Preface

There have been quite a number of topical texts and reviews published recently dealing with clinical diagnostics. So, one question to ask is why another book? This Preface hopefully provides a rationale for this. In a parallel vein, there was a belief in the idea of a “Fountain of Youth”; an aged‐adult body enters the “Fountain” Service and exits with new body components, with as good‐as‐new regeneration. To bring this up to date, even if this was achievable, say by tissue engineering the question arises – would the insurance companies foot the bill? So not only are there residual uncertainties, even in utopia, but context is ever changing.

To return to the present topic, our aim was to bring the reader up to date within the context of rapidly evolving technology and to communicate this through the eyes of research leaders. A broad range of approaches is scoped and the diagnostics needs and bottlenecks surveyed. Both academic and industrial experts are included, all addressing robust tools for dealing with the world of real biological measurement – especially from the perspective of a commonly neglected expert: the end user.

Chapter 1 (by Thompson et al.) and Chapter 2 (by Vadgama et al.) deal with Clinical Diagnostics, both in the laboratory and at the bedside, from the broader picture down to some details. There have been powerful advances in extralaboratory testing enabled by new solid‐state technology encompassing reagent immobilisation and miniaturization. This is a difficult area to monitor and set standards for, because of the distributed nature of such testing across a variety of clinical sites and even the home. Laboratory analysis has taken on major advances with high throughput and small sample volumes, so polarisation between technologies that are aimed at laboratory testing vs. those for extra laboratory testing are inevitable.

Analytical specificity remains a vital issue, still not fully resolved, especially for low‐concentration analytes, regardless of technique, and where sample separation cannot be part of the assay system, as in say in vivo sensors, quite significant effort is required to redesign the basic construct. This latter owes as much to materials science and engineering as to chemistry.

Selectivity in general is discussed in Chapter 1 (by Thompson et al.) with specific regard to Clinical Chemistry. In the in vivo context, sensors need to function selectively given their exposure to unmodified samples. There is the added complication of high local protein concentration and cellular ingress at the implant site. Returning to the selectivity challenge, there are helpful, published techniques for electrochemical bio/sensors reviewed in Chapters 1 and 6 (Thompson et al.; Peteu and Szunerits), including membranes to address solute transport and interfacing issues. Ultimately, one needs to be mindful of the trade‐off between analytical complexity and slower processing as against the goal of high specificity.

This issue of damaging nonspecific adsorption (NSA), represents a true Achilles heel for direct contact sensors, and is examined in detail. With biological matrices constituting highly complex solute mixtures, it becomes clear they could well prevent the detection/quantification of target analytes present at considerably lower concentration, outlined in Chapter 1 (Thompson et al.).

Early advances in this regard, though not always seen as such, are the dry reagent systems developed for glucose as illustrated in Chapter 3 (Wang and Hu). Here, unless the integrated laminates are not tailored to whole‐device function and can be produced in mass numbers, the overall transduction value cannot be realized. This chapter examines the progress and challenges of the blood‐glucose biosensors. Managing one’s diabetes also decreases the occurrence of its serious complications such as nephropathy, neuropathy and retinopathy. The pathogenesis of diabetes and its complications seem to be correlated with the presence of nitro‐oxidative species – including peroxynitrite – potentially implicated in beta‐cells destruction, as highlighted in Chapter 6 (Peteu and Szunerits).

Chapter 4 (Gaspar et al.) critically assess recent progress and many challenges in electrochemical detection of disease‐related diagnostic biomarkers. Mostly, we have relied on biomolecules, but aptamer technology shows how such synthetic structures can be harnessed to give stable “readers” for biochemical targets. These are early days still for the technology, and designer aptamers bred via SELEX (selective evolution of ligands by exponential enrichment), should extend their repertoire. It may also be that here and elsewhere, with use of arrays, absolute selectivity will not be a necessity.

