as diagnostic tools for the CE developing world. AC More recently, polymer-based substrates start attracting great share of attention as flexible smart substrates [12, 15] . Flexible polymer presents higher mechanic resilience, less mechanic stress and, if it is the case, allows a better conformal adjustment between the implantable surface and the sensor. All these features lead to less noise in the analytical signal response surpassing the limitations of conventional rigid substrates [16]. ACCEPTED MANUSCRIPT 3.2. Electrode patterning techniques Regarding patterning techniques, thick-film, through screen-printing [17,18] , stencil-printing [19] or inkjet fabrication process [20,21], or thin-film (lithography) technologies [22], still are the most common used. These technologies are perfect candidates to make reproducible devices at large scales in an inexpensive and easy way. Other technologies such as reagent-free laser scribing have been demonstrated for direct fabrication of nanostructured electrodes with excellent performance [23]. Moreover, hybrid systems that integrate lithography (thin-film) and IP T screen-printing (thick-film) technologies through an “island-bridge” approach for the printing of functional ink materials onto lithographically stretchable patterns are also being reported . These stretchable electronics are playing a key role in the development of soft bio- US CR [24] integrated electrochemical biosensors [24, 25]. 3.3. Wearable electrochemical biosensors Currently, non-wearable sensors still accounted for major market share however it is expected AN that wearable biosensors emerge as a fast growing product. The development of non-invasive wearable electrochemical biosensors for decentralized and continuous monitoring has been receiving enormous attention from researchers in different sectors. By employing wearable M sensors, invasive blood analysis, as the gold-standard procedure, is being replaced by the other biological fluids, such as sweat, saliva, tears and skin interstitial fluid, providing valuable PT ED physiological information for painless analysis of important parameters. Several authors already reported the implementation of wearable sensors in daily-basis objects like contact lenses [26] materials , mouth-guards [9] [27,28] , adhesive bandage [29, 30] , flexible skin tattoos and textile in order to achieve fully integrated wearable systems. The continuous effort in CE integrating the sensing devices for direct and intimate contact with biological tissues is creating unique standards for wearable devices. Even though wearable sensors are relevant AC for decision-making in different fields such as animal health management [31], food analysis [32] or biothreat control [9,33] , it seems that the most promising applications for wearable electrochemical biosensors are in personalized medicine or sports health. 3.3.1. Wearable sensors in diabetes management The measurement of glucose levels in blood have been a constant hot topic in academic/industrial research along the years [34] . Diabetes mellitus still remains one of the principal causes of death and disability in the world and the development of better, even less invasive sensors that helps improving patient life is continuous demanded [35] . The recent ACCEPTED MANUSCRIPT introduction in the market of electrochemical wearable sensors for glycemic continuous monitoring has revolutionized diabetes management [36-38] . These finger-prick free sensors measure glucose continuously in interstitial fluid through a very small filament that is usually inserted just under the patient’s skin during several days. The fact that data is almost continuously reported allows a better control of the effectiveness of the medical treatment and of the patient response to it. IP T 3.3.2. Wearable sensors in sweat analysis In sports medicine, the monitoring of lactate threshold is crucial to optimize performance especially for limiting endurance. Additionally to lactate measurement, other biomarkers, like US CR sodium or potassium, are relevant to control other aspects of the athlete training, such as dehydration levels. All these parameters are accessible and can be easily measured in sweat [39] . For instance, in bibliography can be found different wearable electrochemical sensors based on ion-selective electrodes for the determination of ions in sweat [40-42] , nonetheless [39,40,43] AN electrochemical enzymatic biosensors for lactate and glucose detection were also developed . Sweat, as an accessible biofluid, besides being a rich source of clinical information is also characterized by a non-invasive sampling process [44] . Currently, have been described bracelets [40, 45] or textile materials M some accessories with implanted biosensors for sweat harvesting and analysis such as [46] . Beyond being a tool for controlling athletes’ training PT ED activities, wearable perspiration sensors have been also explored for other fields of application, such as clinical diagnosis [47] or drug abuses control [48]. 