1. bookVolume 66 (2021): Issue 2 (June 2021)
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Design and fabrication of 125I seeds for brachytherapy using capillary-based microfluidic technique

Published Online: 08 Jun 2021
Page range: 55 - 60
Received: 01 Mar 2020
Accepted: 07 May 2020
Journal Details
License
Format
Journal
First Published
25 Mar 2014
Publication timeframe
4 times per year
Languages
English
Abstract

A new kind of 125I seeds with a core-shell structure were synthesized by an easy assembling–disassembling coaxial capillaries microfluidic device. The dose distribution of a 125I brachytherapy source fabricated by arranging six 125I seeds collinearly within a cylindrical titanium capsule was simulated by modelling the source in a water phantom using Monte Carlo N-Particle Transport code. The influence of the motion and the core size of the 125I seeds on the dose distribution was also studied in this work.

Keywords

Introduction

Iodine-125 is a widely used interstitial brachytherapy source employed in the treatment of cancer, especially in eye cancer and prostate cancer treatment [1]. Its radiation characteristics including the 27–32 keV X-ray and 35 keV γ-ray, with a comparatively long half-life (about 60 days) guarantee 125I a recognized status in the radiation therapy modality through interstitial implantation [2]. Currently, the preparations of these implantation sources provided by commercial manufacturers mainly focus on the adsorption of 125I on matrices made of palladium wires, ceramic beads, ion exchange resins, etc. [3, 4, 5]. However, due to the Intellectual Property Rights concerns and the commercial interests, little information about these techniques has been disclosed in the literature. In Majali et al. [6], an approach for the adsorption of 125I on palladium coated sliver wire sealed in titanium capsule as interstitial brachytherapy source was studied. And in the work of Song et al. [4], the optimized experimental conditions were given, which increased the adsorption efficiency of 125I up to 92%. In recent years, Dash et al. [5] came up with a newly designed 125I brachytherapy source, consisted of six 125I-absorbed palladium coated sliver spheres arranged collinearly within a cylindrical titanium capsule. Although the methods of 125I adsorption can assist in the fabrication of a stable and effective 125I brachytherapy source, problems exist mainly in the fluctuation of the total dose and the dose distribution of 125I of different design associated with the sensitivity of the absorption procedure. Therefore, the main aspect of our research effort is to find a more accurate and stable fabrication method.

In this work, to fabricate a new category of 125I brachytherapy source with required properties such as the dosimetric accuracy and the dosage-uniformity, the 125I seeds with a core-shell structure were synthesized by a newly developed microfluidic device with two coaxial capillaries [7]. The core material is sodium iodine solution containing 125I and the shell material is tri(propylene glycol) diacrylate (TPGDA) with photosensitizer. During micro-fluidic and core-shell structure droplets formation processes, the diameters of cores and shells can be precisely controlled at a range of 100–500 μm and at 600 μm, respectively, by adjusting the flow rates [8]. During ultraviolet curing process, the shell phase of core-shell structure droplets is solidified by ultraviolet irradiation, which forms core-shell structure particles and that liquid cores containing 125I are enclosed by solidified poly(tri(propylene glycol) diacrylate) (PTPGDA) shells (this particle hereinafter 125I seed or seed). Then, a couple of 125I seeds are arranged collinearly within a cylindrical titanium capsule (hereinafter 125I brachytherapy source). By this means, the dose of 125I in each 125I seed can be controlled precisely, and the nonuniform dose distribution as a result of the existence of dose gradient during the adsorption process could be eliminated. In addition, it is relatively convenient for physicians to alter the radiological dose by adding or reducing the number of 125I seeds, or by changing the volume of the core. Also, the efficiency of 125I could be raised to nearly 100%. Here, the dose distribution of this new 125I brachytherapy source was simulated by Monte Carlo modelling, and, the influences of the motion of 125I seeds motion within the titanium capsule and the size of core phase on the dose distribution were studied to a greater extent [9, 10].

