Point-of-Care Testing Technologies
Review Article
Existing and Emerging Technologies for Point-of-Care Testing Andrew St John1 and Christopher P Price2
ARC Consulting, Mt Lawley, WA 6050, Australia; 2Department of Primary Care Health Sciences, University of Oxford, United Kingdom. For correspondence: Dr Andrew St John, [email protected] 1
Abstract The volume of point-of-care testing (PoCT) has steadily increased over the 40 or so years since its widespread introduction. That growth is likely to continue, driven by changes in healthcare delivery which are aimed at delivering less costly care closer to the patient’s home. In the developing world there is the challenge of more effective care for infectious diseases and PoCT may play a much greater role here in the future. PoCT technologies can be split into two categories, but in both, testing is generally performed by technologies first devised more than two decades ago. These technologies have undoubtedly been refined and improved to deliver easier-to-use devices with incremental improvements in analytical performance. Of the two major categories the first is small handheld devices, providing qualitative or quantitative determination of an increasing range of analytes. The dominant technologies here are glucose biosensor strips and lateral flow strips using immobilised antibodies to determine a range of parameters including cardiac markers and infectious pathogens. The second category of devices are larger, often bench-top devices which are essentially laboratory instruments which have been reduced in both size and complexity. These include critical care analysers and, more recently, small haematology and immunology analysers. New emerging devices include those that are utilising molecular techniques such as PCR to provide infectious disease testing in a sufficiently small device to be used at the point of care. This area is likely to grow with many devices being developed and likely to reach the commercial market in the next few years.
Introduction The dominant model of laboratory testing throughout the world remains the centralised laboratory in which more and more of the analytical processes are automated to enable the analysis of large numbers of samples at relatively low cost. This trend is well established in biochemistry and haematology and is now extending to other disciplines including microbiology and anatomical pathology. However healthcare is changing, partly as a result of economic pressures, and also because of the general recognition that care needs to be less fragmented and more patient-centred.1 Many countries are facing the reality of having to limit the growth in healthcare budgets or in some cases reduce healthcare spending. One way to achieve this goal is to reduce relatively expensive care in secondary and tertiary hospitals and encourage more patients to be assessed and treated in primary care or the community. It is uncertain whether the central laboratory concept is best suited to the needs of this more primary care orientated care model
which is still in its infancy. Alternative models using PoCT are being increasingly considered, particularly for people in more remote locations such as found in Australia,2 but also in relatively densely populated countries such as the UK where telehealth applications are being actively considered to provide more care in the patient’s home.3 The need to make healthcare more patient-centred is also a global trend and is based on the premise that healthcare should be organised more around the patient rather than the provider. Centralised testing does not represent a convenient process for many patients with the testing process often being disconnected from the consultation process such that more than one visit to the doctor is required to complete the assessment process. This problem applies particularly to those with a chronic disease such as diabetes who require regular monitoring including frequent blood tests. The growth in self-monitoring of blood glucose, which is by far the largest segment of PoCT, is in part a testament to this need for more convenient and, in some cases, more effective care.4
Clin Biochem Rev 35 (3) 2014 155
St John A & Price CP
