3D Printing of Tissue-Simulating Phantoms As a Traceable Standard for Biomedical Optical Measurement

3D printing of tissue-simulating phantoms as a traceable standard for biomedical optical measurement

Erbao Donga, Minjie Wanga, Shuwei Shena,Yilin Hana, Qiang Wua , Ronald Xua,b,*

aDepartment of Precision Machinery and Precision Instrumentation, University of Science and Technology of China, Hefei, Anhui, China bDepartment of Biomedical Engineering, The Ohio State University, Columbus, OH, USA Email: [email protected]

ABSTRACT

Optical phantoms are commonly used to validate and calibrate biomedical optical devices in order to ensure accurate measurement of optical properties in biological tissue. However, commonly used optical phantoms are based on homogenous materials that reflect neither optical properties nor multi-layer heterogeneities of biological tissue. Using these phantoms for optical calibration may result in significant bias in biological measurement. We propose to characterize and fabricate tissue simulating phantoms that simulate not only the multi-layer heterogeneities but also optical properties of biological tissue. The tissue characterization module detects tissue structural and functional properties in vivo. The phantom printing module generates 3D tissue structures at different scales by layer-by-layer deposition of phantom materials with different optical properties. The ultimate goal is to fabricate multi-layer tissue simulating phantoms as a traceable standard for optimal calibration of biomedical optical spectral devices. Keywords: Biomedical optical measurement, Tissue phantoms, 3D printing, Absorption, Scattering

1. INTRODUCTION

Biological optical imaging detects tissue anomalies by studying the interaction of photons with various microstructures and components of biological tissue, such as water, hemoglobin, glucose, protein, fat, and mitochondria [1, 2]. Detecting optical parameters of biological tissue may provide valuable information that helps to understand the physiological processes and detect tissue anomalies. It have been shown that optical phantoms are able to simulate important optical parameters of biological tissues. By mixing fluorophores and other contrast enhancement agents with the base, the scattering and the absorption materials at various compositions, it is possible to simulate multiple tissue optical parameters, such as refractive index, absorption coefficient, scattering coefficient and anisotropy [3-8]. Optical phantoms have been widely developed and used in various clinical applications, such as medical device calibration, validation and clinical training [2, 6]. In fact, the optical phantoms really facilitate the development and improvement of spectroscopy diagnosis, optical imaging and therapeutic intervention techniques. For example, with brain-simulating phantoms simulating brain structural and physiologic properties, we can calibrate spectrophotometric devices used for brain functional studies [9-12]. In order to simulate actual tissue conditions, multilayered phantoms have been fabricated recently using various methods such as multilayered curing [13], integration after mold casting [5], and spin coating [14]. However, optical phantoms produced by the above methods are generally homogenous and do not reflect multilayered structure and

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Downloaded From: http://proceedings.spiedigitallibrary.org/ on 03/05/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx optical heterogeneities observed in actual biological tissue [15, 16]. Consequently, optical measurements calibrated by these phantoms may have significant bias, limited accuracy, and poor traceability [36]. In recent years, three dimensional (3D) printing has been used broadly in the applications of bio- manufacturing [17-20]. It is a material additive process that converts digital information into a three- dimensional object by adding solid material layer by layer. In comparison with conventional manufacturing processes, 3D printing has advantages such as short production cycle and freeform fabrication of objects with complex geometric characteristics and internal structures [21]. The 3D printing method is suitable for fabricating tissue-simulating phantoms for various biomedical and clinical applications, such as curvature correction in spatial frequency domain imaging, cardiovascular surgical training and performance validation in bio-photonic imaging [21-26]. Despite these efforts, it is still challenging for freeform fabrication of phantoms that simulate both optical and structural properties of biological tissue [25, 27-31]. In this paper, we present Fused Deposition Modeling (FDM) [31-33] and PolyJet methods to fabricate tissue phantoms simulating optical properties and structural properties of tissue. The FDM method was used to print the section with relatively low accuracy requirements and the PolyJet method was designed to fabricate the part with multilayer microstructures (≤100μm) [35]. The gel-wax, titanium dioxide (TiO2) powder), graphite powder material were used as the base material, the scattering ingredient and the absorption ingredient in the FDM system. And the colorless light-curable ink, the black light-curable ink containing black dye [33] and white light-curable ink containing TiO2 particles [35,36] were used as base material, absorption material, and scattering material respectively in the PolyJet system. The technical feasibilities of two kinds of fabrication processes both have been verified. However, neither of them can complete all the printing works, so we are trying to combine the two production methods into one system. Since the existing 3D file formats such as STL couldn’t be used for multiple - material printing system, we are also exploring a new 3D file format that can be used for heterogeneous phantom fabrication system and directly displayed by optical instruments.

