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UC Irvine UC Irvine Previously Published Works Title Laser brain cancer surgery in a xenograft model guided by optical coherence tomography. Permalink https://escholarship.org/uc/item/9hn478d1 Journal Theranostics, 9(12) ISSN 1838-7640 Authors Katta, Nitesh Estrada, Arnold D McElroy, Austin B et al. Publication Date 2019 DOI 10.7150/thno.31811 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Theranostics 2019, Vol. 9, Issue 12 3555 Ivyspring International Publisher Theranostics 2019; 9(12): 3555-3564. doi: 10.7150/thno.31811 Research Paper Laser brain cancer surgery in a xenograft model guided by optical coherence tomography Nitesh Katta1, Arnold D Estrada1, Austin B McElroy1, Aleksandra Gruslova2, Meagan Oglesby2, Andrew G Cabe2, Marc D Feldman2, RY Declan Fleming1, Andrew J Brenner2, and Thomas E Milner1 1. University of Texas at Austin 2. University of Texas Health Science Center at San Antonio Corresponding author: [email protected]. © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.11.26; Accepted: 2019.04.24; Published: 2019.05.26 Abstract Higher precision surgical devices are needed for tumor resections near critical brain structures. The goal of this study is to demonstrate feasibility of a system capable of precise and bloodless tumor ablation. An image-guided laser surgical system is presented for excision of brain tumors in vivo in a murine xenograft model. The system combines optical coherence tomography (OCT) guidance with surgical lasers for high-precision tumor ablation (Er:YAG) and microcirculation coagulation (Thulium (Tm) fiber laser). Methods: A fluorescent human glioblastoma cell line was injected into mice and allowed to grow four weeks. Craniotomies were performed and tumors were imaged with confocal fluorescence microscopy. The mice were subsequently OCT imaged prior, during and after laser coagulation and/or ablation. The prior OCT images were used to compute three-dimensional tumor margin and angiography images, which guided the coagulation and ablation steps. Histology of the treated regions was then compared to post-treatment OCT images. Results: Tumor sizing based on OCT margin detection matched histology to within experimental error. Although fluorescence microscopy imaging showed the tumors were collocated with OCT imaging, margin assessment using confocal microscopy failed to see the extent of the tumor beyond ~ 250 µm in depth, as verified by OCT and histology. The two-laser approach to surgery utilizing Tm wavelength for coagulation and Er:YAG for ablation yielded bloodless resection of tumor regions with minimal residual damage as seen in histology. Conclusion: Precise and bloodless tumor resection under OCT image guidance is demonstrated in the murine xenograft brain cancer model. Tumor margins and vasculature are accurately made visible without need for exogenous contrast agents. Key words: Optical Coherence Tomography, laser ablation, image-guided surgery, brain cancer Introduction Considering the critical significance of cell-sized limitations. brain structures, a need exists for surgical tools and OCT is a label-free, three-dimensional imaging procedures that provide sub-millimeter imaging and modality that allows for visualization of intrinsic cutting during intracranial tumor removal. Factors optical scattering properties of tissue [9–11]. OCT has that currently limit surgical practice include relatively a tissue penetration depth of 2 mm with cellular-level large non-specific damage footprints and a lack of depth resolution (5-10 µm). Swept-source OCT intraoperative, depth-resolved image guidance with systems, coupled with GPU data processing, are micron-level resolution. Recent advances in optical capable of displaying tomograms (10-20 mm3) in tomographic imaging [1–5] and fiber laser technology seconds [12, 13], providing a quasi-real-time, [6–8] can improve surgical access and precision with intraoperative imaging tool. OCT has been devices that address both imaging and cutting demonstrated as an effective high-resolution, http://www.thno.org Theranostics 2019, Vol. 9, Issue 12 3556 intra-vital imaging tool applied to excised human requirements of precise ablation and coagulation of in tissue samples and in vivo pre-clinical models [5, 14, vivo cerebral microcirculation. The absorption depth 15]. In addition to standard structural images, by of Tm laser light in tissue (125 µm) can coagulate the recording temporal tissue scattering changes, OCT majority of murine brain blood vessels [14] while still can display high-resolution and high-contrast providing a tight non-specific thermal damage