Pressure on healthcare budgets and the trend to patientcentred care might be perceived as problems confined to the developed world. While true in part, the pace of development in countries such as India and China means that they have a growing middle class with its attendant healthcare problems of chronic disease such as diabetes and cancer. This will lead to the same problems as those being faced by westernised healthcare systems. But poverty and disease remain significant problems in the developing world with many infectious diseases leading to significant mortality. Effective diagnostic testing has been difficult to achieve in this area but PoCT is seen as one way to meet this need and several major global initiatives are devoted to providing such testing.5,6 Consequently it is likely that PoCT will increase substantially in developing countries in the next decade. Market Growth of Point-of-Care Testing Various reports are available to document the growth in in vitro diagnostics (IVD) markets including various categories such as PoCT. While the numbers vary between reports, the total IVD market was believed to be worth US$51 billion in 2011 of which approximately US$15 billion was PoCT. The latter is projected to show compound annual growth of 4% to reach US$18 billion by 2016. Of the total PoCT market in 2011, 55% of it was in the US, 30% in Europe and 12% in Asia.7 The PoCT market is made up of what is termed ‘over the counter’ products such as glucose monitoring and pregnancy testing (also called non-professional testing) and the ‘professional market’ which includes all other testing including critical care, infectious disease, cardiac markers, diabetes, lipids, coagulation and haematology. In 2011 the professional market was worth US$5.66 billion and is projected to grow to US$6.76 billion by 2016. Glucose testing (by healthcare providers rather than patients) is the largest sector followed by pregnancy and critical care testing while infectious disease testing is the fastest growing area.7 Data on the growth of molecular testing is also interesting in the context of the increase in infectious disease PoCT.8 The total molecular diagnostics market is believed to be worth US$4 billion in 2011 and grow to US$7 billion by 2016 with compounded annual growth rates in infectious disease testing of more than 18%. With the emergence of new devices to perform molecular testing at the point of care and the welldocumented needs for more infectious disease testing in the developing world, it will be interesting to see how much of that growth takes place in point of care locations rather than the central laboratory.
156 Clin Biochem Rev 35 (3) 2014
Required Features of PoCT Devices Designers of PoCT devices start with the needs of their users and these needs will to some extent depend on the clinical setting. However some features are common to virtually all users in all settings. As documented by St John et al.,9 these key requirements include: 1. Simple to use. 2. Reagents and consumables are robust in storage and usage. 3. Results should be concordant with an established laboratory method. 4. Device together with associated reagents and consumables are safe to use. With the growing potential for PoCT to improve healthcare in the developing world, particularly through timely detection of infectious diseases, developers of such devices have been guided by more specific design criteria. These are to ensure that the technology can address the needs of the user in a clinically and cost effective manner and avoid the introduction of possibly expensive devices which fail to deliver the required outcomes. Thus the World Health Organisation (WHO) has provided guidelines for those developing PoCT devices for the detection of sexually transmitted infections (STI), a major health problem in the developing world, and in the developed world for diseases such as Chlamydia and HIV.10 These guidelines are known as ASSURED and are shown in Table 1. Table 1. The ASSURED guidelines that indicate the features that should be designed into all PoCT devices. • Affordable – for those at risk of infection • Sensitive – minimal false negatives • Specific – minimal false positives • User-friendly – minimal steps to carry out test • Rapid & Robust – short turnaround time and no need for refrigerated storage • Equipment-free – no complex equipment • Delivered – to end users
The reality of course is that it has been difficult to deliver on all of these technology requirements and a recent paper discusses what compromises and trade-offs would be acceptable to developed world healthcare providers working in the areas of STIs. Hsieh et al. conducted an online survey following a focus group involving clinicians and others offering STI services, to discuss what would be the ideal PoCT device for this area.11 The survey included a section entitled ‘build your
Point-of-Care Testing Technologies
