Polish Journal of Medical Physics and Engineering December 2022 The Journal of Polish Society of Medical Physics Vol 28, Issue 4 ISSN 1898-0309, doi: 10.2478/pjmpe-2022-0020 Review Article Development of a standard phantom for diffusion-weighted magnetic resonance imaging quality control studies: A review Eric Naab MANSON 1,ABCDEF,*, Abdul Nashirudeen MUMUNI1,ACEF, Issahaku SHIRAZU2,ACEF, Francis HASFORD3,ACEF, Stephen INKOOM2,DEF, Edem SOSU2,CEF, Mark Pokoo AIKINS2,ABDF, Gedel Ahmed MOHAMMED3,ABCF 1Department of Medical Imaging, University for Development Studies, Ghana 2Radiological and Medical Sciences Research Institute, Ghana Atomic Energy Commission, Ghana 3Medical Physics, University of Ghana, Ghana *Corresponding author: Eric Naab Manson; mansonericnaab@yahoo.com (received 16 April 2022; revised 4 July, 8 August and 19 September 2022; accepted 3 October 2022) Abstract Various materials and compounds have been used in the design of diffusion-weighted magnetic resonance imaging (DW- MRI) phantoms to mimic biological tissue properties, including diffusion. This review thus provides an overview of the preparations of the various DW-MRI phantoms available in relation to the limitations and strengths of materials/solutions used to fill them. The narrative review conducted from relevant databases shows that synthesizing all relevant compounds from individual liquids, gels, and solutions based on their identified strengths could contribute to the development of a novel multifunctional DW-MRI phantom. The proposed multifunctional material at varied concentrations, when filled into a multi-compartment Perspex container of cylindrical or spherical geometry, could serve as a standard DW-MRI phantom. The standard multifunctional phantom could potentially provide DW-MRI quality control test parameters in one study session. Keywords: diffusion-weighted magnetic resonance imaging; apparent diffusion coefficient; phantom; quality control. Introduction sequence. The amounts of diffusion, measured as the b-value, and nuclear magnetic resonance signal attenuation [S] determine Diffusion-weighted imaging (DWI) offers valuable information the measured apparent diffusion coefficient (ADC) of water that improves the sensitivity of MRI as a diagnostic tool, reduces molecules in biological tissues3 given by Equation 1. the range of possible diagnoses, offers prognostic data, helps −𝑏𝐴𝐷𝐶 with treatment planning, and assesses therapy response.1 𝑆 = 𝑆𝑜𝑒 Eq. 1 Diffusion-weighted magnetic resonance imaging (DW-MRI) Where, So is the MRI signal obtained without diffusion (i.e., b = has proven to be a promising, reliable and dependable technique 0 s/mm2), S is the MRI signal obtained after the diffusion in the early detection of pathologies such as stroke. For example, gradients have been applied, b is the strength of diffusion (in ischemic injury can easily be visualized in diffusion-weighted s/mm2) and ADC is the monoexponential apparent diffusion images of early acute stroke, through the calculated apparent coefficient of water in an image voxel. diffusion coefficient (ADC) value before any changes can be The total ADC in the voxel is also calculated (given in observed in T1- and T2- weighted MRI. Early detection of such Equation 2) by averaging the fast and slow diffusion injury can significantly influence the treatment and potential coefficients in tissues where there is biexponential decay of DW recovery of patients diagnosed with stroke.2 DWI technique signals, such as the brain or pancreas, where both slow diffusion quantifies the amount of water molecules diffusion using a coefficient and fast diffusion coefficient are experienced within monoexponential model. The technique is based on the the extracellular and intracellular spaces of the tissue.4 generation of contrast resulting from the diffusion of randomly 𝑆𝑦 −𝑏𝐷 −𝑏𝐷∗ moving water molecules in tissue. In order to record the = (1 − 𝑓)𝑒 + 𝑓𝑒 Eq. 2 𝑆𝑜 diffusion effect in MRI, two rectangular gradient fields of equal Where b is the strength of diffusion (measured in s/mm2), So is amplitude and duration are applied before and after the 180o the MRI signal obtained before diffusion (b = 0 s/mm2), Sy is the refocusing radiofrequency pulse in the standard spin-echo pulse © 2022 Authors This is an open access article licensed under the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/). Authors’ contribution: A – Research concept and design, B – Collection and/or assembly of data, C – Data analysis and interpretation, D – Writing the article, E – Critical revision of the article, F – Final approval of the article. 169 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 MRI signal obtained after diffusion gradients have been applied, Carbomer-980, and Carbopol-974P. When gels are used for D is the diffusion coefficient in the slow compartment, D* is the phantoms, their images are of better quality (with fewer diffusion coefficient in the fast compartment, and f is the flowing distortions) as compared to images obtained with phantoms fraction. made of liquids due to the reduction of the macroscopic flow In certain regions of biological tissues, the presence of effect.12 Anisotropic phantoms are more suitable and useful for microstructures affects the free flow of water molecules, which diffusion tensor imaging than for diffusion-weighted imaging. results in non-Gaussian behavior. In such situations, the Kurtosis This is owing to anisotropic phantoms' increased stability, which model and the stretched model are frequently used to estimate lowers imaging artifacts brought on by a drop in the macroscopic tissue diffusion deviation from the Gaussian model.5-7 water flux when they are constructed from layers of an isotropic The echo-planar sequence is the magnetic resonance imaging gel based on agar.14 technique that can provide adequate information about the This