Future Perspectives

Intravital microscopy in window models has been providing useful insights into angiogenesis and microcirculation. However, two key challenges remain. First, the most widely used microscopy techniques are surface-weighted. Multi-photon microscopy can provide images at depths of up to ~700 mm, depending on the tissue and tracer used. Other optical methods, such as optical coherence tomography, can image further deeper regions. Systems and applications of these techniques have been rapidly increased recently. With more research in this area, we may someday be able to obtain dynamic images of whole organs or tissues with high spatial resolution.

The second limitation of window models is that they are currently limited to organs accessible from outside of the body. To study internal organs, surgical manipulation is required, which allows only short-term observations. The adaptation of microscopy techniques to use a fiberscope system will enable internal organs to be studied with minimum invasion. Alternately, the future advancement of optics and transponder devices may allow for both the implantation and chronic monitoring of internal organs.

Figure 4 Vessel Formation in a Window Model. (a, b) Angiogenesis and vessel remodeling during adipoge-nesis in the mouse dorsal skinfold chamber after 3T3-F442A cell implantation. (a) Macroscopic image 9 days after implantation. (b) Intravital microscopy image of fluorescence contrast enhanced blood vessels at 28 days after implantation. (c, d) HUVECs and 10T1/2 cells were seeded in a 3-D extracellular matrix and implanted in a mouse cranial window. 3-D images of engineered vessels (EGFP expressing HUVEC, green; functional blood vessels contrast-enhanced with rho-dextran, red) were taken using intravital multi-photon laser-scanning microscopy. (c) Four days after implantation of HUVEC + 10T1/2 construct. Large vacuoles in the tubes resemble the lumens of capillaries (arrows) but they are not perfused (no red). (d) Four months after implantation of HUVEC + 10T1/2 construct. Engineered vessels are stable and functional. Bars indicate 5 mm (a), 100 mm (b), 50 mm (c, d), respectively. (Adapted from Fukumura, D., Ushiyama, A., Duda, D. G., Xu, L., Tam, J., Chatterjee, V. K. K., Garkavtsev, I., and Jain, R. K. (2003). Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ. Res. 93, e88-e97; and Koike, N., Fukumura, D., Gralla, O., Au, P., Schechner, J. S., and Jain, R. K. (2004). Creation of long-lasting blood vessels. Nature 428, 138-139.) (see color insert)

Figure 4 Vessel Formation in a Window Model. (a, b) Angiogenesis and vessel remodeling during adipoge-nesis in the mouse dorsal skinfold chamber after 3T3-F442A cell implantation. (a) Macroscopic image 9 days after implantation. (b) Intravital microscopy image of fluorescence contrast enhanced blood vessels at 28 days after implantation. (c, d) HUVECs and 10T1/2 cells were seeded in a 3-D extracellular matrix and implanted in a mouse cranial window. 3-D images of engineered vessels (EGFP expressing HUVEC, green; functional blood vessels contrast-enhanced with rho-dextran, red) were taken using intravital multi-photon laser-scanning microscopy. (c) Four days after implantation of HUVEC + 10T1/2 construct. Large vacuoles in the tubes resemble the lumens of capillaries (arrows) but they are not perfused (no red). (d) Four months after implantation of HUVEC + 10T1/2 construct. Engineered vessels are stable and functional. Bars indicate 5 mm (a), 100 mm (b), 50 mm (c, d), respectively. (Adapted from Fukumura, D., Ushiyama, A., Duda, D. G., Xu, L., Tam, J., Chatterjee, V. K. K., Garkavtsev, I., and Jain, R. K. (2003). Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ. Res. 93, e88-e97; and Koike, N., Fukumura, D., Gralla, O., Au, P., Schechner, J. S., and Jain, R. K. (2004). Creation of long-lasting blood vessels. Nature 428, 138-139.) (see color insert)

With these improvements, window models will continue to offer new opportunities for discovery in microcirculation research.

Essentials of Human Physiology

Essentials of Human Physiology

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