Materials and methods
Coaxial capillaries microfluidic device

The experimental facilities includes capillaries with hydrophilic (fused silica tubing, Polymicro Technologies, INNOSEP Company, Zheng-Zhou, China) or hydrophobic (PEEK or PTFE tubings, Upchurch Scientific, INNOSEP Company, Zheng-Zhou, China) inner walls, gas-tight syringes, syringe pumps (PHD 2000, Harvard Apparatus), tubings (Polytetrafluoroethylene, Fisher Scientific Bioblock), T-junctions (P-728-01, Upchurch Scientific), line junction, and UV light (Lightning-cure LC8, Hamamatsu), as shown in Fig. 1. Two coaxial capillaries were inserted inside T-junction 1 along its main axis. The coaxial capillaries’ tips exit the T-junction 2 at the center of an outlet PTFE tubing.

Fig. 1

Schematic drawing of capillary-based microfluidic device for synthesis of core-shell microspheres. Inner/outer diameter of the outside capillary (1) is 255 μm/510 μm, and inner/outer diameter of the inner capillary (2) is 100 μm/167 μm.

Materials

There are two types of disperse phase and one type of continuous phase which are mutually immiscible. Simethicone was used in continuous phase, and one of the disperse phase termed as the shell phase used TPGDA (Aldrich), 96 wt%: 1-hydroxycyclohexyl phenyl ketone (HCPK) as photoinitiator (Aldrich), 4 wt% [11]. The encapsulated phase used the core of the droplets consisted of sodium iodide solution (8 wt%) containing radioactive 125I (5 mCi). The mass densities of titanium, TPGDA, and dry air were 4.50, 1.03, and 1.20 × 10−3g/cm3, respectively, and air composition by mass of nitrogen, oxygen, argon, and carbon, was 75.520, 23.176, 1.288, and 0.016%, respectively, were used for computational purposes [12]. Water consisted of two parts hydrogen, one part oxygen, with a mass density of 0.998 g/cm3.

Characterization

An optical microscope (XSP-30E, Shanghai Halibut Instrument Limited Company, China) equipped with a charge-coupled device (CCD) camera (uEye, UI-2220SE, IDS) was used to observe the formation of the core-shell structure droplets directly. The camera captures up to 52 ftps at a full resolution of 768 pixels × 576 pixels. Then during the flowing in the tube, droplets were polymerized under the explosion of UV irradiation by means of an UV source operating at λ = 365 nm online. The overall diameter and the core diameter of the 125I seed were measured with an image analysis software (uEye Cockpit) operating the CCD camera. The dosimetry parameters of the new source were calculated by Version 5 of Monte Carlo N-Particle Transport (MCNP5) code. The results of the tally were fed to a plotting software, SURFER 11.0, used to construct the isodose curves against dose values calculated above.

Results and discussion
Fabrication of 125I seeds for 125I brachytherapy source

For the preparation of 125I seeds, core-shell structure droplets are produced first. A flexible coaxial capillaries microfluidic device was designed by us to produce core-shell droplets consisted of liquid core surrounded by a layer of TPGDA. The main part or element of the liquid core was sodium iodide solution containing radioactive 125I. As shown in Fig. 2b, sodium iodide solution and TPGDA were delivered by the inner capillary and the outside capillary, respectively, with the inner one was fixed inside of the outside one. Q1, Q2, and Q3 were the flow rates of continuous phase, shell phase, and core phase, respectively. The reaction between surface tension and shear force in the shell phase caused the formation of core droplets [13], at the tip of the inner capillary. Subsequently, shell phase generated at the end of the outside capillary due to the shear force of continuous phase happened between the outside capillary and the PTFE tubing. As a result, the core phase was encapsulated in the shell material, and the core-shell structure droplet was fabricated. Then, the TPGDA shell was polymerized downstream by photo-induced polymerization to form the seeds with a 125I core-PTPGDA shell structure. Polyacrylate possesses an as-desired radiation resistance. Researches of poly(tert-butyl acrylate) (PTBA) radiation resistance indicated that the thickness of irradiation-damaged polyacrylate file was about 0.1 Å after 1 minute irradiation under 9.659 keV photons at a flux density of 0.4 × 109 photons/(s·mm2) [14]. For a 0.5 mCi as-prepared 125I seed, it was estimated that the thickness of irradiation-damaged PTPGDA shell would be <1 μm after a year, which assured that TPGDA was a competent material for the shell of the 125I seed.

