The authors thank Daniil Nikitichev and Steffi Mendes for their advice on using Meshmixer and Fernando Perez-Garcia for his advice on using 3D Slicer and for providing us code to automate some of the processing steps.
This work was supported by Wellcome Trust [203145Z/16/Z; 203148/Z/16/Z; WT106882], EPSRC [NS/A000050/1; NS/A000049/1], MRC [MC_PC_17180] and National Brain Appeal [NBA/NSG/SBS] funding. TV is supported by a Medtronic Inc / Royal Academy of Engineering Research Chair [RCSRF1819\7\34].

<ol>
	<li>Culjat, M. O., Goldenberg, D., Tewari, P., Singh, R. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+review+of+tissue+substitutes+for+ultrasound+imaging.">A review of tissue substitutes for ultrasound imaging.</a> Ultrasound in Medicine and Biology. 36 (6), 861-873 (2010).</li><li>Hwang, J., Ramella-Roman, J. C., Nordstrom, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Introduction:+Feature+Issue+on+Phantoms+for+the+Performance+Evaluation+and+Validation+of+Optical+Medical+Imaging+Devices.">Introduction: Feature Issue on Phantoms for the Performance Evaluation and Validation of Optical Medical Imaging Devices.</a> Biomedical Optics Express. 3 (6), 1399 (2012).</li><li>Maul, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ultrasound+simulators:+Experience+with+the+SonoTrainer+and+comparative+review+of+other+training+systems.">Ultrasound simulators: Experience with the SonoTrainer and comparative review of other training systems.</a> Ultrasound in Obstetrics and Gynecology. 24 (5), 581-585 (2004).</li><li>Craven, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+modelled+anatomical+replica+for+training+young+neurosurgeons.">Development of a modelled anatomical replica for training young neurosurgeons.</a> British Journal of Neurosurgery. 28 (6), 707-712 (2014).</li><li>Zhang, L., Kamaly, I., Luthra, P., Whitfield, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Simulation+in+neurosurgical+training:+a+blueprint+and+national+approach+to+implementation+for+initial+years+trainees.">Simulation in neurosurgical training: a blueprint and national approach to implementation for initial years trainees.</a> British Journal of Neurosurgery. 30 (5), 577-581 (2016).</li><li>Leff, D. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Validation+of+an+oncoplastic+breast+simulator+for+assessment+of+technical+skills+in+wide+local+excision.">Validation of an oncoplastic breast simulator for assessment of technical skills in wide local excision.</a> British Journal of Surgery. 103 (3), 207-217 (2016).</li><li>Hunt, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Low+cost+anatomically+realistic+renal+biopsy+phantoms+for+interventional+radiology+trainees.">Low cost anatomically realistic renal biopsy phantoms for interventional radiology trainees.</a> European Journal of Radiology. 82 (4), 594-600 (2013).</li><li>Pacioni, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-specific+ultrasound+liver+phantom:+materials+and+fabrication+method.">Patient-specific ultrasound liver phantom: materials and fabrication method.</a> International Journal of Computer Assisted Radiology and Surgery. 10 (7), 1065-1075 (2015).</li><li>Maneas, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anatomically+realistic+ultrasound+phantoms+using+gel+wax+with+3D+printed+moulds.">Anatomically realistic ultrasound phantoms using gel wax with 3D printed moulds.</a> Physics in Medicine and Biology. 63 (1), (2018).</li><li>Samii, M., Matthies, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Management+of+1000+vestibular+schwannomas+(acoustic+neuromas):+hearing+function+in+1000+tumor+resections.">Management of 1000 vestibular schwannomas (acoustic neuromas): hearing function in 1000 tumor resections.</a> Neurosurgery. 40 (2), 242-248 (1997).</li><li>Cabrelli, L. C., Pelissari, P. I. B. G. B., Deana, A. M., Carneiro, A. A. O., Pavan, T. Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stable+phantom+materials+for+ultrasound+and+optical+imaging.">Stable phantom materials for ultrasound and optical imaging.</a> Physics in Medicine and Biology. 62 (2), 432-447 (2017).</li><li>Vieira, S. L., Pavan, T. Z., Junior, J. E., Carneiro, A. A. O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Paraffin-Gel+Tissue-Mimicking+Material+for+Ultrasound-Guided+Needle+Biopsy+Phantom.">Paraffin-Gel Tissue-Mimicking Material for Ultrasound-Guided Needle Biopsy Phantom.</a> Ultrasound in Medicine &amp; Biology. 39 (12), 2477-2484 (2013).</li><li>Maneas, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gel+wax-based+tissue-mimicking+phantoms+for+multispectral+photoacoustic+imaging.">Gel wax-based tissue-mimicking phantoms for multispectral photoacoustic imaging.</a> Biomedical Optics Express. 9 (3), 1151 (2018).</li><li>Madsen, E. L., Hobson, M. A., Shi, H., Varghese, T., Frank, G. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tissue-mimicking+agar/gelatin+materials+for+use+in+heterogeneous+elastography+phantoms.">Tissue-mimicking agar/gelatin materials for use in heterogeneous elastography phantoms.</a> Physics in Medicine and Biology. 50 (23), 5597-5618 (2005).</li><li>Duboeuf, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Investigation+of+PVA+cryogel+Young&#8217;s+modulus+stability+with+time,+controlled+by+a+simple+reliable+technique.">Investigation of PVA cryogel Young&#8217;s modulus stability with time, controlled by a simple reliable technique.