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1
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Vasudevan J, Vijayakumar R, Reales-Calderon JA, Lam MSY, Ow JR, Aw J, Tan D, Tan AT, Bertoletti A, Adriani G, Pavesi A. In vitro integration of a functional vasculature to model endothelial regulation of chemotherapy and T-cell immunotherapy in liver cancer. Biomaterials 2025; 320:123175. [PMID: 40043483 DOI: 10.1016/j.biomaterials.2025.123175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 04/06/2025]
Abstract
The complex tumor microenvironment (TME) presents significant challenges to the development of effective therapies against solid tumors, highlighting the need for advanced in vitro models that better recapitulate TME biology. To address this, we developed a vascularized human liver tumor model using a microfluidic platform, designed to test both drug and cell-based therapies. This model mimics critical tumorigenic features such as hypoxia, extracellular matrix (ECM), and perfusable vascular networks. Intravascular administration of Sorafenib demonstrated its ability to disrupt vascular structures significantly, while eliciting heterogeneous responses in two distinct liver tumor cell lines, HepG2 and Hep3b. Furthermore, treatment with engineered T-cells revealed that the tumor vasculature impeded T-cell infiltration into the tumor core but preserved their cytotoxic capacity, albeit with reduced exhaustion levels. Cytokine analysis and spatial profiling of vascularized tumor samples identified proinflammatory factors that may enhance T-cell-mediated antitumor responses. By capturing key TME characteristics, this microfluidic platform provides a powerful tool enabling detailed investigation of tumor-immune and tumor-vascular interactions. Its versatility could serve as a promising bridge between preclinical studies and clinical testing, offering opportunities for developing and optimizing personalized therapeutic strategies for solid tumors.
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Affiliation(s)
- Jyothsna Vasudevan
- Mechanobiology Institute, National University of Singapore (NUS), 5A Engineering Drive 1, Singapore, 117411, Republic of Singapore
| | - Ragavi Vijayakumar
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore
| | - Jose Antonio Reales-Calderon
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore
| | - Maxine S Y Lam
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore
| | - Jin Rong Ow
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore
| | - Joey Aw
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore
| | - Damien Tan
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore
| | - Anthony Tanoto Tan
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Republic of Singapore
| | - Antonio Bertoletti
- Duke-NUS Medical School, 8 College Road, Singapore, 169857, Republic of Singapore
| | - Giulia Adriani
- Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A∗STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Republic of Singapore; Department of Biomedical Engineering, National University of Singapore (NUS), 4 Engineering Drive 3, Singapore, 117583, Republic of Singapore
| | - Andrea Pavesi
- Mechanobiology Institute, National University of Singapore (NUS), 5A Engineering Drive 1, Singapore, 117411, Republic of Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Singapore, 138673, Republic of Singapore; Lee Kong Chian School of Medicine (LKCMedicine), Cancer Discovery and Regenerative Medicine Program, Nanyang Technological University, 308232, Republic of Singapore.
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2
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Shrestha B, Stern NB, Zhou A, Dunn A, Porter T. Current trends in the characterization and monitoring of vascular response to cancer therapy. Cancer Imaging 2024; 24:143. [PMID: 39438891 PMCID: PMC11515715 DOI: 10.1186/s40644-024-00767-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 08/26/2024] [Indexed: 10/25/2024] Open
Abstract
Tumor vascular physiology is an important determinant of disease progression as well as the therapeutic outcome of cancer treatment. Angiogenesis or the lack of it provides crucial information about the tumor's blood supply and therefore can be used as an index for cancer growth and progression. While standalone anti-angiogenic therapy demonstrated limited therapeutic benefits, its combination with chemotherapeutic agents improved the overall survival of cancer patients. This could be attributed to the effect of vascular normalization, a dynamic process that temporarily reverts abnormal vasculature to the normal phenotype maximizing the delivery and intratumor distribution of chemotherapeutic agents. Longitudinal monitoring of vascular changes following antiangiogenic therapy can indicate an optimal window for drug administration and estimate the potential outcome of treatment. This review primarily focuses on the status of various imaging modalities used for the longitudinal characterization of vascular changes before and after anti-angiogenic therapies and their clinical prospects.
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Affiliation(s)
- Binita Shrestha
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.
| | - Noah B Stern
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Annie Zhou
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Andrew Dunn
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
| | - Tyrone Porter
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA
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3
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Nguyen TNH, Horowitz LF, Nguyen B, Lockhart E, Zhu S, Gujral TS, Folch A. Microfluidic Modulation of Microvasculature in Microdissected Tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.26.615278. [PMID: 39386436 PMCID: PMC11463410 DOI: 10.1101/2024.09.26.615278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
The microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature in ex vivo systems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculature de novo (e.g., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments.
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Affiliation(s)
- Tran N. H. Nguyen
- Department of Bioengineering, University of Washington, Seattle, 98105, United States
| | - Lisa F. Horowitz
- Department of Bioengineering, University of Washington, Seattle, 98105, United States
| | - Brandon Nguyen
- Department of Bioengineering, University of Washington, Seattle, 98105, United States
| | - Ethan Lockhart
- Department of Bioengineering, University of Washington, Seattle, 98105, United States
| | - Songli Zhu
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, United States
| | - Taranjit S. Gujral
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, United States
| | - Albert Folch
- Department of Bioengineering, University of Washington, Seattle, 98105, United States
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4
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Mohan G, Khan I, Diaz SM, Kamocka MM, Hulsman LA, Ahmed S, Neumann CR, Jorge MD, Gordillo GM, Sen CK, Sinha M, Hassanein AH. Quantification of Lymphangiogenesis in the Murine Lymphedema Tail Model Using Intravital Microscopy. Lymphat Res Biol 2024; 22:195-202. [PMID: 38699876 PMCID: PMC11310576 DOI: 10.1089/lrb.2023.0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2024] Open
Abstract
Background: Lymphedema is chronic limb swelling resulting from lymphatic dysfunction. It affects an estimated five million Americans. There is no cure for this disease. Assessing lymphatic growth is essential in developing novel therapeutics. Intravital microscopy (IVM) is a powerful imaging tool for investigating various biological processes in live animals. Tissue nanotransfection technology (TNT) facilitates a direct, transcutaneous nonviral vector gene delivery using a chip with nanochannel poration in a rapid (<100 ms) focused electric field. TNT was used in this study to deliver the genetic cargo in the murine tail lymphedema to assess the lymphangiogenesis. The purpose of this study is to experimentally evaluate the applicability of IVM to visualize and quantify lymphatics in the live mice model. Methods and Results: The murine tail model of lymphedema was utilized. TNT was applied to the murine tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: TNTpCMV6 group receives pCMV6 (expression vector backbone alone) (n = 6); TNTProx1 group receives pCMV6-Prox1 (n = 6). Lymphatic vessels (fluorescein isothiocyanate [FITC]-dextran stained) and lymphatic branch points (indicating lymphangiogenesis) were analyzed with the confocal/multiphoton microscope. The experimental group TNTProx1 exhibited reduced postsurgical tail lymphedema and increased lymphatic distribution compared to TNTpCMV6 group. More lymphatic branching points (>3-fold) were observed at the TNT site in TNTProx1 group. Conclusions: This study demonstrates a novel, powerful imaging tool for investigating lymphatic vessels in live murine tail model of lymphedema. IVM can be utilized for functional assessment of lymphatics and visualization of lymphangiogenesis following gene-based therapy.
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Affiliation(s)
- Ganesh Mohan
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Imran Khan
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Stephanie M. Diaz
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Malgorzata M. Kamocka
- Indiana Center for Biological Microscopy, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Luci A. Hulsman
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Shahnur Ahmed
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Colby R. Neumann
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Miguel D. Jorge
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Gayle M. Gordillo
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
- McGowan Institute for Regenerative Medicine, Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Chandan K. Sen
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
- McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mithun Sinha
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Aladdin H. Hassanein
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
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5
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Korolj A, Kohler RH, Scott E, Halabi EA, Lucas K, Carlson JC, Weissleder R. Perfusion Window Chambers Enable Interventional Analyses of Tumor Microenvironments. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2304886. [PMID: 37870204 PMCID: PMC10700240 DOI: 10.1002/advs.202304886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/29/2023] [Indexed: 10/24/2023]
Abstract
Intravital microscopy (IVM) allows spatial and temporal imaging of different cell types in intact live tissue microenvironments. IVM has played a critical role in understanding cancer biology, invasion, metastases, and drug development. One considerable impediment to the field is the inability to interrogate the tumor microenvironment and its communication cascades during disease progression and therapeutic interventions. Here, a new implantable perfusion window chamber (PWC) is described that allows high-fidelity in vivo microscopy, local administration of stains and drugs, and longitudinal sampling of tumor interstitial fluid. This study shows that the new PWC design allows cyclic multiplexed imaging in vivo, imaging of drug action, and sampling of tumor-shed materials. The PWC will be broadly useful as a novel perturbable in vivo system for deciphering biology in complex microenvironments.
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Affiliation(s)
- Anastasia Korolj
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
- Department of Systems BiologyHarvard Medical School200 Longwood AveBostonMA02115USA
| | - Rainer H. Kohler
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
| | - Ella Scott
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
| | - Elias A. Halabi
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
| | - Kilean Lucas
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
| | - Jonathan C.T. Carlson
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
- Cancer CenterMassachusetts General Hospital55 Fruit StreetBostonMA02114USA
| | - Ralph Weissleder
- Center for Systems BiologyMassachusetts General Hospital185 Cambridge St, CPZN 5206BostonMA02114USA
- Department of Systems BiologyHarvard Medical School200 Longwood AveBostonMA02115USA
- Cancer CenterMassachusetts General Hospital55 Fruit StreetBostonMA02114USA
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6
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Kim G, Park HS, Shin P, Eom T, Yoon JH, Jeong Y, Oh WY. Direct Blood Cell Flow Imaging in Microvascular Networks. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2302244. [PMID: 37309282 DOI: 10.1002/smll.202302244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/19/2023] [Indexed: 06/14/2023]
Abstract
Blood flow dynamics in microvascular networks are intimately related to the health of tissues and organs. While numerous imaging modalities and techniques have been developed to assess blood flow dynamics for various applications, their utilization has been hampered by limited imaging speed and indirect quantification of blood flow dynamics. Here, direct blood cell flow imaging (DBFI) is demonstrated that provides visualization of individual motions of blood cells over a field of 0.71 mm × 1.42 mm with a time resolution of 0.69 ms (1450 frames s-1 ) without using any exogenous agents. DBFI enables precise dynamic analysis of blood cell flow velocities and fluxes in various vessels over a large field, from capillaries to arteries and veins, with unprecedented time resolution. Three exemplary applications of DBFI, quantification of blood flow dynamics of 3D vascular networks, analysis of heartbeat induced blood flow dynamics, and analysis of blood flow dynamics of neurovascular coupling, illustrate the potential of this new imaging technology.