own PoCT’ using a discrete choice experiment approach, a tool from marketing research that allowed participants to identify which of the ASSURED features they would chose over others. The results of this analysis identified that a longer time to getting a result from the device or TAT was a major barrier to greater use of PoCT for STIs such as Chlamydia and HIV. Irrespective of the test organism being detected, sensitivity of 90–99% was the most important attribute followed by a low cost of US$20 and short detection time of 5 min. However another survey conducted by the same group indicated that industry professionals preferred a 15 min turnaround time. Huang et al. in a comparative effectiveness study found that women attending an STI clinic would be willing to wait for up to 40 min for their result.12 For detection of early HIV and syphilis, sensitivity was still the most important but specificity was ranked second.11 Given the compromises inherent in virtually all measurement technologies, it may be useful to extend needs assessments like these to other areas of PoCT. For PoCT devices that will be used in the developed world, some of the ASSURED criteria will also remain relevant but others will be substantially different. Thus instead of being equipment free, the need will be for relatively sophisticated equipment that at a minimum can provide a quantitative result, presentation of the results, decision support and, ideally, connectivity to other information systems such as the patient’s electronic health record. While the technology to provide all these features undoubtedly exists, they come at a cost which may be difficult to recover using the most common business model for PoCT which is that used for the central laboratory, based on complexity and reagent costs, thus only charging for the test strips/cartridges.13 When one combines these equipment needs with what are seen as other competitive requirements such as a small sample volume, whole blood, production of a result within 10 min of applying the sample, ease of use and requisite analytical performance, it is possible to appreciate the technological challenges involved in building such devices. In recent times a newer challenge has arisen, namely the ability to simultaneously measure multiple analytes on the same cartridge, or multiplexing as it is known. Multiplexing is a rather broad and undefined term but, with the exception of devices used in critical care such as blood gas analysers, the number of multi-analyte PoCT devices is relatively few. Of the few that have appeared, those that have the ability for example to measure multiple cardiac enzymes or several different type of drugs are not universally popular with users because they will be charged for all such parameters, irrespective of whether they need the complete panel. However as more healthcare moves away from the hospital into the community, the demand grows for multi-analyte point of care platforms
since these avoid the need for several devices, all with the attendant needs of multiple training, quality management and interfacing processes and the increased risk of errors. But the technological challenges of meeting all these needs has meant that the introduction of new technologies has been relatively slow with the largest sections of the current PoCT market such as glucose, international normalised ratio (INR), cardiac markers and blood gases all using technology that was introduced at least 20 years ago and sometimes much longer.13 Types of PoCT Technology A typical classification of PoCT technology splits devices into small handheld ones including quantitative and qualitative strips, and those which are larger bench-top devices with more complex built-in fluidics, often variants of ones used in conventional laboratories. It is possible to identify a number of key design components that are incorporated into all devices, the collective aim of which is to achieve, as far as possible, all the desired features that were discussed in the previous section.9 Although not all are present in the simpler devices such as dipsticks, these key design components are shown in Table 2. With the trend of increasing miniaturisation of devices and the application of technologies developed in relation to consumer electronics, it is becoming increasingly possible to make smaller and smaller devices that incorporate all of these key design features. Table 2. Key design components of PoCT devices. • Operator interface • Bar code identification system • Sample delivery devices • Reagent storage and availability • Reaction cell • Sensors to detect the measurement reaction • Control and communication systems • Data management and storage • Manufacturing requirements
Several comprehensive reviews of PoCT technologies exist in the literature, and these remain reasonably current due to the relatively slow pace of new technology development and slow adoption by users.9,14 The commercially available forms of these two major types of devices are briefly discussed below, highlighting some of the latest versions of these technologies. This is followed by a review of technologies which are in development and show promise but are not generally yet available for routine use.