</a> Medical Physics. 36 (2), 656-661 (2009).</li><li>Fromageau, J., Brusseau, E., Vray, D., Gimenez, G., Delachartre, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+PVA+cryogel+for+intravascular+ultrasound+elasticity+imaging.">Characterization of PVA cryogel for intravascular ultrasound elasticity imaging.</a> IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 50 (10), 1318-1324 (2003).</li><li>Fromageau, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Estimation+of+polyvinyl+alcohol+cryogel+mechanical+properties+with+four+ultrasound+elastography+methods+and+comparison+with+gold+standard+testings.">Estimation of polyvinyl alcohol cryogel mechanical properties with four ultrasound elastography methods and comparison with gold standard testings.</a> IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. 54 (3), 498-508 (2007).</li><li>Khaled, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+Material+Parameters+of+PVA+Phantoms+for+Reconstructive+Ultrasound+Elastography.">Evaluation of Material Parameters of PVA Phantoms for Reconstructive Ultrasound Elastography.</a> 2007 IEEE Ultrasonics Symposium Proceedings. , 1329-1332 (2007).</li><li>Chen, S. J. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+anthropomorphic+polyvinyl+alcohol+brain+phantom+based+on+Colin27+for+use+in+multimodal+imaging.">An anthropomorphic polyvinyl alcohol brain phantom based on Colin27 for use in multimodal imaging.</a> Medical Physics. 39 (1), 554-561 (2012).</li><li>Ploch, C. C., Mansi, C. S. S. A., Jayamohan, J., Kuhl, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Using+3D+Printing+to+Create+Personalized+Brain+Models+for+Neurosurgical+Training+and+Preoperative+Planning.">Using 3D Printing to Create Personalized Brain Models for Neurosurgical Training and Preoperative Planning.</a> World Neurosurgery. 90, 668-674 (2016).</li><li>Weinstock, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Creation+of+a+novel+simulator+for+minimally+invasive+neurosurgery:+Fusion+of+3D+printing+and+special+effects.">Creation of a novel simulator for minimally invasive neurosurgery: Fusion of 3D printing and special effects.</a> Journal of Neurosurgery: Pediatrics. 20 (1), 1-9 (2017).</li><li>Grillo, F. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-specific+neurosurgical+phantom:+assessment+of+visual+quality,+accuracy,+and+scaling+effects.">Patient-specific neurosurgical phantom: assessment of visual quality, accuracy, and scaling effects.</a> 3D Printing in Medicine. 4 (1), (2018).</li><li>Tsai, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Creation+and+Validation+of+a+Simulator+for+Neonatal+Brain+Ultrasonography:+A+Pilot+Study.">Creation and Validation of a Simulator for Neonatal Brain Ultrasonography: A Pilot Study.</a> Academic Radiology. 24 (1), 76-83 (2017).</li><li>Reinertsen, I., Collins, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+realistic+phantom+for+brain-shift+simulations.">A realistic phantom for brain-shift simulations.</a> Medical Physics. 33 (9), 3234-3240 (2006).</li><li>Mobashsher, A. T., Abbosh, A. M., Wang, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Microwave+system+to+detect+traumatic+brain+injuries+using+compact+unidirectional+antenna+and+wideband+transceiver+with+verification+on+realistic+head+phantom.">Microwave system to detect traumatic brain injuries using compact unidirectional antenna and wideband transceiver with verification on realistic head phantom.</a> IEEE Transactions on Microwave Theory and Techniques. 62 (9), 1826-1836 (2014).</li><li>Cox, R. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+(sort+of)+new+image+data+format+standard:+NiFTI-1.">A (sort of) new image data format standard: NiFTI-1.</a> 10th Annual Meeting of the Organization for Human Brain Mapping. 22, (2004).</li><li>Cramer, J., Quigley, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advanced+Visualization+and+3D+Printing.">Advanced Visualization and 3D Printing.</a> Learning Lab at the Society for Imaging Informatics in Medicine annual meeting. , (2019).</li><li>Cardoso, M. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Geodesic+Information+Flows:+Spatially-Variant+Graphs+and+Their+Application+to+Segmentation+and+Fusion.">Geodesic Information Flows: Spatially-Variant Graphs and Their Application to Segmentation and Fusion.</a> IEEE Transactions on Medical Imaging. 34 (9), 1976-1988 (2015).</li><li>Dong, J., Zhang, Y., Wei-Ning, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Walled+vessel-mimicking+phantom+for+ultrasound+imaging+using+3D+printing+with+a+water-soluble+filament:+design+principle,+fluid-structure+interaction+(FSI)+simulation,+and+experimental+validation.">Walled vessel-mimicking phantom for ultrasound imaging using 3D printing with a water-soluble filament: design principle, fluid-structure interaction (FSI) simulation, and experimental validation.</a> Physics in Medicine &amp; Biology. , 0 (2020).</li><li>Jiang, S., Liu, S., Feng, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PVA+hydrogel+properties+for+biomedical+application.">PVA hydrogel properties for biomedical application.</a> Journal of the Mechanical Behavior of Biomedical Materials. 4 (7), 1228-1233 (2011).</li></ol>

