Preclinical hybrid in-vivo real-time imaging system (PHiVRIS) Re-submission
Lead Research Organisation:
University of Leicester
Department Name: Physics and Astronomy
Abstract
Although it is well known that imaging studies can greatly improve the scientific outcomes of animal experiments, along with reducing the number of animals needed, such capability is not currently available to the majority of researchers using small animal. In many cases access to imaging systems is limited by the high cost of preclinical imaging equipment. In addition, for researchers studying infectious diseases who have to conduct their research within biosafety cabinets, there are no commercial systems available.
This proposal will translate advanced detector technologies designed for space science to develop a unique, low cost compact preclinical imaging system purpose-built for operation inside a standard laminar-flow biosafety cabinet or an isolator unit.
Based on an intraoperative gamma camera developed by the University of Leicester, our proposed imaging system will be able to detect gamma radiation, visible and near infrared fluorescence. This will allow images in three modalities to be acquired simultaneously, reducing the amount of time mice will need to be anaesthetised and ensuring exact spatial and temporal registration between the images. The small animal holder will be rotatable up to 60 degrees during imaging to provide multiple viewing angles for imaging and an estimation of source depth below the animals surface. This new system will provide an opportunity to conduct longitudinal imaging studies to a far larger range of researchers.
Through collaboration with the Tuberculosis Research Group, University of Leicester and the University of Nottingham the design of this novel imaging system will be guided by end users. This will ensure that the capabilities of the system match the requirements of the small animal researcher. In particular, we will be focussing on the ability to detect and monitor the progression of tuberculosis or other mycobacterial lung infection from an early stage. This highly infectious and debilitating disease will be used as a case study for the prototype system.
PHiVRIS will translate advanced detector technologies proven in X-ray astronomy, into a next generation tool for bioimaging, and will offer a new and unique imaging capability that will provide an innovative approach to live, whole body imaging of small animals.to researchers who may not have access to traditional pre-clinical imaging core facilities.
This proposal will translate advanced detector technologies designed for space science to develop a unique, low cost compact preclinical imaging system purpose-built for operation inside a standard laminar-flow biosafety cabinet or an isolator unit.
Based on an intraoperative gamma camera developed by the University of Leicester, our proposed imaging system will be able to detect gamma radiation, visible and near infrared fluorescence. This will allow images in three modalities to be acquired simultaneously, reducing the amount of time mice will need to be anaesthetised and ensuring exact spatial and temporal registration between the images. The small animal holder will be rotatable up to 60 degrees during imaging to provide multiple viewing angles for imaging and an estimation of source depth below the animals surface. This new system will provide an opportunity to conduct longitudinal imaging studies to a far larger range of researchers.
Through collaboration with the Tuberculosis Research Group, University of Leicester and the University of Nottingham the design of this novel imaging system will be guided by end users. This will ensure that the capabilities of the system match the requirements of the small animal researcher. In particular, we will be focussing on the ability to detect and monitor the progression of tuberculosis or other mycobacterial lung infection from an early stage. This highly infectious and debilitating disease will be used as a case study for the prototype system.
PHiVRIS will translate advanced detector technologies proven in X-ray astronomy, into a next generation tool for bioimaging, and will offer a new and unique imaging capability that will provide an innovative approach to live, whole body imaging of small animals.to researchers who may not have access to traditional pre-clinical imaging core facilities.
Organisations
Publications
Almarhaby A
(2019)
Characterisation of a near-infrared (NIR) fluorescence imaging systems intended for hybrid gamma-NIR fluorescence image guided surgery
in Journal of Instrumentation
Bugby SL
(2021)
Stereoscopic portable hybrid gamma imaging for source depth estimation.