2. MATERIALS AND METHODS

2.1 Materials

2.1.1 The optical properties control of 3D printing materials Considering the requirements of optical characteristics of the tissue phantom, the 3D printing materials must be controllable. The designated optical properties of the printed phantom, such as the absorption coefficient μa and the scattering coefficient μs, can be achieved by mixing the based material, the absorption material and the scattering material at specific mixing ratio. In the case of multiple absorption materials dispersed in the medium, the overall absorption coefficient of the phantom is defined as:

=() +() …() (1)

Where ε1 ε2 …εn are extinction coefficients of different absorption materials; and C1 C2…Cn are material concentrations. It is assumed that no interference exists between individual absorption ingredients. The scattering coefficient of the phantom is defined as the production of the number of the scattering particles dispersed in unit volume ρ and the averaged scattering cross section of the particles бs :

() =б() (2) Similarly, for the phantom that is dispersed with multiple scattering ingredients, the overall scattering coefficient can be expressed as the linear superimposition of individual scattering ingredients, assuming no interference between these ingredients:

() = ∑ ,（） = ∑ б, () (3)

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Downloaded From: http://proceedings.spiedigitallibrary.org/ on 03/05/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx 2.1.2 The optical properties of materials used in FDM system The material system for the proposed FDM technique consists of a mixture of the base ingredient, the absorption ingredient and the scattering ingredient. The selection of these phantom materials should consider the following requirements: (1) the absorption characteristics of the phantom should be finely tunable within the range of biological tissue without affecting the scattering characteristics; (2) the scattering characteristics of the phantom should be finely tunable within the range of biological tissue without affecting the absorption characteristics; (3) the base component should be transparent and present minimal interferences to the overall absorption and scattering characteristics of the printed phantom; (4) the physical dimension, the chemical properties and the optical characteristics of the fabricated phantom should be stable for a relatively long shelf life.

Experimentally, the titanium dioxide (TiO2) powder material (Guangfu Fine Chemical Research Institute, China) was used as the scattering ingredient of the FDM systerm. Slab phantoms at five different levels of TiO2 powder concentrations were tested. Eight points were selected on both top and the bottom surfaces of each slab phantom for the scattering test. The graphite powder material with particle size of 8000 mesh and purity of 99.95% (Shanghai Jingchun Biochemical Technologies, China) was used as the absorption ingredient. The absorption spectra of the graphite phantoms at different concentrations were tested by a UV/VIS spectrophotometer (Shimadzu, Japan).The tests were triplicated and the standard deviations were calculated. As shown in Fig.1, the absorption coefficient levels are linearly proportional to the graphite powder concentration levels, with a linear correlation coefficient R2 of 0.997.

0.18 - Average of experiment sresults 0.16 -

0.14 -

0.12 -

0.10 -

0.08 -

0.06 -

0.04 -

0.02 -

0.00

0 1 2 3 4 5 Concentration of graphite powder( *10 g /ml)

Fig. 1 The fitting linear of absorption coefficients at different graphite powder concentrations.

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0 0.2 0.4 0.6 0.8 1.0 Concentration of TiO2 (g I/50m1) I

Fig. 2 The relationship between reduced scattering coefficients and concentrations of TiO2 powders.