The authors do not have any conflicts of interest to declare.

This protocol details the fabrication process of a patient specific brain phantom, which includes the skull, brain, and vestibular schwannoma tumor. 3D printing methods allowed for anatomically accurate detail to be achieved. The phantom described here was successfully manufactured with the desired level of anatomical detail; CT and ultrasound imaging were used to demonstrate that the tumor was easily visualized with both modalities. The tissue mimicking material, PVA-c, is well established as a tissue-mimicking material for ultrasonic phantoms; its acoustic and mechanical properties can be tuned with additives and the number of freeze-thaw cycles. The material is readily available, simple to use and non-toxic. With repeated use, the phantom had sufficient durability to withstand manipulation and contact with an ultrasound probe during physical simulations of vestibular schwannoma surgery.
Several key steps were identified as being critical to the fabrication process. First, the segmentation of structures for inclusion in the phantom must include the desired level of anatomical detail. The creation of accurate STL files and 3D molds then follows naturally. Secondly, the positioning of planes within the cerebellum mold in step 3.1.9 must be considered carefully, so that the phantom can be readily removed, without damage; it must be cut into enough pieces to allow anatomical details to be retained, whilst enabling the phantom to be removed without getting stuck in the mold. In this case, several iterations were tested and finally the mold was cut into four separate pieces. The third key consideration is that during the PVA-c manufacturing process (section 4), the PVA-c must be left to cool to room temperature (step 4.1.6). If this step is missed and hot PVA-c is added to the molds, it can cause the molds to melt or distort. It is also crucial that once the glass spheres are added (steps 5.1.2 &#8211; 5.1.4), the PVA-c is not left to sit for more than around 10 minutes; if left for a prolonged period of time, the glass spheres will settle to the bottom, and the resulting phantom will have inhomogeneous ultrasound contrast29. Once the glass spheres are added, the PVA-c must be added directly into the molds and placed into the freezer. After the first freeze cycle, the glass spheres will be secured in the place, and the phantom can be used at room temperature. Finally, it is important that the molds are carefully sealed (e.g., with tape) before the PVA-c is added, to minimize leakage of the mixture through gaps where the separate pieced of the mold joined together.
The protocol has several limitations. For example, some specialist equipment is required, including a water bath and an electronic stirrer. A sonicator is also used as part of this protocol, but the sonication step (5.1.3) could be replaced with additional electronic stirring; however, with this alternative, it would take longer to achieve a homogeneous mixture than is possible with the use of sonication. One limitation of PVA-c is that it degrades over time and becomes moldy. The addition of potassium sorbate, as described here, increases the phantom&#8217;s shelf-life, although it must still be kept in an air-tight container. A second limitation of PVA-c is that freeze-thaw cycles are required, which increases the amount of time required to make a phantom. To minimize phantom fabrication time, a key consideration is the speed of freezing and thawing; once the phantom is either fully frozen or fully thawed, the time that it remains in that state does not significantly affect the final phantom16,30. Therefore, the cycle lengths used can be varied, provided that the phantom is fully frozen and thawed at each stage in the cycle. For instance, the tumor in the phantom of this study is very small, so shorter cycles could be used for the tumor than for the brain. Finally, 3D printing the molds and skull is a time-consuming process which consumes a significant portion (3 days) of the total time (1 week) required to fabricate a phantom with this protocol. The printer used was a commercial model from 2018; the printing process could be completed in shorter time frames with the use of newer, faster printers.
The brain phantom presented here could be used directly for clinical training and validation of neuronavigation systems. As the tissue mimicking material, PVA-c enables the resulting phantom to be used repeatedly, for example as a training tool or for the validation of intraoperative ultrasound in vestibular schwannoma surgery, as it is a durable and non-toxic material. As such, the fabrication method is complementary to those previously described in which 3D printing was used to create patient specific brain phantoms20,21,22,23,24,25. The use of PVA-c as the TMM makes the phantom suitable for use in simulation of neurosurgery, as the material can withstand repeated manual manipulation and contact from an ultrasound probe. This work sets the stage for further quantitative validation studies. The phantom method described here is very versatile and could be used to fabricate many types of patient-specific tumor phantoms, extending from the brain to other organs, with compatibility across several imaging modalities.

Phantoms mimicking the specific properties of biological tissues are a useful resource for various experimental and teaching applications. Tissue-mimicking phantoms are essential to characterize medical devices prior to their clinical use1,2 and anatomical phantoms are frequently used in the training of medical staff in all disciplines3,4,5,6,7. Patient-specific anatomical phantoms made with appropriate tissue-mimicking properties are often a critical part of the testing environment and can increase the confidence of clinicians who are learning to use a new device8. However, high manufacturing costs and complex fabrication processes often preclude the routine use of patient-specific phantoms. Here, a method is described for manufacturing a durable, patient-specific brain tumor model using readily available, commercial materials, which can be used for the training and validation of intraoperative ultrasound (US) using computerized tomography (CT) imaging. The phantom described in this study was created using data from a patient with a vestibular schwannoma (a benign brain tumor arising from one of the balance nerves connecting the brain and inner ear) who subsequently underwent surgery and tumor resection via a retrosigmoid suboccipital craniotomy10. The phantom was developed in order to test and validate an integrated intraoperative navigation system for use during this type of brain tumor surgery.
In order to be suitable for this application, the brain tumor phantom needs to possess several key properties. First, it should be made of non-toxic materials, so it can safely be used in a clinical training environment. Second, it should have realistic imaging properties; for the intended application, these specifically include ultrasound attenuation and CT contrast. Third, it should have similar mechanical properties to human tissue so that it can be handled in the same way. Fourth, the phantom should be based on real patient data, so that it is anatomically accurate and can be used for surgical planning and training. Finally, the materials used must be durable, so that the phantom can be used repeatedly.
In general, the tissue-mimicking material and fabrication method chosen for a phantom depends on the intended application. For rigid structures like the skull, the chosen property should not deform or be water-soluble and it should be able to maintain an accurate level of anatomical detail with repeated use; this is especially important when using the phantom for experiments where image registration is used and for surgical simulation purposes. Mineral oil based materials such as gel wax have been promising for ultrasound9,11,12 and photoacoustic13 imaging applications, however, when subjected to repeated mechanical deformation they become friable, so cannot withstand extended use, especially with standard microsurgical neurosurgery instruments. Agar and gelatin are aqueous materials that are also commonly used as tissue-mimicking materials. The additives needed to adjust the acoustic properties of these materials are well known14, but they have limited mechanical strength and are not particularly durable so are not suitable for this application, where the phantom needs to be repeatedly handled.
Polyvinyl alcohol cryogel (PVA-c) is a popular choice of tissue-mimicking material, because its acoustic and mechanical properties can easily be tuned by varying its freeze-thaw cycles. It has been shown that the properties of PVA-c are similar to those of soft tissues15,16,17,18. PVA-c based brain phantoms have been used successfully for ultrasound and CT imaging19. The material is strong enough to be used repeatedly, and it has a high degree of elasticity, so phantom tissue made of PVA-c can be manipulated without being permanently deformed. Polylactic acid (PLA) is a readily available rigid material and was used to manufacture the skull, however, a different printing material can be used in place of PLA, if it has similar mechanical properties and is not water soluble.
Brain phantoms in particular have been fabricated using different methods, depending on the level of complexity required and the tissues that need to be replicated20,21,22,23. Usually, a mold is used, and liquid tissue-mimicking material poured into it. Some studies have used commercial molds24 whilst others use 3D-printed custom molds of a healthy brain, and simulate brain lesions by implanting marker spheres and inflatable catheters19,25. To the best of the author&#8217;s knowledge, this is the first report of a 3D-printed patient-specific brain tumor phantom model created with tissue-mimicking ultrasound and X-ray properties. The total fabrication is visualized by the flowchart in Figure 1; the whole process takes around a week to complete.