Clin Biochem Rev 35 (3) 2014 157
St John A & Price CP
Small Handheld PoCT Devices A myriad of small devices exist for PoCT that range from the humble, so-called dipstick to the sophisticated, small cartridge devices used in blood gas analysis. These devices are truly portable and typically used by the patient themselves or by healthcare professionals at locations adjacent to the patient such as by the bedside, in the clinic or in the patient’s home. Their portability means that how these devices are used, sometimes referred to as the operational workflow, is usually different to the use of larger or bench-top devices. For example, small, portable devices often use fingerstick, capillary samples which are applied directly to the PoCT instrument without the need for sample containers, labelling or transport which are required for analysis by a larger benchtop PoCT instrument some distance from the patient. While avoiding these additional steps is highly convenient, there are risks associated with such procedures and the testing process must be designed to minimise such risks with appropriate training and documentation. The dipstick is a PoCT technology that has stood the test of time and is used frequently today by patients, nurses and doctors in many different locations. In its simplest form a urine sample is applied to a porous pad containing reagent and reflectance technology is used to provide a semi-quantitative estimate of the analyte.15 Dipsticks can detect one or up to 10 analytes and can be used in conjunction with a small reading device in order to reduce potential operator error. To measure analytes in blood the pads contain several layers, one of which is a membrane that prevents red cells from entering the part of the pad where reflectance is measured.16 Dipsticks of this type require more operator care because their performance is dependent upon sample volume as well as the need to cover all the pad, and reading the result after a certain time has elapsed after applying the sample – although even in the case of the latter point, the issue of reading time has been overcome. Such devices can measure a clinically useful range of analytes in urine and whole blood.17 Immunostrips are immunosensors where the recognition agent is an antibody that binds to the analyte with detection by reflectance or fluorescence spectrophotometry. They have been built in a variety of different formats, the first of which was a flow-through design using a porous matrix cell in which a heterogeneous immunoassay enabled the measurement of β-hCG at the point of care.18 Lateral flow designs where the separation takes place as the sample moves along a solid phase are much more common, and in fact are the dominant technology in this sector of the PoCT market. The principles behind lateral flow devices are well described in the literature and over the years, with increasing knowledge about solid phase and surface chemistry technology, the capability and
158 Clin Biochem Rev 35 (3) 2014
reliability of these devices has improved considerably.19 These days they also have built in quality control checks which indicate whether the strip technology is working correctly. The utility of lateral flow strips can be extended from qualitative to quantitative measurement through the use of small reader devices that incorporate multichannel light detectors. The latter are often a charge-coupled device (CCD) or CCD camera which can measure much lower light signals than a conventional reflectometer. These devices are commonly used to measure cardiac markers and other acute care parameters such as D-dimer. The continuing development of strip technology together with meter-type readers is best exemplified by the ubiquitous glucose meter which is by far the largest portion of the PoCT market. Current models reflect several decades of innovation since their introduction in the 1970s, both in terms of strip technology and also in meter design. The overall goals have been to make them easier to use, with less potential for errors, and to minimise the effects of interferences.20 Of the many different types of strip that have been developed, all are biosensors incorporating an enzyme such as glucose oxidase, glucose dehydrogenase (GDH) or hexokinase. They are often termed thick-film sensors because each strip is composed of several layers each with designated functions such as separation, spreading or support. There are two types of detection systems: photometric or electrochemical. The latter detection systems have enabled the design of strips that are less subject to interference although problems still persist. Strips that use glucose oxidase are more substrate-specific but are affected by oxygen tension, with high PO2 values leading to falsely low results. Blood oxygen tension does not affect GDH-based strips but GDH strips that use the pyrroloquinolinequinone form of the enzyme are subject to interference by maltose. Excessive concentration of the latter such as in some parenteral nutrition solutions can cause falsely high glucose results when the patient is actually hypoglycaemic, and several deaths have been attributed to these inaccurate results.21 Haematocrit is another important interference, although the effects have been reduced by some newer strip designs. Many different factors can lead to inaccurate glucose results from strip tests and a comprehensive review of these is provided by Tonyushkina et al.22 Electrochemical detection of glucose also made possible more compact meter designs, smaller sample requirement, the production of non-wipe strips and more rapid result delivery – which are all features that facilitate an easier measurement process, particularly important for patients who are selfmonitoring. A major cause of inaccuracy in many meter-based systems is failure to insert the correct calibration code into the