review provides an overview of the benefits and diffusion of water molecules in biological tissue through the drawbacks of several diffusion-weighted magnetic resonance apparent diffusion coefficient.8 The displacement of water imaging (DW-MRI) phantom construction methods towards molecules measured in biological tissues using the pulse creating a standard DW-MRI phantom for carrying out quality gradient spin-echo nuclear magnetic resonance technique is in control testing. the range of 1.5 – 15 µm.9 The apparent diffusion coefficient is heavily influenced in intracellular regions by the presence of Methods neurofilaments and microtubules than in extracellular regions, Using relevant online databases, such as Scopus, which contain glial cells. As a result, ADC (i.e., 0.75 × 10-9 m2/s) PubMed/Medline, and Google Scholar, a narrative search on is lower in intracellular regions as compared to ADC (i.e., 2.0 × -9 2 general diffusion-weighted MRI phantoms was undertaken from 10 m /s) in extracellular regions.8 1974 to 2020. "Diffusion-weighted," "MRI," and "phantom" DWI phantoms enable the evaluation of fit model-specific bias were among the search terms. Table 1 shows a summary of and uncertainty for quantitative diffusion parameters, which some data extraction from relevant articles. helps to distinguish noise-induced errors from tissue properties and direct the development of a quantitative DWI methodology.10 Phantoms used for DW-MRI quality control Construction of DW-MRI phantoms tests often have higher diffusivity properties, relatively low T1/T2 Ideally, DW-MRI phantoms should be capable of differentiating contrast, and a limited range of molecular diffusivity within the between ADC values of different tissues. For example, the ADC available volume of the phantom. These conditions differ for both normal liver and pancreas ranges from 80 to 440 × significantly from in vivo conditions.11 The random motion of 10-5 mm2 s-1, whiles for a pathological liver and pancreas, the molecular compounds in biological tissues can be described as ADC ranges from 104 to 381 × 10-5 mm2 s-1, and 176 to either isotropic or anisotropic. In isotropic diffusion, the 396 × 10-5 mm2 s-1 respectively.15 Improved anisotropic molecules diffuse freely in all directions without restriction. phantoms are more appropriate for validating ADC However, in anisotropic diffusion, molecular motion is measurements. However, developments of tissue-mimicking asymmetric since motion occurs along a specific direction. phantoms for precise and accurate ADC measurement of The geometry of isotropic phantoms is either spherical, DW-MRI protocols are limited by the complex cellular cylindrical or tubes filled with gels or liquids that exhibit similar environments of living tissues.13 To accurately develop relaxation and/or diffusion properties as the water molecules in protocols for in vivo DW-MRI studies, there is the need to use biological tissues. Examples of such liquids and gels include phantoms that are purposively designed and constructed to meet alkanes, agarose, and polyethylene glycol (PEG). the standards of both geometry and tissue-mimicking contents Polysaccharide-based gels such as carrageenan have also been for DW-MRI. Some proposed requirements include isotropic used for isotropic phantoms.12 Polysaccharides have similar test tube phantoms filled with liquid, fiber phantoms to mimic properties to human tissues, and are thus commonly used in MRI axonal tracts or cardiac muscles, capillary phantoms with phantoms. They are simple sugar monomers with structural diffusion properties and relaxation times similar to biological elements of cell walls containing intracellular spaces and tissues, green asparagus water phantoms, animal tissues that connective tissue. Each monomer unit is made up of one to six simulate axons of pigs or mice, and computational phantoms.12 groups of C-OH which allow for hydrogen bonding in hydrated Table 2 shows some DW phantoms, the components used for gels. The bonding mechanism also permits the water proton T1 their construction, and examples of some tissues they mimic. and T2 relaxation properties to be altered.13 Other gels include sodium alginate, xanthan gum, FAVOR-PAC-300, PNC-, 170 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 Table 1. Summary of data extracted from relevant articles (continued on the next page) Author Year Journal/Publisher Country Aim Results Ref. Bammer 2003 European Journal USA To discuss the fundamentals In-vivo diffusion coefficients could help researchers 3 of Radiology of DWI and Diffusion Tensor better understand normal and pathological physiology Imaging. in the human body. To verify DWI's potential to diagnose illnesses, more clinical trials are needed. Le Bihan 2015 PLOS Biology France To provide a deeper The use of DW-MRI in the diagnosis of brain disease, 24 understanding of DWI and neurological problems, and the detection and mechanisms management of cancer lesions are particularly beneficial. Diffusion allows for high field strength operation, biological molecule interaction, and cell metabolism interaction. Posnansky 2008 Journal of Biological Germany To investigate the impact of The apparent diffusion coefficient is strongly influenced 8 & Shah Physics a wide variety of by the ratio of the microscopic diffusion coefficients microstructural and of the constituent phases, their concentrations, and compositional characteristics the permeability of the cells on the apparent diffusion coefficient using a geometrical model Cooper et al. 1974 Biophysical Journal USA To investigate restricted The presence of bound or trapped water in tissues 9 diffusion in biological systems at short diffusion times is evidenced by diffusivities in tissues. Cell membranes and mitochondria are responsible for limitations in red blood cells and rat liver, respectively. Laubach et