<table><tbody><tr><td>AutodeskFusion 360</td><td>Autodesk Inc., San Rafael, California, United States</td><td>https://www.autodesk.co.uk/products/fusion-360/overview</td><td>CAD software</td></tr><tr><td>Barium sulphate</td><td>Source Chemicals</td><td>-</td><td></td></tr><tr><td>CT scanner</td><td>Medtronic Inc, Minneapolis, USA</td><td>-</td><td>O-arm 3D mobile X-ray imaging system</td></tr><tr><td>Glass microspheres</td><td>Boud Minerals</td><td></td><td></td></tr><tr><td>Mechanical stirrer</td><td>IKA</td><td>4442002</td><td>Eurostar Digital 20, IKA</td></tr><tr><td>Meshmixer</td><td>Autodesk Inc., San Rafael, California, United States</td><td>http://www.meshmixer.com</td><td>3D modelling software. Version 3.5.484 used</td></tr><tr><td>Neuronavigation system</td><td>Medtronic Inc, Minneapolis, USA</td><td>-</td><td>S7 Stealth Station</td></tr><tr><td>PLA</td><td>Ultimaker (Ultimaker BV, Utrecht, Netherlands)</td><td>UM9016</td><td></td></tr><tr><td>Potassium sorbate</td><td>Meridianstar</td><td>-</td><td></td></tr><tr><td>PVA</td><td>Ultimaker</td><td>-</td><td></td></tr><tr><td>PVA powder</td><td>Sigma-Aldrich</td><td>363146</td><td>99%+ hydrolysed, average molecular weight 85,000-140,000</td></tr><tr><td>Sonicator</td><td>Fisher Scientific</td><td>12893543</td><td></td></tr><tr><td>Ultimaker Cura</td><td>Ultimaker BV, Utrecht, Netherlands</td><td>https://ultimaker.com/software/ultimaker-cura</td><td>3D printing software. Version 4.0.0 used</td></tr><tr><td>Ultimaker S5 Printer</td><td>Ultimaker BV, Utrecht, Netherlands</td><td>-</td><td></td></tr><tr><td>Ultrasound scanner</td><td>BK Medical, Luton, UK</td><td>-</td><td>BK 5000 scanner</td></tr><tr><td>Water bath</td><td>IKA</td><td>20009381</td><td>HBR4 control, IKA</td></tr><tr><td>3D Slicer</td><td>http://slicer.org</td><td>-</td><td>Software used to segment patient data. Version 4.10.2 used</td></tr></tbody></table>

patient-specific polyvinyl alcohol phantom fabrication with ultrasound and x-ray contrast for brain tumor surgery planning

Phantoms are essential tools for clinical training, surgical planning and the development of novel medical devices. However, it is challenging to create anatomically accurate head phantoms with realistic brain imaging properties because standard fabrication methods are not optimized to replicate any patient-specific anatomical detail and 3D printing materials are not optimized for imaging properties. In order to test and validate a novel navigation system for use during brain tumor surgery, an anatomically accurate phantom with realistic imaging and mechanical properties was required. Therefore, a phantom was developed using real patient data as input and 3D printing of molds to fabricate a patient-specific head phantom comprising the skull, brain and tumor with both ultrasound and X-ray contrast. The phantom also had mechanical properties that allowed the phantom tissue to be manipulated in a similar manner to how human brain tissue is handled during surgery. The phantom was successfully tested during a surgical simulation in a virtual operating room.
The phantom fabrication method uses commercially available materials and is easy to reproduce. The 3D printing files can be readily shared, and the technique can be adapted to encompass many different types of tumor.

