Development of a Handheld Near-infrared Imager for Dynamic Characterization of in Vivo Biological Tissue Systems

Applied Optics. Oct, 2007  |  Pubmed ID: 17952180

A handheld near-infrared imager was developed for real-time monitoring of tissue physiologic changes in response to dynamic compression stimuli. Both 2D and 3D imaging schemas were developed for reconstruction of tissue heterogeneities based on optical measurements. The handheld imager and the dynamic imaging schema were validated on both benchtop phantoms and in vivo human tissues. The benchtop tests demonstrated that the imager was able to reconstruct absorption properties of the embedded heterogeneity with accuracy and repeatability. The tests on in vivo human tissues demonstrated that the imager was able to generate various dynamic loading profiles with reproducibility and to detect tissue optical, mechanical, and physiologic changes under the dynamic loading condition.

A Prospective Pilot Clinical Trial Evaluating the Utility of a Dynamic Near-infrared Imaging Device for Characterizing Suspicious Breast Lesions

Breast Cancer Research : BCR. 2007  |  Pubmed ID: 18088411

Characterizing and differentiating between malignant tumors, benign tumors, and normal breast tissue is increasingly important in the patient presenting with breast problems. Near-infrared diffuse optical imaging and spectroscopy is capable of measuring multiple physiologic parameters of biological tissue systems and may have clinical applications for assessing the development and progression of neoplastic processes, including breast cancer. The currently available application of near-infrared imaging technology for the breast, however, is compromised by low spatial resolution, tissue heterogeneity, and interpatient variation.

Diffuse Optical Imaging and Spectroscopy for Cancer

Expert Review of Medical Devices. Jan, 2007  |  Pubmed ID: 17187474

Visible light and near infrared light interact with biological tissue by absorption and scattering. Diffuse optical imaging and spectroscopy reconstructs tissue physiologic parameters based on noninvasive measurement of tissue optical properties. This technology can be used to differentiate physiologic and molecular signatures of both malignant and benign tissues, as they relate to the area of cancer research. Major advantages are the use of non-ionizing radiation, real-time continuous data acquisition, low cost, and portability. Limitations include low spatial resolution and limited reproducibility. This paper reviews the currently available state-of-the-art technologies for diffuse optical imaging and spectroscopy and their applications in cancer research.

Dynamic Schema for Near Infrared Detection of Pressure-induced Changes in Solid Tumors

Applied Optics. Jun, 2008  |  Pubmed ID: 18516127

Differentiation among malignant tumors, benign tumors, and normal tissue is highly important in the diagnosis and treatment of many malignancies. We have proposed a dynamic schema for noninvasive characterization of pressure-induced changes in solid tumors. Our hypothesis has been that the altered neovascularization processes within cancer-bearing tissues may significantly increase vascular resistance and cause a much slower response of hemoglobin concentration during a dynamic compression stimulus. This hypothesis was tested by the evaluation of data generated from human tumor clinical testing and from animal tumor model testing. In the human tumor clinical testing, a unified diagnostic criterion was derived that integrated the relative characteristics of tumor oxygen, hemoglobin, and hemoglobin dynamics. By applying such a unified criterion, we were able to differentiate benign breast lesions and malignant breast tumors with high sensitivity and specificity within a subset of 14 suspicious breast lesions with similar size and depth characteristics. In the animal testing, a stepped compression load was applied to the subcutaneous tumor deposit on an athymic NU/NU nude mouse model with subcutaneous xenograft BxPC-3 cancer. Characteristic differences were observed between the premortem tumor and the postmortem tumor in terms of pressure-induced tumor structural and functional changes.

Fabrication of Indocyanine Green Encapsulated Biodegradable Microbubbles for Structural and Functional Imaging of Cancer

Journal of Biomedical Optics. May-Jun, 2009  |  Pubmed ID: 19566313

We developed a novel dual-modal contrast agent for the structural and functional imaging of cancer. The contrast agent was fabricated by encapsulating indocyanine green (ICG) in poly(lactic-co-glycolic acid) (PLGA) microbubbles using a modified double-emulsion method. More stabilized absorption and fluorescence emission characteristics were observed for aqueous and plasma suspensions of ICG-encapsulated microbubbles. The technical feasibility of concurrent structural and functional imaging was demonstrated through a series of benchtop tests in which the aqueous suspension of ICG-encapsulated microbubbles was injected into a transparent tube embedded in an Intralipid phantom at different flow rates and concentrations. Concurrent fluorescence imaging and B-mode ultrasound imaging successfully captured the changes of microbubble flow rate and concentration with high linearity and accuracy. One potential application of the proposed ICG-encapsulated PLGA microbubbles is for the identification and characterization of peritumoral neovasculature for enhanced coregistration between tumor structural and functional boundaries in ultrasound-guided near-infrared diffuse optical tomography.

