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Tissue Compartment Based Kinetic Modeling Using Multiphoton Microscopy in Irradiated Mice and Mice Bearing Acute Lymphoblastic Leukemia

J Brooks1,2*,D Zuro1,2, S Hui1,3, (1) Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA (2) Department of Radiation Oncology, University of Minnesota, Minneapolis, MN (3) Beckman Research Institute, Duarte, CA


(Monday, 7/15/2019) 1:45 PM - 3:45 PM

Room: Stars at Night Ballroom 2-3

Purpose: To establish a method capable of identifying changes in bone marrow vascular permeability and kinetic transfer rate (K(trans)) of molecular compounds at single cell resolution in the murine model.

Methods: Live, time lapsed, multiphoton microscopy (MPM) imaging of 150 kDa fluorescent dextran in skull bone marrow (BM) was performed on healthy mice, healthy mice receiving 4Gy targeted image guided radiation therapy (IGRT) to the left half of the skull and left femur, and mice bearing acute lymphoblastic leukemia (ALL). A two tissue compartment model was applied to images of BM and local BM vasculature, obtaining the fraction of extracellular tissue space (ν(ec)), K(trans), and vascular permeability. Quantification of vascular permeability is performed using K(trans) and vascular surface area per volume measured through quantification of MPM three-dimensional image volumes. Additional compounds and modeling methods were explored to further validate imaging techniques.

Results: Dextran diffusion into the tissue was well defined by the two compartment model used. 4Gy IGRT treated mice had increased ν(ec) and K(trans) compared to healthy mice (P<0.0032, P<0.0313). A significant increase in dextran fluorescence of crushed femur supernatants and a significant decrease in femur cellularity were found for treated femur regions compared to untreated regions, in agreement with fitting parameters(P<0.0003, P<0.0076). Significant increases in K(trans) and vascular permeability were observed in mice with low burden ALL (<40% ALL bone marrow engraftment) compared to healthy mice (P<0.0343, P<0.0231, P<0.0268). Nonlinear changes in K(trans) were observed with the onset of ALL burden.

Conclusion: This work demonstrates the ability of MPM to obtain time lapsed images for kinetic modeling. Local changes in BM vasculature and tissue are induced by IGRT and the onset of ALL. Developed techniques will be used in the future to assess BM vascular changes with disease progression and treatment.

Funding Support, Disclosures, and Conflict of Interest: Research reported in this work is supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572 and partly supported by National Institutes of Health grant 1R01CA154491-01.The authors declare no conflict of interest.


Modeling, Fluorescence, Optical Imaging


IM- Optical : Quantitative imaging/analysis

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