title: Preclinical investigation for developing injectable fiducial markers using a mixture of BaSO4 and biodegradable polymer for proton therapy.
abstract: OBJECTIVE
  The aim of this study is to investigate the use of mixture of BaSO4 and biodegradable polymer as an injectable nonmetallic fiducial marker to reduce artifacts in x-ray images, decrease the absorbed dose distortion in proton therapy, and replace permanent metal markers.
  
  
  METHODS
  Two samples were made with 90 wt. % polymer phosphate buffer saline (PBS) and 10 wt. % BaSO4 (B1) or 20 wt. % BaSO4 (B2). Two animal models (mice and rats) were used. To test the injectability and in vivo gelation, a volume of 200 μl at a pH 5.8 were injected into the Sprague-Dawley rats. After sacrificing the rats over time, the authors checked the gel morphology. Detectability of the markers in the x-ray images was tested for two sizes (diameters of 1 and 2 mm) for B1 and B2. Four samples were injected into BALB/C mice. The polymer mixed with BaSO4 transform from SOL at 20 °C with a pH of 6.0 to GEL in the living body at 37 °C with a pH of 7.4, so the size of the fiducial marker could be controlled by adjusting the injected volume. The detectability of the BaSO4 marker was measured in x-ray images of cone beam CT (CBCT), on-board imager [anterior-posterior (AP), lateral], and fluoroscopy (AP, lateral) using a Novalis-TX (Varian Medical Systems, Palo Alto, CA) repeatedly over 4 months. The volume, HU, and artifacts for the markers were measured in the CBCT images. Artifacts were compared to those of gold marker by analyzing the HU distribution. The dose distortion in proton therapy was computed by using a Monte Carlo (MC) code. A cylindrical shaped marker (diameter: 1 or 2 mm, length: 3 mm) made of gold, stainless-steel [304], titanium, and 20 wt. % BaSO4 was positioned at the center of the spread-out Bragg peak (SOBP) in parallel or perpendicular to the beam entrance. The dose distortion was measured on the depth dose profile across the markers.
  
  
  RESULTS
  Transformation to GEL and the biodegradation were verified. All BaSO4 markers could be detected in the CBCT. In the OBI and fluoroscopy images, all markers visible in the AP, but only B2(2 mm) could be identified in the lateral images. Changes of BaSO4 position were not detected in vivo (mice). The volume of the markers decreased by up to 65% and the HU increased by 22%, on average. The mean HU values around the B1, B2, and gold markers were 121.30 [standard deviation (SD): 54.86], 126.31 (SD: 62.13), and 1070.7 (SD: 235.16), respectively. The MC-simulated dose distortion for the BaSO4 markers was less than that of the commercially used markers. The dose reduction due to the gold marker was largest (15.05%) followed by stainless steel (7.92%) and titanium (6.92%). Dose reduction by B2 (2 mm) was 4.75% and 0.53% in parallel and perpendicular orientations, respectively.
  
  
  CONCLUSIONS
  BaSO4 mixed with PBS is a good contrast agent in biodegradable polymer marker because of minimal artifacts in x-ray images and minimal dose reduction in proton therapy. The flexibility of the size is considered to be an advantage of this material over solid type fiducials.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 135-710, Korea.
authors.forename: Sang Hee
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Sungkyunkwan University School of Chemical Engineering, Suwon 440-746, Korea.
authors.forename: Moon Soo
authors.initials: MS
authors.lastname: Gil
authors.affiliation: Sungkyunkwan University School of Chemical Engineering, Suwon 440-746, Korea.
authors.forename: Doo Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Youngyih
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Sohn
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Seoul 135-710, Korea.
authors.forename: Hye Yeong
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Seoul 135-710, Korea.
authors.forename: Eun Hyuk
authors.initials: EH
authors.lastname: Shin
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Jeong Il
authors.initials: JI
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Noh
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Jun Sang
authors.initials: JS
authors.lastname: Cho
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Doo Ho
authors.initials: DH
authors.lastname: Choi
mesh_terms: D000818:Animals; D016477:Artifacts; D001466:Barium Sulfate; D063566:Biodegradable Plastics; D003198:Computer Simulation; D054893:Cone-Beam Computed Tomography / Q000295:instrumentation / Q000379:methods; D057918:Fiducial Markers; D005471:Fluoroscopy / Q000295:instrumentation / Q000379:methods; D005782:Gels; D017612:Gold Compounds; D006863:Hydrogen-Ion Concentration; D008297:Male; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009010:Monte Carlo Method; D019047:Phantoms, Imaging; D011108:Polymers; D061766:Proton Therapy / Q000379:methods*; D011829:Radiation Dosage; D017207:Rats, Sprague-Dawley; D013193:Stainless Steel; D014025:Titanium
chemical_list: D063566:Biodegradable Plastics; D005782:Gels; D017612:Gold Compounds; D011108:Polymers; D013193:Stainless Steel; D001466:Barium Sulfate; D014025:Titanium