Point-of-Care Testing Technologies
meter for a particular batch of strips, and this can cause errors of up to 30%. Now some strip and meter designs incorporate automatic coding and calibration processes.23 A number of guidelines have been published which document the required accuracy of glucose meters, namely the level of agreement between meter results and those from conventional laboratory testing (Table 3). The most commonly cited guideline is from the International Organisation for Standardisation (ISO) 15197:2003, which states that 95% of results
Review Article
Existing and Emerging Technologies for Point-of-Care Testing Andrew St John1 and Christopher P Price2
ARC Consulting, Mt Lawley, WA 6050, Australia; 2Department of Primary Care Health Sciences, University of Oxford, United Kingdom. For correspondence: Dr Andrew St John, [email protected] 1
Abstract The volume of point-of-care testing (PoCT) has steadily increased over the 40 or so years since its widespread introduction. That growth is likely to continue, driven by changes in healthcare delivery which are aimed at delivering less costly care closer to the patient’s home. In the developing world there is the challenge of more effective care for infectious diseases and PoCT may play a much greater role here in the future. PoCT technologies can be split into two categories, but in both, testing is generally performed by technologies first devised more than two decades ago. These technologies have undoubtedly been refined and improved to deliver easier-to-use devices with incremental improvements in analytical performance. Of the two major categories the first is small handheld devices, providing qualitative or quantitative determination of an increasing range of analytes. The dominant technologies here are glucose biosensor strips and lateral flow strips using immobilised antibodies to determine a range of parameters including cardiac markers and infectious pathogens. The second category of devices are larger, often bench-top devices which are essentially laboratory instruments which have been reduced in both size and complexity. These include critical care analysers and, more recently, small haematology and immunology analysers. New emerging devices include those that are utilising molecular techniques such as PCR to provide infectious disease testing in a sufficiently small device to be used at the point of care. This area is likely to grow with many devices being developed and likely to reach the commercial market in the next few years.
Introduction The dominant model of laboratory testing throughout the world remains the centralised laboratory in which more and more of the analytical processes are automated to enable the analysis of large numbers of samples at relatively low cost. This trend is well established in biochemistry and haematology and is now extending to other disciplines including microbiology and anatomical pathology. However healthcare is changing, partly as a result of economic pressures, and also because of the general recognition that care needs to be less fragmented and more patient-centred.1 Many countries are facing the reality of having to limit the growth in healthcare budgets or in some cases reduce healthcare spending. One way to achieve this goal is to reduce relatively expensive care in secondary and tertiary hospitals and encourage more patients to be assessed and treated in primary care or the community. It is uncertain whether the central laboratory concept is best suited to the needs of this more primary care orientated care model
which is still in its infancy. Alternative models using PoCT are being increasingly considered, particularly for people in more remote locations such as found in Australia,2 but also in relatively densely populated countries such as the UK where telehealth applications are being actively considered to provide more care in the patient’s home.3 The need to make healthcare more patient-centred is also a global trend and is based on the premise that healthcare should be organised more around the patient rather than the provider. Centralised testing does not represent a convenient process for many patients with the testing process often being disconnected from the consultation process such that more than one visit to the doctor is required to complete the assessment process. This problem applies particularly to those with a chronic disease such as diabetes who require regular monitoring including frequent blood tests. The growth in self-monitoring of blood glucose, which is by far the largest segment of PoCT, is in part a testament to this need for more convenient and, in some cases, more effective care.4