Fig.2 shows the reduced scattering coefficient μs' of the phantoms at different TiO2 powder concentrations. According to the figure, the reduced scattering coefficient is linearly correlated with the 2 TiO2 powder concentration, with a linear correlation coefficient R of 0.994.

Phantoms that mix graphite powders and TiO2 powders at different ratios were fabricated. The optical properties of these phantoms were characterized in order to evaluate if crosstalk exists between the absorption and the reduced scattering ingredients. In the first set of experiments, the concentration of the -2 graphite powder increased gradually when the TiO2 powder concentration was fixed at 1.2*10 g/ml. In the second set of experiments, the concentration of the TiO2 powder increased gradually when the graphite powder concentration was fixed at 0. 6*10-4 g/ml.

0.18 - (1) WAbsoibancel (2) 0.16 - Average of experiment results II

0.14 -

0.12 -

0.10 - 5 8 0.08 - rn 4

0.06 - L 2 0.04 - 2

0.02 - ç 000 o 0.3 0.4 0.5 0.6 0.1 0.0 2 3 4 15 Concentration of TiO2 powder (g/50m I) Concentration of graphite powder (g150m1)

Fig. 3 Crosstalk test results between the scattering and the absorption materials: (1) the concentration of the graphite powder increased gradually when the TiO2 powder concentration was fixed at 1.2 *10-2 g/ml; (2) the concentration of the TiO2 powder increased gradually when the graphite powder concentration was fixed at 0. 6*10-4 g/ml. According to Fig.3, adjusting the absorption coefficient had the minimal influence on the reduced scattering property of the phantom, and vice versa. Therefore, it was concluded that the crosstalk between the scattering and the absorption materials used in our FDM printing system was negligible. 2.1.3 The optical properties of materials used in UV system The light-curable ink is a kind of weak-solvent ink-jet ink that cure immediately when exposed to a ultraviolet ray at particular wavelength, and do not easily redissolve in water or other organic solvents. The white light-curable ink is the mixture of matrix material and TiO2, which is used to as the scattering material, and the black light-curable ink made from matrix material and black pigment can be used as the absorption material.

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Downloaded From: http://proceedings.spiedigitallibrary.org/ on 03/05/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx i. .ii -u,. - --the optical property at the wavelength 650mn 3.0 - --the optical property at the wavelength 800nm o ance bsorb

| ` ~'~' 0.5

0.0 0.02 0.04 0.06 0.08 0.10

Amount of black ink/mi

Fig. 4 The optical properties of mixtures with different proportions of black light-curable ink at the wavelength of 500nm, 650nm, and 800nm. The absorption property of the mixtures were tested by spectrophotometer (SOLID3700, Shimadzu Corporation) where the matrix material amount in the mixtures was 10ml. The Fig.4 showed that the absorbance of the total mixture at any wavelengths had a linear relationship with the amount of the black ink within a certain range.

2.2 The 3D printing progress and systems for optical phantoms

2.2.1The 3D printing progress for optical phantoms Fig.5 illustrates the general flow chart for freeform fabrication of tissue-simulating phantoms. The process consists of two consecutive step: modeling and printing. At the modeling step, medical images acquired by various modalities such as Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) are converted into a 3D structural model of biological tissue by a series of imaging processes including denoising, segmentation, reconstruction, format conversion and printing section. In the meantime, optical characteristics of different tissue types are assigned to individual pixels of the digitalized tissue sections based on either published data or direct measurements. At the printing step, the FDM system is suitable for made the large volume and relatively low precision optical phantom, while the PolyJet system is more suitable for fabricate the exquisite and small optical phantom. The digitalized tissue section data is loaded to the 3D printing system, then printed the phantom. By the end of this process, the printed phantoms are removed from the 3D printing system and the morphologic and optical properties of the produced phantoms are further evaluated by photographic imaging and spectrophotometry.

l Medical Model image reconstruction \ J r r 3D digital Cover to 3D printer model control data L L Tissue \ Material ratio optical parameter mapping L J Fig. 5 Schematic flow chart for FDM fabrication of a tissue-simulating phantom. 2.2.2 Development of FDM system The FDM phantom printing system consisted of a host computer for process control, a 3D motion platform, a print head, a material feeding system, and a model temperature controller, as shown in Fig.6.

