Utilization of Window Models

Window models generally allow long-term continuous and/or repeated observation and are thus ideal for time-course studies of physiological and pathological events. Window models are best suited for intravital microscopy and are used to study angiogenesis, microcirculation, tumor and engineered tissue growth, disease process, and treatment response.

Intravital Microscopy

Intravital microscopy is a powerful optical imaging technique that allows noninvasive monitoring of molecular and cellular processes in intact living tissue with 1 to 10 mm resolution. Sophisticated animal models, such as window models, are a prerequisite for this technique. With the use of appropriate tracers, optics, and analysis algorithms, a wide array of morphological and functional vascular parameters—such as blood and lymph vessel architectures, blood and lymph flow, vasomotion, vascular permeability, and leukocyte/platelet-endothelial interactions—can be determined by intravital microscopy. In addition, endogenous and exogenous probes, as well as genetically manipulated cells and animals, can provide other important parameters such as gene expression (promoter activity via GFP imaging), interstitial/intracellular pH, interstitial and microvascular pO2, interstitial diffusion, convection and bindings, and extracellular matrix structure (second harmonic generation of collagen fiber).

Treatments and Manipulations

By observing the same vessels and/or regions repeatedly, window models provide accurate dynamic information on microcirculatory responses. In addition to monitoring the therapeutic effects of systemic treatments, window models are often used to assess the local effects of treatments or manipulations. For example, the occlusion of feeding vessels to the windows or the physical compression of tissues within the windows induces ischemia, followed by reperfusion after release; thus, windows are useful as models of local ischemia reperfusion. For local treatments, test compounds can be applied locally, either by topical application after removal of the cover glass or by injection through a port embedded in the window models. Alternately, a drug-containing matrix can be implanted within the window for continuous release of local treatments. Furthermore, the application of specific optical powers or wavelengths can activate certain drugs or carriers within the light-exposed area.

Cancer Research

A solid tumor is an organ-like structure that consists of cancer cells and nonneoplastic host stromal cells embedded in an extracellular matrix and nourished by a vascular network. The application of intravital microscopy techniques to tumors grown in window models (Figure 3) has provided unprecedented insights into the inner workings of this organ. It has been unequivocally demonstrated that the structure and function of tumor vessels is heterogeneous. The chaotic nature of tumor vessels forms a physiological barrier to the delivery of therapeutic molecules to tumors and hinders the efficacy of various tumor therapies. In vivo microscopy of tumor window models has revealed that certain antiangio-genic treatments can normalize the abnormal tumor vessels so that they become more efficient. Normalization of tumor vessels by antiangiogenesis treatment may overcome physiological resistance to drug delivery and accelerate treatment efficacy.

Angiogenesis Assay

To study angiogenesis, vessel remodeling, and maturation, an extracellular matrix construct containing either

Figure 3 Angiogenesis and Tumor Growth in a Window Model. LS174T human colon cancer was implanted in an SCID mouse dorsal skin chamber. At day 5 after tumor cell implantation, enlargement of host vessels was observed, and by day 10 occasional hemorrhage and sprout formation occurred. At day 15, tumor growth and further angiogenesis became apparent. By day 20, the tumor was fully vascularized. (Adapted from Reference [3].) (see color insert)

Figure 3 Angiogenesis and Tumor Growth in a Window Model. LS174T human colon cancer was implanted in an SCID mouse dorsal skin chamber. At day 5 after tumor cell implantation, enlargement of host vessels was observed, and by day 10 occasional hemorrhage and sprout formation occurred. At day 15, tumor growth and further angiogenesis became apparent. By day 20, the tumor was fully vascularized. (Adapted from Reference [3].) (see color insert)

angiogenic factor(s) or vascular cells (such as endothelial cells, pericytes, vascular smooth muscle cells, and their precursors) are implanted in window models (Figure 4). Angiogenic matrix implants in window models allow for noninvasive, real-time measurements of angiogenic vessel structure and function, from early development to subsequent remodeling and maturation. Other types of animal models also permit chronic monitoring of vessel formation (e.g., the corneal micropocket assay in rabbits, rats and mice; the anterior chamber/iris assay in frogs, rabbits, guinea pigs, swines, goats and sheep; and the chick chorioallantoic membrane model), but these models do not typically use intravital microscopy and are thus unable to provide detailed functional information.

Tissue Engineering

Tissues and organs, or their precursors (stem cells), can be implanted into window models for the study of organogenesis and/or the growth, microcirculation, and biology of the respective tissues. For example, preadipocyte implants exhibit de novo fat tissue formation and reveal reciprocal regulation of angiogenesis and adipose differentiation. Bone implants permit the monitoring of bone regeneration and angiogenesis as well as bone preferential metastasis such as prostate cancer. A major challenge in tissue engineering and regenerative medicine is the creation of stable vasculature. Window models provide an ideal platform for the determination of vessel development and function in an engineered tissue.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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