- Technical note
- Open Access
Twinkling-guided ultrasound detection of polymethyl methacrylate as a potential breast biopsy marker: a comparative investigation
European Radiology Experimental volume 6, Article number: 26 (2022)
Since its first description 25 years ago, color Doppler twinkling has been a compelling ultrasound feature in diagnosing urinary stones. While the fundamental cause of twinkling remains elusive, the distinctive twinkling signature is diagnostically valuable in clinical practice. It can be inferred that if an entity twinkles, it empirically has certain physical features. This work investigates a manipulable polymeric material, polymethyl methacrylate (PMMA), which twinkles and has measurable surface roughness and porosity that likely contribute to twinkling. Comparative investigation of these structural properties and of the twinkling signatures of breast biopsy markers made from PMMA and selected commercially available markers showed how twinkling can improve ultrasound detection of devices intentionally designed to twinkle. While this specific application of detecting breast biopsy markers by twinkling may provide a way to approach an unmet need in the care of patients with breast cancer, this work ultimately provides a platform from which the keys to unlocking the fundamental physics of twinkling can be rigorously explored.
Surface roughness is associated with the color Doppler ultrasound twinkling phenomenon.
Polymethyl methacrylate is a manipulable material with measurable surface roughness and porosity.
Polymethyl methacrylate markers twinkle with multiple transducers using a range of ultrasound frequencies.
The twinkling artifact, described as a radiological sign, on color Doppler ultrasound [1, 2], is characterized by dynamic color fluctuations of adjacent pixels and is either empirically present or absent. Currently, there are no standards for optimizing ultrasound twinkling parameters or quantifying the twinkling signature in the clinical setting, and this is mainly because the mechanistic causes of ultrasound twinkling remain elusive. Surface roughness or irregularities and internal porosity of complicated objects have been described as contributors to the twinkling signature hypothesized to reflect phase-shift phenomena that arise in ultrasound wave propagation, interactions with bubbles or during cavitation [3,4,5,6,7,8]. In recent years, using fiducials detectable by ultrasound twinkling [9, 10] has gained some translation into the clinical setting despite not fully understanding the physics of twinkling or how to optimize the scanning parameters for generating twinkling. Seldom is clinical practice driven more by empiric evidence than by fundamental principles, but the success and inherent safety profile of color Doppler ultrasound satisfy the maxim “First, do no harm.”
Consequently, color Doppler ultrasound, which is generally not used in breast radiology could play a significant role  for example, when consistent and confident ultrasound detection of biopsy markers or clips is needed. Despite the availability of at least 38 commercial biopsy markers , ultrasound detection of these markers, particularly in treated metastatic axillary lymph nodes of patients with breast cancer, remains challenging and sometimes impossible approximately 25% of the time . Color Doppler ultrasound twinkling of markers could provide a novel and specific feature for detection. Some metallic markers demonstrate a twinkling signature [9, 14], and another marker based on microsphere technology  also twinkles. What remains incompletely understood is why and how some markers twinkle better than others. It can be inferred that if an entity twinkles, it empirically has certain physical features.
This work investigates a manipulable polymeric material, polymethyl methacrylate (PMMA)  that twinkles and has measurable surface roughness and porosity that likely contribute to twinkling. Comparative investigation of these structural properties and of the twinkling signatures of breast biopsy markers made from PMMA and selected commercially available markers shows how twinkling can improve ultrasound detection of breast biopsy markers and offer a way to approach an unmet need in the care of patients with breast cancer .
PMMA (Stryker Corporation, Howmedica®, Kalamazoo, MI, USA) mixed according to specifications on the package insert was made into a 1.3-mm diameter, 8-mm long cylindrical construct comparable in size to conventional biopsy markers by extruding the PMMA from a 15-gauge hole punched into the hub of a needle attached to a 3-cc syringe.
Based on earlier developed techniques , a non-contact three-dimensional (3D) coherence scanning interferometer optical profiler (Zygo Corporation, Middlefield, CT, USA) measured the areal surface roughness (Sa) of four commercial metallic breast biopsy markers: TriMark® cork (Hologic®, Marlborough, MA, USA), Tumark® Q (Hologic®), UltraClip™ ribbon (Becton, Dickinson & Co., Franklin Lakes, NJ, USA), and SenoMark™ O clip (Becton, Dickinson & Co.). Optical surface characterization to measure Sa was performed using a consistent magnification of × 20 for all markers. Overall shape and curvature of the markers were removed from the surface characterization using 4th order polynomial curve fitting of the optical measurement data .