As with sampling integrity, so with continuous use sensors for monitoring in vivo, Chapter 5 (by Meyerhoff et al.), shows there is great need to reduce bio‐incompatibility and resultant surface fouling; biofluids are not tolerant of foreign surfaces. In vivo sensors are, however, uniquely positioned to provide site‐related information, in particular at specific extravascular, tissue locations, but face a huge safety and biocompatibility challenge. The fact that this has been resolved in some cases raises the possibility of broader forms of monitoring systems. Even using early proof‐of‐concept systems, it may yet be possible to pick up biological signatures that arise from wider disease sets.

Chapter 5 (Meyerhoff et al.) especially scrutinizes the challenges for sensors long‐term biocompatibility. In spite of the great sensors advances in vitro, the commercial development of implantable chemical sensors has reached a bottleneck. So much so, that, even with the FDA‐required recalibration the output of devices, is still not considered reliable enough. Special coating materials able to say attenuate the activation of platelets or materials able to inhibit the inflammatory response will become important.

In the case of more exotic short‐lived radical species such as peroxynitrite (often ≤1 s lifetime) featured in Chapter 6 (by Peteu and Szunerits) measurement in real environments will be difficult. For species such as peroxynitrite, quantification poses a whole new level of measurement uncertainties, yet they are important: cell signalling, reactivity and tissue damage are mediated by such short‐lived radicals. Mitochondrial oxidation is itself a free‐radical generator. Interestingly, nitric oxide, superoxide, the precursors of peroxynitrite, and peroxynitrite itself have been dubbed “the good, the bad and the ugly” because of their tissue‐level effects. This chapter illustrates the chemical diversity of such reactive species and the way in which electrochemical interfaces and sensor chemistry could track some of these, as a glimpse into future clinical use.

The biomachinery resulting in ineffective haematopoiesis and augmented leukaemia risk in myelodysplastic syndromes is largely known. However, one major challenge illustrated in Chapter 7 (by McNamara et al.) is how to correctly classify and “risk stratify” the patients. Molecular biology assessment could help as diagnostic tools. So often, the right diagnosis – offered early in the game – will affect morbidity and survival.

Chapter 8 (by Barr et al.) describes Raman for noninvasive early cancer diagnosis. Early histological appearances may be difficult to categorise, and there is less interobserver agreement. Some changes may not even be evident by traditional histology, moreover; diagnosis is expensive, time consuming and requires required tissue biopsy. For the specific case of oesophageal neoplasia, there is evidence that a Raman signature can identify molecular change prior to morphological aberrations.

Raman spectroscopy can deliver high sensitivity for degenerating, premalignant, oesophageal epithelium. The gain would be objectivity, speed and a real‐time assessment for early removal of dysplastic tissue and follow up. Raman‐based fibre‐optic interrogation has potential as an in situ surgical adjunct.

Signal handling with arrays is well exemplified in Chapter 9 (by Kendall et al.). Any opportunity to create multiple arrays should be taken, as this adds depth to measurement. Here, for volatiles analysis the power of pattern recognition is well demonstrated. Undoubtedly the principles can be extrapolated to other modes of measurement, including where selectivity and drift are challenges, be it in vivo or in vitro.

Another overarching challenge in clinical diagnostics: the critical need to provide information not just data. With ease of data generation, it could be said that there is too much data for the clinician to deal with, especially if it is real time as with in vivo monitoring devices. Herein lies the problem of what the data is really for; if it is a medical defence strategy it becomes a waste of finances, but if behind the data there is a genuine quest for what the bio/pathological implications might be, then the data becomes of considerably greater value.

As with any scientific quest, one might consider this to be analogous to a person searching for their home keys under a streetlamp, even though these might have been dropped somewhere else, because “that’s where the light is.”… This book has tried to shed some light on some of the important detection challenges impeding future progress in clinical diagnostics. It may be the light is currently in the wrong place, but eventually the home keys will be found. Finally, we would like to thank the team at Royal Society of Chemistry who guided us so patiently through the publication maze and without whom there would be no book: Merlin Fox, Rosalind Searle and Alice Toby-Brant (Commissioning); Lois Bradnam and Sarah Salter (Production).

Pankaj Vadgama London

Serban Peteu Bucharest