angiography images without exogenous contrast margin [28, 33]. agents [14, 16–19]. Furthermore, by characterizing The combination of OCT imaging, Tm optical attenuation, texture or birefringence, OCT has coagulation and Er:YAG laser ablation can improve successfully imaged tumor margins in excised human surgeries by removing brain tumors while sparing brain cancer specimens as well as in live xenograft adjacent normal structures, and preventing bleeding mouse models without exogenous contrast agents [4, that can obscure the operative field. OCT image 5, 20–24]. The combination of high-speed angiography guidance can not only allow for tumor visualization and tumor margin detection make OCT a leading [9–11, 34], but also provide angiography [14, 16–18, candidate imaging modality for intraoperative 35] and tumor margin location [5, 12, 14, 21–24, 36, 37] surgical guidance during resection. The high spatial to the neurosurgeon. In addition to positional resolution and speed of OCT can provide guidance before ablation, real-time OCT imaging of neurosurgeons a detailed moment-by-moment tissue response during ablation can allow radiant tomographic image during tumor excision. Such energy titration to minimize non-specific brain real-time guidance may be complementary to more damage. We present a feasibility study demonstrating conventional intraoperative imaging platforms such capabilities of an image-guided surgical system in an as magnetic resonance imaging (MRI) and X-Ray in vivo brain cancer xenograft murine model for computed tomography (CT), whose limited resolution resecting tumors that provides label-free imaging of and slow image acquisition times prevent vasculature and margins and can guide precise visualization of small changes in tissue shape and coagulation and bloodless tumor resection. position that occur during tumor excision. Although precision of conventional surgical Methods procedures that rely on electrocautery for coagulation A benchtop OCT-guided laser surgical system and hemostasis has improved over the last decades was utilized to image and then remove brain tumors [25, 26], collateral damage zones as large as a few from a xenograft murine cancer model. Brain tumors millimeters are common. Laser-based surgical and the surrounding vasculature were first imaged methods potentially offer many improvements over using a commercial fluorescent microscope and then the existing art for precise ablation and blood vessel by a custom benchtop OCT imaging system. After coagulation. Specifically, infrared laser sources allow tumor pre-imaging, vasculature was coagulated and for fiber-delivery, high rates of tissue removal and are brain tumors were laser-ablated under OCT guidance. decreasing in cost. Because emission wavelength (2.94 µm) of Er:YAG laser radiation coincides with a peak In vivo brain cancer model in water absorption [27], tumor ablation is highly Human glioma tumor cells (U251-luc-RFP) were energy efficient [28] and spatially confined [29, 30]. maintained as neurospheres in neurobasal media However, Er:YAG lasers are not utilized for surgery (GIBCO) with supplements. Cells express firefly in general (outside of dermatological cosmetic luciferase and red fluorescent protein (RFP) as tumor resurfacing) and are not a viable candidate for biomarkers. Prior to intracranial implantation, coagulation of the cerebral microcirculation. neurospheres were dispersed with accutase (MP Recently, researchers have reported experiments Biomedicals) and resuspended to a final concentration demonstrating image-guided laser surgical concepts. of 2x104 cells/µL. Tumors were allowed to grow for Of particular interest here are Chang, F-Y’s work [31] four weeks before laser treatment experiments. on combining OCT feedback with laser coagulation in All animal experiments were performed murine models and Fan, Y’s work [32] on using OCT following a protocol that adheres to the National feedback to guide ex vivo ablation of porcine brain Institutes of Health Guide for the Care and Use of tissue samples. In this report, we demonstrate Experimental Animals. Athymic nude mice (Harlan enhanced in vivo surgical imaging and cutting using a Labs) were anesthetized and placed onto a cranial new surgical platform that combines optical stereotaxic stage and administered dexamethasone coherence tomography (OCT) image guidance with (0.02 ml at 4 mg/ml) and carprofen (4 mg/kg of a 50 thulium (Tm) laser blood vessel coagulation and mg/ml solution) by intramuscular injection erbium (Er:YAG) laser brain tumor ablation. The preoperatively. The scalp was retracted to expose the two-laser approach overcomes competing bregma and the