Scanning electron microscopy (SEM) (Hitachi S-4700, Hitachi High-Tech in America, Schaumburg, IL, USA) images captured the surface irregularities of PMMA and the metallic biopsy markers. Porosity was determined using micro-computed tomography (SkyScan 1272, Bruker Corporation, Allentown, PA, USA) using provided computed tomography analyzer software (CTAn, Bruker Corporation) based on thresholding and regions of interest on 15-μm slice thicknesses .
Ultrasound of the four commercial markers and the PMMA marker was performed in a gel phantom and ex vivo in pork belly meat using a clinical system (Logiq E9, General Electric Healthcare, Wauwatosa, WI, USA) with 9-L and ML6-15 linear array transducers, both generally used in breast ultrasound, and a C1-6 curvilinear transducer typically used in abdominal ultrasound (General Electric Healthcare). To minimize experimental bias, the markers were placed at roughly the same depth between 1 and 2 cm deep and spaced minimally apart so that they could be scanned simultaneously. For the phantom study, two gel phantoms were stacked on top of each other to minimize backscatter from the tabletop.
Scanning parameters such as ultrasound transmit frequency, color scale, and gain were adjusted to optimize twinkling. For radiological assessment, a twinkling score was defined from 0 (least twinkling and least confident detection) to 4 (most twinkling and most confident detection) . In general, a twinkling score of 3 or 4 would provide sufficient confidence for a breast radiologist to place an 125I seed next to it for localization without definite visualization of the marker on B-mode imaging. A twinkling score of 2 and below would require additional imaging features or information before an 125I seed would be used to localize it.
The cork, ribbon, PMMA, O, and Q markers were identified in the phantom and ex vivo pork belly meat by B-mode imaging using the ML6-15 transducer. With color Doppler, a distinct twinkling signature (twinkling score ≥ 3) was noted for the cork, PMMA, and Q markers. Relative to the transducers, the twinkling signature in both the gel phantom and the pork belly meat was most pronounced (highest twinkling scores) with the C1-6 transducer (color transmit frequency 3.1 MHz in the gel phantom and 3.1 MHz in pork belly meat) followed by the 9L transducer (color transmit frequency 5.0 MHz in the gel phantom and 3.1 MHz in pork belly meat), and least with the ML6-15 transducer (color transmit frequency 6.3 MHz in both the gel phantom and pork belly meat). This relationship was particularly evident in the pork belly study. Twinkling signatures that scored a 4 were evident over a range of color frequency settings towards the lower end of the spectrum for each transducer (Fig. 1 and Supplemental Materials). The ribbon and the O markers exhibited no twinkling signature (twinkling score = 0) for all transducers and all parameter settings.
The Sa of the commercially available cork and the Q markers was high (2−10 μm) compared to the ribbon and the O markers (< 1 μm), consistent with previously published results . The Sa of the PMMA marker (5−6 μm) was between that of the cork and Q markers. SEM images capturing the surface irregularities of PMMA and the four metallic biopsy markers used in this study supported the Sa measurements. The color Doppler ultrasound twinkling signature was both present and comparable for the markers with high Sa (PMMA, cork, and Q markers) and essentially absent for markers with low Sa (ribbon and O markers) as shown in Figs. 2 and 3.
The mean porosity, as determined from micro-computed tomography, of six PMMA markers created for patient use was 66.6 ± 13.4% (mean ± standard deviation). The porosity of the cork marker (high Sa) was 60.6%. The porosities of essentially solid wire-based constructs such as the ribbon (low Sa) and the O (low Sa) markers were not measurable. The exception was the Q marker (high Sa) which had non-detectable porosity. Unlike Sa, the association between porosity and twinkling appears weaker, favoring surface roughness as a stronger contributor to twinkling (see Fig. 2).
