INTRODUCTION:

There has been a metamorphosis in the world of analytical chemistry. Increased automation, reduction in size and system integration for multiple tasks have become the key requirements. It is these very same factors that are posing a barrier to the popularity of biosensors which is mostly built to detect a specific or few specific target compounds. It is clear that to be a successful biosensor product to even be considered by venture capitalists or market investors in the first place- they have to be reinvented to be versatile and learn “to support interchangeable biorecognition elements and in addition miniaturization must be feasible to allow automation for parallel sensing with ease of operation at a competitive cost.” ¹

Before we witness the tree of commercial success for biosensors grow strong and ripen with fruits of benefit for the entire society, we must ensure that the roots of research and development grow strong and long. This is crucial for the success of biosensors in today’s competitive and demanding job market.

INSTRUMENTATION:

Biosensors can be broadly viewed as divided into two distinct categories as far as the factor of instrumentation is concerned: (a) complex machines designed to offer high throughput in labs for highly accurate analysis of biological interactions; (b) simple machines designed to offer portability for use by non technical people at home. While the first option may burn a considerable hole in someone’s pocket, the second one is produced in greater volumes and is considerably cheaper.

Medical diagnostics is the major field which has seen the application and success of biosensors. A special mention has to be made of glucose sensor² which is the guiding crutch for diabetic people nowadays as it has truly heralded in the world of personalized medicine³.

The Hulk dominating the scene is for sure the electrochemical biosensors [others being those that incorporate optical, calorimetric, magnetic, thermometric and acoustic transducers] even though they are majorly used for metabolite monitoring while optical techniques are preferred when it comes to bioaffinity monitoring.

The next generation of biosensors will incorporate semi-synthetic and synthetic receptors. This means we can look forward to ore robust, efficient and widely applicable products. Another technology on the horizon is the advent of nanotechnology into this field. This is exciting as nanomaterials will ensure increased sensitivity “and convenient transduction of the resulting binding and catalytic events”⁴. Biosensors are facing a promising future in health care as the industry’s costs along with the consumer demands are on an exponential rise. Thus offering inexpensive, non invasive, portable sensors will surely be well received in the world of diagnostics.

Technology:

Analytical devices that use a sensing element which is biological in nature are termed as biosensors. The sensitivity and specificity of biology and the efficiency of physicochemical transducers procreate to deliver accurate bioanalytical measurements in a user friendly format. Leyland C. Clark first described this “enzyme electrode” in 1962. Today, biosensors are of various types and are usually categorized on the basis of their biological or transducing element. A biosensor includes three main components: a sensitive biological element which will bind to the biomimetic compound, a transducer or a detector which generate a detectable signal followed by a signal reading device⁵.

These biological elements to be detected can be cell organelles, tissues, micro organisms, enzymes or antibodies⁶. Immunosensors refer to antibody sensors. When the binding event is detected, we refer to it as the affinity sensor and when it results in a chemical change due to which alteration of the product concentration or substrate concentration can be quantified is referred to as metabolism sensor. However when the signal takes place not due to chemical change but by changing the auxiliary substrate then such a biosensor is called a catalytic biosensor⁶.

The first example is probably that of the glucose oxidase which was immobilised and converted a platinum electrode into an analytical devise for glucose detection in humans. This changed the way personalised medicine was seen for diabetic patients⁷.

Today optical transducers are changing the face of bioaffinity monitors and the advances have ensured that US sees “a turnover in excess of US $13 billion” which has caught the interest of the medical community⁸. Thus electrochemical sensors have been highly successful in diagnostics, optical sensors in research and development, acoustic resonance is promising but the rest have had no major practical application tested out till date.

Bioaffinity Monitoring:

BIA core™ company along with Ingemar Lundström et al first came up with the designs of the first category of biosensors as mentioned above. The technology basically relied on Surface Plasmon Resonance (SPR). The disadvantage was obviously the associated costs. There were numerous attempts to reduce it and one of the more notable ones was made by Texas Instruments (USA) who came up with an inexpensive SPR chip¹ costing some thousands of US dollars as opposed to the millions spent on sophisticated equipment. All the cheap and non-cheap versions met with conditional success only as the conventional scientist still prefers to operate the traditional equipments which offer ease of use and high efficiency. Increasing popularity of localised surface Plasmon resonance associated with gold nanoparticles is something we need to look out for.