al. 1998 Journal of Magnetic USA To develop MRI diffusion The ADC between agar gels and sucrose solutions was 2 Resonance Imaging phantom that mimics acute similar to the human ADC between GM and acute stroke and normal gray matter stroke. The partial volume effect increased with slice (GM) using agar gel and thickness, resulting in percentage volumetric error sucrose solutions estimations based on the DW EPI of sucrose solution between measured and real volumes of acute stroke compartments. Kato et al. 2005 International Journal Japan To develop and evaluate the The phantom has sufficient strength to represent the 11 of Medical Physics, performance of a NaCl CAG torso and could be useful for electrical conductivity Research and Practice phantom using carrageenan gel, tests, such as those used in MRI and hyperthermia NaCl, agarose, NaN3, GdCl3, research. and water Souza et al. 2017 Research Brazil To explore the proposed DWI Anisotropic and isotropic diffusion phantoms could be 12 on Biomedical and DTI phantoms, the issues constructed using Dyneema and synthetic polymer gels Engineering they pose, and future prospects with T1, T2, and ADC values similar to those found in for DWI and DTI QC biological tissues. standardization. Kıvrak et al. 2013 Diagnostic and Turkey Using a custom-made phantom Various MRI systems used for DW-MRI may have 13 Interventional solution consisting of distilled different ADC values. Radiology water, NaCl, and shampoo When employing DW-MRI in a clinical context, the to compare ADC values type of MRI scanner should be considered. of different MRI scanners. Groch et al. 1991 Magnetic Resonance USA To construct an MRI tissue Using 2-2-diphenyl-1 picrylhydrazyl as a T2 modifier 16 Imaging equivalent lesion phantom and metal phthalocyanines as a T1 modifier, using a polysaccharide material a septumless lesion phantom with varying T2 and T1 TX 150 gel relaxation properties could be created. Mazzara et al. 1996 Magnetic Resonance USA To create a tissue equivalent Gd-DTPA can be used as a T1 and T2 modifier to 17 Imaging MRI phantom with construct phantoms with a wide range of relaxation polysaccharide material, times to resemble various human tissues and organs. TX-151, water, NaCl, and Al The TX-151 gel, when combined with additional powder materials like fat and silicone implants, could be used to construct a human breast phantom for MRI research Vassiliou et al. 2016 Journal UK To test the stability of nickel- All native and post-gadolinium T1 values showed small 18 of Cardiovascular based phantoms utilized for relative changes up to 9.0 %, while phantom ECV Magnetic Resonance myocardial T1/ECV mapping showed a 2.2 percent maximal absolute change. The native and post-gadolinium T2 readings, on the other hand, remained steady over time with <2 % variation. To determine index for rectification in the event of a scanner upgrade or alteration, monthly re-scanning is recommended against phantom drift. 171 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 Table 1. Summary of data extracted from relevant articles (continued from the previous page) Author Year Journal/Publisher Country Aim Results Ref. Lavdas et al. 2013 Journal of Magnetic UK To create tissue-equivalent T1 relaxation times of the gels are determined by sucrose 19 Resonance Imaging diffusivity materials and concentrations, whiles T2 are determined by agarose a spherical diffusion phantom concentration. ADC was affected by only sucrose to mimic biological tissues concentration. To achieve a low ADC value of the gel, using Nickel-doped T1 could be regulated with only sucrose concentration agarose/sucrose gels without affecting T2 relaxation time Captur et al. 2016 Journal UK To develop and check the T1 (0.64 ± 0.45%) and T2 (0.49 ± 0.34 %) values at 1.5 T 20 of Cardiovascular stability of an agarose gel-based and 3 T respectively, assessed in T1MES had 1% or less Magnetic Resonance phantom using a nickel chloride variance between repeat scans, demonstrating high modifier for quality assurance short-term repeatability purposes Kim et al. 2019 PLOS One South Korea To show how a spherical The overall geometry of the phantom could eliminate 21 phantom with spherical inner bulk background phase caused by the air-phantom compartments can be boundary. The spherical geometry of the phantom could constructed using gelatin sphere suppress inhomogeneous spin dephasing and produce dopped with paramagnetic a homogeneous B0 field inside the inclusions spheres, contrast agents with an effective transverse relaxation rate nearly equal to the transverse relaxation rate. Hara et al. 2014 Oncology Letters Japan To create a phantom for 3T The ADC values measured ranged from 0.33 to 3.02 22 MRI that mimics ADC values × 103 mm2/sec, covering the range of ADC values of of normal and tumor tissues the human body measured clinically by 3T MRI. using different sucrose concentrations Kalaitzakis et al. 2020 Physica Medica Greece To create a new DWI-MRI In comparison to sucrose solutions, polyacrylamide gels 15 phantom and compare ADC have a smaller coefficient of variation and therefore measurements using sucrose could be a superior way to simulate ADC values. concentrations and polyacrylamide gels Gatidis et al. 2014 Magnetic Resonance Germany To create a diffusion-weighted Increased PEG concentrations resulted in a significant 23 in Medicine imaging (DWI) phantom with reduction in diffusivity and minor changes in T2 predetermined apparent relaxation times. ADC values and T2 relaxation times diffusion coefficients (ADC) could be adjusted to predefined values by the addition and T2 relaxation times using of gadobutrol to the PEG solutions polyethylene glycol (PEG) solutions Khasawneh et al. 2020 Biomedical Reports Japan To assess if phantoms made The ADC value drops as the PEG concentration rises. 