After 25 years, the fundamental causes of twinkling on color Doppler ultrasound have yet to be determined. This work investigates a manipulable material that twinkles and has measurable surface roughness and porosity characteristics that provide a platform for exploring the association between measurable surface roughness and twinkling and for ultimately understanding the physics of twinkling. A “super twinkler” can conceivably be constructed based on macroscopic (tenths of mm) and microscopic (μm) surface roughness features, once the association between surface roughness and twinkling is better understood. Adding an ultrasound twinkling dimension to biopsy marker detection in the care of patients with breast cancer addresses a clinical need and is readily translatable to practice. By building a platform for defining what surface characteristics create and optimize twinkling, commercially available markers could be optimized to twinkle, and 3D printed makers could be made from material readily available and less expensive, such as PMMA.
Current hypotheses on the causes of twinkling have highlighted the presence of air bubbles that vibrate in response to ultrasound insonification and rough surfaces that cause rapid phase changes in the backscattered ultrasound [17,18,19]. This work does not confirm one hypothesis or the other, and both are supported by the surface roughness observations that we have described.
A twinkling signature associated with a biopsy marker has the potential to improve challenges breast radiologists face during preoperative localization of targets that have responded well to neoadjuvant therapy and are now radiologically normal or occult. While color Doppler ultrasound for detection of twinkling is not a standard part of breast radiology, it is readily available on nearly all cart-based and portable ultrasound vendor platforms. This technological development demonstrates how PMMA with measurable surface roughness features can provide a promising medium to better understand the underlying causes of the twinkling phenomenon on color Doppler ultrasound.
The limitations of using twinkling to detect breast biopsy markers include false-positive entities that twinkle. Sources of false-positive twinkling related to an application in breast radiology include blood flow, microcalcifications , calcifications, post-procedural changes with air within soft tissue, and other breast biopsy markers. Careful attention to clinical history and information provided from other imaging modalities can likely distinguish the sources of twinkling. Another limitation of this study is the use of equipment from a single ultrasound vendor. Given the prevalence of the twinkling artifact described on various vendors in the literature, this limitation can likely be readily addressed through vendor-specific equivalents.
Future work will involve creating biopsy markers that are “super twinklers” by refining their surface roughness. In so doing, the underlying causes of ultrasound twinkling may be better understood.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
- S a :
Areal surface roughness
Scanning electron microscopy
Rahmouni A, Bargoin R, Herment A, Bargoin N, Vasile N (1996) Color Doppler twinkling artifact in hyperechoic regions. Radiology 199:269–271. https://doi.org/10.1148/radiology.199.1.8633158
Lee JY, Kim SH, Cho JY, Han D (2001) Color and power Doppler twinkling artifacts from urinary stones: clinical observations and phantom studies. AJR Am J Roentgenol 176:1441–1445. https://doi.org/10.2214/ajr.176.6.1761441
Shang M, Sun X, Liu Q et al (2017) Quantitative evaluation of the effects of urinary stone composition and size on color Doppler twinkling artifact: a phantom study. J Ultrasound Med 36:733–740. https://doi.org/10.7863/ultra.16.01039
Simon JC, Sapozhnikov OA, Kreider W, Breshock M, Williams JC, Bailey MR (2018) The role of trapped bubbles in kidney stone detection with the color Doppler ultrasound twinkling artifact. Phys Med Biol 63:025011. https://doi.org/10.1088/1361-6560/aa9a2f
Wang M, Li J, Xiao J, Shi D, Zhang K (2011) Systematic analysis of factors related to display of the twinkling artifact by a phantom: an optimized investigation. J Ultrasound Med 30:1449–1457. https://doi.org/10.7863/jum.2011.30.11.1449