Biosensors for Diabetes: Introduction to Market And Its Success:

85% of the world market for biosensors and its popularity come from its use to measure blood glucose in an increasing diabetic population⁷. Not only is this a confirmation of our belief in its potential but also raises the question-is this the only viable application? The answer usually lies in the amount if business plan being proposed to the venture capitalists and the angel investors as it is usually seen as a high risk program. A large corporation usually needs to confirm that a market in which commercial dealings take place to the tune of an excess of US $100 million exists before they will agree to invest in the first place. And this seems to be missing for all biosensor applications except glucose and pregnancy testing. Most of the innovation in the field is happening because of startups and smaller companies who are showing increasing faith in innovation and are content with long term modest incomes.

A text book example of the same was the production of amperometric sensors which detected glucose for patients with diabetes⁹. Initially, a start up, now called MediSense launched this device. This was also one of the major victories for the technology transfer office at Cranfield, UK which housed its research and development lab. Both the technology and the company were later acquired by Abbott, USA in 1996 ². This was followed by an improved technology using a ferricyanide-mediated GOx called Boehringer Mannheim which again relied on technology transfer from a minor corporation on the USA [Tall Oaks]. Another SME, Kyoto Daiichi Kagaku made the first Japanese launch of a similarly altered product and entered the playing field. They introduced the capillary mechanism which drew in blood from a sample obtained from a pin prick. The original research and development team then moved out to Inverness Medical and produced a further improved version of the sensor which was acquired by Johnson and Johnson Lifescan. The capillary – filled devices were then incorporated by Bayer and the US companies Roche, Johnson and Johnson, Abbott and Bayer captured 90% of sales. Thus the multibillion dollar industry was created.

The crucial elements of success include the following factors-first of all, the emergence and expansion of the diabetic community. The Diabetes Control and Complications Trial conducted in 1993 gave irrefutable proof that if constant monitoring of blood sugar was not done and care was not taken to restrict it to acceptable levels, patients would have to experience terrible side effects which included blindness, amputation, kidney and organ failure. The increased awareness that blood sugar has to be monitored several times a day caused widespread acceptance of this seemingly convenient technology. Other factors included the machine production which ensured standardization [earlier biosensors were handmade], slim instrument design which ensured it was portable, incorporation of the capillary fill procedure, switching on of the instrument on insertion of the testing strip etc¹⁰

Implantable biosensors were the next alternative to the disposable strip sensors as companies sought to lower the discomfort people experienced when drawing blood¹¹. Shichiri et al came up with the first needle type subcutaneous electrode in 1982 but it took more than two full decades for the same to become commercially available to the customers for home usage⁴. The Guardian™ became the first sensor which made continuous glucose monitoring possible and was sold by Medtronic, USA. These sensors acted like “artificial pancreas” and initially needed to be replaced after 64 hours while giving a reading every 5 minutes. In 2006, an improved version with a life of 7 days was released by Dexcom, a US based company. People who suffered from Type I diabetes which is also known as Insulin dependent diabetes welcomed the products however since the these sensors had to be self implanted by the user in their abdomen, many of the users were technologically restricted. Also, the US Federal Drug Administration dictated that the users couldn’t act on results of a continuous sensor and administer themselves insulin shots without first confirming the blood sugar values before verifying it with a finger stick blood sample. In Europe, automation has come in as these biosensors switch off the insulin pump should the glucose levels fall too low [hypoglycaemia is a major cause of concern for diabetes I patients].

In a survey conducted six years ago by Anthony P. F. Turner, head of Biosensors and Bioelectronics Centre at Linköping University, it was discerned that close to a hundred companies that they would be able to introduce to market, in the coming two years, a glucose sensing device which would be non invasive in nature. However that was not the case as they could not come up with the technology to ensure the same.

In a recent announcement, Qualcomm Tricorder declared that they would give out US$10 million as reward for “Integrated diagnostic technology, [which] once available on a consumer mobile device that is easy to use, will allow individuals to incorporate health knowledge and decision-making into their daily lives.” As the market grows and customers needs undergo a change, research teams at BetaLogics (Vancouver, Canada) and ViaCyte (San Diego, California) are at work to show that replacement therapy with the foundation of stem cell technology will be an efficient and secure way to treat diabetes-permanently.

If successful, the insulin pump interfaced to biosensor pumps faces redundancy.