25 of polyethylene glycol (PEG) Within a limited range of clinically reported diffusion could be utilized as standard kurtosis imaging (DKI) values, the PEG phantom was phantoms for magnetic found to imitate restricted diffusion. The PEG phantom resonance imaging (MRI) is safer than the ADC standard phantoms - gelatinous substances like agar, agarose, and polyacrylamide, as well as liquid solution materials like ethanol, acetone, Gd-DTPA solution, and cupric sulfate solution - that have been previously described. Fieremans & Lee 2018 Neuroimage USA To provide an overview of how Understanding all parameters affecting microstructural 28 to create, implement, or choose MR contrasts, both experimentally and in simulations, the proper phantom for could be crucial to comprehending phantom behavior microstructure mapping. and building a universal multimodal microstructural phantom. Yoshida et al. 2016 The British Journal Japan To evaluate image quality Due to image noise and artefacts associated with the PI 29 of Radiology and ADC values of single-shot approach, TSE-DWI images had lower SNRs, impairing turbo spin echo (TSE) DW ADC measurements. images using a parallel imaging (PI) technique 172 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 Table 2. DW phantoms components and tissues they mimic Types of DWI phantom Components Geometry Examples of tissues Polysaccharide powder, distilled water, de-gassed water, paramagnetic metal complex solution, gelling solution, propyl paraben material, Polysaccharide gel phantom phthalocyanine dye, picrylhydrazyl cylindrical breast Polysaccharide material, water, NaCl, Al power and Gd-DTPA Nickel (II) chloride hexahydrate (NiCl2.6H2O) stock solutions, deionized cylindrical water, distilled water, agarose powder Nickel chloride phantoms Nickel (II) chloride hexahydrate, agarose, sucrose, sodium chloride myocardial tissues and native blood solution, deionized water, diazolidinyl urea, paramagnetically doped spherical agarose or carrageenan gels Acrylic perspex spheres, aqueous solution of gelatin powder, nickel, Acrylic perspex phantom spherical cyst, fat agarose, and sucrose concentrations normal tissues (e.g., brain, muscle, prostate, breast) Sucrose phantom Sucrose, NaN3 antiseptic, distilled water cylindrical lesions (e.g., brain, thyroid gland, pancreas, uterine cervix, ovary, prostate) Acrylamide solution containing acrylamide:bisacrylamide, whole range of human physiologic and Polyacrylamide phantom deionized water, cylindrical pathologic soft tissues ammonium persulfate solution, N,N,N',N'-tetramethylethylenediamine Agarose gel, distilled water, acrylamide:bisacrylamide, ammonium whole range of human physiologic and Agarose phantom persulfate solution, cylindrical pathologic soft tissues N,N,N',N'-tetramethylethylenediamine Polyethylene glycol (PEG) PEG and gadobutrol compounds, deionized water, agarose gel grade II glioma, squamous cell carcinoma, cylindrical phantom PEG diffusion modifier, NaN3 antiseptic, distilled water, NaCl olfactory neuroblastoma, brain lymphoma CMRI diffusion phantom Polyvinylpyrrolidone (PVP) powder, water, distilled H2O spherical brain Polysaccharide/water gel phantom spatial confinement of the modifying agents can be evaluated Different samples of polysaccharide/water gel phantoms have using a two-compartment cylinder filled with polysaccharide been prepared using polysaccharide powder, distilled water, de- water gel phantom of different modifier solutions. For example, gassed water, paramagnetic metal complex solution, gelling by measuring the diameters of both inner and outer cylinders, solution, T modifier, and propylparaben material. These the interface between the inner and outer cylinders can be 2 samples are prepared to examine the effect of paramagnetic determined quantitatively using regions of interest (ROIs) on oxygen and the influence of the propylparaben material on T different image slices. In addition, by measuring the variations 1 and T values of the gels, as well as their long-term stability. in signal intensity, the diffusion characteristics of the phantom 2 16 Appropriate samples of these components are obtained by can be assessed. weighing them on a scale, after which they are mixed and stirred together until a partly solid mixture is produced. With the aid of Nickel chloride (NiCl2) phantoms a syringe, each prepared mixture is transferred into a nuclear Quality control MRI phantom for evaluation of myocardial T1 magnetic resonance (NMR) tube, marked and sealed with a and extracellular volume fraction (ECV) mapping has also been paraffin polymer wax. Phthalocyanine dye is used as T1 modifier developed using Nickel chloride (NiCl2) agarose gel. The due to its ability to electrostatically bind to the organic substrates phantom is formulated to mimic specific T1 and T2 myocardial used for the gel phantom. A stable water-insoluble free-radical and native blood values. In its construction, nickel-doped gels such as 2-2-diphenyl-1 picrylhydrazyl is used as T2 modifier in are carefully selected to vary proton T1 rates whiles T2 rates are the phantom.16 In some circumstances, the polysaccharide determined by agarose concentrations. material/water is used together with sodium chloride, Al To create the phantom, nickel (II) chloride hexahydrate powder, and Gd-DTPA to develop the phantom. The Gd-DTPA (NiCl2·6H2O) stock solutions of different concentrations are is used as a T1 and/or T2 modifier, whiles the Al powder aids the made and frozen in a refrigerator. A suitable quantity of phantoms to produce a desirable range of relaxation times NiCl2·6H2O is washed with deionized water into a flask and similar to human tissues by reducing high T2 values.17 intermittently filled with distilled water and stirred until the The concentration of the gel, size of the modifier, temperature desired volume of the final stock solution is reached at room of the