There are clear advantages to dried blood spot (DBS) sampling compared with routine wet sampling in many situations. However, DBS – as a technology with potential to replace wet sampling – has fallen out of favor with clinical laboratories because of its inherent limitations. Technology is advancing, though, and what were once obstacles to an accurate result, are no longer issues of concern – next-generation blood microsampling devices now have a clear place in clinical labs. Hitesh Pandya, Senior Lecturer in Pediatric Respiratory & High Dependency Unit Medicine, and Bikalpa Neupane, Clinical Research Fellow, University Hospitals of Leicester NHS Trust, UK, tell us why.
What has driven the development of microsample technology?
There are some obvious advantages to any system that will allow us to acquire and test very low blood volumes. A particular urgency for this type of technology was stimulated around a decade ago by changes to procedures for new drug applications to the FDA and EMA. Where new drugs had a pediatric indication, it was now mandated that these drugs be “tested” in children and not just in adults. Resultantly, a substantially higher number of pharmacokinetic (PK) studies, and therefore blood samples, during clinical development were needed. The solution at the time was to use GUTHRIE (DBS) cards – basically cards that collect blood droplet samples for testing. While these cards filled an unmet need, there were two vital boxes they didn’t tick – accuracy and precision, and spoilage and loss. These cards were impractical in real-life settings – “hematocrit issues” were substantial, and each dried blood spot had to be “punched” out manually, so staff time and costs were high. There was also a lot of wastage, too; in the population of new-born infants routinely screened for congenital disorders, such as cystic fibrosis, I would estimate that around 10 percent of GUTHRIE cards needed to be repeated as they were unacceptable for analysis. That number is not insignificant, in particular when you’re dealing with huge populations – the UK birth rate, for example, is ~700,000 per annum. It’s clear that an alternative was needed.Aren’t wet samples good enough?
As we know, most routine sampling in hospitals is performed using wet samples, which is fine in most cases, but there are intrinsic issues associated with them. The requirement for high sample volumes (a minimum of 200 μl) makes testing, in particular regular testing and screening, near-impossible in some pediatric patients. Ongoing monitoring of chronic diseases and general screening are hampered by the high workload that accompany high-volume wet sampling too. The preanalytical error that we are exposed to as a result of routine blood sampling are also well-known – errors that can creep in at the acquisition, storage, transport and testing stages. These are processes that have to be tightly controlled if we are to have confidence in the accuracy of our results.How do you currently use microsampling?
We use it (specifically Mitra® microsampling devices, Neoteryx®) for research purposes only, in particular for PK studies, but we see a clear need for its expanded use clinically; in our opinion it overcomes the key limitations of traditional DBS testing. Our experience after using hundreds of Mitra tips has been very positive, the obvious instant advantage being volume – we only need 10 μl of sample to conduct a test. We can collect a sample very quickly, simply with a fingerpick – no venepuncture is required – and we’ve never had a test case denied because of the inadequate blood volume. Our team required minimal training, in fact, we would go as far as to say it’s foolproof and its accurate. By that we mean that blood collection is very simple, there is little to no risk of spoilt samples and, importantly, storage requirements are straightforward and minimal; the ability to store and transport tips in normal room temperature is extremely useful and cost-effective too. Plasma processing steps are eliminated, which is a great advantage. To date, we have not encountered any specific issues relating to collection of blood samples, storage or transportation of tips. From an end-user’s perspective, we can confidently say that microsampling shortens and simplifies our work considerably, its automatable and the risk of infection is minimized too. A specialist team of doctors or phlebotomists aren’t needed either; literally anybody, including patients, could take a sample.Could you please outline any challenges to introducing microsampling into a clinical laboratory?
The biggest challenge with any dried blood microsampling technology is to develop a uniform collection method and establish normal ranges / values for blood parameters. So much of what we do is on plasma so we do need to define normative values for our blood samples. User economics also presents an obstacle – microsampling technology requires an initial financial investment to integrate it into a lab. With resources already being stretched in most labs, this may be a difficult argument to win, but we can say that the long-term economics of the introduction should be favorable. We feel the quality benefits are huge, too. And although microsampling is not the solution for every analyte, we would remind that a universal wet sample system doesn’t exist either (EDTA sample bottle, plasma sample bottles, etc.).
What is your prediction for the future role of microsampling in the future?
There are many potential uses. First and foremost, in clinical trials, in particular for pediatric patients as explained, but also in preclinical testing – think of how many fewer animals you would need if only tiny amounts of blood were required for testing. We also see a big role for it in screening and at-home testing. For example, screening young children for disorders, like cystic fibrosis, that are disabling if not picked up early. The same could be applied to adults too. We already have good biomarkers for very common conditions, in particular in aging populations. Imagine a patient testing themselves for vitamin D deficiency, COPD, heart failure markers, and also to manage their diabetes, through HbA1c testing at home. A Mitra tip can be given to patients to do their own sampling, and they post it to the lab. The result is then waiting for them at the clinic when they arrive. There are important applications for this type of sampling in research too. When it comes to the search for new diagnostics, often you don’t know what you’re looking for so high volumes of samples are needed. Think of how much more simple and cost- effective the process will be if microsamples were used to support the discovery of new analytes or biomarkers. While liquid chromatography/mass spectrometry (LC/MS) equipment is already capable of effectively analyzing low blood volumes, imagine trying to get some mass spec equipment out to Mount Everest, for example. It’s not going to happen. This technology ought to be a winner for the developing world where standard wet sample acquisition and testing is difficult, while offering big advantages for developed countries too. The benefits of microsampling for pediatric patients, for screening and chronic disease management are clear, but is its use commonplace in the clinic? Not yet, but it should be. In our opinion, microsampling will supersede current collection methods and this will be driven by the revolution in at-home testing by patients.Newsletters
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