MedAccel

Towards reliable surgical mass spectrometry and use of similar surgical devices in pre-clinical sciences

The ‘iKnife’ is an electrosurgical device that uses an electrical current to heat tissue rapidly, cutting through it while minimising blood loss. This creates a surgical smoke that is actually a complex mixture of ionised molecules caused by the rapid evaporative ionisation of tissue constituents, including metabolites, lipids, peptides and proteins. The iKnife exploits this source of biochemical information by coupling the surgical knife with a mass spectrometer for the real-time analysis of the surgical smoke. With appropriate metrological validation, this approach could enable immediate decision making regarding the continuation of the surgical intervention. There is also significant interest from industry in using such a REIMS (rapid evaporative ionisation mass spectrometry) type device for rapid sampling of cell pellets in support of drug development and preclinical research programmes.

Through the National Centre of Excellence in Mass Spectroscopy Imaging (NiCE-MSI), NPL will be working closely with industrial and clinical partners to deliver fundamental metrology for REIMS devices, in an effort to support the uptake of this technology. The feasibility of developing a new generation model REIMS device will also be investigated.

Supporting drug development

High resolution multiplexed imaging of small molecules and proteins allows the study, at a cellular level, of proof-of-principle and proof-of-mechanism activities in the disposition of a pharmaceutical compound within an organism. The ability to image metabolites and proteins in single experiments provides vital information about the localisation of the target in the cell environment.

Working with pharmaceutical companies, this project will address the measurement challenges associated with each of the main stages in pharmaceutical development, and develop reliable routines and sample preparation methods for high resolution surveys of drugs. It will establish new metrology to support imaging of macromolecular therapies, metal containing drugs, cancer biomarkers and developmental contrast agents for MRI and PET.

MRI multi-site reproducibility study

Despite careful calibration and quality assurance, MRI scanners from different vendors and at different sites produce differing images. This is a challenge for advanced methods aimed at imaging tissue microstructure. Individual standardised pipelines would be highly valuable in running multicentre MRI trials. Reproducibility is critical when translating the approaches into clinical application, and is the first step in allowing more hospitals and institutions to participate in studies of advanced MRI methods.

This project assesses the variability of advanced diffusion MRI studies of the brain in healthy volunteers performed at University College London, Cardiff University and University of Cambridge. The results of the work will enable a quantified understanding of how reproducible and reliable tissue microstructure images are when measured by different teams at different sites.

Quantitative analysis MRI phantom for longitudinal assessments

With the growth of imaging modalities based on quantitative analysis of MRI data, it is imperative that there also exists a mechanism to apply an uncertainty to any stated quantity. For the successful transition of these techniques into the clinical environment, a quantitative measure of inter-site scan data quality is necessary in order to compare results taken in different hospitals. A suitable test object must be developed that allows for the characterisation of fundamental MR parameters to be measured in a repeatable, traceable way.

This project will develop a novel quantitative MRI phantom, which will be used to perform a nationwide study of fundamental MRI capability through longitudinal multisite studies. This information will allow for an understanding of quantitative uncertainties throughout different imaging modalities and will lend confidence to drug trial studies, biomarker analysis and machine learning based algorithms.

MRI T1 relaxation time phantom development

Although phantom devices for calibration of MRI scanners can be purchased from a small number of providers, they suffer from a number of drawbacks including that the T_1, relaxation time, values of the phantom materials are not guaranteed by the manufacturers, and that the geometry of the phantoms are typically only designed for head coils, so cannot fit within coils designed for imaging other parts of the body.

To resolve these and other issues, this project is developing magnetic resonance imaging phantoms suitable for specific anatomies. This will ensure that MRI scanners being used in clinical trials are equally and accurately calibrated and that they behave in a uniform manner throughout the lifetime of the trial. These phantoms are needed for multi-centre trials all over the world to ensure that the quality of the trials are of the highest standard.

Duchenne muscular dystrophy biomarker

Duchenne muscular dystrophy is an invariably fatal genetic, muscle-wasting condition affecting approximately 1 in 3,600 boys in the UK. The genetic basis of the disease is well-understood and a number of potential therapies have been developed, but the comparative rareness of the condition means that regulatory approval for new therapies is challenging to obtain because of the difficulties in powering a clinical trial – there are simply not enough patients to be able to draw robust conclusions given current effect sizes.