gelling solution, and gelling retardant can influence image temperature. To formulate a required phantom with specific T1 uniformity. To access image uniformity, the polysaccharide and T2 values, a prescribed weight of agarose powder is mixed water gel must be prepared such that it is homogeneous. The with a specific volume of the stock solution and poured into a 173 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 conical flask (of volume ≥ 150 ml). Distilled water is added and relationship between the relaxation rates, agarose, and NiCl2 stirred to titrate up to the 150 ml volume. To ensure that the concentrations. Using the modeled equation, for any given agarose is completely dissolved so that the desired T1 and T2 concentrations of agarose and NiCl2, the desired combinations values are obtained, the NiCl2 agarose gel mixture is further of T2 and T1 values could be calculated for 1.5 T and 3 T heated in a microwave oven to approximately the boiling point phantoms.20 equivalent to the T1 and T2 values of myocardial tissue. To ensure minimal vessel permeability and to avoid potential Gel-filled acrylic Perspex spherical phantom contact with air, the heated final NiCl2 agarose gel mixture is This consists of acrylic Perspex spheres of different dimensions transferred carefully into a smaller narrow neck glass bottle (of filled with different concentrations of gels to mimic free volume ≈ 60 ml) and cooled.18 diffusivity and diffusion properties of healthy tissues and benign During the formulation process, it is important to ensure that lesions (or cysts). The inclusion of smaller compartments in the no air bubbles are present in the gel, as the presence of air lower part of the phantom is to provide a means for the bubbles could be trapped in the solidified gel which could assessment of certain important properties of EPI DW-MRI such potentially increase distortions in the main static magnetic field as fat suppression techniques and artifacts resulting from (B0), cause cracks on the narrow neck bottle during cooling of susceptibility effects. The concentrations of the gels in the the phantom and introduce inaccuracies in drawing of ROI to various compartments are determined through measurements of obtain intensity values for T1 and ADC calculations.18 their relaxation and diffusion properties while in the centrifuge Alternatively, Nickel (II) nitrate hexahydrate has been used to tubes.19 Alternative acrylic gel phantom compartments are made develop a spherical diffusion phantom that mimics biological from an aqueous solution of gelatin powder, where diffusion of tissues. Such phantoms have been formulated from a mixture of water molecules between the boundaries of the gel is reduced by agarose, sucrose, and sodium chloride solutions. The solutions mixing the gel solution with buffered formalin solution.21 are mixed together with deionized water, stirred, and heated in a microwave to dissolve the agarose until a clear solution is Sucrose phantom formed. The hot mixture is continuously stirred until the This has been purposively designed for the calculation and temperature drops to below 80°C. Nickel (II) nitrate hexahydrate comparison of ADC measurement in the ranges of normal and and 6 g/L of Diazolidinyl urea are added. To ensure that all the tumor tissues. It contains a mixture of sucrose, NaN3 antiseptic, components are completely dissolved, the resulting mixture is and distilled water which is heated and stirred to completely further stirred until the temperature reduces to less than 60°C. dissolve the contents. The resulting solution is cooled, from The whole mixture is transferred into centrifuge tubes and which different concentrations are produced by varying the allowed to settle at room temperature. The purpose of adding levels of both sucrose and NaN3. The different concentration sodium chloride and Diazolidinyl urea to the gel is to mimic the levels of the final solution represent normal (brain, muscle, and electrical conductivity of biological tissues and to preserve the prostate) tissues and lesions (brain, thyroid gland, pancreas, tissue-mimicking gels, respectively. The gels are prepared in uterine cervix, ovary, prostate, and transition zone) with distinct three different ways; (1) the sucrose and agarose concentrations ADC values. The ADC represents specific characteristics of are kept constant, whiles the nickel concentration is varied. (2) tissues. The solution is poured into different cylindrical the nickel and agarose concentrations are kept constant, whiles containers.15,22 the sucrose concentration is varied. (3) the sucrose and nickel The case container (containing different sucrose phantoms) is concentrations are kept constant whiles the agarose fixed in a heating box made of Styrofoam and heated in the bore concentration is varied. The reason for these variations is to of the MRI scanner at different temperatures (within the body make it possible to independently measure the relaxation and temperature range at 1°C interval) with the aid of a temperature- diffusion properties of the various gel concentrations.19 regulated water bath. DW images are acquired of at least four Also, the initial formulation of the nickel chloride phantom sucrose phantoms, each from 28 to 39°C, using echo-planar involves designing several prototypes, such that the resulting T1 imaging techniques. Finally, ADC values are calculated from and T2 values are within a reasonable range, whiles mimicking Equation 1 using the signal intensity values obtained from a native blood and myocardium tissues. Several test mixtures specific region of interest (ROI) in each of the sucrose phantom containing varying concentrations of NiCl2, water, and agarose DW images.22 were prepared by dissolving them at 95°C in 50 ml test tubes in order to characterize the relationship between T1, T2, agarose, and