Following the described protocol, an anatomically realistic phantom was fabricated, which consists of a patient-specific skull, brain and tumor. The relevant anatomical structures for the phantom (skull, brain, tumor) are segmented using patient MRI and CT data (Figure 2a,b). The patient intra-operative ultrasound data (Figure 2c; Figure 2d shows the same image as Figure 2c, but with the tumor outlined) was used to compare the phantom images to the real patient images.
Meshes were created for each piece of the model (Figure 3), and these were then used to manufacture the 3D molds. The molds were easily printed on a commercial printer and assembled by slotting the pieces together. The cerebellum mold was the most complex to design and assemble (Figure 4). The skull (Figure 5a) was the most difficult part to print as it required support material, so was a slow process; the whole print took a total of three days to complete, which is a limiting factor in the protocol.
The completed phantom (Figure 5) was a realistic model of a patient skull, brain and tumor. The two brain hemispheres (Figure 5b) were produced separately, and have a realistic appearance, featuring the gyri and sulci of the brain. The whole phantom is white in color, as this is the natural color of PVA-c; this can easily be changed by adding dye but was not necessary for the application. The cerebellum (Figure 5c) fits comfortably into the base of the printed skull and the brain hemispheres sit on top of this. The tumor is easily visible in the cerebellum, as the extra contrast added to the tumor results in it being an off-white color that separates it from the surrounding material, which is it securely attached to.
The phantom was imaged with both CT and ultrasound (Figure 6a,b). Barium sulfate was used to give the tumor appropriate CT contrast, and the phantom image (Figure 6a) shows that this was achieved, as the tumor is clearly visualized. The skull was not printed with 100% infill, in order to reduce the time taken for printing. Therefore, the skull does not look entirely realistic in the CT images, because the lattice structure of the print can be seen. This is not a problem for the application, as only the outline of the skull is needed for the neuronavigation system. The skull could be printed with 100% infill to avoid this reduced accuracy of the CT image, but would add time onto the printing process. Glass microspheres were added to the cerebellum, brain hemispheres and tumor for ultrasound contrast. The results show that the tumor is also visible with ultrasound imaging (Figure 6b) and can be distinguished from the surrounding tissue. On visual inspection, the ultrasound images obtained from the phantom (Figure 6b), and those obtained from the patient (Figure 2c) show that the contrast agents used in the phantom were effective for creating realistic imaging properties.
The phantom was tested during surgical simulation in a virtual operating room (Figure 7). The phantom model was positioned on the surgical operating table using a standard skull clamp and the CT scan of the phantom was registered using a clinical neuronavigation system. A retrosigmoid approach to the tumor was simulated and the tumor was imaged using a clinical ultrasound system with a burr hole ultrasound transducer. During the surgical simulation, the phantom model proved to be stable and no damage was observed from manipulating the phantom in the same way the human brain would be during this procedure, so it could be used repeatedly under the same conditions.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/61344/61344fig01.jpg" /> 
Figure 1: Flowchart to show the steps required to make a patient specific PVA-c brain phantom. <a href="https://www.jove.com/files/ftp_upload/61344/61344fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/61344/61344fig02.jpg" /> 
Figure 2: Patient data used to create phantom model.&#160;Data sources of a patient with a left sided vestibular schwannoma: (a) axial contrast-enhanced T1-weighted MRI, white arrow pointing towards tumor; (b) axial non-contrast CT scan windowed to highlight bone, white arrow pointing towards an expanded internal auditory meatus caused by the tumor; (c) intraoperative ultrasound image obtained during vestibular schwannoma surgery; (d) annotated intraoperative ultrasound image <img alt="Equation 1" src="/files/ftp_upload/61344/icon01.jpg" />: tumor (hyperechoic on ultrasound), <img alt="Equation 4" src="/files/ftp_upload/61344/icon04.jpg" />: brain (cerebellum). <a href="https://www.jove.com/files/ftp_upload/61344/61344fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/61344/61344fig03.jpg" /> 
Figure 3: Completed meshes for each section of the phantom.&#160;STL mesh for (a,b) skull, <img alt="Equation 2" src="/files/ftp_upload/61344/icon02.jpg" />: left sided retrosigmoid craniotomy; (c,d) cerebral hemispheres; (e,f) tumor and cerebellum, <img alt="Equation 1" src="/files/ftp_upload/61344/icon01.jpg" />: tumor. <a href="https://www.jove.com/files/ftp_upload/61344/61344fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/61344/61344fig04.jpg" /> 
Figure 4: 3D printed cerebellum mold.&#160;3D printed cerebellum mold fully constructed (top left) and the separate pieces, which are numbered from 1 to 4. The hole in piece 2 (denoted by &#8216;H&#8217;) enables the PVA-c to be poured into the mold. <a href="https://www.jove.com/files/ftp_upload/61344/61344fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/61344/61344fig05.jpg" /> 
Figure 5: Completed phantom.&#160;The finished phantom (a) skull&#160;(b) phantom with skull top removed: <img alt="Equation 2" src="/files/ftp_upload/61344/icon02.jpg" />: retrosigmoid craniotomy, <img alt="Equation 1" src="/files/ftp_upload/61344/icon01.jpg" />: tumor, <img alt="Equation 4" src="/files/ftp_upload/61344/icon04.jpg" /> brain (cerebellum), <img alt="Equation 5" src="/files/ftp_upload/61344/icon05.jpg" />brain (right cerebral hemisphere); (c) cerebellum and tumor: <img alt="Equation 1" src="/files/ftp_upload/61344/icon01.jpg" />: tumor, <img alt="Equation 4" src="/files/ftp_upload/61344/icon04.jpg" /> brain (cerebellum). <a href="https://www.jove.com/files/ftp_upload/61344/61344fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/61344/61344fig06.jpg" /> 
Figure 6: CT and ultrasound images acquired with the phantom.&#160;(a) Axial CT image of complete phantom through the level of the skull base and tumor, (b) Intraoperative ultrasound image of phantom acquired with burr hole ultrasound probe through the retrosigmoid craniotomy in a plane approximately perpendicular to the skull (Simulating surgery, the cerebellum was retracted slightly in order to image directly on the tumor). <img alt="Equation 1" src="/files/ftp_upload/61344/icon01.jpg" />: tumor, <img alt="Equation 4" src="/files/ftp_upload/61344/icon04.jpg" /> brain (cerebellum), <img alt="Equation 2" src="/files/ftp_upload/61344/icon02.jpg" />: left sided retrosigmoid craniotomy. <a href="https://www.jove.com/files/ftp_upload/61344/61344fig06large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/61344/61344fig07.jpg" /> 
Figure 7: Testing the phantom during surgical simulation.&#160;Testing the phantom model through surgical simulation in a virtual operating room. <img alt="Equation 6" src="/files/ftp_upload/61344/icon06.jpg" />: neuronavigation system displaying the registered scan of the CT phantom model, <img alt="Equation 3" src="/files/ftp_upload/61344/icon03.jpg" />: ultrasound system used to image the phantom with a burr hole ultrasound transducer (seen positioned next to the ultrasound monitor). Note the model pictured here is based on data acquired from different patient with a right sided tumor. <a href="https://www.jove.com/files/ftp_upload/61344/61344fig07large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Patient-Specific Polyvinyl Alcohol Phantom Fabrication with Ultrasound and X-Ray Contrast for Brain Tumor Surgery Planning at JoVE.com

Patient-Specific Polyvinyl Alcohol Phantom Fabrication with Ultrasound and X-Ray Contrast for Brain Tumor Surgery Planning

This protocol describes the fabrication of a patient specific skull, brain and tumor phantom. It uses 3D printing to create molds, and polyvinyl alcohol (PVA-c) is used as the tissue mimicking material.

Phantoms are essential tools for clinical training, surgical planning and the development of novel medical devices. However, it is challenging to create ...

patient-specific-polyvinyl-alcohol-phantom-fabrication-with

Research

JoVE Journal

Bioengineering

8.3K Views.  University College London. Phantom modellen zijn belangrijke instrumenten, maar het is een uitdaging om ze anatomisch nauwkeurig te maken. Dit protocol maakt gebruik van CT en echografie om een patiënt-specifieke fantoom dat een tumor omvat te creëren. We gebruiken complexe heterogene modellen en 3D-printen om een hoge mate van anatomisch realisme te bereiken.Patiëntspecifieke hersentooms zijn zeer nuttig omdat ze chirurgische planning en klinische training mogelijk maken, en ze stellen chirurgen in staat om ...