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Affiliation(s)
- Gyounghwan Kim
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Hyun-Sang Park
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Paul Shin
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Taeguk Eom
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Jin-Hui Yoon
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Yong Jeong
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Wang-Yuhl Oh
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
- KI for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
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7
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Liu L, Qu Y, Cheng L, Yoon CW, He P, Monther A, Guo T, Chittle S, Wang Y. Engineering chimeric antigen receptor T cells for solid tumour therapy. Clin Transl Med 2022; 12:e1141. [PMID: 36495108 PMCID: PMC9736813 DOI: 10.1002/ctm2.1141] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/22/2022] [Accepted: 11/26/2022] [Indexed: 12/13/2022] Open
Abstract
Cell-based immunotherapy, for example, chimeric antigen receptor T (CAR-T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR-based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR-T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR-T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR-T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME-associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME-associated factors. Lastly, the future directions for engineering efficient CAR-T cells for solid tumour therapy will be discussed.
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Affiliation(s)
- Longwei Liu
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Yunjia Qu
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Leonardo Cheng
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Chi Woo Yoon
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Peixiang He
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Abdula Monther
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Tianze Guo
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Sarah Chittle
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Yingxiao Wang
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
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8
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Intravital microscopy for real-time monitoring of drug delivery and nanobiological processes. Adv Drug Deliv Rev 2022; 189:114528. [PMID: 36067968 DOI: 10.1016/j.addr.2022.114528] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/10/2022] [Accepted: 08/30/2022] [Indexed: 01/24/2023]
Abstract
Intravital microscopy (IVM) expands our understanding of cellular and molecular processes, with applications ranging from fundamental biology to (patho)physiology and immunology, as well as from drug delivery to drug processing and drug efficacy testing. In this review, we highlight modalities, methods and model organisms that make up today's IVM landscape, and we present how IVM - via its high spatiotemporal resolution - enables analysis of metabolites, small molecules, nanoparticles, immune cells, and the (tumor) tissue microenvironment. We furthermore present examples of how IVM facilitates the elucidation of nanomedicine kinetics and targeting mechanisms, as well as of biological processes such as immune cell death, host-pathogen interactions, metabolic states, and disease progression. We conclude by discussing the prospects of IVM clinical translation and examining the integration of machine learning in future IVM practice.
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9
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Qureshi MM, Allam N, Peters T, Demidov V, Vitkin A. Detection and differentiation of semi-transparent materials simulating biological structures using optical coherence tomography: a phantom study. JOURNAL OF BIOMEDICAL OPTICS 2022; 27:100501. [PMID: 36221173 PMCID: PMC9553520 DOI: 10.1117/1.jbo.27.10.100501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/14/2022] [Indexed: 06/16/2023]
Abstract
SIGNIFICANCE Lymphatic and peripheral nervous system imaging is of prime importance for monitoring various important pathologic processes including cancer development and metastasis, and response to therapy. AIM Optical coherence tomography (OCT) is a promising approach for this imaging task but is challenged by the near-transparent nature of these structures. Our aim is to detect and differentiate semi-transparent materials using OCT texture analysis, toward label-free neurography and lymphography. APPROACH We have recently demonstrated an innovative OCT texture analysis-based approach that used speckle statistics to image lymphatics and nerves in-vivo that does not rely on negative contrast. However, these two near-transparent structures could not be easily differentiated from each other in the texture analysis parameter space. Here, we perform a rigorous follow-up study to improve upon this differentiation in controlled phantoms mimicking the optical properties of these tissues. RESULTS The results of the three-parameter Rayleigh distribution fit to the OCT images of six types of tissue-mimicking materials varying in transparency and biophysical properties demonstrate clear differences between them, suggesting routes for improved lymphatics-nerves differentiation. CONCLUSIONS We demonstrate a novel OCT texture analysis-based lymphatics-nerves differentiation methodology in tissue-simulating phantoms. Future work will focus on longitudinal in-vivo lymphangiography and neurography in response to cancer therapeutics toward adaptive personalized medicine.
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Affiliation(s)
- Muhammad Mohsin Qureshi
- Princess Margaret Cancer Centre, Division of Biophysics and Bioimaging, Toronto, Ontario, Canada
| | - Nader Allam
- University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
| | - Taylor Peters
- University of Toronto, Division of Engineering Science, Ontario, Canada
| | - Valentin Demidov
- Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Alex Vitkin
- Princess Margaret Cancer Centre, Division of Biophysics and Bioimaging, Toronto, Ontario, Canada
- University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
- University of Toronto, Department of Radiation Oncology, Toronto, Ontario, Canada
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10
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Sahu A, Kose K, Kraehenbuehl L, Byers C, Holland A, Tembo T, Santella A, Alfonso A, Li M, Cordova M, Gill M, Fox C, Gonzalez S, Kumar P, Wang AW, Kurtansky N, Chandrani P, Yin S, Mehta P, Navarrete-Dechent C, Peterson G, King K, Dusza S, Yang N, Liu S, Phillips W, Guitera P, Rossi A, Halpern A, Deng L, Pulitzer M, Marghoob A, Chen CSJ, Merghoub T, Rajadhyaksha M. In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response. Nat Commun 2022; 13:5312. [PMID: 36085288 PMCID: PMC9463451 DOI: 10.1038/s41467-022-32738-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/12/2022] [Indexed: 12/03/2022] Open
Abstract
Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into ‘hot’ and ‘cold’ is static, relying solely on T-cell infiltration in single-time single-site biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients. Standard assessment of immune infiltration of biopsies is not sufficient to accurately predict response to immunotherapy. Here, the authors show that reflectance confocal microscopy can be used to quantify dynamic vasculature and inflammatory features to better predict treatment response in skin cancers.
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Affiliation(s)
- Aditi Sahu
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Kivanc Kose
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lukas Kraehenbuehl
- Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Candice Byers
- Roux Institute, Northeastern University, Portland, ME, USA.,Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA
| | - Aliya Holland
- Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Teguru Tembo
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | | | - Anabel Alfonso
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Madison Li
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Miguel Cordova
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melissa Gill
- SUNY Downstate Health Sciences University, Brooklyn, NY, USA.,Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital Solna, Stockholm, Sweden.,Faculty of Medicine and Health Sciences, University of Alcala, Madrid, Spain
| | - Christi Fox
- Caliber Imaging and Diagnostics, Rochester, NY, USA
| | - Salvador Gonzalez
- Faculty of Medicine and Health Sciences, University of Alcala, Madrid, Spain
| | - Piyush Kumar
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | | | - Shen Yin
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paras Mehta
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Cristian Navarrete-Dechent
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gary Peterson
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kimeil King
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stephen Dusza
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ning Yang
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shuaitong Liu
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Pascale Guitera
- Sydney Melanoma Diagnostic Center, Sydney, NSW, Australia.,Melanoma Institute Australia, Wollstonecraft, NSW, Australia
| | - Anthony Rossi
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Allan Halpern
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liang Deng
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medicine, New York, NY, USA
| | | | | | | | - Taha Merghoub
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Parker Institute for Cancer Immunotherapy, Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Weill Cornell Medicine, New York, NY, USA
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11
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Martin JD, Lanning RM, Chauhan VP, Martin MR, Mousa AS, Kamoun WS, Han HS, Lee H, Stylianopoulos T, Bawendi MG, Duda DG, Brown EB, Padera TP, Fukumura D, Jain RK. Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition. Clin Cancer Res 2022; 28:3076-3090. [PMID: 35584239 PMCID: PMC9355624 DOI: 10.1158/1078-0432.ccr-22-0486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/14/2022] [Accepted: 05/11/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. EXPERIMENTAL DESIGN We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). RESULTS We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. CONCLUSIONS High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.
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Affiliation(s)
- John D. Martin
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.,Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Ryan M. Lanning
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.,Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts
| | - Vikash P. Chauhan
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.,School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts
| | - Margaret R. Martin
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ahmed S. Mousa
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Walid S. Kamoun
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Hee-Sun Han
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Hang Lee
- Biostatistics Center, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts
| | - Triantafyllos Stylianopoulos
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Moungi G. Bawendi
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Dan G. Duda
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Edward B. Brown
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Timothy P. Padera
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Rakesh K. Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.,Corresponding Author: Rakesh K. Jain, Department of Radiation Oncology, 100 Blossom Street, Cox 7, Boston, MA 02114. E-mail:
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12
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Chaigneau E, Charpak S. Measurement of Blood Velocity With Laser Scanning Microscopy: Modeling and Comparison of Line-Scan Image-Processing Algorithms. Front Physiol 2022; 13:848002. [PMID: 35464098 PMCID: PMC9022085 DOI: 10.3389/fphys.2022.848002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/22/2022] [Indexed: 11/13/2022] Open
Abstract
Laser scanning microscopy is widely used to measure blood hemodynamics with line-scans in physiological and pathological vessels. With scans of broken lines, i.e., lines made of several segments with different orientations, it also allows simultaneous monitoring of vessel diameter dynamics or the activity of specific cells. Analysis of red blood cell (RBC) velocity from line-scans requires specific image-processing algorithms, as angle measurements, Line-Scanning Particle Image Velocimetry (LSPIV) or Fourier transformation of line-scan images. The conditions under which these image-processing algorithms give accurate measurements have not been fully characterized although the accuracy of measurements vary according to specific experimental parameters: the vessel type, the RBC velocity, the scanning parameters, and the image signal to noise ratio. Here, we developed mathematical models for the three previously mentioned line-scan image-processing algorithms. Our models predict the experimental conditions in which RBC velocity measurements are accurate. We illustrate the case of different vessel types and give the parameter space available for each of them. Last, we developed a software generating artificial line-scan images and used it to validate our models.
