National Physical Laboratory

Healthy population A healthy population

Healthcare systems in the future will provide personalised medicine tailored to the needs, lifestyle and living environment of the individual that will increase well-being throughout their life using point of care diagnostics, better-targeted therapies, and 24/7 assessment of critical patient parameters and health indicators.

New measurement techniques will be essential discovery tools that provide the knowledge that is critical to develop personalised diagnostics and therapies that are economically viable and clinically effective.

Explore NPL's progress towards meeting the challenge below:

Ultrasound


The next generation of air quality measurement faces conflicting demands.

Medical ultrasound

Ultrasound is the established treatment of choice for kidney stones, many soft tissue injuries and a range of surgical applications including cataracts. Over the past decade new therapeutic uses have emerged: for instance, more than 40,000 prostate cancer treatments using HIFU without surgery or radiotherapy, and there is a steady stream of innovative applications.

Patients and doctors assume that treatments are based on a good understanding of the required dose in tissue (as in radiotherapy) but no such metrological infrastructure exists. This means that treatments can be inconsistent - with potential harm arising from over-treatment or under-treatment - and that valuable new treatments are not taken up because their outcomes are too uncertain.

A major problem s is the lack of appropriate measurement methods and detectors (especially for high intensity ultrasound fields which can be extremely destructive) which leads to a lack of agreed international standards to support regulation and access to markets. Even more fundamentally, there are no accepted definitions of dose parameters, and traceable methods for determining these quantities, which prevents detailed and reliable treatment planning.

Solving these two problems will enable the development of improved equipment, clinical procedures and regulations, bringing health and financial benefits across the board.

  • Patients will benefit from improved therapies (leading to better disease management and improved quality of life), from less invasive cancer treatments (with fewer side-effects and shorter recovery times), and from more personalized treatment planning and patient management.
  • Doctors and healthcare providers will see the availability of an increased range of reliable therapies and treatment planning tools; and access to enhanced information to underpin patient care and to guide procurement, leading to more efficient use if resources.
  • Manufacturers and regulators will find it easier to bring new modalities to market and enjoy more homogenous global regulatory and purchasing requirements.

Progress:

  • Dosimetry for Therapeutic Ultrasound (DUTy): this is an EMRP-funded project involving 9 partner institutes and coordinated by NPL which started in June 2012 and will last until May 2015. The vison of the project is 'The establishment of a global metrology infrastructure for ultrasound exposure and dose to tissue that will enable more effective and safer treatments'. The project will develop the metrological infrastructure (definitions, validated measurement and modelling methods) for traceable dosimetry to improve the quality of life for patients. It will benefit the medical manufacturing industry, and give healthcare providers optimised treatment planning methods.
  • Metrology for High Intensity Therapeutic Ultrasound: this is an NMO-funded project which aims to enhance measurement capabilities and develop measurement services for High Intensity Therapeutic Ultrasound equipment. This project will assist the wider acceptance of new therapeutic ultrasound applications, which is currently hindered by the lack of underpinning metrology. A coherent measurement service will also benefit customers with other types of ultrasound therapy devices.
  • External Beam Cancer Therapy: this was an EMRP-funded project which finished in March 2011. The ultrasound part involved four NMIs and was led by NPL: its aim was to provide validated methods for ultrasonic field characterization, HITU system performance testing, quality assurance and patient exposure monitoring with the ultimate goal of improving the efficacy, safety and range of applicability of clinical HITU treatments. The work was grouped into four major tasks: the measurement of acoustic power output and efficiency, the characterization of pressure fields in water, the measurement of temperature distributions and the detection and quantification of cavitation.
  • IEC standards. NPL drove the IEC strategy for Standards for High Intensity Therapeutic Ultrasound which led the development of IEC 62555 on power measurement and the Safety Standard IEC 60601-2-62 (both now published) and the field measurement standard IEC62556 (now approved and awaiting final publication).