Video: Patient-Specific Polyvinyl Alcohol Phantom Fabrication with Ultrasound and X-Ray Contrast for Brain Tumor Surgery Planning

Construction of a Preclinical Multimodality Phantom Using Tissue-mimicking Materials for Quality Assurance in Tumor Size Measurement

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for radiologic assessment of solid tumors in response to anti-tumor drug therapy in the 1980s and 1990s, respectively. WHO criteria measure solid tumors in two-dimensions, whereas RECIST measurements use only one-dimension which is considered to be more reproducible 1, 2, 3,4,5. These criteria have been widely used as the only imaging biomarker approved by the United States Food and Drug Administration (FDA) 6. In order to measure tumor response to anti-tumor drugs on images with accuracy, therefore, a robust quality assurance (QA) procedures and corresponding QA phantom are needed.
To address this need, the authors constructed a preclinical multimodality (for ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI)) phantom using tissue-mimicking (TM) materials based on the limited number of target lesions required by RECIST by revising a Gammex US commercial phantom 7. The Appendix in Lee et al. demonstrates the procedures of phantom fabrication 7. In this article, all protocols are introduced in a step-by-step fashion beginning with procedures for preparing the silicone molds for casting tumor-simulating test objects in the phantom, followed by preparation of TM materials for multimodality imaging, and finally construction of the preclinical multimodality QA phantom. The primary purpose of this paper is to provide the protocols to allow anyone interested in independently constructing a phantom for their own projects. QA procedures for tumor size measurement, and RECIST, WHO and volume measurement results of test objects made at multiple institutions using this QA phantom are shown in detail in Lee et al. 8.

This paper describes in-house procedures of constructing a preclinical multimodality phantom made of tissue-mimicking (TM) materials for quality assurance (QA) of tumor size measurement in animal imaging modalities such as ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI).

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for ...

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a novel platform that allows for direct long-term visualization of tissue structure changes intracranially. Imaging at a single cell resolution in a real-time fashion provides supplementary dynamic information beyond that provided by standard end-point histological analysis, which looks solely at 'snap-shot' cross sections of tissue.
Establishing this intravital imaging technique in fluorescent chimeric mice, we are able to image four fluorescent channels simultaneously. By incorporating fluorescently labeled cells, such as GFP+ bone marrow, it is possible to track the fate of these cells studying their long-term migration, integration and differentiation within tissue. Further integration of a secondary reporter cell, such as an mCherry glioma tumor line, allows for characterization of cell:cell interactions. Structural changes in the tissue microenvironment can be highlighted through the addition of intra-vital dyes and antibodies, for example CD31 tagged antibodies and Dextran molecules.
Moreover, we describe the combination of our ICW imaging model with a small animal micro-irradiator that provides stereotactic irradiation, creating a platform through which the dynamic tissue changes that occur following the administration of ionizing irradiation can be assessed.
Current limitations of our model include penetrance of the microscope, which is limited to a depth of up to 900 &mu;m from the sub cortical surface, limiting imaging to the dorsal axis of the brain. The presence of the skull bone makes the ICW a more challenging technical procedure, compared to the more established and utilized chamber models currently used to study mammary tissue and fat pads 5-7. In addition, the ICW provides many challenges when optimizing the imaging.

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We describe a novel in vivo imaging technique that couples fluorescent chimeric mice with intracranial windows and high-resolution 2-photon microscopy. This imaging platform aids studies of dynamic changes in brain tissue and microvasculature, at a single-cell level, following pathological insults and is adaptable to assess intracranial drug delivery and distribution.

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a ...

Medicine

Controllable Nucleation of Cavitation from Plasmonic Gold Nanoparticles for Enhancing High Intensity Focused Ultrasound Applications

In this study, plasmonic gold nanoparticles were simultaneously exposed to pulsed near-infrared laser light and high intensity focused ultrasound (HIFU) for the controllable nucleation of cavitation in tissue-mimicking gel phantoms. This in vitro protocol was developed to demonstrate the feasibility of this approach, for both enhancement of imaging and therapeutic applications for cancer. The same apparatus can be used for both imaging and therapeutic applications by varying the exposure duration of the HIFU system. For short duration exposures (10 &#181;s), broadband acoustic emissions were generated through the controlled nucleation of inertial cavitation around the gold nanoparticles. These emissions provide direct localization of nanoparticles. For future applications, these particles may be functionalized with molecular-targeting antibodies (e.g. anti-HER2 for breast cancer) and can provide precise localization of cancerous regions, complementing routine diagnostic ultrasound imaging. For continuous wave (CW) exposures, the cavitation activity was used to increase the localized heating from the HIFU exposures resulting in larger thermal damage in the gel phantoms. The acoustic emissions generated from inertial cavitation activity during these CW exposures was monitored using a passive cavitation detection (PCD) system to provide feedback of cavitation activity. Increased localized heating was only achieved through the unique combination of nanoparticles, laser light and HIFU. Further validation of this technique in pre-clinical models of cancer is necessary.

This protocol demonstrates the controllable nucleation of cavitation in gel phantoms, through simultaneous exposure to both near-infrared pulsed laser light and high intensity focused ultrasound (HIFU). The cavitation activity can then be used for enhancing imaging and/or therapeutic uses of HIFU.

In this study, plasmonic gold nanoparticles were simultaneously exposed to pulsed near-infrared laser light and high intensity focused ultrasound (HIFU) ...

Engineering

Evaluating Targeting Accuracy in the Focal Plane for an Ultrasound-guided High-intensity Focused Ultrasound Phased-array System

Phased arrays are increasingly used as high-intensity focused ultrasound (HIFU) transducers in the existing extracorporeal ultrasound-guided HIFU (USgHIFU) systems. The HIFU transducers in such systems are usually spherical in shape with a central hole where a US imaging probe is mounted and can be rotated. The image on the plane of treatment can be reconstructed through the image sequence acquired during the rotation of the probe. Therefore, the treatment plan can be made on the reconstructed images. In order to evaluate the targeting accuracy in the focal plane of such systems, the protocol of a method using a bovine muscle and marker-embedded phantom is described. In the phantom, four solid balls at the corners of a square resin model serve as the reference markers in the reconstructed image. The target should be moved so that both its center and the center of the square model can coincide according to their relative positions in the reconstructed image. Swine muscle with a thickness of about 30 mm is placed above the phantom to mimic the beam path in clinical settings. After sonication, the treatment plane in the phantom is scanned and the boundary of the associated lesion is extracted from the scanned image. The targeting accuracy can be evaluated by measuring the distance between the centers of target and lesion, as well as three derivative parameters. This method cannot only evaluate the targeting accuracy of the target consisting of multiple focal spots rather than a single focal spot in a clinically relevant beam path of the USgHIFU phased-array system, but it can be also used in the preclinical evaluation or regular maintenance of USgHIFU systems configured with phased-array or self-focused HIFU transducer.