Clin Biochem Rev 35 (3) 2014 155
St John A & Price CP
Pressure on healthcare budgets and the trend to patientcentred care might be perceived as problems confined to the developed world. While true in part, the pace of development in countries such as India and China means that they have a growing middle class with its attendant healthcare problems of chronic disease such as diabetes and cancer. This will lead to the same problems as those being faced by westernised healthcare systems. But poverty and disease remain significant problems in the developing world with many infectious diseases leading to significant mortality. Effective diagnostic testing has been difficult to achieve in this area but PoCT is seen as one way to meet this need and several major global initiatives are devoted to providing such testing.5,6 Consequently it is likely that PoCT will increase substantially in developing countries in the next decade. Market Growth of Point-of-Care Testing Various reports are available to document the growth in in vitro diagnostics (IVD) markets including various categories such as PoCT. While the numbers vary between reports, the total IVD market was believed to be worth US$51 billion in 2011 of which approximately US$15 billion was PoCT. The latter is projected to show compound annual growth of 4% to reach US$18 billion by 2016. Of the total PoCT market in 2011, 55% of it was in the US, 30% in Europe and 12% in Asia.7 The PoCT market is made up of what is termed ‘over the counter’ products such as glucose monitoring and pregnancy testing (also called non-professional testing) and the ‘professional market’ which includes all other testing including critical care, infectious disease, cardiac markers, diabetes, lipids, coagulation and haematology. In 2011 the professional market was worth US$5.66 billion and is projected to grow to US$6.76 billion by 2016. Glucose testing (by healthcare providers rather than patients) is the largest sector followed by pregnancy and critical care testing while infectious disease testing is the fastest growing area.7 Data on the growth of molecular testing is also interesting in the context of the increase in infectious disease PoCT.8 The total molecular diagnostics market is believed to be worth US$4 billion in 2011 and grow to US$7 billion by 2016 with compounded annual growth rates in infectious disease testing of more than 18%. With the emergence of new devices to perform molecular testing at the point of care and the welldocumented needs for more infectious disease testing in the developing world, it will be interesting to see how much of that growth takes place in point of care locations rather than the central laboratory.
156 Clin Biochem Rev 35 (3) 2014
Required Features of PoCT Devices Designers of PoCT devices start with the needs of their users and these needs will to some extent depend on the clinical setting. However some features are common to virtually all users in all settings. As documented by St John et al.,9 these key requirements include: 1. Simple to use. 2. Reagents and consumables are robust in storage and usage. 3. Results should be concordant with an established laboratory method. 4. Device together with associated reagents and consumables are safe to use. With the growing potential for PoCT to improve healthcare in the developing world, particularly through timely detection of infectious diseases, developers of such devices have been guided by more specific design criteria. These are to ensure that the technology can address the needs of the user in a clinically and cost effective manner and avoid the introduction of possibly expensive devices which fail to deliver the required outcomes. Thus the World Health Organisation (WHO) has provided guidelines for those developing PoCT devices for the detection of sexually transmitted infections (STI), a major health problem in the developing world, and in the developed world for diseases such as Chlamydia and HIV.10 These guidelines are known as ASSURED and are shown in Table 1. Table 1. The ASSURED guidelines that indicate the features that should be designed into all PoCT devices. • Affordable – for those at risk of infection • Sensitive – minimal false negatives • Specific – minimal false positives • User-friendly – minimal steps to carry out test • Rapid & Robust – short turnaround time and no need for refrigerated storage • Equipment-free – no complex equipment • Delivered – to end users
The reality of course is that it has been difficult to deliver on all of these technology requirements and a recent paper discusses what compromises and trade-offs would be acceptable to developed world healthcare providers working in the areas of STIs. Hsieh et al. conducted an online survey following a focus group involving clinicians and others offering STI services, to discuss what would be the ideal PoCT device for this area.11 The survey included a section entitled ‘build your
Point-of-Care Testing Technologies