Standardized and Reproducible Methodology for the Comprehensive and Systematic Assessment of Surgical Resection Margins During Breast-conserving Surgery for Invasive Breast Cancer

BMC Cancer. 2009  |  Pubmed ID: 19635166

The primary goal of breast-conserving surgery (BCS) is to completely excise the tumor and achieve "adequate" or "negative" surgical resection margins while maintaining an acceptable level of postoperative cosmetic outcome. Nevertheless, precise determination of the adequacy of BCS has long been debated. In this regard, the aim of the current paper was to describe a standardized and reproducible methodology for comprehensive and systematic assessment of surgical resection margins during BCS.

Heat-sensitive Microbubbles for Intraoperative Assessment of Cancer Ablation Margins

Biomaterials. Feb, 2010  |  Pubmed ID: 19942283

A heat-sensitive microbubble (HSM) agent, comprising a core of liquid perfluorocarbon (PFC) compound and a shell of biodegradable poly lactic-co-glycolic acid (PLGA), was fabricated using an emulsion evaporation method. Optical microscopic imaging showed that heating the HSM suspension to 55 degrees C activated the HSMs for significant volumetric expansion. After placing a HSM-dispersed agar-agar gel phantom in a 55 degrees C water bath for 10 min, the phantom became ultrasonically hyperechoic due to the HSM expansion. In an ex vivo test, a porcine tissue sample was injected with the HSM suspension and placed in a 55 degrees C water bath for 10 min. US imaging clearly identified the hyperechoic regions resulted from the HSM activation. The hyperechoic regions in the tissue sample kept a strong US contrast for more than 1 h. In a simulated ablation process, a HSM-dispersed agar-agar gel phantom was ablated by a cylindrical heating element. US imaging accurately estimated the ablation margin propagation while thermographic imaging underestimated the ablation margin. Our experiments demonstrated that the HSM agent could be used as a novel contrast agent for intraoperative assessment of ablation margins in cancer thermal ablation therapies.

Synthesizing and Binding Dual-mode Poly (lactic-co-glycolic Acid) (PLGA) Nanobubbles for Cancer Targeting and Imaging

Biomaterials. Mar, 2010  |  Pubmed ID: 20006382

Accurate assessment of tumor boundaries and recognition of occult disease are important oncologic principles in cancer surgeries. However, existing imaging modalities are not optimized for intraoperative cancer imaging applications. We developed a nanobubble (NB) contrast agent for cancer targeting and dual-mode imaging using optical and ultrasound (US) modalities. The contrast agent was fabricated by encapsulating the Texas Red dye in poly (lactic-co-glycolic acid) (PLGA) NBs and conjugating NBs with cancer-targeting ligands. Both one-step and three-step cancer-targeting strategies were tested on the LS174T human colon cancer cell line. For the one-step process, NBs were conjugated with the humanized HuCC49 Delta C(H)2 antibody to target the over-expressed TAG-72 antigen. For the three-step process, cancer cells were targeted by successive application of the biotinylated HuCC49 Delta C(H)2 antibody, streptavidin, and the biotinylated NBs. Both one-step and three-step processes successfully targeted the cancer cells with high binding affinity. NB-assisted dual-mode imaging was demonstrated on a gelatin phantom that embedded multiple tumor simulators at different NB concentrations. Simultaneous fluorescence and US images were acquired for these tumor simulators and linear correlations were observed between the fluorescence/US intensities and the NB concentrations. Our research demonstrated the technical feasibility of using the dual-mode NB contrast agent for cancer targeting and simultaneous fluorescence/US imaging.

An Automatic Occlusion Device for Remote Control of Tumor Tissue Ischemia

Technology in Cancer Research & Treatment. Feb, 2010  |  Pubmed ID: 20082532

We developed an automatic occlusion device for remote control of tumor tissue ischemia. The device consists of a flexible cannula encasing a shape memory alloy wire with its distal end connected to surgical suture. Regional tissue occlusion was tested on both the benchtop and the animal models. In the benchtop test, the occlusion device introduced quantitative and reproducible changes of blood flow in a tissue simulating phantom embedding a vessel simulator. In the animal test, the device generated a cyclic pattern of reversible ischemia in the right hinder leg tissue of a black male C57BL/6 mouse. We also developed a multimodal detector that integrates near infrared spectroscopy and electron paramagnetic resonance spectroscopy for continuous monitoring of tumor tissue oxygenation, blood content, and oxygen tension changes. The multimodal detector was tested on a cancer xenograft nude mouse undergoing reversible tumor ischemia. The automatic occlusion device and the multimodal detector can be potentially integrated for closed-loop feedback control of tumor tissue ischemia. Such an integrated occlusion device may be used in multiple clinical applications such as regional hypoperfusion control in tumor resection surgeries and thermal ablation processes. In addition, the proposed occlusion device can also be used as a research tool to understand tumor oxygen transport and hemodynamic characteristics.