NiCl2. The prepared samples were transferred into NMR Polyethylene glycol (PEG) phantom tubes and analyzed with a Bruker minispec mq60 relaxometer Polyethylene glycol (PEG) is another class of compounds that after allowing them to settle. Results obtained from the analysis has been used successfully to create a DW-MRI phantom. To are fitted exponentially to determine T and T relaxation times. make the phantom, PEG and gadobutrol compounds are 1 2 Finally, T1 and T2 values are modeled to determine the dissolved in a graduated cylindrical plastic tube using deionized 174 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 water to produce different concentrations of PEG solution.23 At Discussion a temperature of 37°C, the self-diffusion coefficient of free -9 2 24 The microstructural properties of the phantom material can water is approximately 3.0 × 10 m /s. Since a DW image is affect the NMR properties of the liquids, gels, or solutions that T2 weighted, a specific average molar mass of the PEG fill them. This may lead to restricted diffusivity, and cause local compound is used for adjustment of water diffusivity whiles field inhomogeneities due to magnetic susceptibility effects. gadobutrol (a gadolinium-based compound) is used to adjust T2 Quality control phantoms can be made to completely mimic MR relaxation times. By fitting the values of the resulting properties. For example, effects such as relaxation, diffusion, concentrations of both PEG and gadobutrol solution with and susceptibility properties of brain phantoms can be created defined ADC values of specific tissues using monoexponential by doping water or gel such that its microstructural parameters and bi-exponential models, the behaviors of T2 relaxation times 23 mimic the tissues in the human brain. Ideally, the materials used and water diffusivity can be predicted respectively. Results in the preparation of DW-MRI phantoms should be accessible, obtained from the fits are used to estimate the exact cost-effective, stable, independent of T relaxation times, non- concentrations of both PEG and gadobutrol solution required to 2 toxic, and must have ADC similar to biological tissues.28 develop the final phantoms. To prepare the final phantoms, The average distance between biological fibers and average different concentrations of PEG and gadobutrol solution are displacement of the water molecule is between 12 – 18 µm and prepared in plastic tubes such that possible combinations of 8 – 35 µm respectively. To obtain a uniform attenuation in selected ADC and T2 relaxation values are similar to specific biological tissues and the desired MRI signal, it is critical to biological tissues. Each of the phantoms in the plastic tubes is 23 ensure that, diffusion-weighted MRI phantoms are developed placed in a plastic box and covered with a 2% agarose gel. such that they have several compartments that fall within the Alternatively, PEG diffusion modifier, NaN3 antiseptic, and range of distances in biological fibers. Also, the average distilled water have also been used to create a PEG phantom. A translation of solutions used for the preparation of the phantoms mixture of diffusion modifier and the antiseptic is heated and should reflect the displacement range of water molecules.8 later diluted using distilled water to achieve different There have been suggestions that MRI phantoms made from concentrations with 0.03% w/w NaN3. Empirical formulae are agarose gel should contain concentrations of agar up to 2% used to calculate the concentrations of the PEG such that they (w/v).2 This would ensure that the proton density and relaxation correspond to arbitrary ADC values. The resulting solutions are properties of these gels are within the range of human soft transferred into microcuvettes, from which each microcuvette is tissues.2 As the concentration of agar in DW-MRI phantoms installed in a phantom case containing 0.9% NaCl and used as increases above 2%, its estimated T2 values decrease. At agar PEG phantoms. With the aid of a heating device connected to a solution concentrations between 0.25 and 2% (w/v), ADC values circulating thermostat chamber, the temperature of the phantom are independent of agar concentration. For sucrose solutions, is set to the body temperature of about 37°C. As the concentration levels in MRI phantoms have an influence on T concentration of the PEG phantom increases, its ADC values 2 25 relaxation and ADC of the solution. When the sucrose decrease. concentration is increased from 2.5 to 30% (w/w), the T2 and ADC values decrease from 250.5 to 54.6 ms and 1.974 to 1.082 Polyacrylamide phantom × 10-3 mm2/s, respectively. ADC values of human soft tissues In the presence of a catalyst and a polymerization reaction can only be attained at a sucrose solution of ≥ 20% (w/w).2 initiator, a mixture of acrylamide and bisacrylamide (a cross- Since DWI depends on T2 relaxation times, when chemical linker) is chemically polymerized to create polyacrylamide gels compounds such as sucrose and agarose gel, gelatine, dairy phantoms26-27 that can mimic the ADC values of biological cream, and polyethylene glycol (PEG) are added to MRI tissues. Higher polyacrylamide gel monomer concentrations phantoms, they restrict the diffusivity of water molecules (between 60 and 90%) are advised to evaluate lower ADC through them. This may result in a change in T2 relaxation times values. Similar to this, lower polyacrylamide gel monomer out of the range for soft tissues, produce mixed diffusion and concentrations (20 – 40%) are required for larger ADC affect the contrast of DW- and T2-weighted images of the readings.15 To replicate lower ADC values of biological tissues, phantom. The resulting effect on image contrast may cause T2 different test tubes are filled to about two-thirds with lower shine-through effect, which also may influence the ADC values