Growth of Biosensor Industry:

With the success of the above models, the biosensor industry boomed and quickly got classified into two main categories: a] companies developing biosensor based devices and b] companies which developed those technologies in the first place. The main players working on the technology today include Cranfield Biotechnology Center, AgaMatrix Inc., LifeSensors Inc., and Nova Biomedical. The front runners in the manufacture of biosensor based devices include Abbott Point Of Care Inc., Neosensors Limited, Siemens Healthcare Diagnostics Inc, Animas Corporation, LifeScan Inc., Medtronic Diabetes, and Roche Diagnostics Ltd.¹².

The Asia Pacific region is witnessing an encouraging growth with 11% expected growth for the time period of 2008-2018 which is followed by the 10.7% expected growth in US which is a developed market economy. With approximately $2.6 billion value, Europe stands as second after the US^{23, 22}. Four broad classifications of biosensors have come out to be as: body implantable sensors which can be used for monitoring the entire body, for handling large volumes we have flow type sensors, lab friendly sensors and simple portable hand use devices.

Some Commercial Biosensors:

As the biosensors caught the fancy of the industry, the technology forayed into various disciplines. According to Frost and Sullivan, as of 2009 point of care dominated the market share with 47.9% stronghold followed by personalised medicine [19.2%], Environmental surveillance [12.4%], Research and Development [11.2%], Food process industries [6.8%] and defence [2.6%] (see figure 1].

Fig. 1: Total Biosensor Market: Percent Revenues [World] 2009

Over 500 companies across the globe are currently involved in the field of biosensors and bioelectronics. While few some of them are focussing on the manufacture and marketing biosensors others focus on delivering the required raw materials or instruments for their fabrication (e.g., Uniscan Instruments Ltd., Chemie, Gwent Electronic Materials Ltd., Dupont Ltd., Eco, Palm Instruments, Biozyme Laboratories Applied Enzyme Technologies etc). A lot of these companies are simply building up on the biosensor technologies that were developed over ten years ago. A small number are developing new technologies. Hence, it is a matter of perspective as to who gets credit of development of commercial biosensors.

The biosensor used to measure blood glucose is definitely the handheld biosensor which has seen the most commercial success till date. It is based on electrochemical transduction technology¹³.

Affymetrix and Agilent, two major companies, have come up with micro-array optical detectors and scanners for proteomic and genomic analysis. Surface Plasmon resonance (SPR) detection is used by optical biosensor devices and has been successfully used in many research labs and universities¹⁴. In terms of implantable biosensors, companies need to come up with innovative ways to implement the technology.

Medtronic Minimed developed an enzyme-based sensor that is a skin implant lasting for three days. Alternatively, VeriChip is presently working on an implantable microprocessor. Still the limitations are many as far as these devices are concerned. It is crucial to notice that numerous MNCs have made a stronghold dominate the biosensor industry as opposed to the start when only start-ups were willing to implement the ideas. According to Newmann, Roche Diagnostics and MediSense are the occupying the giant’s share in the world market for “hand held meter style devices” which contain electrodes which are dispensable in nature⁸. Pharmacia Biosensor AB, which is presently named as BIAcore AB, brought to life the commercial based SPR and at one point had close to 90% of the market in this technology¹⁴. Unfortunately, most of the SPR instruments are more costly than those offered by the competitors and are hardly portable rendering them unsuitable for field studies. Some reports suggest that technology developed by Texas Instruments, which allowed field studies to happen, is less sensitive in contrast to the regularly used ELISA test (Spangler et al., 2001). Still, there is a general preference for manufacture and use of small hold able devices. The production of use and throw sensors which are portable are the need of home care today.

Micro-fabrication technology has heralded the age of miniaturised biosensors. Such technology has made the availability of inexpensive above described devices possible. A bio recognition event results in some changes which can be easily detected using methods which are electrochemical in nature. On subjecting such methods to the micro fabrication process, the birth of various portable devices has been possible.

Interestingly, the globe’s first such device was built by i-STAT. Conductometric, potentiometric and amperometric transduction designs have been included in this biosensor array. This company is only targeting the development and sale of diagnostic products which can be used to analyse blood. The i-STAT Portable Clinical Analyser™ can be described as a hand-held based on silicon array which can analyse multiple target analytes parallel. Electrolytes found in blood like Na+, K+, Cl-, Ca++, gases like CO2, O2 and molecules like urea and C6H12O6 can thus be easily checked. They are also used for detection of cholesterol. Multisense™ is one device that has been created by Oxford Biosensors that has been constructed similar to the above discussed points as it incorporates use and throw microelectrode tests strips and the detection equipment is electrochemical in nature.

SenDx Medical Inc., acquired by Radiometer, has designed a “portable potentiometric array” of sensors which can be applied determination of various ions in the blood.