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Fig. 6 The photo of FDM 3D printing system for optical phantom fabrication. 2.2.3 Development of the PolyJet system for phantom printing As shown in Fig.7, the 3D printing system for fabricating tissue phantoms were composed of a 3D printer modified from R2000 HP piezoelectric inkjet printer, a computer and UV curing lamp system. The paper feed signal of printer was converted to a drive pusher plate, and the plate declines after each layer printed to keep the distance between the nozzle and plate surface constant. The water-cooled curing light was fixed on the printing head to cure the results printed instantly. With the parameters Y, C, M, K of the images controlling the spray of colorless light-curable ink, black light-curable ink, white light-curable ink and colorless light-curable in the first four nozzles respectively, the 3D printer accurately piled up the materials by layers completing fabrication of tissue phantoms. Water -cooled -- - 3D Printer Machines

Fig.7 3D printing system for freeform fabrication of skin-simulating phantoms.

3. EXPERIMENTS AND RESULTS

3.1 Optical property characterization by double integrating spheres

3.1.1 The basic setup of the double integrating spheres system

It is difficult to measure the reflected power at very angle α with a goniometer. However, an integrating sphere could be used to get the total reflection from a sample from each angle for it integrating the reflections over all spatial angles (as show Fig.8). Theoretically, both reflectance and transmittance could be measured by the same sphere. It is also difficult to alignment and calibration, therefore two dedicated spheres are used to measure reflectance and one to measure transmittance dividedly. The spheres we used had an inner diameter of 5.3inch (Labsphere, USA, 4P-GPS-053-SL). The spheres feature four ports: an input port, a detector port, a sample port and a north pole port. Being equipped in the detector port, the calibrated silicone photodetector had the wavelength range of 600nm- 1100nm.

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Fig. 8. The double integrating spheres measuring system There are three optical parameters to be required in principle to reconstruct the optical values: reflectance, transmittance and the fraction of the transmitted light that passed the phantom without being scattered, which is called unscattered transmittance [13]. We measured the values of reflectance and transmittance of the same material at different thicknesses. 3.1.2 Parameter reconstruction Using the reflectance and transmittance measurements, we reconstructed the optical properties ,, and , then solved the inverse problem. From the function f(Rm,Tm) we could get the parameter of μa, μs, g and n . Terms absorption coefficient(unit ) scattering coefficient(unit )

g scattering anisotropy(unit-less,-1≤g≤1)

n refractive index（unit-less，n≥1） We reconstructed the optical parameters in three steps. First of all, we used the Monte-Carlo simulation model to obtain the values of reflection and transmittance of a sample being given a series of optical parameters. At the next step, the genetic algorithm could search the optimal parameter. The final step, the optimal parameter set were compared to the measured values and the simulated values from the Monte-Carlo simulation model. To build the database, we set the

(0.001, 2.0),(0.1, 200.0),(0, 1.0),n (1.3, 1.7) While there is a variable thickness h. through the above step, we can build up the MC-lookup table.

Then we searched for the fitness of a series of values ρ=,, ,n which was determined by the relative error ε.

() () ε= d ∈ (1,2,3,4) (4) ()

Subscripts d thickness of the sample Terms

reflectance of the sample

reflectance of the MC simulation

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transmission of the MC simulation

3.2 3D printing of human brain optical phantom

The four regions of the simplified MR images were printed to represent the structural heterogeneity of human brain. Considering the complex pattern of photon migration in CSF layer [33] and the contrast difference between MRI and optical imaging, the CSF region of the brain phantom was printed in black pigment instead. The optical properties of the other regions (i.e., scalp and skull, gray matter, and white matter) were determined based on the previous publications [34-36], as listed in Table 1. Table 1 Optical properties for each type of brain tissue used in a four-layer model.