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Affiliation(s)
- Emmanuelle Chaigneau
- Institut de la Vision, INSERM U968, Paris, France
- Institut de la Vision, CNRS UMR 7210, Paris, France
- Institut de la Vision, Sorbonne Université, Paris, France
- *Correspondence: Emmanuelle Chaigneau,
| | - Serge Charpak
- Institut de la Vision, INSERM U968, Paris, France
- Institut de la Vision, CNRS UMR 7210, Paris, France
- Institut de la Vision, Sorbonne Université, Paris, France
- Serge Charpak,
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13
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Chapelin F, Gedaly R, Sweeney Z, Gossett LJ. Prognostic Value of Fluorine-19 MRI Oximetry Monitoring in cancer. Mol Imaging Biol 2022; 24:208-219. [PMID: 34708396 DOI: 10.1007/s11307-021-01648-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 11/24/2022]
Abstract
Hypoxia is a key prognostic indicator in most solid tumors, as it is correlated to tumor angiogenesis, metastasis, recurrence, and response to therapy. Accurate measurement and mapping of tumor oxygenation profile and changes upon intervention could facilitate disease progression assessment and assist in treatment planning. Currently, no gold standard exists for non-invasive spatiotemporal measurement of hypoxia. Magnetic resonance imaging (MRI) represents an attractive option as it is a clinically available and non-ionizing imaging modality. Specifically, perfluorocarbon (PFC) beacons can be externally introduced into the tumor tissue and the linear dependence of their spin-lattice relaxation rate (R1) on the local partial pressure of oxygen (pO2) exploited for real-time tissue oxygenation monitoring in vivo. In this review, we will focus on early studies and recent developments of fluorine-19 MRI and spectroscopy (MRS) for evaluation of tumor oximetry and response to therapy.
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Affiliation(s)
- Fanny Chapelin
- F. Joseph Halcomb III, M.D. Department of Biomedical Engineering, University of Kentucky, 514F RMB, 143 Graham Avenue, Lexington, KY, USA.
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
| | - Roberto Gedaly
- Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, USA
- Department of Surgery, Transplant Division, University of Kentucky, Lexington, KY, USA
| | - Zachary Sweeney
- College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Liza J Gossett
- F. Joseph Halcomb III, M.D. Department of Biomedical Engineering, University of Kentucky, 514F RMB, 143 Graham Avenue, Lexington, KY, USA
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14
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Agrud A, Subburaju S, Goel P, Ren J, Kumar AS, Caldarone BJ, Dai W, Chavez J, Fukumura D, Jain RK, Kloner RA, Vasudevan A. Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction. Sci Rep 2022; 12:4922. [PMID: 35318369 PMCID: PMC8941104 DOI: 10.1038/s41598-022-08806-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/04/2022] [Indexed: 11/17/2022] Open
Abstract
Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABAA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABAA receptor β3 subunit endothelial cell conditional knockout (Gabrb3ECKO) mice, the β3 subunit is deleted selectively from endothelial cells, therefore endothelial GABAA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3ECKO telencephalon that persists in the adult neocortex. Gabrb3ECKO mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3ECKO mice by evaluating cortical blood flow, examine the consequences of loss of endothelial Gabrb3 on cardiac tissue, and define more in-depth altered behaviors. Red blood cell velocity and blood flow were increased in the cortical microcirculation of the Gabrb3ECKO mice. The Gabrb3ECKO mice had a reduction in vessel densities in the heart, similar to the brain; exhibited wavy, myocardial fibers, with elongated 'worm-like' nuclei in their cardiac histology, and developed hypertension. Additional alterations in behavioral function were observed in the Gabrb3ECKO mice such as increased spontaneous exploratory activity and rearing in an open field, reduced short term memory, decreased ambulatory activity in CLAMS testing, and altered prepulse inhibition to startle, an important biomarker of psychiatric diseases such as schizophrenia. Our results imply that vascular Gabrb3 is a key player in the brain as well as the heart, and its loss in both organs can lead to concurrent development of psychiatric and cardiac dysfunction.
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Affiliation(s)
- Anass Agrud
- grid.280933.30000 0004 0452 8371Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105 USA
| | - Sivan Subburaju
- grid.280933.30000 0004 0452 8371Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105 USA ,grid.38142.3c000000041936754XDepartment of Psychiatry, Harvard Medical School, Boston, MA 02215 USA ,grid.240206.20000 0000 8795 072XDivision of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478 USA
| | - Pranay Goel
- grid.280933.30000 0004 0452 8371Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105 USA
| | - Jun Ren
- grid.32224.350000 0004 0386 9924Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA
| | - Ashwin Srinivasan Kumar
- grid.32224.350000 0004 0386 9924Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA ,grid.116068.80000 0001 2341 2786Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
| | - Barbara J. Caldarone
- grid.38142.3c000000041936754XMouse Behavior Core, Department of Genetics, Harvard Medical School, Boston, MA USA
| | - Wangde Dai
- grid.280933.30000 0004 0452 8371Huntington Medical Research Institutes, Pasadena, CA USA ,grid.42505.360000 0001 2156 6853Division of Cardiovascular Medicine, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA USA
| | - Jesus Chavez
- grid.280933.30000 0004 0452 8371Huntington Medical Research Institutes, Pasadena, CA USA ,grid.42505.360000 0001 2156 6853Division of Cardiovascular Medicine, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA USA
| | - Dai Fukumura
- grid.32224.350000 0004 0386 9924Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA
| | - Rakesh K. Jain
- grid.32224.350000 0004 0386 9924Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA
| | - Robert A. Kloner
- grid.280933.30000 0004 0452 8371Huntington Medical Research Institutes, Pasadena, CA USA ,grid.42505.360000 0001 2156 6853Division of Cardiovascular Medicine, Department of Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA USA
| | - Anju Vasudevan
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA, 91105, USA.
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15
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Abstract
Atherosclerosis is a lipid-driven inflammatory disorder that narrows the arterial lumen and can induce life-threatening complications from coronary artery disease, cerebrovascular disease, and peripheral artery disease. On a mechanistic level, the development of novel cellular-resolution intravital microscopy imaging approaches has recently enabled in vivo studies of underlying biological processes governing disease onset and progress. In particular, multiphoton microscopy has emerged as a promising intravital imaging tool utilizing two-photon-excited fluorescence and second-harmonic generation that provides subcellular resolution and increased imaging depths beyond confocal and epifluorescence microscopy. In this chapter, we describe the state-of-the-art multiphoton microscopy applied to the study of murine atherosclerosis.
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16
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Wang X, Zhang D, Zhang X, Xing Y, Wu J, Sui X, Huang X, Chang G, Li L. Application of Multiphoton Microscopic Imaging in Study of Gastric Cancer. Technol Cancer Res Treat 2022; 21:15330338221133244. [PMID: 36379591 PMCID: PMC9676310 DOI: 10.1177/15330338221133244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2024] Open
Abstract
Multiphoton microscopy (MPM) imaging relies on the nonlinear interaction between ultrashort optical pulses and the samples to achieve image contrast. Featuring larger penetration depth, less phototoxicity, 3-dimensional sectioning capability, no need for labeling, MPM become a powerful medical imaging technique that can identify structural characteristics of tissues at the cellular and subcellular levels. In this review paper, we introduce the working principle of MPM imaging, present the current results of MPM imaging applied to the study of gastric tumors, and discuss the future prospects of this interdisciplinary research field.
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Affiliation(s)
- Xiaoying Wang
- Strategic Support Force Medical Center, Beijing, China
| | - Di Zhang
- Ningxia Jingyuan County People's Hospital, Ningxia, China
| | - Xiaochun Zhang
- General Hospital of Ningxia Medical University, Ningxia, China
| | - Yuting Xing
- Institute of Physics, Chinese Academy of Sciences, Beijing, China
| | - Jihua Wu
- Strategic Support Force Medical Center, Beijing, China
| | - Xinke Sui
- Strategic Support Force Medical Center, Beijing, China
| | - Xin Huang
- Strategic Support Force Medical Center, Beijing, China
| | - Guoqing Chang
- Institute of Physics, Chinese Academy of Sciences, Beijing, China
| | - Lianyong Li
- Strategic Support Force Medical Center, Beijing, China
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17
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Eckrich J, Ruan Y, Jiang S, Frenis K, Rodriguez-Blanco G, Maas AP, Jimenez MTB, Kuntic M, Oelze M, Hahad O, Li H, Steven S, Strieth S, von Kriegsheim A, Münzel T, Daiber A, Gericke A, Ernst BP. In vivo analysis of noise dependent activation of white blood cells and microvascular dysfunction in mice. MethodsX 2021; 8:101540. [PMID: 34754808 PMCID: PMC8563683 DOI: 10.1016/j.mex.2021.101540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/05/2021] [Indexed: 11/22/2022] Open
Abstract
This article contains supporting information on data collection for the research article entitled “Aircraft noise exposure drives the activation of white blood cells and induces microvascular dysfunction in mice” by Eckrich et al. We found that noise-induced stress triggered microvascular dysfunction via involvement of innate immune-derived reactive oxygen species. In this article, we present the instrumentation of mice with dorsal skinfold chambers for in vivo microscopic imaging of blood flow, interaction of leukocytes with the vascular wall (also by fluorescent labelling of blood cells) and vessel diameter. In addition, we explain the preparation of cerebral arterioles for measurement of vascular reactivity in vitro.
visualization of noise-dependent effects in dorsal skinfold chamber. in vivo microscopy of noise-dependent activation of white blood cells. analysis of noise-dependent microvascular dysfunction in dorsal skinfold chamber and cannulated cerebral arterioles.
