Name: patient-specific polyvinyl alcohol phantom fabrication with ultrasound and x-ray contrast for brain tumor surgery planning
Uploaded: 2020-07-14T14:00:00
Duration: 8 min 41 s
Description: 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

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].

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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 ...

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