One way to address this is via more effective imaging. By partnering with researchers from University College London and Great Ormond Street Hospital, this project aims to demonstrate that fractional diffusion MRI imaging is a practical and feasible method for detecting microstructural tissue change in a clinical setting, thus supporting the translation of new treatments for Duchenne muscular dystrophy.

Tractography in Neurosurgery

Tractography is a technique for reconstructing white matter structures in the brain in vivo non-invasively from diffusion MRI data. The technique has developed significantly since it was first published in the 1990s but there is currently no way to attach confidence or uncertainty to white matter reconstructions. This is a serious barrier to routine clinical deployment as it is imperative that excising healthy tissue is avoided during brain surgery, since this causes permanent damage.

Partnering with imaging experts at University College London’s Institute of Child Health and a neurosurgery team at Great Ormond Street Hospital, this project will investigate how uncertainty in the imaging data affects tractography-based reconstructions of brain tissue, leading to new visualisation schemes and software for surgical planning and intra-operative monitoring that allow for robust estimation of uncertainty in tractography. Surgeons will be able to have more confidence in where healthy tissue structures are, and the extent of unhealthy tissue to be removed.

Assessment of the impact of a strong magnetic field on radiation response in MRI-guided radiotherapy

A recent development in radiotherapy combines magnetic resonance (MR) and linear accelerator (Linac) treatment units. This allows for improved imaging of the patient during radiotherapy, but the strong magnet is also likely to affect the distribution of the therapeutic dose at the tissue level, due to interactions between the magnetic field and the charged secondary electrons that mediate the effects of photon irradiation. In addition, at the nanoscale level, the presence of the magnetic field may have significant effects on the production and distribution of reactive radical species and cellular repair mechanisms.

This project will investigate how a strong magnetic field changes the cellular effects of radiation, in an advanced tissue engineering construct which recreates the in vivo environment. This will help to determine whether this new type of commercial radiotherapy unit, the MR-Linac, has radiobiological implications that can be safely discounted, compensated for or exploited, prior to clinical implementation.

3D printed radioactive phantoms

There is a clear need for realistic test objects, known as phantoms, to support the development of new radiation imaging technologies. In the case of internally administered radiopharmaceutical imaging, to allow for meaningful testing these objects must reproduce the physical tissue properties with respect to gamma ray attenuation, as well as allowing anatomically realistic 3D distributions of activity. The main challenge is to manufacture phantoms reproducibly which are based on a standard digital model, allowing test measurements to be linked to existing research and standards.

This project will produce a prototype 3D printed pelvis model using ‘bone equivalent’ material developed at NPL. The model will have fillable organ inserts for the testing of new radionuclide imaging systems and intraoperative devices. The phantom will form part of the testing protocol for a new intraoperative medical device.

Radiobiological investigation of theranostic radionuclides

Molecular imaging with radionuclides can pinpoint disease locations and measure changes in metabolism and gene expression. Reporter gene imaging is a technique which has long been used to monitor cellular processes but has only recently been used with radionuclides for non-invasive, whole body imaging of cancer or immune cells. However, the biological effects of radionuclides remain poorly understood. Several radionuclides used for imaging show complex decay patterns, with some releasing Auger electrons that generate complex DNA damage.

This project will determine the sensitivity of cancer cells and immune cells to various radionuclides that are used in traditional targeted imaging techniques as well as in reporter gene imaging. This will allow determination of the radiobiological effects that different radioisotopes exert on these cells in the short and long term, and what cellular doses can be applied without safety concerns. The work will provide data and methodology that can be used by pharmaceutical companies with an interest in Auger radionuclei-based products.

Improvement of tumour imaging quantification via partial volume correction

Molecular radiotherapy delivers radiation to malignant tissue via the interaction of a radiopharmaceutical with molecular sites and receptors. This is a rapidly evolving discipline, particularly with regard to quantification of uptake in normal and malignant tissue. Partial volume effects caused by the limited resolution of imaging systems give rise to an apparent reduction in radiopharmaceutical uptake in tumours. However, these effects are not routinely considered clinically, despite being the dominant source of degradation in quantitative accuracy.

