Seamlessly integrated multi-modal imaging system through transparent ultrasound transducer in vivo

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats’ eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.

Download Full-text

Multi-mode light microscopy of microtubule assembly dynamics and chromosome movement in vivo and In vitro

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166117 ◽

1996 ◽

Vol 54 ◽

pp. 730-731

Author(s):

E. D. Salmon ◽

J. C. Waters ◽

C. Waterman-Storer

Keyword(s):

Imaging System ◽

Ccd Camera ◽

Transmitted Light ◽

Microtubule Assembly ◽

Live Cells ◽

Optical Efficiency ◽

Multiple Band ◽

Multi Mode

We have developed a multi-mode digital imaging system which acquires images with a cooled CCD camera (Figure 1). A multiple band pass dichromatic mirror and robotically controlled filter wheels provide wavelength selection for epi-fluorescence. Shutters select illumination either by epi-fluorescence or by transmitted light for phase contrast or DIC. Many of our experiments involve investigations of spindle assembly dynamics and chromosome movements in live cells or unfixed reconstituted preparations in vitro in which photodamage and phototoxicity are major concerns. As a consequence, a major factor in the design was optical efficiency: achieving the highest image quality with the least number of illumination photons. This principle applies to both epi-fluorescence and transmitted light imaging modes. In living cells and extracts, microtubules are visualized using X-rhodamine labeled tubulin. Photoactivation of C2CF-fluorescein labeled tubulin is used to locally mark microtubules in studies of microtubule dynamics and translocation. Chromosomes are labeled with DAPI or Hoechst DNA intercalating dyes.

Download Full-text

Nanotechnology: from In Vivo Imaging System to Controlled Drug Delivery

Nanoscale Research Letters ◽

10.1186/s11671-017-2249-8 ◽

2017 ◽

Vol 12 (1) ◽

Cited By ~ 41

Author(s):

Maria Mir ◽

Saba Ishtiaq ◽

Samreen Rabia ◽

Maryam Khatoon ◽

Ahmad Zeb ◽

...

Keyword(s):

Drug Delivery ◽

In Vivo Imaging ◽

Imaging System ◽

Controlled Drug Delivery ◽

In Vivo Imaging System

Download Full-text

MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00823-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yipengchen Yin ◽

Yongjing Li ◽

Sheng Wang ◽

Ziliang Dong ◽

Chao Liang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Membranes ◽

Imaging System ◽

Fluorescence Signal ◽

Bimodal Imaging ◽

Red Blood Cell Membranes ◽

Magnetic Resonance Imaging Mri ◽

Tumor Accumulation

Abstract Background The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as “self”, evade the surveillance of the immune system, and accumulate to the tumor sites actively. Results Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate—an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. Conclusions These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

Download Full-text

Targeted Liposomal Chemotherapies to Treat Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13153749 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3749

Author(s):

Yingnan Si ◽

Ya Zhang ◽

Hanh Giai Ngo ◽

Jia-Shiung Guan ◽

Kai Chen ◽

...

Keyword(s):

Targeted Delivery ◽

Laser Scanning ◽

Triple Negative ◽

Imaging System ◽

Laser Scanning Microscopy ◽

Confocal Laser ◽

Surface Binding ◽

Synthesis Inhibitor ◽

Tnbc Cell

Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.

Download Full-text

Performance of a novel protease-activated fluorescent imaging system for intraoperative detection of residual breast cancer during breast conserving surgery

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06106-w ◽

2021 ◽

Vol 187 (1) ◽

pp. 145-153

Author(s):

Conor R. Lanahan ◽

Bridget N. Kelly ◽

Michele A. Gadd ◽

Michelle C. Specht ◽

Carson L. Brown ◽

...