3.4. Smartphones role in electrochemical biosensing The combination between sensor electronics and Internet of Things opened a new window of CE opportunities for personalized health and other sectors where continuously real-time monitoring of specific parameters has been demanded. The development of more AC autonomous hand-held readout systems definitely contribute to the expansion of electrochemical biosensors in the market and in giving the final shape to the concept out-oflab analysis. Consequently, smartphones, and other similar remote base stations, have recently received much attention as a potential tool for multiple functions in analytical testing [49,50] . The possibility of real-time data acquisition combined with the portability and ubiquitous availability that characterize these devices, real truly garnered biosensor market interest for their potential [49] . Data communication between the sensor electronics and the mobile receptor, usually via bluetooth or near-field communication, has been employed in the development of powerful lab-on-smartphone applications [27, 29, 43]. ACCEPTED MANUSCRIPT 3.5. Self-powering challenge The ultimate goal to meet full portability is to develop reliable and robust self-powered biosensors. The employment of self-powered electrochemical biosensors could replace the use of the potentiostat and other high-power consuming electronics [51] . Thus, all the sensing system is simplified. Biofuel cell are environmental-friendly alternatives that work as selfpower sensors, fulfilling simultaneously the role of biosensor and power source [51,52]. Intensive research is being carried out in this field and interesting applications employing powered devices [26, 56] IP T nanostructured screen-printed electrodes [53], paper-based biofuel cells [54,55], or wearable self, have been reported. Highly stretchable enzymatic biofuel cell with been already published [15] US CR improved response against the usual mechanical deformation of wearable devices have also . Even so, self-powered biosensors have important obstacles to overcome such as the instability of enzymes or other biocomponents and the reduced lifetime as power supply because do not reach the energy demands of most sensors and applications . AN [51] 4. Remaining challenges and future prospects for electrochemical biosensing In the last 2 years, the scientific track record of academic publications under the topic M “electrochemical biosensor” remained high and significant progresses were accomplished. Nonetheless, very few new developments achieved commercialization. The market of PT ED biosensors would be probably larger if the gap between academic research and industry decreases. For that purpose there are many important tasks that still need to be addressed in developing biosensor technology. Some of the relevant problems, such as sensitivity, specificity and instability, are well-known and are intrinsic to the nature of the biological [3] . Other aspects are associated to more CE recognition element employed in the biosensor recent challenges, as the study of non-enzymatic electrocatalytic materials [57] and the [16] . The AC development of miniaturized implantable biosensors with long-term biocompatibility automation attainable by increasing the life-time of small-sized devices with rechargeable batteries or self-powered systems also requires improvement. Regarding wireless sensing communication, ensuring transmission of high volume of data with the absence of interferences in signal processing, is an issue that remains to solve [16]. Other progresses should be done in terms of speed of data communication. Additionally, careful selection of the relevant data that the wireless device user should manage, without being overwhelmed by unnecessary information, is also a sensitive topic [16] . Moreover, the development of security ACCEPTED MANUSCRIPT algorithms to protect data transmission and storage is a priority subject [58] where blockchain technology maybe could play a key role in a near future [59]. The elevated costs of innovative R&D, difficulty towards the replacement of established methods, and legal aspects such as regulatory approvals or clinical trials, are other barriers that slow down the generalization of electrochemical sensors to final market applications. IP T 5. Final remarks In our opinion, these are extraordinary times for biosensor development. Even though the issues that remain to solve, outstanding improvements in electrochemical biosensing are being US CR performed. Nonetheless, despite the excellent evolution that we have witnessed, the future remains challenging. Still are key technical barriers to overcome in order to boost the commercialization of new technologic electrochemical biosensing devices. It is necessary to invest in innovative R&D and productive collaborations between universities and companies in order to answer to the continuous market demands on the development of simpler, faster, AN cheaper, automated and decentralized applications for different sectors. Electrochemical biosensors are expected to continue to grow in the next years occupying strongly their place in AC CE PT ED M the market as analytical trusting tools. ACCEPTED MANUSCRIPT References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: •of special interest ••of outstanding interest. References 1. Thévenot DR, Toth K, Durst RA, Wilson GS: Electrochemical biosensors: recommended definitions and classification. Biosens Bioelectron 2001, 16:121–131. IP T 2. 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