Fig. 2

(a1–a3) Formation of core-shell structure droplet, Q1 = 120 μL/min, Q2 = 3.75 μL/min, Q3 = 0.25 μL/min; (b) optical image of as-prepared 125I seeds.

The droplet formation from two continuous flowing liquids was achieved through either dripping or jetting mode [15], and the key parameters for mastering the droplet formation mode are the flow rates of the continuous and dispersed phase. In this work, by adjusting the fluid flow rate, the droplets were formed in the dripping mode which ensured the formation of highly monodisperse core-shell structure droplets [16]. The formation of the core-shell structure droplet and the as-prepared 125I seeds with uniform core size and overall seed size were shown in Fig. 2.

Control of 125I contents in a 125I seed

For the treatment of different tumour sites, a source with various radiation doses for brachytherapy is required. The dose delivered by as-prepared 125I brachytherapy source is controlled by the dosage of 125I in each 125I seed and the number of the seeds sealed in the titanium capsule. Because of the limitation on the length of the source in practical utilization, controlling the content of 125I in each seed precisely to meet the radiation dose requirements has to be approached realistically. The 125I content of each seed is related to the 125I concentration in feed solution of the core and the core size of as-designed seed. By keeping size of the core droplet constant, it is easy to understand that the proportional increase of radiation dose rate of the seeds with the increase of the 125I concentration in core feed solution. While keeping the concentration of 125I in core feed solution fixed, the content of 125I in each seed can be controlled by changing the size of core droplet, and increases as the core size increases. In our previous work, the control of overall core-shell structure’s droplet size, core size, and shell size were studied in detail by adjusting the flow rates of different phase in the coaxial capillary microfluidic device and the relationship between core size and flow rate of the related fluids can be described by the formula: rcore=Q3Q2+Q3ε×rseed{r_{{\rm{core}}}} = \root \varepsilon \of {{{{Q_3}} \over {{Q_2} + {Q_3}}}} \times {r_{{\rm{seed}}}} where rcore and rseed, are the diameter of the core droplet and the seed, respectively, whereas Q2 and Q3 are the flow rate of the shell phase and the core phase, respectively. In the experiments, the precise control of core size can be achieved by adjusting flow rate of core and shell phase. Also, the size-designated overall core-shell structure droplet can also be obtained by changing the flow rate of core, shell, and continuous phase, respectively. The shell phase of the core-shell structure droplets were subsequently polymerized while flowing in the tubing under ultraviolet irradiation, and 125I seeds were fabricated finally. The as-prepared seeds with the same overall size but with different core sizes were shown in Fig. 3 and were of narrow size distribution of the cores and seeds, which were beneficial in keeping the same dose rate of the seeds. If a reduction in PTPGDA shell thickness by less than 10% is considered and still to ensure that the 125I-containing solution was not leaked during a half-life period of 125I (about 60 days), a single 125I seed with the maximum radioactivity 49 mCi, with core diameter of 500 μm and shell thickness of 50 μm, calculated based on the radiation resistance of acrylate was used.

Fig. 3

Optical images of 125I seeds with a various core diameter and the same overall diameter of 600 μm. (a) Core diameter of 400 μm, Q1 = 120 μL/min, Q2 = 3 μL/min, Q3 = 1 μL/min, the radioactivity of a single 125I-encapsulated microsphere was about 0.17 mCi; (b) core diameter of 200 μm, Q1 = 120 μL/min, Q2 = 3.83 μL/min, Q3 = 0.17 μL/min, the radioactivity of a single 125I-encapsulated microsphere was about 0.02 mCi.