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Affiliation(s)
- Jonas Eckrich
- Department of Otorhinolaryngology, University Medical Center Bonn (UKB), Bonn, Germany
| | - Yue Ruan
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Subao Jiang
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Katie Frenis
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | | | | | - Maria Teresa Bayo Jimenez
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marin Kuntic
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Matthias Oelze
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Omar Hahad
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Huige Li
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Sebastian Steven
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Sebastian Strieth
- Department of Otorhinolaryngology, University Medical Center Bonn (UKB), Bonn, Germany
| | | | - Thomas Münzel
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
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18
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Tsakanova G, Arakelova E, Matevosyan L, Petrosyan M, Gasparyan S, Harutyunyan K, Babayan N. The role of women scientists in the development of ultrashort pulsed laser technology-based biomedical research in Armenia. Int J Radiat Biol 2021; 98:489-495. [PMID: 34623213 DOI: 10.1080/09553002.2021.1987566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE To describe the contribution of women scientists in the development of biomedical studies conducted on research facilities based on the ultrashort pulsed laser technologies in Armenia. CONCLUSION Given the opportunities provided by the ultrashort pulsed laser driven two-photon microscopy and electron beam linac facilities at CANDLE Synchrotron Research Institute, the Armenian women scientists initiated and conducted interdisciplinary research to understand of the biomedical effects of ultrashort pulsed electron beam irradiation, as well as to experience and apply the advantages of the two-photon microscopy in their fields of research. Women scientists had a crucial role and unique impact in the development of ultrashort pulsed laser technology-based biomedical studies in Armenia.
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Affiliation(s)
- Gohar Tsakanova
- CANDLE Synchrotron Research Institute, Yerevan, Armenia.,Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
| | - Elina Arakelova
- Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
| | | | - Mariam Petrosyan
- Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
| | - Seda Gasparyan
- Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
| | | | - Nelly Babayan
- Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia.,Department of Genetics and Cytology, Faculty of Biology, Yerevan State University, Yerevan, Armenia
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19
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Taranda J, Turcan S. 3D Whole-Brain Imaging Approaches to Study Brain Tumors. Cancers (Basel) 2021; 13:cancers13081897. [PMID: 33920839 PMCID: PMC8071100 DOI: 10.3390/cancers13081897] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/05/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Brain tumors integrate into the brain and consist of tumor cells with different molecular alterations. During brain tumor pathogenesis, a variety of cell types surround the tumors to either inhibit or promote tumor growth. These cells are collectively referred to as the tumor microenvironment. Three-dimensional and/or longitudinal visualization approaches are needed to understand the growth of these tumors in time and space. In this review, we present three imaging modalities that are suitable or that can be adapted to study the volumetric distribution of malignant or tumor-associated cells in the brain. In addition, we highlight the potential clinical utility of some of the microscopy approaches for brain tumors using exemplars from solid tumors. Abstract Although our understanding of the two-dimensional state of brain tumors has greatly expanded, relatively little is known about their spatial structures. The interactions between tumor cells and the tumor microenvironment (TME) occur in a three-dimensional (3D) space. This volumetric distribution is important for elucidating tumor biology and predicting and monitoring response to therapy. While static 2D imaging modalities have been critical to our understanding of these tumors, studies using 3D imaging modalities are needed to understand how malignant cells co-opt the host brain. Here we summarize the preclinical utility of in vivo imaging using two-photon microscopy in brain tumors and present ex vivo approaches (light-sheet fluorescence microscopy and serial two-photon tomography) and highlight their current and potential utility in neuro-oncology using data from solid tumors or pathological brain as examples.
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20
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Fate Mapping of Cancer Cells in Metastatic Lymph Nodes Using Photoconvertible Proteins. Methods Mol Biol 2021. [PMID: 33704727 DOI: 10.1007/978-1-0716-1205-7_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The lymph node microenvironment is extremely dynamic and responds to immune stimuli in the host by reprogramming immune, stromal, and endothelial cells. In normal physiological conditions, the lymph node will initiate an appropriate immune response to clear external threats that the host may experience. However, in metastatic disease, cancer cells often colonize local lymph nodes, disrupt immune function, and even leave the lymph node to create additional metastases. Understanding how cancer cells enter, colonize, survive, proliferate, and interact with other cell types in the lymph node is challenging. Here, we describe the use of photoconvertible fluorescent proteins to label and trace the fate of cancer cells once they enter the lymph node.
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21
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Shen M, Xu M, Zhong F, Crist MC, Prior AB, Yang K, Allaire DM, Choueiry F, Zhu J, Shi H. A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2. Cells 2021; 10:cells10020455. [PMID: 33672651 PMCID: PMC7924215 DOI: 10.3390/cells10020455] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.
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Affiliation(s)
- Minqian Shen
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Mengyang Xu
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - Fanyi Zhong
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - McKenzie C. Crist
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Anjali B. Prior
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Kundi Yang
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (F.Z.); (K.Y.)
| | - Danielle M. Allaire
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
| | - Fouad Choueiry
- Department of Human Sciences, College of Education and Human Ecology, Columbus, OH 43210, USA;
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Jiangjiang Zhu
- Department of Human Sciences, College of Education and Human Ecology, Columbus, OH 43210, USA;
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: (J.Z.); (H.S.); Tel.: +1-614-685-2226 (J.Z.); +1-513-529-3162 (H.S.)
| | - Haifei Shi
- Department of Biology, Miami University, Oxford, OH 45056, USA; (M.S.); (M.X.); (M.C.C.); (A.B.P.); (D.M.A.)
- Correspondence: (J.Z.); (H.S.); Tel.: +1-614-685-2226 (J.Z.); +1-513-529-3162 (H.S.)
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Notohamiprodjo S, Varasteh Z, Beer AJ, Niu G, Chen X(S, Weber W, Schwaiger M. Tumor Vasculature. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00090-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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24
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Liang Y, Walczak P. Long term intravital single cell tracking under multiphoton microscopy. J Neurosci Methods 2020; 349:109042. [PMID: 33340557 DOI: 10.1016/j.jneumeth.2020.109042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022]
Abstract
Visualizing and tracking cells over time in a living organism has been a much-coveted dream before the invention of intravital microscopy. The opaque nature of tissue was a major hurdle that was remedied by the multiphoton microscopy. With the advancement of optical imaging and fluorescent labeling tools, intravital high resolution imaging has become increasingly accessible over the past few years. Long-term intravital tracking of single cells (LIST) under multiphoton microscopy provides a unique opportunity to gain insight into the longitudinal changes in the morphology, migration, or function of cells or subcellular structures. It is particularly suitable for studying slow-evolving cellular and molecular events during normal development or disease progression, without losing the opportunity of catching fast events such as calcium signals. Here, we review the application of LIST under 2-photon microscopy in various fields of neurobiology and discuss challenges and new directions in labeling and imaging methods for LIST. Overall, this review provides an overview of current applications of LIST in mammals, which is an emerging field that will contribute to a better understanding of essential molecular and cellular events in health and disease.
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Affiliation(s)
- Yajie Liang
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Piotr Walczak
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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25
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Gopal AA, Kazarine A, Dubach JM, Wiseman PW. Recent advances in nonlinear microscopy: Deep insights and polarized revelations. Int J Biochem Cell Biol 2020; 130:105896. [PMID: 33253831 DOI: 10.1016/j.biocel.2020.105896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 11/16/2022]
Abstract
Nonlinear microscopy is a technique that utilizes nonlinear interactions between light and matter to image fluorescence and scattering phenomena in biological tissues. Very high peak intensities from focused short pulsed lasers are required for nonlinear excitation due to the extremely low probability of the simultaneous arrival of multiple photons of lower energy to excite fluorophores or interact with selective structures for harmonic generation. Combined with reduced scattering from the utilization of longer wavelengths, the inherent spatial confinement associated with achieving simultaneous arrival of photons within the focal volume enables deep imaging with low out-of-focus background for nonlinear imaging. This review provides an introduction to the different contrast mechanisms available with nonlinear imaging and instrumentation commonly used in nonlinear microscopy. Furthermore, we discuss some recent advances in nonlinear microscopy to extend the imaging penetration depth, conduct histopathological investigations on fresh tissues and examine the molecular order and orientation of molecules using polarization nonlinear microscopy.
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Affiliation(s)
- A A Gopal
- Center for Systems Biology and Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Chemistry, McGill University, Montreal, Quebec, Canada
| | - A Kazarine
- Department of Chemistry, McGill University, Montreal, Quebec, Canada
| | - J M Dubach
- Center for Systems Biology and Institute for Innovation in Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - P W Wiseman
- Department of Chemistry, McGill University, Montreal, Quebec, Canada; Department of Physics, McGill University, Montreal, Quebec, Canada.
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26
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Haase K, Offeddu GS, Gillrie MR, Kamm RD. Endothelial Regulation of Drug Transport in a 3D Vascularized Tumor Model. ADVANCED FUNCTIONAL MATERIALS 2020; 30:2002444. [PMID: 33692661 PMCID: PMC7939067 DOI: 10.1002/adfm.202002444] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Indexed: 05/06/2023]
Abstract
Drug discovery and efficacy in cancer treatments are limited by the inability of pre-clinical models to predict successful outcomes in humans. Limitations remain partly due to their lack of a physiologic tumor microenvironment (TME), which plays a considerable role in drug delivery and tumor response to therapy. Chemotherapeutics and immunotherapies rely on transport through the vasculature, via the smallest capillaries and stroma to the tumor, where passive and active transport processes are at play. Here, a 3D vascularized tumor on-chip is used to examine drug delivery in a relevant TME within a large bed of perfusable vasculature. This system demonstrates highly localized pathophysiological effects of two tumor spheroids (Skov3 and A549) which cause significant changes in vessel density and barrier function. Paclitaxel (Taxol) uptake is examined through diffusivity measurements, functional efflux assays and accumulation of the fluorescent-conjugated drug within the TME. Due to vascular and stromal contributions, differences in the response of vascularized tumors to Taxol (shrinkage and CD44 expression) are apparent compared with simpler models. This model specifically allows for examination of spatially resolved tumor-associated endothelial dysfunction, likely improving the representation of in vivo drug distribution, and has potential for development into a more predictable model of drug delivery.