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Mass Spectrometry Imaging

3D nano-SIMS instrument

A National Centre of Excellence in Mass Spectrometry Imaging

NPL has established a National Centre of Excellence in Mass Spectrometry Imaging (NiCE-MSI). This world-class centre, formed through impetus and needs of stakeholders identified during Metrology for the 2020s, provides measurement at the frontiers and beyond the boundaries of today's measurement capabilities.

Mass spectrometry is, arguably, the most powerful analytical technique for chemical analysis and when combined with the ability to image in 2 and 3 dimensions it has the power to solve measurements issues in a wide range of industry sectors, from pharmaceuticals to organic electronics. New scientific discoveries and innovation in technology is rapidly increasing analytical demands. These forces have led to rapid evolution and revolution in imaging techniques.

A consequence of this is substantially increased cost of ownership of techniques, increased sophistication requiring specialists as well as increasing requirements for interpretation of big data. Consequently, the industrial trend is to use centres of excellence. This also provides industry with the opportunity to try new and emerging techniques before investing.

The centre covers all the major mass spectrometry imaging methods including secondary ion mass spectrometry (SIMS), ambient mass spectrometries and matrix assisted laser desorption ionisation mass spectrometry (MALDI MS). It is a joint venture with the School of Pharmacy at the University of Nottingham.

A high impact example of Metrology 2020 in action for measurement at the frontiers comes from strategic measurement needs identified by the pharmaceutical company GlaxoSmithKline. Currently, one of the major challenges to the pharmaceutical industry is the measurement of the intracellular drug concentration.

NPL is leading a project to design an instrument which could go beyond the micrometre resolution imaging currently available, by developing a 3D label-free molecular imaging system with nanometric spatial resolution. This powerful new instrument could help identify where drugs go at the cellular level, even within specific organelles, answering long-standing questions about whether drug concentrations are sufficiently high in the right places to have a therapeutic effect, or if the medicine is lodging within cellular components and causing toxicity. If anomalies were spotted earlier it might help to explain toxicities or lack of efficacy of a medicine and reduce costly late-stage failures.

Objectives:

  • Develop the fundamentals of key techniques
  • Advance measurement capability
  • Provide essential metrology for reliability and standardisation
  • Support the uptake of the techniques in industry and academia

2020 themes:

Measurement at the frontiersDesigning measurements that go beyond the micrometre resoltuion imaging currently available for the pharmaceutical industry.

 

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Synthetic and systems biology

Biotechnology lab

Some of the greatest research challenges in the life sciences that require quantitative measurements are in synthetic and systems biology.

These include:

  • Biomolecular synthesis - large DNA and cell-free protein synthesis as indispensable tools for advanced manufacturing and industrial biotechnology
  • Traceable measurements of biomolecular structure in cellular environments and with atomistic detail
  • Biophysical and imaging characterisation at the molecular, cellular and tissue levels to understand molecular individualism and enable directed micro-to-nano manipulation

Current strategy

The fundamental advantage of scale-up technologies for sustainable industrial production is modularity which allows engineering complex systems by combining simpler components. This engineering strategy focuses on the development and standardisation of modular functional elements that can be re-used and re-purposed in many different contexts, from new advanced therapeutics and diagnostics (e.g. scaffolds for tissue engineering, biosensors), new fuels (e.g. 'designer' fuels for combustion engines) to new processes for existing and new pharmaceuticals and fine chemicals.

Our main emphasis is on the 'synthetic' part of the area which is prerequisite for 'biology' aspects in advancing industrial applications. The focus is on biophysical and mechanistic aspects of synthetic biology to provide design rules and constraints for interoperable elements or parts to be physically constructed (the synthetic aspect). These elements can be assembled together into complex systems (the biological aspect) that are functional at length scales from molecular to macroscopic.