Keyword(s):

Breast Cancer ◽

Real Time ◽

Imaging System ◽

Ex Vivo ◽

Menopausal Status ◽

Fluorescent Imaging ◽

Cancer Subtypes ◽

Surgical Workflow ◽

Tumor Types

Abstract Purpose Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20–40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. Methods We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. Results Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81–5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. Conclusions Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

Download Full-text

A Tumbling Magnetic Microrobot System for Biomedical Applications

Micromachines ◽

10.3390/mi11090861 ◽

2020 ◽

Vol 11 (9) ◽

pp. 861

Author(s):

Elizabeth E. Niedert ◽

Chenghao Bi ◽

Georges Adam ◽

Elly Lambert ◽

Luis Solorio ◽

...

Keyword(s):

Ultrasound Imaging ◽

Biomedical Applications ◽

Imaging System ◽

Ex Vivo ◽

Negative Control ◽

Circular Path ◽

Rotational Axis ◽

Significant Difference

A microrobot system comprising an untethered tumbling magnetic microrobot, a two-degree-of-freedom rotating permanent magnet, and an ultrasound imaging system has been developed for in vitro and in vivo biomedical applications. The microrobot tumbles end-over-end in a net forward motion due to applied magnetic torque from the rotating magnet. By turning the rotational axis of the magnet, two-dimensional directional control is possible and the microrobot was steered along various trajectories, including a circular path and P-shaped path. The microrobot is capable of moving over the unstructured terrain within a murine colon in in vitro, in situ, and in vivo conditions, as well as a porcine colon in ex vivo conditions. High-frequency ultrasound imaging allows for real-time determination of the microrobot’s position while it is optically occluded by animal tissue. When coated with a fluorescein payload, the microrobot was shown to release the majority of the payload over a 1-h time period in phosphate-buffered saline. Cytotoxicity tests demonstrated that the microrobot’s constituent materials, SU-8 and polydimethylsiloxane (PDMS), did not show a statistically significant difference in toxicity to murine fibroblasts from the negative control, even when the materials were doped with magnetic neodymium microparticles. The microrobot system’s capabilities make it promising for targeted drug delivery and other in vivo biomedical applications.

Download Full-text

Real-Time In Vivo Bioluminescent Imaging for Evaluating the Efficacy of Antibiotics in a Rat Staphylococcus aureus Endocarditis Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.1.380-387.2005 ◽

2005 ◽

Vol 49 (1) ◽

pp. 380-387 ◽

Cited By ~ 68

Author(s):

Yan Q. Xiong ◽

Julie Willard ◽

Jagath L. Kadurugamuwa ◽

Jun Yu ◽

Kevin P. Francis ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Real Time ◽

Imaging System ◽

Bioluminescent Imaging ◽

Vancomycin Therapy ◽

Treatment Groups ◽

Highly Sensitive ◽

Relevant Animal Model ◽

And Control

ABSTRACT Therapeutic options for invasive Staphylococcus aureus infections have become limited due to rising antimicrobial resistance, making relevant animal model testing of new candidate agents more crucial than ever. In the present studies, a rat model of aortic infective endocarditis (IE) caused by a bioluminescently engineered, biofilm-positive S. aureus strain was used to evaluate real-time antibiotic efficacy directly. This strain was vancomycin and cefazolin susceptible but gentamicin resistant. Bioluminescence was detected and quantified daily in antibiotic-treated and control animals with IE, using a highly sensitive in vivo imaging system (IVIS). Persistent and increasing cardiac bioluminescent signals (BLS) were observed in untreated animals. Three days of vancomycin therapy caused significant reductions in both cardiac BLS (>10-fold versus control) and S. aureus densities in cardiac vegetations (P < 0.005 versus control). However, 3 days after discontinuation of vancomycin therapy, a greater than threefold increase in cardiac BLS was observed, indicating relapsing IE (which was confirmed by quantitative culture). Cefazolin resulted in modest decreases in cardiac BLS and bacterial densities. These microbiologic and cardiac BLS differences during therapy correlated with a longer time-above-MIC for vancomycin (>12 h) than for cefazolin (∼4 h). Gentamicin caused neither a reduction in cardiac S. aureus densities nor a reduction in BLS. There were significant correlations between cardiac BLS and S. aureus densities in vegetations in all treatment groups. These data suggest that bioluminescent imaging provides a substantial advance in the real-time monitoring of the efficacy of therapy of invasive S. aureus infections in live animals.