Dose distribution of the new 125I brachytherapy source

A structured source with a titanium capsule size of 800 μm outer diameter, 700 μm inner diameter, and 4 mm length was used in clinical medicine conventionally and the capsules filled with six as-prepared seeds of 600 μm diameter (shown in Fig. 4) were used for an evaluation of its dose distribution, and the dosimetry parameters of the source were calculated by MCNP5 code [17]. The simulation considered a spherical water phantom and the dose values in water were calculated at radial distances of 0–2 cm. The DLC-189 cross section was used for transport calculations and the Integrated TIGER Series (ITS) three-dimensional (3D) code system was used for coupled photon–electron transport. In order to determine relevant dose distribution accurately, different size of voxel computational cells were placed in select positions. The total number of photons transported per calculation run was 109 with statistical uncertainties below 3.6%. A plotting software, SURFER 11.0 was used to construct the isodose curves.

Fig. 4

Isodose curves of the 125I brachytherapy sources with different orientation of cores in the sources. Overall diameter of the 125I seeds was 600 μm, and core diameter was 300 μm. (a) Each seed of core and shell is of homocentricity. (b–d) Each seed of core and shell was of nonhomocentricity.

If the core and shell of each seed have concentricity, a 125I brachytherapy source containing six seeds that lined the capsule appears to have an ellipsoid-like uniform dose distribution, as shown in Fig. 4a. In fact, it is difficult to synthesize a homocentric seed in the microfluidic system since the core droplet is free to move in the double droplet before polymerization of the seed shell, which will induce nonuniform distribution of the dose.

The core center usually deviates from the seed center in microfluidic fabrication of the seed with a core-shell structure. The maximum deviation of the core center from shell center, in that the core tangent to surface of the seed, was modelled for exploring the influence of the core position on dose distribution of the source. The position of six cores was described by setting x, y coordinates in xy plane. Obviously, the more deviation of the core center from the seed center is, the less uniform dose distribution of the source exists. For a size- and position-confined seed in the capsule, the increase in the core size decreases the deviation of core center from its ideal center and more uniform dose distribution of the 125I brachytherapy source was produced. The model of the core orientation in the source was randomly selected, as shown in Fig. 4b–d, to illustrate the influences of the core position on the dose distribution of the 125I brachytherapy source.

The isodose curves of cores with diameter of 150, 300, 400, and 500 μm constructed by SURFER 11.0 were shown in Fig. 5, respectively, and found that when the diameter of core was 150 μm, the dose distribution had a less uniformity within ±5 mm in x axis, but beyond ±5 mm, the dose distribution was uniform. When core size was increased from 150 μm to 400 μm, the uniform dose distribution within ±5 mm was improved, but was still nonuniform. But with core size 500 μm, the dose distribution of the 125I brachytherapy source was close to the ideal model.

Fig. 5

Isodose curves of the 125I brachytherapy sources with different core size under the same orientation in the source. Each seed diameter was 600 μm, and core diameter was (a) 150 μm, (b) 300 μm, (c) 400 μm, and (d) 500 μm.

By keeping the core diameter of 500 μm, the dose distribution of other modelled sources with a different orientation of the cores was also computed, as shown in Fig. 6. The results indicated that the dose distribution of the 125I brachytherapy sources with various orientations of the cores exhibited negligible differences or variations and so we can conclude that all of them were uniform even within ±5 mm in x axis and y axis. Therefore, the 125I seeds with a core size of 500 μm and seed size of 600 μm were designed and fabricated. Additionally, an inactive dummy 125I brachytherapy source was fabricated by encapsulating six as-prepared 125I seeds in a glass tube with the size of 600 μm/850 μm inside/outside diameter (ID/OD), as shown in Fig. 7.

Fig. 6

Isodose curves of the 125I brachytherapy sources with a different orientation of the cores. Overall diameter of the 125I seeds was 600 μm, and the diameter of core was 500 μm.

Fig. 7

Optical image of a 125I brachytherapy source consisted of six 125I seeds within a glass tubing. The overall diameter of the seeds was 600 μm, and the diameter of core was 500 μm.

Conclusions

A new 125I seeds with core-shell structure for 125I brachytherapy source was fabricated in a capillary-based microfluidic device. In comparison with the conventional adsorption methods for the fabrication of 125I seed, an encapsulating approach provided a precise load of the quantity-demanded 125I in a seed with a close to 100% of encapsulation efficiency. The 125I seed and its core size can be controlled by simply adjusting the flow rates of the fluids in the microfluidic system. The dose distribution of the 125I brachytherapy source consisted of the as-prepared seeds and titanium capsule was calculated by MCNP5, and the results showed that the nonuniformity of the dose distribution induced by the deviation of the core from the center of the whole seed could be eliminated by increasing the core size for a size-prescribed capsule.