Wood BG, Urban MW (2020) Detecting kidney stones using twinkling artifacts: survey of kidney stones with varying composition and size. Ultrasound Med Biol 46:156–166. https://doi.org/10.1016/j.ultrasmedbio.2019.09.008
Jamzad A, Setarehdan SK (2014) A novel approach for quantification and analysis of the color Doppler twinkling artifact with application in noninvasive surface roughness characterization: an in vitro phantom study. J. Ultrasound Med 33:597–610. https://doi.org/10.7863/ultra.33.4.597
Jamzad A, Setarehdan SK (2018) Noninvasive prediction of renal stone surface irregularities by numerical analysis of the color Doppler twinkling artifact: an ex vivo study. J. Ultrasound Med 37:1211–1224. https://doi.org/10.1002/jum.14465
Tan MP, Bi Z, Ong EMW (2020) The 'twinkle' artifact - a novel method of clip identification to facilitate targeted axillary surgery following neoadjuvant chemotherapy in breast cancer patients. Clin Imaging 68:36–44. https://doi.org/10.1016/j.clinimag.2020.06.009
Voss RK, Ward EP, Ojeda-Fournier H, Blair SL (2018) Doppler ultrasound-visible SignalMark microspheres are better identified than HydroMARK(®) clips in a simulated intraoperative setting in breast and lung tissue. Ann Surg Oncol 25:3740–3746. https://doi.org/10.1245/s10434-018-6707-z
Madjar H (2010) Role of breast ultrasound for the detection and differentiation of breast lesions. Breast Care (Basel) 5: 109-114. 10.1159%2F000297775
Portnow LH, Thornton CM, Milch HS, Mango VL, Morris EA, Saphier NB (2019) Biopsy marker standardization: what's in a name? AJR Am J Roentgenol 212:1–6. https://doi.org/10.2214/ajr.18.20577
Portnow LH, Kwak E, Senapati GM, Kwait DC, Denison CM, Giess CS (2020) Ultrasound visibility of select breast biopsy markers for targeted axillary node localization following neoadjuvant treatment: simulation using animal tissue models. Breast Cancer Res Treat 184:185–192. https://doi.org/10.1007/s10549-020-05840-x
Lee CU, Hesley GK, Uthamaraj S, Larson NB, Greenleaf JF, Urban MW (2021) Using ultrasound color Doppler twinkling to identify biopsy markers in the breast and axilla. Ultrasound Med Biol 47:3122–3134. https://doi.org/10.1016/j.ultrasmedbio.2021.04.018
Frazer RQ, Byron RT, Osborne PB, West KP (2005) PMMA: an essential material in medicine and dentistry. J Long Term Eff Med Implants 15:629–639. https://doi.org/10.1615/jlongtermeffmedimplants.v15.i6.60
Ahmad Fadzil MH, Prakasa E, Asirvadam VS, Nugroho H, Affandi AM, Hussein SH (2013) 3D surface roughness measurement for scaliness scoring of psoriasis lesions. Comput Biol Med 43:1987–2000. https://doi.org/10.1016/j.compbiomed.2013.08.009
Rokni E, Zinck S, Simon JC (2021) Evaluation of stone features that cause the color Doppler ultrasound twinkling artifact. Ultrasound Med Biol 47:1310–1318. https://doi.org/10.1016/j.ultrasmedbio.2021.01.016
Kang J, Han K, Kim KS, Jang WS, Kim MJ, Yoo Y (2020) 3D microcalcification detection using a color Doppler twinkling artifact with optimized transmit conditions: preliminary results. Med Phys 47:6171–6178. https://doi.org/10.1002/mp.14342
Lu W, Sapozhnikov OA, Bailey MR, Kaczkowski PJ, Crum LA (2013) Evidence for trapped surface bubbles as the cause for the twinkling artifact in ultrasound imaging. Ultrasound Med Biol 39:1026–1038. https://doi.org/10.1016/j.ultrasmedbio.2013.01.011
Relea A, Alonso JA, González M et al (2018) Usefulness of the twinkling artifact on Doppler ultrasound for the detection of breast microcalcifications. Radiologia (Engl Ed) 60:413–423. https://doi.org/10.1016/j.rx.2018.04.004
We thank Jon Charlesworth for SEM data, Brian Waletzki for micro-CT data, and Lauren Muraco for photography.
This investigation was supported in part by funding from the Center for Individualized Medicine (CIM).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lee, C.U., Urban, M.W., Lee Miller, A. et al. Twinkling-guided ultrasound detection of polymethyl methacrylate as a potential breast biopsy marker: a comparative investigation. Eur Radiol Exp 6, 26 (2022). https://doi.org/10.1186/s41747-022-00283-z
- Polymethyl methacrylate
- Surface properties