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Affiliation(s)
- Kristina Haase
- Massachusetts Institute of Technology, Massachusetts, 02139, USA
| | | | - Mark R Gillrie
- Massachusetts Institute of Technology, Massachusetts, 02139, USA; University of Calgary, Calgary, T2N 1N4, Canada
| | - Roger D Kamm
- Massachusetts Institute of Technology, Massachusetts, 02139, USA
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Solimando AG, Summa SD, Vacca A, Ribatti D. Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling. Cancers (Basel) 2020; 12:cancers12113380. [PMID: 33203154 PMCID: PMC7696032 DOI: 10.3390/cancers12113380] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/08/2020] [Accepted: 11/12/2020] [Indexed: 12/11/2022] Open
Abstract
Simple Summary A clinical decision and study design investigating the level and extent of angiogenesis modulation aimed at vascular normalization without rendering tissues hypoxic is key and represents an unmet medical need. Specifically, determining the active concentration and optimal times of the administration of antiangiogenetic drugs is crucial to inhibit the growth of any microscopic residual tumor after surgical resection and in the pre-malignant and smolder neoplastic state. This review uncovers the pre-clinical translational insights crucial to overcome the caveats faced so far while employing anti-angiogenesis. This literature revision also explores how abnormalities in the tumor endothelium harm the crosstalk with an effective immune cell response, envisioning a novel combination with other anti-cancer drugs and immunomodulatory agents. These insights hold vast potential to both repress tumorigenesis and unleash an effective immune response. Abstract Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically.
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Affiliation(s)
- Antonio Giovanni Solimando
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine ‘G. Baccelli’, University of Bari Medical School, 70124 Bari, Italy;
- Istituto di Ricovero e Cura a Carattere Scientifico-IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy
- Correspondence: (A.G.S.); (D.R.); Tel.: +39-3395626475 (A.G.S.); +39-080-5478326 (D.R.)
| | - Simona De Summa
- Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy;
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine ‘G. Baccelli’, University of Bari Medical School, 70124 Bari, Italy;
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (A.G.S.); (D.R.); Tel.: +39-3395626475 (A.G.S.); +39-080-5478326 (D.R.)
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Subburaju S, Kaye S, Choi YK, Baruah J, Datta D, Ren J, Kumar AS, Szabo G, Fukumura D, Jain RK, Elkhal A, Vasudevan A. NAD +-mediated rescue of prenatal forebrain angiogenesis restores postnatal behavior. SCIENCE ADVANCES 2020; 6:6/41/eabb9766. [PMID: 33036972 PMCID: PMC7546698 DOI: 10.1126/sciadv.abb9766] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/26/2020] [Indexed: 06/11/2023]
Abstract
Intrinsic defects within blood vessels from the earliest developmental time points can directly contribute to psychiatric disease origin. Here, we show that nicotinamide adenine dinucleotide (NAD+), administered during a critical window of prenatal development, in a mouse model with dysfunctional endothelial γ-aminobutyric acid type A (GABAA) receptors (Gabrb3 endothelial cell knockout mice), results in a synergistic repair of impaired angiogenesis and normalization of brain development, thus preventing the acquisition of abnormal behavioral symptoms. The prenatal NAD+ treatment stimulated extensive cellular and molecular changes in endothelial cells and restored blood vessel formation, GABAergic neuronal development, and forebrain morphology by recruiting an alternate pathway for cellular repair, via previously unknown transcriptional mechanisms and purinergic receptor signaling. Our findings illustrate a novel and powerful role for NAD+ in sculpting prenatal brain development that has profound implications for rescuing brain blood flow in a permanent and irreversible manner, with long-lasting consequences for mental health outcome.
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Affiliation(s)
- Sivan Subburaju
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA
- Division of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA
| | - Sarah Kaye
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA
- Division of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA
| | - Yong Kee Choi
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA
- Division of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA
| | - Jugajyoti Baruah
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA
- Division of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA
| | - Debkanya Datta
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA
- Division of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA
| | - Jun Ren
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Ashwin Srinivasan Kumar
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Gabor Szabo
- Institute of Experimental Medicine, Medical Gene Technology Unit, 1083 Budapest, Hungary
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Abdallah Elkhal
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Division of Transplantation, Brigham and Women's Hospital, 221 Longwood Avenue, EBRC 309, Boston, MA 02115, USA
| | - Anju Vasudevan
- Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA.
- Department of Psychiatry, Harvard Medical School, Boston, MA, 02215, USA
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McKinley KL, Castillo-Azofeifa D, Klein OD. Tools and Concepts for Interrogating and Defining Cellular Identity. Cell Stem Cell 2020; 26:632-656. [PMID: 32386555 PMCID: PMC7250495 DOI: 10.1016/j.stem.2020.03.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Defining the mechanisms that generate specialized cell types and coordinate their functions is critical for understanding organ development and renewal. New tools and discoveries are challenging and refining our definitions of a cell type. A rapidly growing toolkit for single-cell analyses has expanded the number of markers that can be assigned to a cell simultaneously, revealing heterogeneity within cell types that were previously regarded as homogeneous populations. Additionally, cell types defined by specific molecular markers can exhibit distinct, context-dependent functions; for example, between tissues in homeostasis and those responding to damage. Here we review the current technologies used to identify and characterize cells, and we discuss how experimental and pathological perturbations are adding increasing complexity to our definitions of cell identity.
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Affiliation(s)
- Kara L McKinley
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA
| | - David Castillo-Azofeifa
- Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, USA
| | - Ophir D Klein
- Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
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30
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Fan L, Luo T, Guan Z, Chow YT, Chen S, Wei T, Shakoor A, Lam RHW, Sun D. Gravitational sedimentation-based approach for ultra-simple and flexible cell patterning coculture on microfluidic device. Biofabrication 2020; 12:035005. [PMID: 32182591 DOI: 10.1088/1758-5090/ab80b5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Combining patterning coculture technique with microfluidics enables the reconstruction of complex in-vivo system to facilitate in-vitro studies on cell-cell and cell-environment interactions. However, simple and versatile approaches for patterning coculture of cells on microfluidic platforms remain lacking. In this study, a novel gravitational sedimentation-based approach is presented to achieve ultra-simple and flexible cell patterning coculture on a microfluidic platform, where multiple cell types can be patterned simultaneously to form a well-organized cell coculture. In contrast to other approaches, the proposed approach allows the rapid patterning of multiple cell types in microfluidic channels without the use of sheath flow and a prepatterned functional surface. This feature greatly simplifies the experimental setup, operation, and chip fabrication. Moreover, cell patterning can be adjusted by simply modifying the cell-loading tubing direction, thereby enabling great flexibility for the construction of different cell patterns without complicating the chip design and flow control. A series of physical and biological experiments are conducted to validate the proposed approach. This research paves a new way for building physiologically realistic in-vitro coculture models on microfluidic platforms for various applications, such as cell-cell interaction and drug screening.
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Affiliation(s)
- Lei Fan
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, People's Republic of China
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31
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Matsuda M, Terai K. Experimental pathology by intravital microscopy and genetically encoded fluorescent biosensors. Pathol Int 2020; 70:379-390. [PMID: 32270554 PMCID: PMC7383902 DOI: 10.1111/pin.12925] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/13/2020] [Accepted: 03/16/2020] [Indexed: 01/03/2023]
Abstract
The invention of two‐photon excitation microscopes widens the potential application of intravital microscopy (IVM) to the broad field of experimental pathology. Moreover, the recent development of fluorescent protein‐based, genetically encoded biosensors provides an ideal tool to visualize the cell function in live animals. We start from a brief review of IVM with two‐photon excitation microscopes and genetically encoded biosensors based on the principle of Förster resonance energy transfer (FRET). Then, we describe how IVM using biosensors has revealed the pathogenesis of several disease models.
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Affiliation(s)
- Michiyuki Matsuda
- Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Kenta Terai
- Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
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32
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Lim WY, Zohrabi M, Gopinath JT, Bright VM. Calibration and characteristics of an electrowetting laser scanner. IEEE SENSORS JOURNAL 2020; 20:3496-3503. [PMID: 33746623 PMCID: PMC7977153 DOI: 10.1109/jsen.2019.2959792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
We present a calibration method to correct for fabrication variations and optical misalignment in a two-dimensional electrowetting scanner. These scanners are an attractive option due to being transmissive, nonmechanical, having a large scan angle (±13.7°), and low power consumption (μW). Fabrication imperfections lead to non-uniform deposition of the dielectric or hydrophobic layer which results in actuation inconsistency of each electrode. To demonstrate our calibration method, we scan a 5 × 5 grid target using a four-electrode electrowetting prism and observe a pincushion type optical distortion in the imaging plane. Zemax optical simulations verify that the symmetric distortion is due to the projection of a radial scanning surface onto a flat imaging plane, while in experiment we observe asymmetrical distortion due to optical misalignment and fabrication imperfections. By adjusting the actuation voltages through an iterative Delaunay triangulation interpolation method, the distortion is corrected and saw an improvement in the mean error across 25 grid points from 43 μm (0.117°) to 10 μm (0.027°).
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Affiliation(s)
- Wei Yang Lim
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309 USA
| | - Mo Zohrabi
- Department of Electrical Engineering, University of Colorado, Boulder, CO 80309 USA
| | - Juliet T Gopinath
- Department of Electrical Engineering and Department of Physics, University of Colorado, Boulder, CO 80309 USA
| | - Victor M Bright
- Department of Mechanical Engineering, University of Colorado, Boulder, CO, 80309 USA
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33
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You J, Pan C, Park K, Li A, Du C. In vivo detection of tumor boundary using ultrahigh-resolution optical coherence angiography and fluorescence imaging. JOURNAL OF BIOPHOTONICS 2020; 13:e201960091. [PMID: 31778294 PMCID: PMC7446292 DOI: 10.1002/jbio.201960091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/22/2019] [Accepted: 11/17/2019] [Indexed: 06/01/2023]
Abstract
Accurate detection of early tumor margin is of great preclinical and clinical implications for predicting the survival rate of subjects and assessing the response of tumor microenvironment to chemotherapy or radiation therapy. Here, we report a multimodality optical imaging study on in vivo detection of tumor boundary by analyzing neoangiogenesis of tumor microenvironment (microangiography), microcirculatory blood flow (optical Doppler tomography) and tumor proliferation (green fluorescent protein [GFP] fluorescence). Microangiography demonstrates superior sensitivity (77.7 ± 6.4%) and specificity (98.2 ± 1.7%) over other imaging technologies (eg, optical coherence tomography) for tumor margin detection. Additionally, we report longitudinal in vivo imaging of tumor progression and show that the abrupt tumor cell proliferation did not occur until local capillary density and cerebral blood flow reached their peak approximately 2 weeks after tumor implantation. The unique capability of longitudinal multimodality imaging of tumor angiogenesis may provide new insights in tumor biology and in vivo assessment of the treatment effects on anti-angiogenesis therapy for brain cancer.
