From lab to the theatre: the evolution of mass spectrometry

Mike Morris discusses the ‘iKnife’ – a new concept that potentially differentiates tissue samples in real-time  Although few people outside of medicine and the sciences will have heard of it, there can be no doubting the transformative impact mass spectrometry has had on healthcare diagnostics over the past decade. MS is a method of measuring the isotopic chemical signature of samples and today is used for a wide array of routine diagnostics; everything from neonatal metabolic screening to vitamin D metabolite monitoring and pharmaceutical profiling. Whereas in the past the complexity and cost of MS dictated that it could only be offered in a scattering of specialist locations across the country, innovations throughout the past ten years mean that the technology is now easier to use than ever and economically viable. Today, any major hospital can be expected to have several MS machines running routine chemistry diagnostics day in, day out. In this respect, the rise of MS is analogous to that other great healthcare innovation: MRI, and its impact on healthcare is no less important. The rise of MS is, moreover, a revolution that is still in progress. Over the next decade we anticipate that the technology will advance further and will, importantly, make the leap from lab to theatre. One innovative application of MS that is catching the imagination of analytical scientists and physicians is Rapid Evaporative Ionisation Mass Spectrometry; REIMS for short. REIMS has shown potential to analyse biological tissue samples in real-time, such as while the patient is still on the operating table. As we shall see, this innovation has the potential to transform patient outcomes while driving huge efficiency benefits for healthcare providers. REIMS is an ion source technology that generates ‘smoke’ via an electronic scalpel. That smoke can then be analysed through an MS system to detect the chemical ‘fingerprint’ of a given sample. Importantly, REIMS allows MS analysis direct-from-sample, and potentially could enable real-time tissue characterisation for the first time. While REIMS is by no means a new introductory technique for MS, in recent years a significant breakthrough has thrust the technology into the limelight; namely the use of REIMS to probe tissue samples. With this specific application in mind, Waters Corporation took part in a three-year collaborative project with Imperial College and MediMass (a company set up to commercialise in vivo analysis technologies) to develop a conceptual-stage system that could potentially be used for real-time diagnostics in surgery. This partnership culminated in July, when Waters Corporation bought all assets relating to REIMS from MediMass, including patent applications, software, databases and REIMS expertise. This acquisition brought together Waters' expertise in MS with the REIMS enabling technology to develop what is hoped to be a truly revolutionary surgical tool: the iKnife. The iKnife concept involves the use of electricity to cauterise surgical incisions as they are made. This process will create a ‘smoke’ which can then be analysed through MS to determine the nature of what is being cut. The implications of this process are huge. Let’s take the example of tumour surgery, where surgeons need to be certain that they have removed as much of a tumour as possible before they close the patient. This involves sending a tissue sample for analysis at the lab, a process that can take up to 30 minutes. During this time the patient remains under anaesthetic and lies open on the surgery table. Consequentially they are at risk of infection or ill effects from the anaesthetic.

The novelty of the iKnife places it in something of a regulatory grey-area, as it will need to be determined whether it falls under the regulations required for in vitro diagnostic devices or those for medical devices

The ideal solution – and one that has historically evaded the medical profession – is a device that can instantly differentiate between healthy tissue and diseased tissue in vivo. Current approaches to sourcing material for MS analysis require either chemicals or high voltages, both are unconscionable for in vivo analysis due to the potential damage they could cause to the patient. What is required is a standard surgical device that doesn’t harm the patient but can deliver accurate and immediate diagnostics. The iKnife concept offers what we believe to be an achievable solution to this challenge. With the ability to diagnose in vivo the device can provide results much more quickly – theoretically within seconds. The result: the patient is able to leave surgery in a significantly reduced timeframe while the surgeon can be assured they have removed as much of the tumour as possible. The latter is particularly important for two reasons. Firstly, diagnostic accuracy at the border between diseased and healthy tissue means as much healthy tissue as possible is left behind. Secondly, accuracy and precision is important when it comes to reducing instances of re-intervention (i.e. when a patient needs to return to hospital because the initial surgery failed to capture the entire tumour). Re-intervention is clearly bad for the patient: as well as the stress placed on the body through a second round of surgery, re-intervention can also be assumed to have a negative psychological effect. For the hospital, re-interventions are challenging from a resourcing perspective, with each instance being costly for the institution. If you could halve the rates of re-intervention, the savings to each individual hospital and to healthcare systems as a whole would be huge. We believe that by improving the accuracy of cancer tissue clearance, the iKnife could bring about such savings. As the iKnife moves from its conceptual stage, it is clear that there are going to be a number of significant regulatory challenges that will need to be addressed. As with any device or process intended for the healthcare industry, there will need to be rigorous research studies, patient trials and testing before it receives regulatory approval for commercial sale. The main issue is that the novelty of the iKnife places it in something of a regulatory grey-area, as it will need to be determined whether it falls under the regulations required for in vitro diagnostic devices or those for medical devices. Defining what exactly the iKnife is will therefore be vital in pushing through to regulatory approval. Beyond that, we will be working hard over the next few years to prove that the product works, that it adds value to hospitals and benefits patients. Early research studies on tumour boundary definition are already underway, marking the next important stage in the development of the iKnife. REIMS is still some way off from being used in hospitals. As a rough estimate, if the process of meeting regulatory requirements progresses smoothly, we are still several years out from having a commercial product. If and when that stage is met however, (and to date, no regulatory approvals have been sought for this device) REIMS really does offer great potential. Indeed, in terms of clinical mass spectrometry this would be the biggest innovation since the implementation of MS in neonatal metabolic screening – now the global standard for the metabolic screening of newborn children. This once-in-a-generation technology could transform a wide range of invasive surgeries, making them faster and more accurate than ever, thereby improving patient outcomes. And the potential applications of REIMS do not stop there – it can in theory be used on any tissue sample, opening up the prospect of REIMS being used in everything from meat speciation in the food chain through to microbiological applications. In terms of MS, REIMS is an important new chapter in its history, a history that has been marked throughout by transformative innovation. Author Mike Morris is Senior Director, Mass Spectrometry Research at Waters Corporation. Morris has worked at Waters Corporation for 20 years and in the field of mass spectrometry for 30 years.