Targeted Delivery of Microbubbles and Nanobubbles for Image-guided Thermal Ablation Therapy of Tumors

Expert Review of Medical Devices. May, 2010  |  Pubmed ID: 20420552

Multifunctional Microbubbles for Image-guided Antivascular Endothelial Growth Factor Therapy

Journal of Biomedical Optics. May-Jun, 2010  |  Pubmed ID: 20614998

We synthesize multifunctional microbubbles (MBs) for targeted delivery of antivascular endothelial growth factor (antiVEGF) therapy with multimodal imaging guidance. Poly-lactic-co-glycolic acid (PLGA) MBs encapsulating Texas Red dye are fabricated by a modified double-emulsion process. Simultaneous ultrasound and fluorescence imaging are achieved using Texas Red encapsulated MBs. The MBs are conjugated with Avastin, an antiVEGF antibody for treating neovascular age-related macular degeneration (AMD). The conjugation efficiency is characterized by enzyme-linked immunosorbent assay (ELISA). The efficiency for targeted binding of Avastin-conjugated MBs is characterized by microscopic imaging. Our work demonstrates the technical potential of using multifunctional MBs for targeted delivery of antiVEGF therapy in the treatment of exudative AMD.

124I-HuCC49deltaCH2 for TAG-72 Antigen-directed Positron Emission Tomography (PET) Imaging of LS174T Colon Adenocarcinoma Tumor Implants in Xenograft Mice: Preliminary Results

World Journal of Surgical Oncology. 2010  |  Pubmed ID: 20691066

18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is widely used in diagnostic cancer imaging. However, the use of 18F-FDG in PET-based imaging is limited by its specificity and sensitivity. In contrast, anti-TAG (tumor associated glycoprotein)-72 monoclonal antibodies are highly specific for binding to a variety of adenocarcinomas, including colorectal cancer. The aim of this preliminary study was to evaluate a complimentary determining region (CDR)-grafted humanized CH2-domain-deleted anti-TAG-72 monoclonal antibody (HuCC49deltaCH2), radiolabeled with iodine-124 (124I), as an antigen-directed and cancer-specific targeting agent for PET-based imaging.

Drug-loaded Biodegradable Microspheres for Image-guided Combinatory Epigenetic Therapy in Cells

Journal of Biomedical Optics. Feb, 2011  |  Pubmed ID: 21361663

We synthesize drug-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres for image-guided combinatory epigenetic therapy in MCF-10A human mammary epithelial cells. LY294002 and Nile Red are encapsulated in microspheres for sustained drug release and fluorescence microscopic imaging. Drug-loaded microspheres target MCF-10A cells through a three-step binding process involving biotinylated antibody, streptavidin, and biotinylated microspheres. LY294002 loaded microspheres and 5-Aza-2-deoxycytidine are applied to MCF-10A cells for combinatory PI3K∕AKT inhibition and deoxyribonucleic acid (DNA) demethylation. Our study implies the technical potential of disease targeting and image-guided combinatory epigenetic therapy using drug-loaded multifunctional biodegradable PLGA microspheres.

Multifunctional Microbubbles and Nanobubbles for Photoacoustic Imaging

Contrast Media & Molecular Imaging. Sep-Oct, 2011  |  Pubmed ID: 22025340

Photoacoustic imaging is an emerging imaging modality for noninvasive detection of tissue structural and functional anomalies. Multifunctional microbubbles (MBs) and nanobubbles (NBs) are contrast agents integrating multiple disease-targeting, imaging and therapeutic functions. Multifunctional MBs and NBs represent an enabling technology for many potential applications in the field of photoacoustic imaging. Highly absorbing optical contrast agents, such as gold nanoparticles, India ink and Indocyanine Green, can be encapsulated in MBs and NBs for stable absorption properties and multimodal imaging contrasts. The surface of MBs and NBs can be modified for high disease-targeting affinity, reduced immunogenicity and prolonged circulation lifetime. Low boiling point perfluorocarbon compounds can be encapsulated in MBs and NBs for selective activation by external energy sources. The activation of these MBs and NBs may introduce significant contrast enhancement and facilitate a variety of potential clinical applications, such as image-guided drug delivery and therapeutic margin assessment. MB and NB enhanced photoacoustic imaging is still in its infancy. Further development and validation works are necessary for successful translation of the technology from the benchtop to the bedside.