Lab-on-chips and DNA chips have now become the cynosure of numerous companies. One such company is DiagnoSwiss. It has mastered the process of investigating protein using “miniaturized platforms”¹⁵. Recently, they have been able to formulate a biochip which ensures increased performance levels and high throughput testing used for immunology studies. Micro fluidics and electrochemistry techniques came together to give birth to this device which is similar to an “ultra fast ELISA” kit.

GeneOhm Sciences, Inc., was acquired by Becton, Dickinson and Company in 2006¹⁶. It offers in vitro diagnostic test kits for in vitro detection of MRSA and group B Staphylococcus in pregnant women along with numerous other nucleic acid based devices. Motorola Life Sciences was looking promising too as far as the business and development-Insightful’s analytic technology combined with its semiconductor technology promised high quality biochips for genomic studies and data mining projects-of their biochips seemed to go¹⁷. However, it seems they have now decided to put up their life sciences unit for sale. Good figures of small companies signal a better future concerning the creation of more portable devices.

Chemel AB (Lund, Sweden) is famous for its SIRE based biosensor which they created using a patented technology¹⁸. It is based on the analysis of bio chemicals like sugars etc. Sensor Tech. Ltd. (Cambridge, UK) is commercialising on the biosensors it has developed for the food industry which can be used for quality control and has also produced an immunosensor for in vitro diagnostic purposes known as the Universal Transducer system.

Market Scenario:

Leaving the medical world, there is also a growing call for improved methods for monitoring the environment¹⁹ and for rapidly detecting pathogens. Thus the biosensors industry is undergoing an expansion into non clinical application which include, but are not limited to, defence, food and beverage industry²⁰ and environmental monitoring²¹.

Emergence of nano technology or nano biosensors along with technological progress seen in the recent years and growing market for providing personal care at home and point of care products are the emerging forces shaping the commercial biosensor market. The limiting factors for this expected growth are the huge investments required for research and development, the reluctance to try anything new and the crawling pace of commercialization. Despite these conflicting forces, it’s expected to see a growth majorly because people are looking forward to wearable devices.

In 2013, the industry got some happy news as the valuation of the biosensor world came at $11.39 billion and was projected to touch $22.68 billion by 2020 reporting an approximate jump of 10% during the period of 2014-2020²².

The key players in this industry comprise Life Scan Inc., Medtronic and Abbott Point-of-Care based in the U.S., Bayer Healthcare AG and Siemens Healthcare based in Germany and F. Hoffmann-La Roche Ltd. Based in Switzerland. The market is driven by technology and thus the R and D department has become the primary focus of these technology producers.

We can segregate the market and analyse it based on four sections- firstly, on the basis of product. This basically refers to the type of device-whether it’s wearable [on the wrist, eye, foot, neck, body or ingested] or non wearable.

Secondly, on the basis of technology that was incorporated. This refers to the type of biosensor [electrochemical, piezoelectric, optical, thermal, fibre optics or luminometric]^9,23,24. Electrochemical biosensors lead the coverage in the technological segment of the market.

Thirdly, on the basis of application including research labs, defense, environmental surveillance, point-of-care, home diagnostics and food industries. The point-of-care generated the most revenue in the market in 2013 [approximately holding 57% of the market share ]^22,
6.

Lastly, on the basis of geographical location, the market can be segregated into four regional divisions which are Asia Pacific [AP], Europe [E], North America [NA] and Rest of the World [RoW]. North America is the leading user of biosensors with an estimated market share of 42% but Asia Pacific region is also expected to see a boom in its usage owing to growing economies and developing infrastructure and is expected to gather as much as 22 % by 2020. Figure 3 describes the expected growth of all regions by 2020 [US leads with 9, 522 USD million expected business].

Fig.2: Global Biosensors Market Size-Region wise distribution. North America [NA]: 43%, Europe [E]:27%, Asia Pacific[AP]:20%, Rest of the World[RoW]:9%

Market Opportunities:

Technavio’s market analysts have forecasted that soon even in the medical field excluding glucose testing, innovative biosensor tools will be available for cholesterol testing, infectious disease testing, cardiac markers testing, blood gas testing, pregnancy testing, cancer testing etc²⁵. Currently these new applications are expected to have only 8% of the market share corresponding to US$ 4.6 million. Still it’s an encouraging number and a positive signal to entrepreneurs to invest in them.