This study describes a protocol to evaluate the targeting accuracy in the focal plane of an ultrasound-guided high-intensity focused ultrasound phased-array system.

Phased arrays are increasingly used as high-intensity focused ultrasound (HIFU) transducers in the existing extracorporeal ultrasound-guided HIFU ...

Tissue-simulating Phantoms for Assessing Potential Near-infrared Fluorescence Imaging Applications in Breast Cancer Surgery

Inaccuracies in intraoperative tumor localization and evaluation of surgical margin status result in suboptimal outcome of breast-conserving surgery (BCS). Optical imaging, in particular near-infrared fluorescence (NIRF) imaging, might reduce the frequency of positive surgical margins following BCS by providing the surgeon with a tool for pre- and intraoperative tumor localization in real-time. In the current study, the potential of NIRF-guided BCS is evaluated using tissue-simulating breast phantoms for reasons of standardization and training purposes.
Breast phantoms with optical characteristics comparable to those of normal breast tissue were used to simulate breast conserving surgery. Tumor-simulating inclusions containing the fluorescent dye indocyanine green (ICG) were incorporated in the phantoms at predefined locations and imaged for pre- and intraoperative tumor localization, real-time NIRF-guided tumor resection, NIRF-guided evaluation on the extent of surgery, and postoperative assessment of surgical margins. A customized NIRF camera was used as a clinical prototype for imaging purposes.
Breast phantoms containing tumor-simulating inclusions offer a simple, inexpensive, and versatile tool to simulate and evaluate intraoperative tumor imaging. The gelatinous phantoms have elastic properties similar to human tissue and can be cut using conventional surgical instruments. Moreover, the phantoms contain hemoglobin and intralipid for mimicking absorption and scattering of photons, respectively, creating uniform optical properties similar to human breast tissue. The main drawback of NIRF imaging is the limited penetration depth of photons when propagating through tissue, which hinders (noninvasive) imaging of deep-seated tumors with epi-illumination strategies.

Near-infrared fluorescence (NIRF) imaging may improve therapeutic outcome of breast cancer surgery by enabling intraoperative tumor localization and evaluation of surgical margin status. Using tissue-simulating breast phantoms containing fluorescent tumor-simulating inclusions, potential clinical applications of NIRF imaging in breast cancer patients can be assessed for standardization and training purposes.

Inaccuracies in intraoperative tumor localization and evaluation of surgical margin status result in suboptimal outcome of breast-conserving surgery ...

Fabrication and Characterization of Optical Tissue Phantoms Containing Macrostructure

The rapid development of new optical imaging techniques is dependent on the availability of low-cost, customizable, and easily reproducible standards. By replicating the imaging environment, costly animal experiments to validate a technique may be circumvented. Predicting and optimizing the performance of in vivo and ex vivo imaging techniques requires testing on samples that are optically similar to tissues of interest. Tissue-mimicking optical phantoms provide a standard for evaluation, characterization, or calibration of an optical system. Homogenous polymer optical tissue phantoms are widely used to mimic the optical properties of a specific tissue type within a narrow spectral range. Layered tissues, such as the epidermis and dermis, can be mimicked by simply stacking these homogenous slab phantoms. However, many in vivo imaging techniques are applied to more spatially complex tissue where three dimensional structures, such as blood vessels, airways, or tissue defects, can affect the performance of the imaging system. 
This protocol describes the fabrication of a tissue-mimicking phantom that incorporates three-dimensional structural complexity using material with optical properties of tissue. Look-up tables provide India ink and titanium dioxide recipes for optical absorption and scattering targets. Methods to characterize and tune the material optical properties are described. The phantom fabrication detailed in this article has an internal branching mock airway void; however, the technique can be broadly applied to other tissue or organ structures.

Optical tissue phantoms are essential tools for calibration and characterization of optical imaging systems and validation of theoretical models. This article details a method for phantom fabrication that includes replication of tissue optical properties and three-dimensional tissue structure.

The rapid development of new optical imaging techniques is dependent on the availability of low-cost, customizable, and easily reproducible standards. By ...

Plasmonic Photothermal Cancer Therapy: Nanoparticle-embedded Tumor-tissue-mimicking Phantoms for Visualizing Photothermal Temperature Distribution

Plasmonic photothermal therapy (PPTT), an emerging cancer treatment, involves delivering nanoparticles (NPs) to a tumor, followed by near-infrared (NIR) irradiation to generate localized heat that destroys cancer cells. Before administering PPTT, the therapeutic parameters -- NP concentration, irradiation intensity, and duration -- need to be estimated. For this, numerical simulations are performed. However, to ensure robust computation, these simulations must be validated through photothermal experiments on tumor-tissue-mimicking phantoms replicating the optical properties of tumor tissue. For PPTT, therapeutic parameters are governed by the scattering and absorption of incident radiation by the tissue and NPs. Therefore, validation experiments can be conducted on phantoms mimicking the reduced scattering coefficient (&#181;s&#39;) and absorption coefficient (&#181;a) of the target tumor/tissue.
Specifically, this protocol provides instructions for preparing phantoms mimicking &#181;s&#39; and &#181;a of breast tumor injected with gold nanorods, surrounded by normal breast tissue. The protocol also details NIR irradiation, temperature monitoring, and validation of numerical results by comparing spatiotemporal temperatures with those measured using thermocouples. The protocols presented in this study facilitated the preparation of hydrogel-based cylindrical breast tumor-tissue phantoms with dimensions (&#981;40 x 12 mm) and a central tumor region (&#981;20 x 6 mm), comprising 1% agarose as the base matrix and intralipid as the scattering constituent and tumor region embedded with gold nanorods at 25 &#181;g/mL concentration. Representative results from a case study illustrate the application of fabricated phantoms for validating numerical simulations for PPTT. The study concludes that the demonstrated protocols are valuable for conducting photothermal experiments aimed at optimizing and planning therapeutic parameters prior to in vivo experiments and validating numerical simulations for PPTT.

This article presents the protocol for preparing tumor-tissue phantoms that replicate optical properties for plasmonic photothermal therapy. It details phantom preparation, photothermal evaluations, and validation of the developed numerical model based on photothermal temperature measurements for assessing therapeutic parameters, offering an ethical, cost-effective alternative to in vivo studies for preliminary testing.