In this light, NPL is developing metrology capability that can be broadly defined as:

  • Design: standardised design rules of composition and abstraction for the predictable performance of construction parts
  • Operation: measurement approaches and reference materials to enable the predictable exploitation of operational parameters (interactions) between different parts across changing application contexts
  • Characterisation: reference methodologies to measure critical performance parameters of parts, their activities and dependencies
  • Fabrication: standardised fabrication rules to enable a diverse and commercially transferable manufacturing ecosystem

Objectives:

  • Provide advanced synthetic capabilities and definitive structural measurements for biopolymers (polypeptides, polynucleotides) and their properties in native and near-native environments
  • Validate the generic rules using the scientific and technological methodologies developed
  • Enable polypeptide sequence-to-function prediction from first design principles
  • Provide quantitative methodologies as reference tools for optimising advanced medicinal products and devices for controlled cell differentiation in culture or 'smart' niches
  • Introduce metrics to assess cellular responses in changing environments
  • Develop measurement approaches for higher order bio-systems
  • Provide a reference measure for functional self-assembled structures
  • Build a reference methodology enabling bottom-up bionanofabrication

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Advanced therapies and drug delivery using ultrasound

Microbubbles

Lipid coated microbubbles (typically 2-3 microns in diameter) are routinely used in hospitals across the world to enhance contrast in ultrasound scans. The use of microbubbles in conjunction with an ultrasonic scanner has been found to increase the probability of correctly diagnosing heart disease and tumours to over 90%, while more expensive and time-consuming techniques (e.g. MRI, PET) currently have a 30% chance of sending patients home with an incorrect result. In addition, microbubbles are much shorter lived than nanoparticles, meaning they are less toxic, and have been shown to work in the brain.

Manufacturers need a reliable means to check that all the bubbles they produce adhere to the health protection agencies' standards and perform equally well as a product. The latter is crucial to reduce the production price, as it has been estimated that only 30% of the bubbles produced are actually useful.

Researchers all over the world are looking at ways load microbubbles with drugs, transforming them into point-delivery vectors. Bubbles are engineered using single- or multi- layered shells, with each layer a few nanometres thick, in such a way that the bubbles can attach themselves to specific tissues (e.g. atherosclerosis plaques). The acoustically-activated 'capsules' will then deliver their payload exactly where needed. These techniques are being used to produce a novel chemotherapy treatment tailored to each patient's specific needs with potentially no side effects.

The more complicated microbubbles become, the more there is a need for precise characterisation techniques that can investigate the shell and its characteristics. To optimise drug delivery by microbubbles, however, it is also important to have reliable measurement tools to quantify the interactions of bubbles with tissues and with the acoustic waves used to activate them.

Solving these two problems will enable the development of improved clinical procedures and regulations, bringing health and financial benefits across the board. It might also allow calibrated microbubbles to be used as local sensors for blood pressure and viscosity and targeted microbubbles as detectors for sensitive biomarkers.

Objectives:

  • Project 'Bubbles: sensors for the micro-world' in collaboration with the University of Oxford and University College London: NPL researchers have created a microfluidic device (a.k.a. 'NPL's sono-optical tweezers') where single bubbles can be simultaneously manipulated using light and sound in channels the size of a capillary. Funded by the NPL Strategic Research Programme, the project is aimed at creating a metrologically reliable environment where microbubbles engineered elsewhere can be characterised as never before, using their acoustic emission and their dynamics. In this environment we are designing the metrology needed to take microbubble technologies to next step.
  • Project 'Towards a cavitation dose': In this NMO-funded project we are laser-seeding clouds of up to 100 bubbles in a liquid and activating their dynamics using ultrasound, to build dose-effect relationships with effects like kidney stone disruption (i.e. how many bubbles are actually needed to destroy a kidney stones?) and investigate the presence of collective modes that could be exploited for sensing and optimising drug delivery.
  • Science communication activities: 'POP! The sound of bubbles' was designed as a stand for the Royal Society Summer Science Exhibition 2012 and in its first year of life was presented to more than 50,000 people (not counting those reached by TEDx lectures). The stand is aimed at promoting the science of bubbles and their importance for a better quality of life, and has led to discussions and collaborations with other research centres such as Sheffield, Leeds, Glasgow, Imperial College London, and St Thomas' Hospital.
  • Activities within the newly-formed ISO TC-281 on 'fine bubble technologies', aimed at standardising the methods to characterise bubbles with a diameter below 100 microns.

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