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Article ; Online: Real time optical Biopsy: Time-resolved Fluorescence Spectroscopy instrumentation and validation.

Kittle, David S / Vasefi, Fartash / Patil, Chirag G / Mamelak, Adam / Black, Keith L / Butte, Pramod V

2016 Volume 6, Page(s) 38190

Abstract: The Time-resolved fluorescence spectroscopy (TR-FS) has the potential to differentiate tumor and normal tissue in real time during surgical excision. In this manuscript, we describe the design of a novel TR-FS device, along with preliminary data on ... ...

Abstract	The Time-resolved fluorescence spectroscopy (TR-FS) has the potential to differentiate tumor and normal tissue in real time during surgical excision. In this manuscript, we describe the design of a novel TR-FS device, along with preliminary data on detection accuracy for fluorophores in a mixture. The instrument is capable of near real-time fluorescence lifetime acquisition in multiple spectral bands and analysis. It is also able to recover fluorescence lifetime with sub-20ps accuracy as validated with individual organic fluorescence dyes and dye mixtures yielding lifetime values for standard fluorescence dyes that closely match with published data. We also show that TR-FS is able to quantify the relative concentration of fluorescence dyes in a mixture by the unmixing of lifetime decays. We show that the TR-FS prototype is able to identify in near-real time the concentrations of dyes in a complex mixture based on previously trained data. As a result, we demonstrate that in complex mixtures of fluorophores, the relative concentration information is encoded in the fluorescence lifetime across multiple spectral bands. We show for the first time the temporal and spectral measurements of a mixture of fluorochromes and the ability to differentiate relative concentrations of each fluorochrome mixture in real time.
Language	English
Publishing date	2016-12-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep38190
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Article ; Online: Polymalic acid chlorotoxin nanoconjugate for near-infrared fluorescence guided resection of glioblastoma multiforme.

Patil, Rameshwar / Galstyan, Anna / Sun, Tao / Shatalova, Ekaterina S / Butte, Pramod / Mamelak, Adam N / Carico, Christine / Kittle, David S / Grodzinski, Zachary B / Chiechi, Antonella / Ding, Hui / Black, Keith L / Ljubimova, Julia Y / Holler, Eggehard

Biomaterials

2019 Volume 206, Page(s) 146–159

Abstract: Maximal surgical resection of glioma remains the single most effective treatment. Tools to guide the resection while avoiding removal of normal brain tissues can aid surgeons in achieving optimal results. One strategy to achieve this goal is to rely upon ...

Abstract	Maximal surgical resection of glioma remains the single most effective treatment. Tools to guide the resection while avoiding removal of normal brain tissues can aid surgeons in achieving optimal results. One strategy to achieve this goal is to rely upon interoperative fluorescence staining of tumor cells in vivo, that can be visualized by the surgeon during resection. Towards this goal we have designed a biodegradable fluorescent mini nano imaging agent (NIA) with high specificity for U87MG glioma cells and previously unmet high light emission. The NIA is the conjugate of polymalic acid (PMLA) with chlorotoxin for tumor targeting, indocyanine green (ICG) for NIR fluorescence and the tri-leucin peptide as fluorescence enhancer. PMLA as a multivalent platform carries several molecules of ICG and the other ligands. The NIA recognizes multiple sites on glioma cell surface, demonstrated by the effects of single and combined competitors. Systemic IV injection into xenogeneic mouse model carrying human U87MG glioblastoma indicated vivid tumor cell binding and internalization of NIA resulting in intensive and long-lasting tumor fluorescence. The NIA is shown to greatly improve tumor removal supporting its utility in clinical applications.
MeSH term(s)	Animals ; Cell Line, Tumor ; Female ; Glioblastoma/surgery ; Humans ; Indocyanine Green/chemistry ; Malates/chemistry ; Mice ; Nanoconjugates/chemistry ; Polymers/chemistry ; Scorpion Venoms/chemistry ; Spectroscopy, Near-Infrared ; Xenograft Model Antitumor Assays
Chemical Substances	Malates ; Nanoconjugates ; Polymers ; Scorpion Venoms ; poly(malic acid) ; Chlorotoxin (06UV5RFW57) ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2019-03-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2019.03.029
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Article: Polymalic acid chlorotoxin nanoconjugate for near-infrared fluorescence guided resection of glioblastoma multiforme