monomer concentrations of polyacrylamide gel or in co- quantitatively. In such situations, adding gadolinium salt and monomer ratios of 1/20, 1/30, and 1/40. This is then followed by gadobutrol to the contents of the phantom has been suggested as the addition of tetramethylethylenediamine and ammonium means of controlling the T2 relaxation times.23 persulfate to catalyze the polymerization of acrylamide. The N-tridecane has been identified to have ADC similar to that of final mixture is then placed in a plastic holder embedded in a the brain.12 However, it is toxic and therefore has limited use in water tank at a room temperature of 22 ± 1°C.15 practice. On the other hand, solutions such as sucrose and agarose gel have ADC values close to biological tissue and are 175 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 non-toxic. However, they undergo biological degradation and Compounds such as aqueous solutions of polyvinylpyrrolidone therefore are not suitable for long-term scanning since they are (PVP) could be substitutes for agarose because of their non-toxic not durable. PEG can efficiently control ADC values but has an nature and long-term stability. In the same way, active effect on T 122 relaxation time. compounds that enable PEG to efficiently control ADC values Considering these identified limitations, advances in the could equally be isolated. So, when all these active compounds design and construction of reference DW-MRI phantoms for are used in the preparation of a single multifunctional substance, quality control tests should focus on novel approaches that can it is possible to have a novel phantom that would satisfy all the compensate for the individual limitations of these materials, ideal requirements needed to perform DW imaging quality liquids, and solutions that make up the phantoms. Compensating control with good reliability. Using this synthesized compound, for these limitations would require the development of a various types of DW-MRI quality control phantoms can be made multifunctional substance that exhibits all the characteristics to mimic specific human tissues. Table 3 shows a summary of ideal for a DW-MRI phantom. It is possible to synthesize all some DWI phantoms in terms of ADCs achieved, stability, and relevant compounds from each of the individual liquids, gels, T2 values. and solutions into a single substance that would compensate for The geometry of the phantom affects its MR image quality. the individual limitations. Because of their long-term stability For instance, a non-uniform geometry would cause a non- and ease of manufacturing, synthetic polymer-based gels can be homogeneous magnetic field to introduce geometrical an excellent alternative to agar. For example, if n-tridecane is distortions in the diffusion-weighted image of the phantom. found to be stable but toxic, it is possible to synthesize the active Therefore, the use of well-defined geometries such as spheres compounds that prevent n-tridecane from undergoing biological and cylinders would help reveal all possible distortions without degradation. Similarly, it is also possible to synthesize the active necessarily corrupting the signal-to-noise ratio (SNR) of the compound that makes agarose and sucrose gel non-toxic. image.12 Table 3. Behavior of DWI phantoms with respect to ADC range, temperature, stability, and T2 values obtained from available literature Types of DWI phantom Description of concentrations ADC range achieved Temp. Stability T2 Values Ref. (oC) (%CV) (ms) Polysaccharide gel 3 to 21 % TX-150 composition No ADC 5-15 No CV 57 - 287 16 (TX-150) phantom by weight according to the study according to the study Nickel chloride phantom 0.48 to 3.7 mM No ADC 37 1.9 - 3.4 48 - 234 18 according to the study 31.8 mm/L Nickel Chloride [(2.0 ± 0.363) to 19 No CV No T2 values 32 in water (2.1 ± (0.109)] × 10-3 mm2s-1 according to the study according to the study Ni doped agarose sucrose concentration 14 to 38 (%w/v), 0.74 - 1.91 × 10-3 mm2s-1 21 No CV 33 and sucrose agarose concentration 0.8 to 1.2 (%w/v), according to the study nickel concentration 0.6 to 1.8 (%w/v) Acrylic perspex phantom concentration of 0.5% 37 No CV 1453.29 ± 13 34 (Carbomer-980) according to the study Sucrose phantom concentration 0 to 57% 34.9 and 231 × 10-5 mm2s-1 21-23 <5 No T2 values 15 according to the study 0 to 1.2 M 0.33 and 3.02 × 10-3 mm2/sec-1 37 No CV No T2 values 22 according to the study according to the study Polyethylene glycol PEG concentrations < 1.0 × 10–3 mm2s-1 22 1.20 - 4.62 No T2 values 35 (PEG) phantom from 2.5 to 20 mM according to the study PEG concentrations 0.37 - 3.67 × 10-3 mm2s-1 18-45 No CV No T2 values 36 from 0 to 120 mM according to the study according to the study Polyacrylamide gels concentration 10% to 50% (w/v) (55.82 - 155.18) × 10-5 mm2s-1 20-22 5.1 1995.8 - 110.8 37 concentration 0% to 40% (77.3 - 231) ×10-5 mm2s-1 21-23 ≤5 No T2 values 15 (co-monomer ratio = ¼) according to the study Agarose gel concentration 1% to 6% (w/v) 199.31 - 207.76 mm2s-1 20-22 <5 26.5 - 136.3 37 PVP PVP-concentrations ranging 1.594 - 0.3326 μm2/ms 20 No CV No T2 values 38 from 10% (w/w) to 50% (w/w) according to the study according to the study PVP 15% to 65% (w/v) average diffusivity 22 2 196 39 800 × 10-12 m2/s 176 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 In addition to geometrical distortion, the single-shot echo-planar images due to their high diffusivity, unlike biological tissues. imaging (SS-EPI) sequence mostly used for DWI also Additionally, they have T1 that is almost identical to T2, which introduces some level of distortion in diffusion-weighted images is not found in biological tissues.12 However, NiCl2 phantoms as it is compromised by the presence of artifacts. To optimize have proven to have long stability for more than 1-year period.20 SNR and obtain the desired ADC