own PoCT’ using a discrete choice experiment approach, a tool from marketing research that allowed participants to identify which of the ASSURED features they would chose over others. The results of this analysis identified that a longer time to getting a result from the device or TAT was a major barrier to greater use of PoCT for STIs such as Chlamydia and HIV. Irrespective of the test organism being detected, sensitivity of 90–99% was the most important attribute followed by a low cost of US$20 and short detection time of 5 min. However another survey conducted by the same group indicated that industry professionals preferred a 15 min turnaround time. Huang et al. in a comparative effectiveness study found that women attending an STI clinic would be willing to wait for up to 40 min for their result.12 For detection of early HIV and syphilis, sensitivity was still the most important but specificity was ranked second.11 Given the compromises inherent in virtually all measurement technologies, it may be useful to extend needs assessments like these to other areas of PoCT. For PoCT devices that will be used in the developed world, some of the ASSURED criteria will also remain relevant but others will be substantially different. Thus instead of being equipment free, the need will be for relatively sophisticated equipment that at a minimum can provide a quantitative result, presentation of the results, decision support and, ideally, connectivity to other information systems such as the patient’s electronic health record. While the technology to provide all these features undoubtedly exists, they come at a cost which may be difficult to recover using the most common business model for PoCT which is that used for the central laboratory, based on complexity and reagent costs, thus only charging for the test strips/cartridges.13 When one combines these equipment needs with what are seen as other competitive requirements such as a small sample volume, whole blood, production of a result within 10 min of applying the sample, ease of use and requisite analytical performance, it is possible to appreciate the technological challenges involved in building such devices. In recent times a newer challenge has arisen, namely the ability to simultaneously measure multiple analytes on the same cartridge, or multiplexing as it is known. Multiplexing is a rather broad and undefined term but, with the exception of devices used in critical care such as blood gas analysers, the number of multi-analyte PoCT devices is relatively few. Of the few that have appeared, those that have the ability for example to measure multiple cardiac enzymes or several different type of drugs are not universally popular with users because they will be charged for all such parameters, irrespective of whether they need the complete panel. However as more healthcare moves away from the hospital into the community, the demand grows for multi-analyte point of care platforms
since these avoid the need for several devices, all with the attendant needs of multiple training, quality management and interfacing processes and the increased risk of errors. But the technological challenges of meeting all these needs has meant that the introduction of new technologies has been relatively slow with the largest sections of the current PoCT market such as glucose, international normalised ratio (INR), cardiac markers and blood gases all using technology that was introduced at least 20 years ago and sometimes much longer.13 Types of PoCT Technology A typical classification of PoCT technology splits devices into small handheld ones including quantitative and qualitative strips, and those which are larger bench-top devices with more complex built-in fluidics, often variants of ones used in conventional laboratories. It is possible to identify a number of key design components that are incorporated into all devices, the collective aim of which is to achieve, as far as possible, all the desired features that were discussed in the previous section.9 Although not all are present in the simpler devices such as dipsticks, these key design components are shown in Table 2. With the trend of increasing miniaturisation of devices and the application of technologies developed in relation to consumer electronics, it is becoming increasingly possible to make smaller and smaller devices that incorporate all of these key design features. Table 2. Key design components of PoCT devices. • Operator interface • Bar code identification system • Sample delivery devices • Reagent storage and availability • Reaction cell • Sensors to detect the measurement reaction • Control and communication systems • Data management and storage • Manufacturing requirements
Several comprehensive reviews of PoCT technologies exist in the literature, and these remain reasonably current due to the relatively slow pace of new technology development and slow adoption by users.9,14 The commercially available forms of these two major types of devices are briefly discussed below, highlighting some of the latest versions of these technologies. This is followed by a review of technologies which are in development and show promise but are not generally yet available for routine use.