Biomaterials. 2019 June, v. 206

2019

Abstract	Maximal surgical resection of glioma remains the single most effective treatment. Tools to guide the resection while avoiding removal of normal brain tissues can aid surgeons in achieving optimal results. One strategy to achieve this goal is to rely upon interoperative fluorescence staining of tumor cells in vivo, that can be visualized by the surgeon during resection. Towards this goal we have designed a biodegradable fluorescent mini nano imaging agent (NIA) with high specificity for U87MG glioma cells and previously unmet high light emission. The NIA is the conjugate of polymalic acid (PMLA) with chlorotoxin for tumor targeting, indocyanine green (ICG) for NIR fluorescence and the tri-leucin peptide as fluorescence enhancer. PMLA as a multivalent platform carries several molecules of ICG and the other ligands. The NIA recognizes multiple sites on glioma cell surface, demonstrated by the effects of single and combined competitors. Systemic IV injection into xenogeneic mouse model carrying human U87MG glioblastoma indicated vivid tumor cell binding and internalization of NIA resulting in intensive and long-lasting tumor fluorescence. The NIA is shown to greatly improve tumor removal supporting its utility in clinical applications.
Keywords	animal models ; biodegradability ; brain ; fluorescence ; glioblastoma ; humans ; image analysis ; intravenous injection ; ligands ; neoplasm cells ; peptides ; resection ; staining
Language	English
Dates of publication	2019-06
Size	p. 146-159.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	603079-8
ISSN	0142-9612
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2019.03.029
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Joint segmentation and reconstruction of hyperspectral data with compressed measurements.

Zhang, Qiang / Plemmons, Robert / Kittle, David / Brady, David / Prasad, Sudhakar

Applied optics

2011 Volume 50, Issue 22, Page(s) 4417–4435

Abstract: This work describes numerical methods for the joint reconstruction and segmentation of spectral images taken by compressive sensing coded aperture snapshot spectral imagers (CASSI). In a snapshot, a CASSI captures a two-dimensional (2D) array of ... ...

Abstract	This work describes numerical methods for the joint reconstruction and segmentation of spectral images taken by compressive sensing coded aperture snapshot spectral imagers (CASSI). In a snapshot, a CASSI captures a two-dimensional (2D) array of measurements that is an encoded representation of both spectral information and 2D spatial information of a scene, resulting in significant savings in acquisition time and data storage. The reconstruction process decodes the 2D measurements to render a three-dimensional spatio-spectral estimate of the scene and is therefore an indispensable component of the spectral imager. In this study, we seek a particular form of the compressed sensing solution that assumes spectrally homogeneous segments in the two spatial dimensions, and greatly reduces the number of unknowns, often turning the underdetermined reconstruction problem into one that is overdetermined. Numerical tests are reported on both simulated and real data representing compressed measurements.
MeSH term(s)	Data Compression ; Image Processing, Computer-Assisted/statistics & numerical data ; Imaging, Three-Dimensional/statistics & numerical data ; Optical Phenomena
Language	English
Publishing date	2011-08-01
Publishing country	United States
Document type	Journal Article
ISSN	1539-4522
ISSN (online)	1539-4522
DOI	10.1364/AO.50.004417
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Article ; Online: A testbed for wide-field, high-resolution, gigapixel-class cameras.

Kittle, David S / Marks, Daniel L / Son, Hui S / Kim, Jungsang / Brady, David J

The Review of scientific instruments

2013 Volume 84, Issue 5, Page(s) 53107

Abstract: The high resolution and wide field of view (FOV) of the AWARE (Advanced Wide FOV Architectures for Image Reconstruction and Exploitation) gigapixel class cameras present new challenges in calibration, mechanical testing, and optical performance ... ...