Gujarat State Forensic Science University has come up with a nanoparticle based biosensor which can help detect intoxicants in blood in just fifteen minutes. There is a need to recognise such inventions and commercialise them on a global scale.

Enzyme biosensors can be used for detection of organophosphates. Currently, bacteria like Rhodococcus erythropolis have aided in the development of BOD [biological oxygen demand] analysers which are used for maintaining quality control of waste water and have been immensely successful as commercial biosensors²⁶.

Immunosensors are highly needed for ensuring pathogen contamination free food. These enzyme sensors can be used in food and beverage [wine, milk, cheese etc industries]²⁷ as essential part of quality control mechanism. The only restrictions in these industries are, as of today, the sterility requirements, need for frequently calibrating the sensors and risk of analyte dilution. These points should be improved as biosensors can push these multibillion dollar industries towards process optimisation which in turn will generate increased profits. They can also be used to detect food allergens so that people prone to hypersensitivity reactions can first test the product they are going to consume for presence of allergens before actually eating it.

Biosensors can help in environmental surveillance by helping agencies like EPA to continuously monitor bioremediation sites, municipal waste treatment plants and groundwater monitoring¹⁹. Sensors can help improve effectiveness and efficiency of the above mentioned processes and offers a wealth of opportunities for investors to consider.

Biosensors can also be considered for use in oil and gas generation industries. They will ensure speedy contamination level check at each processing step thereby bypassing the expensive traditional quality control methods.

The academic prototypes for the above have already been described in many journals till date. It’s the need of the hour to ensure technology transfer takes place and industries invest in Biosensors and make the world a faster, safer and easier place to live in. The major reason why biosensor technology is not progressing faster than it already is because the academic world needs to be interested in seeing their hypothetical inventions tried and tested in real life. If by the opening of more technology transfer offices, we can impress upon the minds that a bridge between the paper and the market thus exist, the speed of innovative development will exponentially increase²⁸.

CONCLUSION:

Thus it’s easy to understand why biosensors have become the cynosure of the academic world as well as the commercial market. It was inevitable if we remember all the advantages it offers as it is innovative, ahead of its times, personalised and designed to suit the increasing demand of hoe care products. The mammoth sale of the glucose sensor is just an example of the same. It is just an indication of this technology’s potential in other fields as well. The potential uses of biosensors in non clinical fields have already been described many a times on paper and its time they are tested out in a widely receptive world market.

Theranostics offers a vital “financial model” in order to impel the progress biosensors as the major buyer most times is not the person needing care but the company which is responsible to provide it-the pharma companies or the food industry or the treatment plants which seeks to bring to the common man, an efficacious therapeutic or safe food or just a cleaner environment. Therefore there is a need to promote biosensors as a customary sales process rather than separating the diagnostic device as a disconnected and optional prerequisite which has to be specially thought and budgeted for if the customer so wishes. This could have significant mercantile implications.

An added incentive which is fuelling the increasing sales is the rising purchase power of patients along with their private health accounts, insurances etc., buyers with increased health consciousness and growing concern for a better environment and a cleaner planet. Since the infiltration of technology is near perfect in our everyday lives, more and more people are turning to Google to find out what devices to use and where to get them. Many such freely available biosensors which do not need prescription are aiding this practise. This boom has resulted in an escalating market in the field of personal diagnostics which in turn will fuel the development of new, easy on the devices. A similar need will rise slowly but surely for other fields as well. If there is no market, then create a market for it. Awareness fuels change in customer buying patterns and industries need to promote biosensors accordingly. New age biosensors are consequently targeting increased integration to construct absolute sensors which can share data with telecommunications networks and allow integration of data using the smart phone and tablets technology.

Ongoing research and development in this field is focusing on becoming smart enough to diagnose the molecular basis of all events-heralding the age of synthetic molecules in the use of sensing systems-which will make the use of and dependency on unstable natural ligands redundant. Hybrid devices which rely on nanotechnology for their fabrication are also a potential application or form in which this technology may choose to evolve. The successful realization of these marvels needs the culmination of motivated visualization of the industry, revolutionary engineering, and intelligent and advanced fabrication techniques along with ground breaking marketing strategies to ensure that demand and sales curve keep rising.

ACKNOWLEDGEMENT:

We want to express our sincere gratitude to Dr. G. Viswanathan, Chancellor for his constant support and encouragement.

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Received on 24.06.2016 Modified on 28.05.2016

Research J. Pharm. and Tech 2017; 10(10):3573-3579.

DOI: 10.5958/0974-360X.2017.00647.3