values, the shortest echo time One major advantage of PEG and agarose is their wide range of and parallel imaging techniques should be applied for EPI- ADC values for both free and restricted diffusion in magnetic DWI.29 Complex tissue properties such as anisotropy and resonance images, whiles sucrose can control large ADC values. perfusion should be incorporated into the design features of As a result, NiCl2 could be dopped with agarose or sucrose, or DWI reference phantoms in tissue compartments. Anisotropic PEG to accurately mimic biological tissues. The major challenge diffusion properties should be straightforward to create, with associated with the sucrose phantom is that the ADC values measurable pore geometrics (e.g., water-filled glass capillary obtained are based on changes in free diffusion only, unlike array). This could allow diffusion MRI signals to be computed restricted diffusion in human tissues as a result of high tissue based on their estimated pore morphology.30 On the other hand, cellularity and perfusion effect. On the other hand, phantoms perfusion design and configuration can be modeled to include a made of polyacrylamide have less bacterial infiltration, and variety of tissues in the overall phantom, verified and validated longer shelf life. Due to the utilization of cross-linking to cover the full physiological range.31 These properties could be polymerization rather than a thermal gelation method, used to evaluate quality control diffusion parameters such as polyacrylamide phantoms may offer more mechanical strength SNR, geometrical accuracy, low contrast object detectability and robustness than agarose.26 Additional advantages and and signal intensity uniformity. disadvantages of the gels and solutions used for DWI phantoms MRI phantoms filled with paramagnetic solutions such as are presented in Table 4. those containing NiCl2 may not be the best choice for DWI QC Table 4. Advantages and disadvantages of solutions and gels used for DW phantoms Type of gel/solution Advantages Disadvantages Agarose gel • non-toxic • prone to bacteriological attacks • ease, and low-cost fabrication • not suitable for long-term scanning, need high thermal treatment • sufficient mechanical strength, can be formulated in different (80–100°C) during the preparation process shapes and layered structures • cooling rate and liquid temperature affect phantom homogeneity • ADC values are closer to biological tissue when attempting to target a particular tissue's relaxation times • excellent MR signal characteristics • the concentration of agarose impacts the gel's structural integrity and relaxation qualities. Polyacrylamide gels • excellent optical transparency • highly toxic before polymerization • solid elastic and easily shaped into complex forms • more difficult to prepare and handle compared to agarose gels • inherent absence of air inside the gel volume, more resistant for • new gel is needed for each experiment diameters ranging from 5 to 50 μm • better at simulating ADC values of human tissues and human body fluids measured at ambient temperatures of 20-22°C as compared to agarose gels Sucrose solution • non-toxic • not suitable for long-term scanning • ADC values are closer to biological tissue • air in the form of air bubbles is most of the time present in sucrose • can efficiently measure and control ADC values solutions • enables the simulation of T2 relaxation in breast tissues PEG • PEG decreased restricted diffusion • restrictions on accurately simulating restricted diffusion after a • can efficiently control ADC values certain point since it lacks a physical restricting structure (e.g., • low-cost and transparent membrane) • mimics a large range of ADC values for both free and restricted • low mechanical stability diffusion Polysaccharides • polysaccharide materials of the CAGN phantom are not expensive • short term preservation due to water evaporation and bacterial and are readily available growth • strong and elastic and can be formed into a torso, PVP • the ADC values of PVP at higher temperatures (like 37°C) • T2 and ADC values do not cover the entire physiological range encompass the entire spectrum of isotropic diffusion in the human body • reproducibility of ADC values from cancerous tumors to normal breast tissue is achievable Nickel chloride • high stability • temporal stability solution • homogeneous • water-soluble • ease of creating phantoms with relaxation times within the range usual for biological tissue 177 Eric Naab Manson et al: Quality Control Phantom for MRI-DWI Pol J Med Phys Eng 2022;28(4):169-179 Conclusion Recommendations Optimization of DW-MRI requires routine monitoring of the A single multifunctional tissue-mimicking substance that fills performance of the MRI scanner with a standard DWI phantom. the phantom should be developed. The geometry of the vessel However, there is not yet a one-fits-all reference phantom and containing the multifunctional substance should either be established protocol for performing diffusion-weighted spherical or cylindrical. The materials making up this substance imaging. The major challenge limiting the development of a should be easily accessible, reproducible, cost-effective, non- reference DWI phantom is the appropriateness of solutions degradable, and non-toxic. The ADC and T2 values should cover and/or gels used to fill the phantom. There is however the a wide range of those of biological tissues with a coefficient of potential in synthesizing a standard multifunctional compound variation ≤ 5%. Multi-centre studies could be commissioned to to fill the phantom, by utilizing the strengths of the already establish DWI quality control protocols across different scanner available gels and solutions for various DWI phantom designs. types, if necessary, using the phantom. 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