Abstract	The high resolution and wide field of view (FOV) of the AWARE (Advanced Wide FOV Architectures for Image Reconstruction and Exploitation) gigapixel class cameras present new challenges in calibration, mechanical testing, and optical performance evaluation. The AWARE system integrates an array of micro-cameras in a multiscale design to achieve gigapixel sampling at video rates. Alignment and optical testing of the micro-cameras is vital in compositing engines, which require pixel-level accurate mappings over the entire array of cameras. A testbed has been developed to automatically calibrate and measure the optical performance of the entire camera array. This testbed utilizes translation and rotation stages to project a ray into any micro-camera of the AWARE system. A spatial light modulator is projected through a telescope to form an arbitrary object space pattern at infinity. This collimated source is then reflected by an elevation stage mirror for pointing through the aperture of the objective into the micro-optics and eventually the detector of the micro-camera. Different targets can be projected with the spatial light modulator for measuring the modulation transfer function (MTF) of the system, fiducials in the overlap regions for registration and compositing, distortion mapping, illumination profiles, thermal stability, and focus calibration. The mathematics of the testbed mechanics are derived for finding the positions of the stages to achieve a particular incident angle into the camera, along with calibration steps for alignment of the camera and testbed coordinate axes. Measurement results for the AWARE-2 gigapixel camera are presented for MTF, focus calibration, illumination profile, fiducial mapping across the micro-camera for registration and distortion correction, thermal stability, and alignment of the camera on the testbed.
Language	English
Publishing date	2013-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	209865-9
ISSN	1089-7623 ; 0034-6748
ISSN (online)	1089-7623
ISSN	0034-6748
DOI	10.1063/1.4804199
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Article ; Online: Autofocus for a multiscale gigapixel camera.

Nakamura, Tomoya / Kittle, David S / Youn, Seo Ho / Feller, Steven D / Tanida, Jun / Brady, David J

Applied optics

2013 Volume 52, Issue 33, Page(s) 8146–8153

Abstract: In recent studies, the advanced wide field of view architectures for image reconstruction and exploitation (AWARE) multiscale camera, which is composed of a monocentric objective lens and an array of microcameras, was developed for the realization of ... ...

Abstract	In recent studies, the advanced wide field of view architectures for image reconstruction and exploitation (AWARE) multiscale camera, which is composed of a monocentric objective lens and an array of microcameras, was developed for the realization of snapshot wide field of view and high resolution imaging. This paper describes accelerated autofocus (AF) methods for the AWARE system based on a hierarchical spatial algorithm and an iterative temporal algorithm. In the algorithms, sensor positions of each microcamera are hierarchically scanned with contrast detection to effectively search for a focusing distance. The positions are then updated iteratively for dynamic scenes using temporal information. The algorithms are theoretically analyzed and experimentally demonstrated. The developed AF methods can be used for the realization of the temporal gigapixel imaging by the AWARE system.
Language	English
Publishing date	2013-11-20
Publishing country	United States
Document type	Journal Article
ISSN	1539-4522
ISSN (online)	1539-4522
DOI	10.1364/AO.52.008146
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Article ; Online: Multiframe image estimation for coded aperture snapshot spectral imagers.

Kittle, David / Choi, Kerkil / Wagadarikar, Ashwin / Brady, David J

Applied optics

2010 Volume 49, Issue 36, Page(s) 6824–6833

Abstract: A coded aperture snapshot spectral imager (CASSI) estimates the three-dimensional spatiospectral data cube from a snapshot two-dimensional coded projection, assuming that the scene is spatially and spectrally sparse. For less spectrally sparse scenes, we ...

Abstract	A coded aperture snapshot spectral imager (CASSI) estimates the three-dimensional spatiospectral data cube from a snapshot two-dimensional coded projection, assuming that the scene is spatially and spectrally sparse. For less spectrally sparse scenes, we show that the use of multiple nondegenerate snapshots can make data cube recovery less ill-posed, yielding improved spatial and spectral reconstruction fidelity. Additionally, data acquisition can be easily scaled to meet the time/resolution requirements of the scene with little modification or extension of the original CASSI hardware. A multiframe reconstruction of a 640 × 480 × 53 voxel datacube with 450-650 nm white-light illumination of a scene reveals substantial improvement in the reconstruction fidelity, with limited increase in acquisition and reconstruction time.
Language	English
Publishing date	2010-12-20
Publishing country	United States
Document type	Journal Article
ISSN	1539-4522
ISSN (online)	1539-4522
DOI	10.1364/AO.49.006824
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Article ; Online: Real-time Visualization of Breast Carcinoma in Pathology Specimens From Patients Receiving Fluorescent Tumor-Marking Agent Tozuleristide.

Dintzis, Suzanne M / Hansen, Stacey / Harrington, Kristi M / Tan, Lennart C / Miller, Dennis M / Ishak, Laura / Parrish-Novak, Julia / Kittle, David / Perry, Jeff / Gombotz, Carolyn / Fortney, Tina / Porenta, Stephanie / Hales, Lisa / Calhoun, Kristine E / Anderson, Benjamin O / Javid, Sara H / Byrd, David R

Archives of pathology & laboratory medicine

2018 Volume 143, Issue 9, Page(s) 1076–1083

Abstract: Context.—: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin ... ...