Plasmonic photothermal therapy (PPTT), an emerging cancer treatment, involves delivering nanoparticles (NPs) to a tumor, followed by near-infrared (NIR) ...

Cancer Research

Manufacturing Abdominal Aorta Hydrogel Tissue-Mimicking Phantoms for Ultrasound Elastography Validation

Ultrasound (US) elastography, or elasticity imaging, is an adjunct imaging technique that utilizes sequential US images of soft tissues to measure the tissue motion and infer or quantify the underlying biomechanical characteristics. For abdominal aortic aneurysms (AAA), biomechanical properties such as changes in the tissue's elastic modulus and estimates of the tissue stress may be essential for assessing the need for the surgical intervention. Abdominal aortic aneurysms US elastography could be a useful tool to monitor AAA progression and identify changes in biomechanical properties characteristic of high-risk patients.
A preliminary goal in the development of an AAA US elastography technique is the validation of the method using a physically relevant model with known material properties. Here we present a process for the production of AAA tissue-mimicking phantoms with physically relevant geometries and spatially modulated material properties. These tissue phantoms aim to mimic the US properties, material modulus, and geometry of the abdominal aortic aneurysms. Tissue phantoms are made using a polyvinyl alcohol cryogel (PVA-c) and molded using 3D printed parts created using computer aided design (CAD) software. The modulus of the phantoms is controlled by altering the concentration of PVA-c and by changing the number of freeze-thaw cycles used to polymerize the cryogel. The AAA phantoms are connected to a hemodynamic pump, designed to deform the phantoms with the physiologic cyclic pressure and flows. Ultra sound image sequences of the deforming phantoms allowed for the spatial calculation of the pressure normalized strain and the identification of mechanical properties of the vessel wall. Representative results of the pressure normalized strain are presented.

Here we describe a method to manufacture aneurysmal, aortic tissue-mimicking phantoms for the use in testing ultrasound elastography. The combined use of computer-aided design (CAD) and 3-dimensional (3D) printing techniques produce aortic phantoms with predictable, complex geometries to validate the elastographic imaging algorithms with controlled experiments.

Ultrasound (US) elastography, or elasticity imaging, is an adjunct imaging technique that utilizes sequential US images of soft tissues to measure the ...

A High-Throughput Image-Guided Stereotactic Neuronavigation and Focused Ultrasound System for Blood-Brain Barrier Opening in Rodents

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a physiological barrier preventing large molecules (&#62;500 Da) from entering the brain tissue. Microbubble-mediated focused ultrasound (FUS) can be used to induce a transient local BBB opening, allowing larger drugs to enter the brain parenchyma.
In addition to large-scale clinical devices for clinical translation, preclinical research for therapy response assessment of drug candidates requires dedicated small animal ultrasound setups for targeted BBB opening. Preferably, these systems allow high-throughput workflows with both high-spatial precision as well as integrated cavitation monitoring, while still being cost effective in both initial investment and running costs.
Here, we present a bioluminescence and X-ray guided stereotactic small animal FUS system that is based on commercially available components and fulfills the aforementioned requirements. A particular emphasis has been placed on a high degree of automation facilitating the challenges typically encountered in high-volume preclinical drug evaluation studies. Examples of these challenges are the need for standardization in order to ensure data reproducibility, reduce intra-group variability, reduce sample size and thus comply with ethical requirements and decrease unnecessary workload. The proposed BBB system has been validated in the scope of BBB opening facilitated drug delivery trials on patient-derived xenograft models of glioblastoma multiforme and diffuse midline glioma.

The blood-brain barrier (BBB) can be temporarily disrupted with microbubble-mediated focused ultrasound (FUS). Here, we describe a step-by-step protocol for high-throughput BBB opening in vivo using a modular FUS system accessible for non-ultrasound experts.

The blood-brain barrier (BBB) has been a major hurdle for the treatment of various brain diseases. Endothelial cells, connected by tight junctions, form a ...

Neuroscience

Fabrication of a Stable, Biologically Relevant Phantom Material

A Stable Phantom Material for Optical and Acoustic Imaging

Establishing tissue-mimicking biophotonic phantom materials that provide long-term stability are imperative to enable the comparison of biomedical imaging devices across vendors and institutions, support the development of internationally recognized standards, and assist the clinical translation of novel technologies. Here, a manufacturing process is presented that results in a stable, low-cost, tissue-mimicking copolymer-in-oil material for use in photoacoustic, optical, and ultrasound standardization efforts.
The base material consists of mineral oil and a copolymer with defined Chemical Abstract Service (CAS) numbers. The protocol presented here yields a representative material with a speed of sound c(f) = 1,481 &#177; 0.4 m&#183;s-1 at 5 MHz (corresponds to the speed of sound of water at 20 &#176;C), acoustic attenuation &#945;(f) = 6.1 &#177; 0.06 dB&#183;cm-1 at 5 MHz, optical absorption &#181;a(&#955;) = 0.05 &#177; 0.005 mm-1 at 800 nm, and optical scattering &#181;s&#39;(&#955;) = 1 &#177; 0.1 mm-1 at 800 nm. The material allows independent tuning of the acoustic and optical properties by respectively varying the polymer concentration or light scattering (titanium dioxide) and absorbing agents (oil-soluble dye). The fabrication of different phantom designs is displayed and the homogeneity of the resulting test objects is confirmed using photoacoustic imaging.
Due to its facile, repeatable fabrication process and durability, as well as its biologically relevant properties, the material recipe has high promise in multimodal acoustic-optical standardization initiatives.

Author Spotlight: A Stable Phantom Material for Optical and Acoustic Imaging  

This protocol describes the fabrication of a stable, biologically relevant phantom material for optical and acoustic biomedical imaging applications, featuring independently tunable acoustic and optical properties.

Establishing tissue-mimicking biophotonic phantom materials that provide long-term stability are imperative to enable the comparison of biomedical imaging ...

Patient-Specific Polyvinyl Alcohol Phantom Fabrication with Ultrasound and X-Ray Contrast for Brain Tumor Surgery Planning

Samenvatting

Meer video's verkennen

Hoofdstukken in deze video