-1 -1 Tissue type μa(mm ) μ’s(mm ) Scalp and skull 0.016 0.740 Gray matter 0.019 0.673 White matter 0.021 1.011

Fig.9 shows the stack of 5 layers of the human brain phantom sections printed based on the simplified MRI images. In this experiment, the simplified MRI slice images were scaled down to 65% of the original MRI images in order to fit in the working area of the FDM system. Four layers of the transparent base material were printed at the bottom of the phantom as the support before the brain phantom was printed. The thickness of each printed section was 0.4 mm and each MRI section was repetitively printed for three layers. After all the five MRI sections were printed, a layer of transparent base material was printed on the top of phantom as protection.

Fig. 9 The photo of the stacked brain phantom fabricated by FDM based on the simplified MRI images. Each big grid on the bottom of the phantom corresponds to 30 mm. As Fig.10 shows, in order to evaluate the similarity between the simplified image (i.e., original image) of each MRI brain section and the image of the corresponding FDM printed brain section (i.e., printed image), we defined contour similarity as the ratio between the overlapped area S’ of two images and the area S of the original image for each material composition. First, Matlab image processing toolkit was used to co-register between the printed image and the original image. Second, binary images were generated based on the co-registered images for different material compositions. Finally, the ratio of S’/S was calculated. The imaging analysis showed that the average similarity of the outer contour of the skin/skull was above 95%; and the average similarity of the inner contours was above 93 %. These similarity results demonstrated that our FDM system was able to fabricate tissue-simulating phantoms with fidelity.

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Downloaded From: http://proceedings.spiedigitallibrary.org/ on 03/05/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx MRI ',inqiliticJ l'rinrrl .lice .licc. I;13 er,

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Fig. 10 Images of MRI slices, simplified MRI slices and 3D printed layers The above similarity evaluation method had several limitations. First, the boundary of the overlapping areas was typically fuzzy, partially owing to the limited resolution of the existing FDM system (0.5 mm). Second, the morphologic characteristics of the original brain MRI images were too complicated to simulate. Therefore, an improved FDM system and an automatic segmentation algorithm were necessary for FDM fabrication of the 3D brain model to improve structural fidelity. Technical feasibility of printing tissue-simulating phantoms with optical fidelity was demonstrated by testing optical properties of a two-layered phantom in comparison with those of Monte Carlo simulation.

a 05 004 500 500 MCML simulation result 0.05 {Experiment measure result MCML simulation mutt 500 of plmMOm A O Expettmenr measure result 0.05 top layer: u0.124 u 34.875 400 á of phantom o 0.04 bottom layer 0. 0.170 0, 7.357 toplayer u ano u'1.a51 Ose borlan Myer: U. 0.124 u;8.875 E 300 0.05 0.02 300 ó rc 200 5 rc 200 0.02 E 0.01

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Fig. 11 Comparison between the normalized reflectance measurements and the Monte Carlo simulation results for different two-layered phantom configurations: (1) phantom A. (2) phantom B. Fig. 11 shows the normalized reflectance measurements at different source-detector distances in comparison with simulation results for different phantom configurations. The averaged deviation between the measured and the simulated reflectance results was below 10% indicating that the 3D printing process was able to produce multilayered tissue-simulating phantoms with optical fidelity.