Fig. 1

Schematic drawing of capillary-based microfluidic device for synthesis of core-shell microspheres. Inner/outer diameter of the outside capillary (1) is 255 μm/510 μm, and inner/outer diameter of the inner capillary (2) is 100 μm/167 μm.
Schematic drawing of capillary-based microfluidic device for synthesis of core-shell microspheres. Inner/outer diameter of the outside capillary (1) is 255 μm/510 μm, and inner/outer diameter of the inner capillary (2) is 100 μm/167 μm.

Fig. 2

(a1–a3) Formation of core-shell structure droplet, Q1 = 120 μL/min, Q2 = 3.75 μL/min, Q3 = 0.25 μL/min; (b) optical image of as-prepared 125I seeds.
(a1–a3) Formation of core-shell structure droplet, Q1 = 120 μL/min, Q2 = 3.75 μL/min, Q3 = 0.25 μL/min; (b) optical image of as-prepared 125I seeds.

Fig. 3

Optical images of 125I seeds with a various core diameter and the same overall diameter of 600 μm. (a) Core diameter of 400 μm, Q1 = 120 μL/min, Q2 = 3 μL/min, Q3 = 1 μL/min, the radioactivity of a single 125I-encapsulated microsphere was about 0.17 mCi; (b) core diameter of 200 μm, Q1 = 120 μL/min, Q2 = 3.83 μL/min, Q3 = 0.17 μL/min, the radioactivity of a single 125I-encapsulated microsphere was about 0.02 mCi.
Optical images of 125I seeds with a various core diameter and the same overall diameter of 600 μm. (a) Core diameter of 400 μm, Q1 = 120 μL/min, Q2 = 3 μL/min, Q3 = 1 μL/min, the radioactivity of a single 125I-encapsulated microsphere was about 0.17 mCi; (b) core diameter of 200 μm, Q1 = 120 μL/min, Q2 = 3.83 μL/min, Q3 = 0.17 μL/min, the radioactivity of a single 125I-encapsulated microsphere was about 0.02 mCi.

Fig. 4

Isodose curves of the 125I brachytherapy sources with different orientation of cores in the sources. Overall diameter of the 125I seeds was 600 μm, and core diameter was 300 μm. (a) Each seed of core and shell is of homocentricity. (b–d) Each seed of core and shell was of nonhomocentricity.
Isodose curves of the 125I brachytherapy sources with different orientation of cores in the sources. Overall diameter of the 125I seeds was 600 μm, and core diameter was 300 μm. (a) Each seed of core and shell is of homocentricity. (b–d) Each seed of core and shell was of nonhomocentricity.

Fig. 5

Isodose curves of the 125I brachytherapy sources with different core size under the same orientation in the source. Each seed diameter was 600 μm, and core diameter was (a) 150 μm, (b) 300 μm, (c) 400 μm, and (d) 500 μm.
Isodose curves of the 125I brachytherapy sources with different core size under the same orientation in the source. Each seed diameter was 600 μm, and core diameter was (a) 150 μm, (b) 300 μm, (c) 400 μm, and (d) 500 μm.

Fig. 6

Isodose curves of the 125I brachytherapy sources with a different orientation of the cores. Overall diameter of the 125I seeds was 600 μm, and the diameter of core was 500 μm.
Isodose curves of the 125I brachytherapy sources with a different orientation of the cores. Overall diameter of the 125I seeds was 600 μm, and the diameter of core was 500 μm.

Fig. 7

Optical image of a 125I brachytherapy source consisted of six 125I seeds within a glass tubing. The overall diameter of the seeds was 600 μm, and the diameter of core was 500 μm.
Optical image of a 125I brachytherapy source consisted of six 125I seeds within a glass tubing. The overall diameter of the seeds was 600 μm, and the diameter of core was 500 μm.

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