This project will provide best practice guidelines on the practical implementation of partial volume corrections and will support harmonisation of imaging in multi-centre studies, leading to improved assessment of the radiation doses delivered to the cancerous and healthy tissues. This will allow a better understanding of the relationship between the radiation doses delivered and the biological effects of molecular radiotherapy, providing the evidence for patient-specific and cost-effective treatments and improving the quality of life of patients undergoing cancer treatments.

Development of long-lived ⁶⁸Ge NEMA phantom to support UK PET harmonisation and commercial medical imaging services

PET-CT scanning is a powerful weapon to image cancer in the whole body and inform treatment choices. To ensure scanners work correctly it is necessary to perform accurate quality assurance to confirm spatial and quantitative efficacy is preserved in scans. This is currently performed using a NEMA image quality acrylic phantom filled with Fluorine-18 (¹⁸F) which decays quickly with a 110 minute half-life. Due to the short half-life the phantom must be filled with ¹⁸F for each use. Human error and inaccuracy can lead to large variations when filling this complex phantom, leading to increased uncertainties when performing multicentre studies using phantoms that require filling.

This project will use a new accurate, safe, solid, prefabricated image quality phantom which utilises Germanium-68 (⁶⁸Ge), with a half-life of 271 days, to overcome these problems. The long half-life of this phantom enables accurate reproducibility measurements between PET centres and will be used to perform an inter-comparison across UK PET/CT scanning services, providing competitive advantage, delivering better patient outcomes and increasing the power of clinical trials, potentially accelerating new drug development.

Optimising Doppler transducers

Doppler ultrasound devices transmit and receive ultrasound waves to non-invasively obtain continuous real-time measurements of displacement.  By detecting the relative phase changes of the received ultrasound waves, they can reconstruct images or produce audio sounds.  Typically they are used for vascular blood flow or foetal cardiac motion measurement.

Many Doppler ultrasound devices are hand-assembled, which can lead to inconsistencies in acoustic output and variability in clinical performance. The transmitter set-up is designed to optimise acoustic output, but can produce unwanted vibration modes which create local ‘hot-spots’, potentially exceeding internationally agreed limits on exposure.

NPL and Huntleigh Diagnostics, the world’s largest manufacturer of Doppler ultrasound devices, are working together to optimise the design of Doppler devices. The project will investigate the effect of wire bonding locations in Doppler transmitters on acoustic output. It will test new transmitters manufactured with alternative configurations, predicted by theoretical methods, to show improvements in consistency of output and performance.

Nanoparticle-enhanced ultrasound imaging

The potential of ultrasound imaging is currently limited by the lack of effective contrast agents. In particular, the current generation of acoustic contrast agents, known as microbubbles, is primarily limited due to their large size and due to health concerns regarding gas release into the body. Nanosized contrast agents represent an interesting alternative as they are able to extravasate, or be forced out of the cell, due to their small size. In particular, phosphate-based nanoparticles are ideal as contrast agents for sustainable therapeutic drug delivery due to their controlled solubility and the fact that they do not release toxic components after injection.

This project will investigate the suitability of mesoporous phosphate-based glass nanospheres (MPGN) as multifunctional ultrasound contrast agents that function both as imaging tools and vehicles for drug delivery. This has the potential to make the UK a world-leader in the production and commercialisation of bioresorbable MPGN as new generation of ultrasound contrast agents.

Intercomparison of ultrasound phantoms

There are least three manufacturers who provide ultrasound scanning test phantoms into the UK. Users of these include clinical practitioners, medical physicists, engineers and service technicians. There is a deficit of objective information on the best phantom to quality assure a particular clinical machine or modality. The majority of procurement specifications are based upon a replacement for a failed phantom, or simply to repeat studies carried out by peers.