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Affiliation(s)
- Jiang You
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Chelsea Pan
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Kicheon Park
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Ang Li
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
| | - Congwu Du
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York
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High spatiotemporal resolution and low photo-toxicity fluorescence imaging in live cells and in vivo. Biochem Soc Trans 2020; 47:1635-1650. [PMID: 31829403 DOI: 10.1042/bst20190020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 12/18/2022]
Abstract
Taking advantage of high contrast and molecular specificity, fluorescence microscopy has played a critical role in the visualization of subcellular structures and function, enabling unprecedented exploration from cell biology to neuroscience in living animals. To record and quantitatively analyse complex and dynamic biological processes in real time, fluorescence microscopes must be capable of rapid, targeted access deep within samples at high spatial resolutions, using techniques including super-resolution fluorescence microscopy, light sheet fluorescence microscopy, and multiple photon microscopy. In recent years, tremendous breakthroughs have improved the performance of these fluorescence microscopies in spatial resolution, imaging speed, and penetration. Here, we will review recent advancements of these microscopies in terms of the trade-off among spatial resolution, sampling speed and penetration depth and provide a view of their possible applications.
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35
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Si P, Honkala A, de la Zerda A, Smith BR. Optical Microscopy and Coherence Tomography of Cancer in Living Subjects. Trends Cancer 2020; 6:205-222. [PMID: 32101724 DOI: 10.1016/j.trecan.2020.01.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 01/05/2020] [Accepted: 01/07/2020] [Indexed: 12/16/2022]
Abstract
Intravital microscopy (IVM) and optical coherency tomography (OCT) are two powerful optical imaging tools that allow visualization of dynamic biological activities in living subjects with subcellular resolutions. Recent advances in labeling and label-free techniques empower IVM and OCT for a wide range of preclinical and clinical cancer imaging, providing profound insights into the complex physiological, cellular, and molecular behaviors of tumors. Preclinical IVM and OCT have elucidated many otherwise inscrutable aspects of cancer biology, while clinical applications of IVM and OCT are revolutionizing cancer diagnosis and therapies. We review important progress in the fields of IVM and OCT for cancer imaging in living subjects, highlighting key technological developments and their emerging applications in fundamental cancer biology research and clinical oncology investigation.
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Affiliation(s)
- Peng Si
- Department of Structural Biology, Stanford University, Stanford, CA 94305, USA; Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA
| | - Alexander Honkala
- Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
| | - Adam de la Zerda
- Department of Structural Biology, Stanford University, Stanford, CA 94305, USA; Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA; The Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
| | - Bryan Ronain Smith
- Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA; Department of Biomedical Engineering and Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, USA.
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36
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Allende Motz AM, Czerski J, Adams DE, Durfee C, Bartels R, Field J, Hoy CL, Squier J. Two-dimensional random access multiphoton spatial frequency modulated imaging. OPTICS EXPRESS 2020; 28:405-424. [PMID: 32118968 PMCID: PMC7053501 DOI: 10.1364/oe.378460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/15/2019] [Accepted: 12/16/2019] [Indexed: 05/17/2023]
Abstract
Spatial frequency modulated imaging (SPIFI) enables the use of an extended excitation source for linear and nonlinear imaging with single element detection. To date, SPIFI has only been used with fixed excitation source geometries. Here, we explore the potential for the SPIFI method when a spatial light modulator (SLM) is used to program the excitation source, opening the door to a more versatile, random access imaging environment. In addition, an in-line, quantitative pulse compensation and measurement scheme is demonstrated using a new technique, spectral phase and amplitude retrieval and compensation (SPARC). This enables full characterization of the light exposure conditions at the focal plane of the random access imaging system, an important metric for optimizing, and reporting imaging conditions within specimens.
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Affiliation(s)
- Alyssa M. Allende Motz
- Department of Physics, Colorado School of Mines, 1532 Illinois St., Golden, CO 80401, USA
| | - John Czerski
- Department of Physics, Colorado School of Mines, 1532 Illinois St., Golden, CO 80401, USA
| | - Daniel E. Adams
- Department of Physics, Colorado School of Mines, 1532 Illinois St., Golden, CO 80401, USA
| | - Charles Durfee
- Department of Physics, Colorado School of Mines, 1532 Illinois St., Golden, CO 80401, USA
| | - Randy Bartels
- Department of Electrical Engineering, Colorado State University, 400 Isotope Dr., Ft. Collins, CO 80523, USA
- Department of Biomedical Engineering, and Molecular Biology, Colorado State University, 400 Isotope Dr., Ft. Collins, CO 80523, USA
| | - Jeff Field
- Department of Electrical Engineering, Colorado State University, 400 Isotope Dr., Ft. Collins, CO 80523, USA
- Department of Biomedical Engineering, and Molecular Biology, Colorado State University, 400 Isotope Dr., Ft. Collins, CO 80523, USA
- Microscope Imaging Network Foundation Core Facility, Colorado State University, 400 Isotope Dr., Ft. Collins, CO 80523, USA
| | | | - Jeff Squier
- Department of Physics, Colorado School of Mines, 1532 Illinois St., Golden, CO 80401, USA
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37
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Wang J, Zhang G, You Z. Design rules for dense and rapid Lissajous scanning. MICROSYSTEMS & NANOENGINEERING 2020; 6:101. [PMID: 34567710 PMCID: PMC8433367 DOI: 10.1038/s41378-020-00211-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 06/10/2020] [Accepted: 08/21/2020] [Indexed: 05/17/2023]
Abstract
Lissajous microscanners are very popular in compact laser-scanning applications, such as solid-state light detection and ranging (LIDAR), owing to their high-quality factor and low power consumption. In the Lissajous scanner driven by a two-axis micro-electro-mechanical system scanning mirror (MEMS-SM), the design theory is insufficient to meet the temporal and spatial resolution at the same time. In this paper, the greatest common divisor of the two-axis driving frequency is used as the temporal resolution, the concept of the fill factor (FF) is used to describe the spatial resolution of the scanner, and a general algorithm for calculating the FF is presented. Combined with the characteristics of the Lissajous trajectory, three design rules of the general Lissajous scanner are proposed, and the design theory of the Lissajous scanner enabling MEMS LIDAR is perfected. Experimental results show that the proposed design rules can effectively meet the LIDAR design requirements.
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Affiliation(s)
- Junya Wang
- Department of Precision Instrument, Tsinghua University, Beijing, China
- State Key Laboratory of Precision Testing Technology and Instruments, Tsinghua University, 10084 Beijing, China
- Information Engineering University, Zhengzhou, China
| | - Gaofei Zhang
- Department of Precision Instrument, Tsinghua University, Beijing, China
- State Key Laboratory of Precision Testing Technology and Instruments, Tsinghua University, 10084 Beijing, China
| | - Zheng You
- Department of Precision Instrument, Tsinghua University, Beijing, China
- State Key Laboratory of Precision Testing Technology and Instruments, Tsinghua University, 10084 Beijing, China
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38
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Lin H, Fan T, Sui J, Wang G, Chen J, Zhuo S, Zhang H. Recent advances in multiphoton microscopy combined with nanomaterials in the field of disease evolution and clinical applications to liver cancer. NANOSCALE 2019; 11:19619-19635. [PMID: 31599299 DOI: 10.1039/c9nr04902a] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Multiphoton microscopy (MPM) is expected to become a powerful clinical tool, with its unique advantages of being label-free, high resolution, deep imaging depth, low light photobleaching and low phototoxicity. Nanomaterials, with excellent physical and chemical properties, are biocompatible and easy to prepare and functionalize. The addition of nanomaterials exactly compensates for some defects of MPM, such as the weak endogenous signal strength, limited imaging materials, insufficient imaging depth and lack of therapeutic effects. Therefore, combining MPM with nanomaterials is a promising biomedical imaging method. Here, we mainly review the principle of MPM and its application in liver cancer, especially in disease evolution and clinical applications, including monitoring tumor progression, diagnosing tumor occurrence, detecting tumor metastasis, and evaluating cancer therapy response. Then, we introduce the latest advances in the combination of MPM with nanomaterials, including the MPM imaging of gold nanoparticles (AuNPs) and carbon dots (CDs). Finally, we also propose the main challenges and future research directions of MPM technology in HCC.
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Affiliation(s)
- Hongxin Lin
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Taojian Fan
- Shenzhen Engineering Laboratory of Phosphorene and Optoelectronics and Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Shenzhen University, Shenzhen, 518060, China.
| | - Jian Sui
- Department of Gastrointestinal surgery, Fujian Provincial Hospital, Fuzhou, 350000, China
| | - Guangxing Wang
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Jianxin Chen
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Shuangmu Zhuo
- Fujian Normal University, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fuzhou, 350007, China.
| | - Han Zhang
- Shenzhen Engineering Laboratory of Phosphorene and Optoelectronics and Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Shenzhen University, Shenzhen, 518060, China.
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39
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Di Martino JS, Mondal C, Bravo-Cordero JJ. Textures of the tumour microenvironment. Essays Biochem 2019; 63:619-629. [PMID: 31654075 PMCID: PMC6839695 DOI: 10.1042/ebc20190019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023]
Abstract
In this review, we present recent findings on the dynamic nature of the tumour microenvironment (TME) and how intravital microscopy studies have defined TME components in a spatiotemporal manner. Intravital microscopy has shed light into the nature of the TME, revealing structural details of both tumour cells and other TME co-habitants in vivo, how these cells communicate with each other, and how they are organized in three-dimensional space to orchestrate tumour growth, invasion, dissemination and metastasis. We will review different imaging tools, imaging reporters and fate-mapping strategies that have begun to uncover the complexity of the TME in vivo.