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Downloaded From: http://proceedings.spiedigitallibrary.org/ on 03/05/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx 3.3 3D printing of skin tissue optical phantom

iV sw.1.4* seeaw5001{.0a ex i w... xpa1AseI MC Fig.12. The broken sectional surface scan image of different phantoms printed at different scales We used the PolyJet system to print different skin tissue phantoms by different layers. Fig.12 shows the results obtained from a SIRION200 Scanning electron microscopy (FEI, USA) of these skin phantoms. From the images we could get that the absorbing and scattering particles were uniformly dispersed at the broken sectional surface, so it came to the conclusion that the absorbing and scattering particles were evenly distributed in the phantoms. Table 2. The total thickness of different layers printed under the resolution of 2880×2880 and 40% inkjet amount

Layers Thickness 30 30μm 40 42μm 50 55μm

The thickness was measured by using Wyko NT1100 ( Bruker Corporation, United States). Every thickness data in table 2 was an average of three times measured results. The thickness of the skin epidermis and dermal were 100μm and 2mm respectively, so the printer had the ability to print granules to simulate the microstructures in skin. We created a model containing curve pipes, whose diameter range from 0.05mm to 1mm in CAD software SolidWork 2010, and sliced it at the interval step of 0.05mm. As Fig.13 shows, using the images converted from the slices, we printed the vessel model with two different light-incurable inks that had high degree of similarity with vascular, which demonstrated the ability to print microchannel network.

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Fig.13. (1) The pipelines printed. (2) The phantom printed by 40 layers In this experiment, the phantoms printed were tested by the double integrating spheres system, and the Fig.14 shows the relationship between the absorption coefficient of phantoms printed and corresponding parameter M (the amount of black ink and M parameter linear correlation)of source files within a certain range. The Fig.9 shows the test results obtaining from the double integrating spheres system presented that

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Downloaded From: http://proceedings.spiedigitallibrary.org/ on 03/05/2016 Terms of Use: http://spiedigitallibrary.org/ss/TermsOfUse.aspx the parameter C (the amount of white ink and C parameter linear correlation) of the original pictures affect the absorption linearly within a certain range.

38.7773 0.12 (1) 40 (2) 35.148 .r 35 0.10 32.3031 30.3445 o E Zu 30 ac 0.08 V 125 25 Ñ 0.06 4,2020 V 8 i ep15 oc 0.04 C 10 á z 80.02 aV1 5 Q0.00 o I 4 8 8 e 18 20 23 2 4 6 8 10 12 III The parameters M of Pictures The parameters C of Pictures

Fig.14. (1) The absorption coefficient changes with the parameters of M corresponding to the black ink. (2) The Scattering coefficient changes with the parameters of C corresponding to the white ink.

4. CONCLUSIONS AND FUTURE WORK

In this study, we explored the technical feasibility of the FDM and PolyJet 3D printing process to fabricate multilayered heterogeneities phantoms that simulate the structural and optical properties of human tissues. First, the FDM system is composed of computer, a three dimensional mobile platform with nozzle integrated and a materials feeding system. And the experimental and simulating results show that: (1) the interference between the absorption and the scattering ingredients used in our FDM process is negligible; (2) the FDM process is able to duplicate the structural characteristics of a simplified human brain model with fidelity; (3) the FDM process is able to duplicate the optical characteristics of multilayered biologicalal tissue with fidelity. Second, The PolyJet 3D printing system for fabricating optical tissue phantoms consists of a computer, a 3D printer and a UV curing lamp system. The colorless light-curable ink, black light- curable ink and white light-curable inks were used as the matrix material, absorption material, and scattering material respectively. The linear correlation between the resultant optical properties and the corresponding source file parameters indicate the technical feasibility of changing phantom optical properties by varying the source files. We have successfully demonstrated the technical feasibilities of fabricating phantoms to simulate the morphologic, optical characteristics of tissue with FDM and PolyJet 3D printing methods. The tissue phantoms made by either FDM or PolyJet system have their own characteristics, however, no one can meet all of optical phantoms requirements, which brings about a lot of inconvenience in the applications, and hindered the standardization of tissue phantoms to a certain degree. So it is necessary to integrate two different phantom fabrication methods together, and we are designing a system that integrate different fabrication methods with self-calibration feature.

5. ACKOWLEDGEMENT

The work was supported by the National Natural Science Foundation of China (Grant Nos. 81327803 and 11002139 ) and the Fundamental Research Funds for the Central Universities.

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