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NC3Rs: National Centre for the Replacement Refinement & Reduction of Animals in Research
PhD Studentship

Development of a biologically-relevant preclinical radiotherapy dosimetry phantom

Test tubes

At a glance

Completed
Award date
September 2017
Grant amount
£90,000
Principal investigator
Professor Karen Kirkby

Co-investigator(s)

Institute
University of Manchester

R

  • Reduction
  • Refinement
Read the abstract
View the grant profile on GtR

Overview

Project background

More than half of cancer patients receive radiotherapy as part of their treatment, which is becoming increasingly personalised based on the predicted sensitivity of the tumour to radiation. In order to increase the accuracy of predictions, preclinical studies using small animals are needed to translate in vitro findings to the clinic. The predictive ability of animal models in preclinical radiotherapy studies is dependent on being able to deliver an accurate dose of radiation to the target tissue or organ. However, the actual dose of radiation delivered to the animal is not routinely measured and current dosimetry techniques measure the physical dose of radiation without consideration of the biological and physiological features of the animal. Tissue-equivalent and water phantoms can be used to measure absorbed dose, but have been found to produce inconsistent results compared to euthanised mice and rats. This is a major source of experimental error in preclinical studies.

Why we funded it

This PhD Studentship aims to develop a mouse imaging phantom using 3D printing technology suitable to accurately measure delivered radiation dose.

Guidelines from the Clinical and Translational Radiotherapy Research Working Group (CTRad) of the National Cancer Research Institute suggest a minimum of two cell lines from seven tumour types are needed for the evaluation of a single novel drug that induces radiation sensitivity. Seven to ten mice will be required per experimental group which results in an average of 120 mice needed for evaluation per drug. Accurate dosimetry of the delivered radiation dose to the animal will reduce experimental error and signal to noise ratio leading to a reduction in the number of animals required to generate statistical power. The potential for reduction will be calculated retrospectively by comparing studies using an accurate dose and those performed without dose measurement.

Research methods

The imaging phantom to be developed in this proposal will mimic the size and structures of a mouse. Phantoms will also include purpose built cavities to house detectors or biological material, such as tumour tissue. These detectors use novel technology to detect radiation dose at a micrometre scale, which allows the determination of delivered radiation dose in tumour tissue compared to the normal tissue mimicked by the phantom. Radiation is affected by the density of tissue through which it passes impacting on the delivered dose of radiation. Phantoms currently are homogeneous and do not reflect this complexity. This project aims to also investigate the ability to 3D print phantoms of varying density to mimic the heterogeneous tissue densities within a mouse.

Application abstract

Greater than 50% of patients with cancer receive radiotherapy; therefore preclinical radiotherapy studies provide a vital link between in vitro experiments and clinical application. In addition to the pivotal role in cancer research, preclinical radiation is vital in other fields. The predictive ability of such animal models is critically dependent on the ability to deliver an accurate dose of radiation to the target. Unfortunately, prominent research associations and numerous studies report discrepancies in preclinical radiotherapy dosimetry and QA which may be compromising research outputs. Dosimetry techniques measure the physical dose of radiation, without regard of the biological and physiological features of the animal that modulate delivered radiation dose, representing a major source of error in preclinical experiments. Importantly, nothing exists that can currently perform this function, and a need for international standardisation is imperative. Development of the proposed phantom, using 3D printing technology based on CT scans of a nude mouse will provide a phantom mimicking the size, heterogeneous tissue densities and structures of a mouse. Inclusion of novel 3D radiation detector technology and customisable biological input will allow accurate assessment of delivered radiation dose distribution with
resolution and tissue mimicking densities applicable to mouse tissues, linking physical and biological dose with animal physiology that modulates dose deposition. Robust validation using traceable standards means that this could be developed into an international standard, with technology transferrable into other species, fields and the clinic, bringing preclinical dosimetry in line with clinically accepted standards. Accurate dosimetry of the delivered dose to the animal will reduce experimental error, reducing signal to noise ratios, reducing the number of animals required whilst building confidence and reproducibility in preclinical radiation studies.

Publications

  1. Biglin ER et al. (2022). A preclinical radiotherapy dosimetry audit using a realistic 3D printed murine phantom. Scientific Reports 12: e6826. doi: 10.1038/s41598-022-10895-5
  2. Warmenhoven J et al. (2020). Insights into the non-homologous end joining pathway and double strand break end mobility provided by mechanistic in silico modelling. DNA Repair 85:102743. doi: 10.1016/j.dnarep.2019.102743
  3. Biglin ER et al. (2019). Preclinical dosimetry: exploring the use of small animal phantoms. Radiation Oncology 14(134). doi: 10.1186/s13014-019-1343-8
  4. Shortall J et al. (2019). Assessing localized dosimetric effects due to unplanned gas cavities during pelvic MR‐guided radiotherapy using Monte Carlo simulations. Medical Physics 46(12):5807-5815. doi: 10.1002/mp.13857