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Affiliation(s)
- Julie S Di Martino
- Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at
Mount Sinai, New York, New York, USA
| | - Chandrani Mondal
- Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at
Mount Sinai, New York, New York, USA
| | - Jose Javier Bravo-Cordero
- Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at
Mount Sinai, New York, New York, USA
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40
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Yan S, Zhou N, Zhang D, Zhang K, Zheng W, Bao Y, Yang W. PFKFB3 Inhibition Attenuates Oxaliplatin-Induced Autophagy and Enhances Its Cytotoxicity in Colon Cancer Cells. Int J Mol Sci 2019; 20:5415. [PMID: 31671668 PMCID: PMC6862230 DOI: 10.3390/ijms20215415] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/12/2019] [Accepted: 10/28/2019] [Indexed: 02/06/2023] Open
Abstract
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a glycolytic enzyme highly expressed in cancer cells, has been reported to participate in regulating metabolism, angiogenesis, and autophagy. Although anti-cancer drug oxaliplatin (Oxa) effectively inhibits cell proliferation and induces apoptosis, the growing resistance and side-effects make it urgent to improve the therapeutic strategy of Oxa. Although Oxa induces the autophagy process, the role of PFKFB3 in this process remains unknown. In addition, whether PFKFB3 affects the cytotoxicity of Oxa has not been investigated. Here, we show that Oxa-inhibited cell proliferation and migration concomitant with the induction of apoptosis and autophagy in SW480 cells. Both inhibition of autophagy by small molecule inhibitors and siRNA modification decreased the cell viability loss and apoptosis induced by Oxa. Utilizing quantitative PCR and immunoblotting, we observed that Oxa increased PFKFB3 expression in a time- and dose-dependent manner. Meanwhile, suppression of PFKFB3 attenuated both the basal and Oxa-induced autophagy, by monitoring the autophagic flux and phosphorylated-Ulk1, which play essential roles in autophagy initiation. Moreover, PFKFB3 inhibition further inhibited the cell proliferation/migration, and cell viability decreased by Oxa. Collectively, the presented data demonstrated that PFKFB3 inhibition attenuated Oxa-induced autophagy and enhanced its cytotoxicity in colorectal cancer cells.
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Affiliation(s)
- Siyuan Yan
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Nan Zhou
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Deru Zhang
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Kaile Zhang
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Wenao Zheng
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Yonghua Bao
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Wancai Yang
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
- Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA.
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41
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Lee JH, Rico-Jimenez JJ, Zhang C, Alex A, Chaney EJ, Barkalifa R, Spillman DR, Marjanovic M, Arp Z, Hood SR, Boppart SA. Simultaneous label-free autofluorescence and multi-harmonic imaging reveals in vivo structural and metabolic changes in murine skin. BIOMEDICAL OPTICS EXPRESS 2019; 10:5431-5444. [PMID: 31646056 PMCID: PMC6788598 DOI: 10.1364/boe.10.005431] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/11/2019] [Accepted: 09/24/2019] [Indexed: 05/10/2023]
Abstract
Simultaneous quantification of multifarious cellular metabolites and the extracellular matrix in vivo has been long sought. Simultaneous label-free autofluorescence and multi-harmonic (SLAM) microscopy has achieved simultaneous four-channel nonlinear imaging to study tissue structure and metabolism. In this study, we implemented two laser systems and directly compared SLAM microscopy with conventional two-photon microscopy for in vivo imaging. We found that three-photon imaging of adenine dinucleotide (phosphate) (NAD(P)H) in SLAM microscopy using our tailored laser source provided better resolution, contrast, and background suppression than conventional two-photon imaging of NAD(P)H. We also integrated fluorescence lifetime imaging with SLAM microscopy, and enabled differentiation of free and bound NAD(P)H. We imaged murine skin in vivo and showed that changes in tissue structure, cell dynamics, and metabolism can be monitored simultaneously in real-time. We also discovered an increase in metabolism and protein-bound NAD(P)H in skin cells during the early stages of wound healing.
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Affiliation(s)
- Jang Hyuk Lee
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Co-first authors with equal contribution
| | - Jose J. Rico-Jimenez
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Co-first authors with equal contribution
| | - Chi Zhang
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Aneesh Alex
- GlaxoSmithKline, Collegeville, PA 19426, USA
| | - Eric J. Chaney
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Ronit Barkalifa
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Darold R. Spillman
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Marina Marjanovic
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Zane Arp
- GlaxoSmithKline, Collegeville, PA 19426, USA
| | | | - Stephen A. Boppart
- Center for Optical Molecular Imaging, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
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42
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Desa DE, Bhanote M, Hill RL, Majeski JB, Buscaglia B, D’Aguiar M, Strawderman R, Hicks DG, Turner BM, Brown EB. Second-harmonic generation directionality is associated with neoadjuvant chemotherapy response in breast cancer core needle biopsies. JOURNAL OF BIOMEDICAL OPTICS 2019; 24:1-9. [PMID: 31456385 PMCID: PMC6983524 DOI: 10.1117/1.jbo.24.8.086503] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/05/2019] [Indexed: 05/30/2023]
Abstract
Neoadjuvant chemotherapy (NACT) is routinely administered to subsets of breast cancer patients, including triple negative (TN) or human epidermal growth factor receptor 2-positive (HER2+) cancers. After NACT and subsequent surgical resection, 5% to 30% of patients have no residual invasive carcinoma, termed pathological complete response. Unfortunately, many patients experience little-to-no response after NACT and unnecessarily suffer its side effects. Methods are needed to predict an individual patient’s response to NACT. Core needle biopsies, taken before NACT, consist of tumor cells and the surrounding extracellular matrix. We performed second-harmonic generation (SHG) imaging of fibrillar collagen in core needle biopsy sections as a possible predictor of response to NACT. The ratio of forward-to-backward scattering (F/B) SHG was assessed in the “tumor bulk” and “tumor–host interface” in HER2+ and TN core needle biopsy sections. Patient response was classified post-treatment using the Residual Cancer Burden (RCB) score. In HER2+ biopsies, RCB class was associated with F/B derived from the tumor–stromal interface, but not tumor bulk. F/B was not associated with RCB class in TN biopsies. These findings suggest that F/B from needle biopsy sections may be a useful predictor of which patients will respond favorably to NACT, with the potential to help reduce overtreatment.
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Affiliation(s)
- Danielle E. Desa
- University of Rochester, Hajim School of Engineering and Applied Sciences, Department of Biomedical Engineering, Rochester, New York, United States
| | - Monisha Bhanote
- University of Rochester Medical Center, School of Medicine and Dentistry, Department of Pathology and Laboratory Medicine, Rochester, New York, United States
| | - Robert L. Hill
- Harmonigenic Corporation, Rochester, New York, United States
| | - Joseph B. Majeski
- University of Rochester, Hajim School of Engineering and Applied Sciences, Department of Biomedical Engineering, Rochester, New York, United States
| | - Brandon Buscaglia
- Rochester Institute of Technology, Kate Gleason College of Engineering, Department of Biomedical Engineering, Rochester, New York, United States
| | - Marcus D’Aguiar
- Rochester Institute of Technology, Kate Gleason College of Engineering, Department of Biomedical Engineering, Rochester, New York, United States
| | - Robert Strawderman
- University of Rochester Medical Center, School of Medicine and Dentistry, Department of Biostatistics and Computational Biology, Rochester, New York, United States
| | - David G. Hicks
- University of Rochester Medical Center, School of Medicine and Dentistry, Department of Pathology and Laboratory Medicine, Rochester, New York, United States
| | - Bradley M. Turner
- University of Rochester Medical Center, School of Medicine and Dentistry, Department of Pathology and Laboratory Medicine, Rochester, New York, United States
| | - Edward B. Brown
- University of Rochester, Hajim School of Engineering and Applied Sciences, Department of Biomedical Engineering, Rochester, New York, United States
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43
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Chaigneau E, Roche M, Charpak S. Unbiased Analysis Method for Measurement of Red Blood Cell Size and Velocity With Laser Scanning Microscopy. Front Neurosci 2019; 13:644. [PMID: 31316334 PMCID: PMC6610068 DOI: 10.3389/fnins.2019.00644] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/05/2019] [Indexed: 12/28/2022] Open
Abstract
Two-photon laser scanning microscopy is widely used to measure blood hemodynamics in brain blood vessels. Still, the algorithms used so far to extract red blood cell (RBC) size and velocity from line-scan acquisitions have ignored the extent to which scanning speed influences the measurements. Here, we used a theoretical approach that takes into account the velocity and direction of both scanning mirrors and RBCs during acquisition to provide an algorithm that measures the real RBC size and velocity. We validate our approach in brain vessels of anesthetized mice, and demonstrate that it corrects online measurement errors that can reach several 10s of percent as well as data previously acquired. To conclude, our analysis allows unbiased comparisons of blood hemodynamic parameters from brain capillaries and large vessels in control and pathological animal models.
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Affiliation(s)
| | | | - Serge Charpak
- INSERM U1128, Laboratory of Neurophysiology and New Microscopy, Université Paris Descartes, Paris, France
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44
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A cerebellopontine angle mouse model for the investigation of tumor biology, hearing, and neurological function in NF2-related vestibular schwannoma. Nat Protoc 2019; 14:541-555. [PMID: 30617350 DOI: 10.1038/s41596-018-0105-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Neurofibromatosis type II (NF2) is a disease that lacks effective therapies. NF2 is characterized by bilateral vestibular schwannomas (VSs) that cause progressive and debilitating hearing loss, leading to social isolation and increased rates of depression. A major limitation in NF2 basic and translational research is the lack of animal models that allow the full spectrum of research into the biology and molecular mechanisms of NF2 tumor progression, as well as the effects on neurological function. In this protocol, we describe how to inject schwannoma cells into the mouse brain cerebellopontine angle (CPA) region. We also describe how to apply state-of-the-art intravital imaging and hearing assessment techniques to study tumor growth and hearing loss. In addition, ataxia, angiogenesis, and tumor-stroma interaction assays can be applied, and the model can be used to test the efficacy of novel therapeutic approaches. By studying the disease from every angle, this model offers the potential to unravel the basic biological underpinnings of NF2 and to develop novel therapeutics to control this devastating disease. Our protocol can be adapted to study other diseases within the CPA, including meningiomas, lipomas, vascular malformations, hemangiomas, epidermoid cysts, cerebellar astrocytomas, and metastatic lesions. The entire surgical procedure takes ~45 min per mouse and allows for subsequent longitudinal imaging, as well as neurological and hearing assessment, for up to 2 months.