By collaborating with Royal Sussex Hospital, who have access to a broad range of ultrasound scanners, this project aims to compare the performance of up to three commercially-available test phantoms, using a machine cohort of up to six identical ultrasound imaging platforms. This will provide a new, user-independent information resource, comparing phantom results across manufacturers, which will in turn enable the customers of phantom manufacturers and distributers to make more informed choices on ultrasound QA procurement.

Development of validated quantitative photoacoustic phantoms

Photoacoustic imaging (PAI) provides a tissue map of chromophores at ultrasonic resolutions. These can be endogenous (of internal origin, such as melanin, haemoglobin) or exogenous (of external origin) and can be used to derive imaging biomarkers for improved patient management, for example in aiding early cancer diagnosis or identifying high-risk tumours. Appropriate technical validation of PAI systems is still however lacking and this a key requirement for successful translation from research and development to adoption in healthcare systems.

This project will develop standardised test phantoms, allowing the precision and accuracy of photoacoustic imaging systems to be evaluated. A procedure for reproducible fabrication of the test phantoms will be developed and transferred to a phantom manufacturer for commercialisation.

Threshold evaluation

A common problem in imaging is to define where the boundary of an object is. In the medical arena this is an issue in evaluation of tumours, leading to ambiguity regarding the size of a given tumour, the type of tumour and what type of remedial action should be taken.

In collaboration with users and manufacturers of medical phantoms, this project aims to design and construct a phantom to enable users to evaluate the variation in boundaries due to changes in variation of thresholding values when employing X-ray computed tomography (XCT) scanners. The phantom is of simple design and construction that enables the user to determine the variation in the boundary defined by selected thresholding values. The phantom, once manufactured, does not need calibrating and, due to its simplicity, is well within the budget of all XCT users.

This phantom will improve reproducibility and help users to gain an understanding of the variation caused by different methods used to select threshold values. The phantom will also help towards dimensional traceability of XCT systems, thus leading to a reduction in ambiguity of associated medical diagnostics, ultimately leading to better outcomes for patients.

Developing and enhancing metrology tools for dental samples

Precision dimensional measurement and characterisation of free-form and structured surfaces is a long-standing issue for manufacturing. Until recently, the main application areas for free-form surfaces in medicine were body implants, such as knee joints. However, with the increasing demand from medical research, precision dimensional metrology of complex surfaces such as dental surfaces has become important.

This project focuses on the quantification of wear of dental surfaces. It is important that the dental surface is measured to a high data density over the whole wear area, and to a higher precision than the surface roughness, both before and after wear occurs. Different measurement techniques, including optical techniques and X-ray computed tomography (XCT), will be used to provide comprehensive information of the dental surfaces and different alignment algorithms will be studied and their robustness investigated. The project also looks into the data fusion of XCT and optical measurements, and the quantification of dental wear.

Real-time, remote viewing of radiotherapy patient irradiation

There is a current unmet clinical need for a low cost technology to enable real-time, remote viewing of radiotherapy patient irradiation. It would be provided to significant numbers of radiotherapy patients worldwide for complex radiotherapy treatments. Current systems based upon amorphous silicon imaging panels are complex and difficult to implement for advanced radiotherapy.

This project aims to develop a prototype device combining:

• an organic–inorganic hybrid direct conversion, flexible X-ray detector
• a plug-and-play energy harvester based on advanced photovoltaic technology to provide cable-less powering under typical indoor lighting conditions
• X-ray detection and real-time, remote viewing technology.

The new technology will undergo extensive metrological testing under clinical conditions in NPL’s linear accelerator facility, giving it the potential not only to reduce significant mis-administrations of radiation dose, but also to contribute to assurance of accuracy in radiotherapy dose delivery.

Assessment and estimation of suitable techniques for measuring flat panel X-ray sources

Flat panel X-ray sources have the potential to improve the accuracy and mobility of 3D imaging by making portable, low radiation-dose 3D imaging more accessible and lower-cost than systems currently available on the market. The technology will also allow hospitals to provide faster and more definitive diagnoses. The sources require metrological testing to provide reliable information for specification and dosimetry.

This project will determine focal spot size, dose spectrum and dose rates for a flat panel dental source and specify appropriate medical physics checks as well as overall collimation and shielding. This information will then provide input into the design of a larger four-panel chest imaging source.