Abstract	Context.—: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens. Objectives.—: To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins. Design.—: Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin-stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements. Results.—: Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively. Conclusions.—: Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.
MeSH term(s)	Breast Carcinoma In Situ/diagnostic imaging ; Breast Carcinoma In Situ/pathology ; Breast Carcinoma In Situ/surgery ; Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/surgery ; Carcinoma, Ductal, Breast/diagnostic imaging ; Carcinoma, Ductal, Breast/pathology ; Carcinoma, Ductal, Breast/surgery ; Carcinoma, Lobular/diagnostic imaging ; Carcinoma, Lobular/pathology ; Carcinoma, Lobular/surgery ; Female ; Fluorescent Dyes ; Humans ; Indocyanine Green/analogs & derivatives ; Intraoperative Care/methods ; Margins of Excision ; Mastectomy ; Mastectomy, Segmental ; Neoplasm Invasiveness/diagnostic imaging ; Neoplasm Invasiveness/pathology ; Prognosis ; Scorpion Venoms
Chemical Substances	Fluorescent Dyes ; Scorpion Venoms ; Chlorotoxin (06UV5RFW57) ; tozuleristide (835UH424TU) ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2018-12-14
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2018-0197-OA
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Article ; Online: Coded aperture compressive temporal imaging.

Llull, Patrick / Liao, Xuejun / Yuan, Xin / Yang, Jianbo / Kittle, David / Carin, Lawrence / Sapiro, Guillermo / Brady, David J

Optics express

2013 Volume 21, Issue 9, Page(s) 10526–10545

Abstract: We use mechanical translation of a coded aperture for code division multiple access compression of video. We discuss the compressed video's temporal resolution and present experimental results for reconstructions of > 10 frames of temporal data per coded ...

Abstract	We use mechanical translation of a coded aperture for code division multiple access compression of video. We discuss the compressed video's temporal resolution and present experimental results for reconstructions of > 10 frames of temporal data per coded snapshot.
MeSH term(s)	Algorithms ; Data Compression/methods ; Equipment Design ; Equipment Failure Analysis ; Image Interpretation, Computer-Assisted/instrumentation ; Image Interpretation, Computer-Assisted/methods ; Photography/instrumentation ; Photography/methods ; Video Recording/instrumentation ; Video Recording/methods
Language	English
Publishing date	2013-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1491859-6
ISSN	1094-4087 ; 1094-4087
ISSN (online)	1094-4087
ISSN	1094-4087
DOI	10.1364/OE.21.010526
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Article ; Online: Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas.

Patil, Chirag G / Walker, David G / Miller, Dennis M / Butte, Pramod / Morrison, Beth / Kittle, David S / Hansen, Stacey J / Nufer, Kaitlin L / Byrnes-Blake, Kelly A / Yamada, Miko / Lin, Lynlee L / Pham, Kim / Perry, Jeff / Parrish-Novak, Julia / Ishak, Laura / Prow, Tarl / Black, Keith / Mamelak, Adam N

Neurosurgery

2019 Volume 85, Issue 4, Page(s) E641–E649

Abstract: Background: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate ... ...

Abstract	Background: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. Objective: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. Methods: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. Results: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. Conclusion: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.
MeSH term(s)	Adult ; Aged ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/metabolism ; Brain Neoplasms/surgery ; Dose-Response Relationship, Drug ; Female ; Fluorescent Dyes/administration & dosage ; Fluorescent Dyes/pharmacokinetics ; Glioma/diagnostic imaging ; Glioma/metabolism ; Glioma/surgery ; Humans ; Indocyanine Green/administration & dosage ; Indocyanine Green/analogs & derivatives ; Indocyanine Green/pharmacokinetics ; Injections, Intravenous ; Male ; Middle Aged ; Neoplasm Recurrence, Local/diagnostic imaging ; Neoplasm Recurrence, Local/metabolism ; Neoplasm Recurrence, Local/surgery ; Optical Imaging/methods ; Scorpion Venoms/administration & dosage ; Scorpion Venoms/pharmacokinetics
Chemical Substances	Fluorescent Dyes ; Scorpion Venoms ; tozuleristide (835UH424TU) ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2019-05-08
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	135446-2
ISSN	1524-4040 ; 0148-396X
ISSN (online)	1524-4040
ISSN	0148-396X
DOI	10.1093/neuros/nyz125
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