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45
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Ogunlade O, Ho JO, Kalber TL, Hynds RE, Zhang E, Janes SM, Birchall MA, Butler CR, Beard P. Monitoring neovascularization and integration of decellularized human scaffolds using photoacoustic imaging. PHOTOACOUSTICS 2019; 13:76-84. [PMID: 30805295 PMCID: PMC6374504 DOI: 10.1016/j.pacs.2019.01.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/21/2018] [Accepted: 01/04/2019] [Indexed: 05/22/2023]
Abstract
Tissue engineering is a branch of regenerative medicine that aims to manipulate cells and scaffolds to create bioartificial tissues and organs for patients. A major challenge lies in monitoring the blood supply to the new tissue following transplantation: the integration and neovascularization of scaffolds in vivo is critical to their functionality. Photoacoustic imaging (PAI) is a laser-generated ultrasound-based technique that is particularly well suited to visualising microvasculature due to the high optical absorption of haemoglobin. Here, we describe an early proof-of-concept study in which PAI in widefield tomography mode is used to image biological, decellularized human tracheal scaffolds. We found that PAI allowed the longitudinal tracking of scaffold integration into subcutaneous murine tissue with high spatial resolution at depth over an extended period of time. The results of the study were consistent with post-imaging histological analyses, demonstrating that PAI can be used to non-invasively monitor the extent of vascularization in biological tissue-engineered scaffolds. We propose that this technique may be a valuable tool for studies designed to test interventions aimed at improving the speed and extent of scaffold neovascularization in tissue engineering. With technological refinement, it could also permit in vivo monitoring of revascularization in patients, for example to determine timing of heterotopic graft transfer.
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Affiliation(s)
- Olumide Ogunlade
- Department of Medical Physics & Biomedical Engineering, University College London, London, UK
| | | | - Tammy L. Kalber
- UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, UK
| | - Robert E. Hynds
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK
| | - Edward Zhang
- Department of Medical Physics & Biomedical Engineering, University College London, London, UK
| | - Sam M. Janes
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK
| | | | - Colin R. Butler
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK
| | - Paul Beard
- Department of Medical Physics & Biomedical Engineering, University College London, London, UK
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46
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Hassan AM, Wu X, Jarrett JW, Xu S, Yu J, Miller DR, Perillo EP, Liu YL, Chiu DT, Yeh HC, Dunn AK. Polymer dots enable deep in vivo multiphoton fluorescence imaging of microvasculature. BIOMEDICAL OPTICS EXPRESS 2019; 10:584-599. [PMID: 30800501 PMCID: PMC6377892 DOI: 10.1364/boe.10.000584] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/12/2018] [Accepted: 12/20/2018] [Indexed: 06/09/2023]
Abstract
Deep in vivo imaging of vasculature requires small, bright, and photostable fluorophores suitable for multiphoton microscopy (MPM). Although semiconducting polymer dots (pdots) are an emerging class of highly fluorescent contrast agents with favorable advantages for the next generation of in vivo imaging, their use for deep MPM has never before been demonstrated. Herein, we characterize the multiphoton properties of three pdot variants and perform deep in vivo MPM imaging of cortical rodent microvasculature. We find pdot brightness exceeds conventional fluorophores, including quantum dots, and their broad multiphoton absorption spectrum permits imaging at wavelengths better-suited for biological imaging and confers compatibility with a range of longer excitation wavelengths. This results in substantial improvements in signal-to-background ratio (>3.5-fold) and greater cortical imaging depths (z = 1,300 µm). Ultimately, pdots are a versatile tool for MPM due to their extraordinary brightness and broad absorption, enabling interrogation of deep structures in vivo.
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Affiliation(s)
- Ahmed M Hassan
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
| | - Xu Wu
- Department of Chemistry and Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Jeremy W Jarrett
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
| | - Shihan Xu
- Department of Chemistry and Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Jiangbo Yu
- Department of Chemistry and Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - David R Miller
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
| | - Evan P Perillo
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
| | - Yen-Liang Liu
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
| | - Daniel T Chiu
- Department of Chemistry and Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Hsin-Chih Yeh
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
- Texas Materials Institute, The University of Texas at Austin, Austin, TX 78712, USA
| | - Andrew K Dunn
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton C0800, Austin, TX 78712, USA
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47
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Chen J, Ning C, Zhou Z, Yu P, Zhu Y, Tan G, Mao C. Nanomaterials as photothermal therapeutic agents. PROGRESS IN MATERIALS SCIENCE 2019; 99:1-26. [PMID: 30568319 PMCID: PMC6295417 DOI: 10.1016/j.pmatsci.2018.07.005] [Citation(s) in RCA: 416] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Curing cancer has been one of the greatest conundrums in the modern medical field. To reduce side-effects associated with the traditional cancer therapy such as radiotherapy and chemotherapy, photothermal therapy (PTT) has been recognized as one of the most promising treatments for cancer over recent years. PTT relies on ablation agents such as nanomaterials with a photothermal effect, for converting light into heat. In this way, elevated temperature could kill cancer cells while avoiding significant side effects on normal cells. This theory works because normal cells have a higher heat tolerance than cancer cells. Thus, nanomaterials with photothermal effects have attracted enormous attention due to their selectivity and non-invasive attributes. This review article summarizes the current status of employing nanomaterials with photothermal effects for anti-cancer treatment. Mechanisms of the photothermal effect and various factors affecting photothermal performance will be discussed. Efficient and selective PTT is believed to play an increasingly prominent role in cancer treatment. Moreover, merging PTT with other methods of cancer therapies is also discussed as a future trend.
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Affiliation(s)
- Junqi Chen
- College of Material Science and Engineering, South China University of Technology, Guangzhou 510641, China
- Guangdong Key Laboratory for Biomedical Engineering, Guangzhou 510641, China
| | - Chengyun Ning
- College of Material Science and Engineering, South China University of Technology, Guangzhou 510641, China
- Guangdong Key Laboratory for Biomedical Engineering, Guangzhou 510641, China
| | - Zhengnan Zhou
- College of Material Science and Engineering, South China University of Technology, Guangzhou 510641, China
- Guangdong Key Laboratory for Biomedical Engineering, Guangzhou 510641, China
| | - Peng Yu
- College of Material Science and Engineering, South China University of Technology, Guangzhou 510641, China
- Guangdong Key Laboratory for Biomedical Engineering, Guangzhou 510641, China
| | - Ye Zhu
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, Institute for Biomedical Engineering, Science and Technology, University of Oklahoma, Oklahoma, United States
| | - Guoxin Tan
- Institute of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
| | - Chuanbin Mao
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, Institute for Biomedical Engineering, Science and Technology, University of Oklahoma, Oklahoma, United States
- School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China
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48
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Si P, Yuan E, Liba O, Winetraub Y, Yousefi S, SoRelle ED, Yecies DW, Dutta R, de la Zerda A. Gold Nanoprisms as Optical Coherence Tomography Contrast Agents in the Second Near-Infrared Window for Enhanced Angiography in Live Animals. ACS NANO 2018; 12:11986-11994. [PMID: 30422624 DOI: 10.1021/acsnano.8b03862] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Optical coherence tomography angiography (OCTA) is an important tool for investigating vascular networks and microcirculation in living tissue. Traditional OCTA detects blood vessels via intravascular dynamic scattering signals derived from the movements of red blood cells (RBCs). However, the low hematocrit and long latency between RBCs in capillaries make these OCTA signals discontinuous, leading to incomplete mapping of the vascular networks. OCTA imaging of microvascular circulation is particularly challenging in tumors due to the abnormally slow blood flow in angiogenic tumor vessels and strong attenuation of light by tumor tissue. Here, we demonstrate in vivo that gold nanoprisms (GNPRs) can be used as OCT contrast agents working in the second near-infrared window, significantly enhancing the dynamic scattering signals in microvessels and improving the sensitivity of OCTA in skin tissue and melanoma tumors in live mice. With GNPRs as contrast agents, the postinjection OCT angiograms showed 41 and 59% more microvasculature than preinjection angiograms in healthy mouse skin and melanoma tumors, respectively. By enabling better characterization of microvascular circulation in vivo, GNPR-enhanced OCTA could lead to better understanding of vascular functions during pathological conditions, more accurate measurements of therapeutic response, and improved patient prognoses.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Adam de la Zerda
- The Chan Zuckerberg Biohub , San Francisco , California 94158 , United States
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49
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Ying Z, Minghui T, Feng B, Ke W. Tanshinone II A improves distribution and anti-tumor efficacy of pegylated liposomal doxorubicin via normalizing the structure and function of tumor vasculature in hepa1-6 hepatoma mice model. J TRADIT CHIN MED 2018. [DOI: 10.1016/s0254-6272(18)30980-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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50
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Ata MM, Ashour AS, Guo Y, Elnaby MMA. Centroid tracking and velocity measurement of white blood cell in video. Health Inf Sci Syst 2018; 6:20. [PMID: 30425827 DOI: 10.1007/s13755-018-0060-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 10/16/2018] [Indexed: 11/25/2022] Open
Abstract
Automated blood cells tracking system has a vital role as the tracking process reflects the blood cell characteristics and indicates several diseases. Blood cells tracking is challenging due to the non-rigid shapes of the blood cells, and the variability in their videos along with the existence of different moving objects in the blood. To tackle such challenges, we proposed a green star based centroid (GSBC) moving white blood cell (WBC) tracking algorithm to measure its velocity and draw its trajectory. The proposed cell tracking system consists of two stages, namely WBC detection and blob analysis, and fine tuning the tracking process by determine the centroid of the WBC, and mark the centroid for further fine tracking and to exclude the bacteria from the bounding box. Furthermore, the speed and the trajectory of the WBC motion are recorded and plotted. In the experiments, an optical flow technique is compared with the proposed tracking system showing the superiority of the proposed system as the optical flow method failed to track the WBC. The proposed system identified the WBC accurately, while the optical flow identified all other objects lead to its disability to track the WBC.
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Affiliation(s)
- Mohamed Maher Ata
- Misr Higher Institute of Engineering and Technology, Mansoura, Egypt
| | - Amira S Ashour
- 2Department of Electronics and Electrical Communications Engineering, Faculty of Engineering, Tanta University, Tanta, Egypt
| | - Yanhui Guo
- 3Department of Computer Science, University of Illinois at Springfield, Springfield, IL USA
| | - Mustafa M Abd Elnaby
- 2Department of Electronics and Electrical Communications Engineering, Faculty of Engineering, Tanta University, Tanta, Egypt
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