in Physics in medicine and biology
| Description | A compact, low-cost proof-of-concept multi-modal imaging system has been created for preclinical research into infectious disease using animal models. In this use case, all in-vivo research is required to be performed in either isolators or biosafety cabinets. This prototype device provides in-vivo real-time imaging of gamma, optical reflectance and near-infrared fluorescence from identical viewpoints to allow the image streams to be accurately combined and quantitatively compared. For the life sciences researcher, this capability allows live-animal imaging that reduces costs and complexity associated with multiple experimental endpoints. The system incorporates a rotating stage onto which an anaesthetised, immobilised mouse can mounted and axially rotated in a stepwise fashion (<1.0-degree increments) to enable imaging from multiple viewing angles as a basis for the depth estimation of signal sources buried within tissue volumes (ref gamma stereo paper # - summarise achievable depth resolution) The system is based around a low-cost microcontroller and functions independently as a standalone unit. Software has been written to present a graphical user interface to permit the user to control optical imaging exposure time, fluorescence excitation and mechanical scanning parameters. The customised mechanical components required were designed by constructive solid geometry based on computational models integrating both the geometric and optical constraints imposed by the need to image at short working distances to enable high resolution gamma imaging to the target resolution of 1mm. These parts were fabricated by additive 3D printing and so can be easily reproduced (and customised) at low cost to replicate the system. Similarly, the support structures and casing were produced by laser cutting based on design files and so can be easily reproduced and customised for different use cases that biological researchers may require in the future. Electronic and optical components are available off the shelf and could be interchanged allowing customisation for different fluorescent markers and their operating wavelengths. A modular structure has been incorporated to allow selective attachment of the gamma camera and its controller which have a high-cost relative to the optical modes. This modularity anticipates the value of the system being able to operate predominantly for optical and fluorescence imaging with the gamma camera selectively incorporated depending on experimental needs and facilities. This would allow multiple optical imaging units to be purchased to monitor experiments and a mobile gamma unit to be shared between them as and when required. To address safety requirements a screened cladding for the case based on layered stainless steel and lead has been designed to ensure user protection when operating with gamma emitting radioactive tracers. |
| Exploitation Route | The first iteration proof-of-concept system has been released for evaluation by our life sciences research collaborators [JEP] and will be developed and adapted in response to feedback from biological researchers as they incorporate it into their work. Once use cases have been established there is the opportunity for it to be used for a wider range of research purposes. The technical challenges of designing this imaging system relate closely to those of multi-modal image guided surgery combining radio-guided surgery (RGS) and fluorescence guided surgery (FGS) from a single common viewpoint and this is being proposed as a follow-on collaboration between three UK universities. As a consequence of imaging system development, we have also developed a unique 3D printed physiologically accurate imaging target system that can replicate bones, internal viscera and some circulatory features similar to those found in mice. The impact of this imaging target system is that we have anatomically realistic mouse model that, as it improves in fidelity in terms of its material optical scattering characteristics, will progressively replace and reduce the need for animal use for evaluation and development of the preclinical imaging prototype. The multimodal capability with accurate registration of the gamma and optical imagery may be applicable to the challenge of quantitative laboratory screening of multi-modally labelled samples held in microwell arrays. The imaging platform brings together advances in mechanical, electronic, optical and software design. Along with the exploration of its use for specific biological goals these aspects provide a rich range of potential projects for students to optimise and customise its function. Educational use of this kind is already being explored by the project partners at their respective Universities. A case in point is a planned a comparison of established fluorescent labels such as indocyanine green (ICG) to more recent options such as IrDye 800CW and conjugated polymer nanoparticles (CPNs). |
| Sectors | Healthcare,Manufacturing, including Industrial Biotechology |
| Description | Tiger Team - Time and Space Imaging Team - Ivan Reading |
| Amount | £5,000 (GBP) |
| Organisation | University of Leicester |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 02/2020 |
| End | 07/2020 |
| Title | Anatomically realistic 3D printed mouse model |
| Description | As a consequence of imaging system development, we have also developed a unique 3D printed physiologically accurate imaging target system that can replicate bones, internal viscera and some circulatory features. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2019 |
| Provided To Others? | No |
| Impact | The impact of this imaging target system is that we have anatomically realistic mouse model that, as it improves in fidelity in terms of its optical scattering characteristics, will progressively replace and reduce the need for animal use for evaluation and development of the preclinical imaging prototype. |
| Title | Small footprint preclinical imaging system (gamma/NIR) |
| Description | A new small animal imaging device that can be operated inside a biosafety cabinet or isolator for live or euthanized imaging in circumstances that prevent the small laboratory animal [e.g., mouse, xenopus, etc.] Included here rather than the technology section due to its potential to reduce the number of animals used in research and it's applicability to the National Centre for the Replacement, Refinement & Reduction of Animals in Research. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | Technology has been presented at conferences. Currently in prototype stage, with proof of concept testing in animal models of tuberculosis and related pathogens. Evaluation for use with animal models of SARS-CoV-2 under consideration. This outcome will be updated in future years. This outcome will be updated in future years. |
| Title | Small footprint preclinical imaging system (gamma/NIR) |
| Description | See research tools and methods section. |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2020 |
| Impact | See research tools and methods section. |
| Description | Midlands NC3Rs Symposium |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | Symposium for research technicians working with animal models (and alternative to animal models). E.g. suggested end users of technology. |
| Year(s) Of Engagement Activity | 2019,2020 |