Clin Biochem Rev 35 (3) 2014 157
St John A & Price CP
Small Handheld PoCT Devices A myriad of small devices exist for PoCT that range from the humble, so-called dipstick to the sophisticated, small cartridge devices used in blood gas analysis. These devices are truly portable and typically used by the patient themselves or by healthcare professionals at locations adjacent to the patient such as by the bedside, in the clinic or in the patient’s home. Their portability means that how these devices are used, sometimes referred to as the operational workflow, is usually different to the use of larger or bench-top devices. For example, small, portable devices often use fingerstick, capillary samples which are applied directly to the PoCT instrument without the need for sample containers, labelling or transport which are required for analysis by a larger benchtop PoCT instrument some distance from the patient. While avoiding these additional steps is highly convenient, there are risks associated with such procedures and the testing process must be designed to minimise such risks with appropriate training and documentation. The dipstick is a PoCT technology that has stood the test of time and is used frequently today by patients, nurses and doctors in many different locations. In its simplest form a urine sample is applied to a porous pad containing reagent and reflectance technology is used to provide a semi-quantitative estimate of the analyte.15 Dipsticks can detect one or up to 10 analytes and can be used in conjunction with a small reading device in order to reduce potential operator error. To measure analytes in blood the pads contain several layers, one of which is a membrane that prevents red cells from entering the part of the pad where reflectance is measured.16 Dipsticks of this type require more operator care because their performance is dependent upon sample volume as well as the need to cover all the pad, and reading the result after a certain time has elapsed after applying the sample – although even in the case of the latter point, the issue of reading time has been overcome. Such devices can measure a clinically useful range of analytes in urine and whole blood.17 Immunostrips are immunosensors where the recognition agent is an antibody that binds to the analyte with detection by reflectance or fluorescence spectrophotometry. They have been built in a variety of different formats, the first of which was a flow-through design using a porous matrix cell in which a heterogeneous immunoassay enabled the measurement of β-hCG at the point of care.18 Lateral flow designs where the separation takes place as the sample moves along a solid phase are much more common, and in fact are the dominant technology in this sector of the PoCT market. The principles behind lateral flow devices are well described in the literature and over the years, with increasing knowledge about solid phase and surface chemistry technology, the capability and
158 Clin Biochem Rev 35 (3) 2014
reliability of these devices has improved considerably.19 These days they also have built in quality control checks which indicate whether the strip technology is working correctly. The utility of lateral flow strips can be extended from qualitative to quantitative measurement through the use of small reader devices that incorporate multichannel light detectors. The latter are often a charge-coupled device (CCD) or CCD camera which can measure much lower light signals than a conventional reflectometer. These devices are commonly used to measure cardiac markers and other acute care parameters such as D-dimer. The continuing development of strip technology together with meter-type readers is best exemplified by the ubiquitous glucose meter which is by far the largest portion of the PoCT market. Current models reflect several decades of innovation since their introduction in the 1970s, both in terms of strip technology and also in meter design. The overall goals have been to make them easier to use, with less potential for errors, and to minimise the effects of interferences.20 Of the many different types of strip that have been developed, all are biosensors incorporating an enzyme such as glucose oxidase, glucose dehydrogenase (GDH) or hexokinase. They are often termed thick-film sensors because each strip is composed of several layers each with designated functions such as separation, spreading or support. There are two types of detection systems: photometric or electrochemical. The latter detection systems have enabled the design of strips that are less subject to interference although problems still persist. Strips that use glucose oxidase are more substrate-specific but are affected by oxygen tension, with high PO2 values leading to falsely low results. Blood oxygen tension does not affect GDH-based strips but GDH strips that use the pyrroloquinolinequinone form of the enzyme are subject to interference by maltose. Excessive concentration of the latter such as in some parenteral nutrition solutions can cause falsely high glucose results when the patient is actually hypoglycaemic, and several deaths have been attributed to these inaccurate results.21 Haematocrit is another important interference, although the effects have been reduced by some newer strip designs. Many different factors can lead to inaccurate glucose results from strip tests and a comprehensive review of these is provided by Tonyushkina et al.22 Electrochemical detection of glucose also made possible more compact meter designs, smaller sample requirement, the production of non-wipe strips and more rapid result delivery – which are all features that facilitate an easier measurement process, particularly important for patients who are selfmonitoring. A major cause of inaccuracy in many meter-based systems is failure to insert the correct calibration code into the
Point-of-Care Testing Technologies
meter for a particular batch of strips, and this can cause errors of up to 30%. Now some strip and meter designs incorporate automatic coding and calibration processes.23 A number of guidelines have been published which document the required accuracy of glucose meters, namely the level of agreement between meter results and those from conventional laboratory testing (Table 3). The most commonly cited guideline is from the International Organisation for Standardisation (ISO) 15197:2003, which states that 95% of results