Download Full-text

Design and Implementation Guidelines for a Modular Spectral-Domain Optical Coherence Tomography Scanner

International Journal of Optics ◽

10.1155/2018/3726207 ◽

2018 ◽

Vol 2018 ◽

pp. 1-22 ◽

Cited By ~ 4

Author(s):

Farid Atry ◽

Israel Jacob De La Rosa ◽

Kevin R. Rarick ◽

Ramin Pashaie

Keyword(s):

Optical Coherence Tomography ◽

Imaging System ◽

Optical Design ◽

Spectral Domain ◽

Design Parameters ◽

Optical Coherence ◽

Custom Made ◽

Essential Knowledge ◽

Sd Oct

In the past decades, spectral-domain optical coherence tomography (SD-OCT) has transformed into a widely popular imaging technology which is used in many research and clinical applications. Despite such fast growth in the field, the technology has not been readily accessible to many research laboratories either due to the cost or inflexibility of the commercially available systems or due to the lack of essential knowledge in the field of optics to develop custom-made scanners that suit specific applications. This paper aims to provide a detailed discussion on the design and development process of a typical SD-OCT scanner. The effects of multiple design parameters, for the main optical and optomechanical components, on the overall performance of the imaging system are analyzed and discussions are provided to serve as a guideline for the development of a custom SD-OCT system. While this article can be generalized for different applications, we will demonstrate the design of a SD-OCT system and representative results for in vivo brain imaging. We explain procedures to measure the axial and transversal resolutions and field of view of the system and to understand the discrepancies between the experimental and theoretical values. The specific aim of this piece is to facilitate the process of constructing custom-made SD-OCT scanners for research groups with minimum understanding of concepts in optical design and medical imaging.

Download Full-text

MR-GUIDED PULSE OXIMETRY IMAGING OF BREAST IN VIVO

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545811001459 ◽

2011 ◽

Vol 04 (02) ◽

pp. 199-208

Author(s):

ZHIQIU LI ◽

SHUDONG JIANG ◽

VENKATARAMANAN KRISHNASWAMY ◽

SCOTT C. DAVIS ◽

SUBHADRA SRINIVASAN ◽

...

Keyword(s):

Breast Tissue ◽

Near Infrared ◽

Imaging System ◽

Structural Information ◽

Human Subjects ◽

Nir Spectroscopy ◽

Tomography System ◽

Finger Pulse ◽

Lock In

A near-infrared (NIR) tomography system with spectrally-encoded sources in two wavelength bands was built to quantify the temporal oxyhemoglobin and deoxyhemoglobin contrast in breast tissue at a 20 Hz bandwidth. The system was integrated into a 3 T magnetic resonance (MR) imaging system through a customized breast coil interface for simultaneous optical and MRI acquisition. In this configuration, the MR images provide breast tissue structural information for NIR spectroscopy of adipose and fibro-glandular tissue in breast. Spectral characterization performance of the NIR system was verified through dynamic phantom experiments. Normal human subjects were imaged with finger pulse oximeter (PO) plethysmogram synchronized to the NIR system to provide a frequency-locked reference. Both the raw data from the NIR system and the recovered absorption coefficients of the breast at two wavelengths showed the same frequency of about 1.3 Hz as the PO output. The frequency lock-in approach provided a practical platform for MR-localized recovery of small pulsatile variations of oxyhemoglobin and deoxyhemoglobin in the breast, which are related to the heartbeat and vascular resistance of the tissue.

Download Full-text