1. Field of the Invention
The present invention relates generally to a method for inducing neovascularization and, in particular, to a method of inducing neovascularization mimicking age related macular degeneration, cancer, tumors, atherosclerosis, and wound healing for purposes of further research.
2. Brief Description of the Related Art
Neovascularization or angiogenesis is the formation of new blood vessels from existing vessels. Neovascularization aids in the natural process of wound healing. By increasing the rate of neovascularization, the rate of wound healing is also accelerated. Neovascularization is also the hallmark of the development of macular degeneration, tumors, cancer, and atherosclerosis. However, a method of inducing neovascularization can be a valuable tool in further research investigations of these conditions.
Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of the choroid, the neural retina and/or the retinal pigment epithelium (RPE). Under the retina is the choroid, a collection of blood vessels embedded within fibrous (connective) tissue, and the pigmented epithelium, which overlays the choroid layer. The choroidal blood vessels provide nutrition to the retina. The RPE cells produce, store, and transport a variety of factors that are responsible for the normal function and survival of photoreceptors [1].
Age-related macular degeneration (AMD), the most prevalent macular degeneration, is associated with progressive loss of visual activity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity. Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form, and the wet, or exudative, form [1-4].
Wet AMD is caused by choroidal neovascularization (CNV) and vascular leakage, resulting in displacement of the retina, hemorrhage and scar formation. As the blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina. Wet AMD with choroidal neovascularization leads to reduction of vision and blindness in 75% of cases [5]. There are no current methods of prevention or cure of AMD and only palliative treatment is available.
AMD has numerous causative factors and a complex pathogenesis. However, induction of CNV is known to be a critical event in the progression of the disease. Polyethylene glycol (PEG) is a newly discovered activator of the complement system [7-8]. It was recently discovered that activation of the complement system plays a key role in the development of CNV [9-17]. Animal models mimicking the pathological processes during wet AMD are limited to laser induced CNV. Very limited animal models reproduce CNV: laser treatment, surgical debridement of the RPE cells and mechanical rupture of Bruch's membrane, increased expression of growth factors or use of transgenic animals [18-26].
The laser induced models require expensive laser machinery and microscopes. The laser model also causes substantial damage to other portions of the eye, including the retina. CNV was detected in rabbits after penetrating retinal injury [27]. As in the case of laser induced CNV, RPE cells, Bruch's membrane and choroid damage resulted [27]. Subretinal injection models have been utilized to induce CNV, but these models are limited in their applicability. Specifically, CNV was induced in rabbits after subretinal injection of vitreous without rupture of Bruch's membrane, but it was a technically complex method of vitreous aspiration and this model is not applicable on mice because of extremely low amount of vitreous in mouse eye [28, 29]. In addition, models with subretinal injection of bFGF microspheres [23] or [VEGF]-impregnated microspheres [24] requires at least these microspheres and does not reflect completely pathogenesis of AMD with involvement of complement system. Transgenic mice models for inducing have also be used with variable results. CNV in CCL2−/− mice was noted [18] but not confirmed by others [30]. CNV in SOD1−/−mice was detected only in some animals [31]. Apolipoprotein E4 transgenic mice showed signs of CNV in approximately in 20% of cases in second year of life [32].
It would therefore be desirable to develop a method for inducing neovascularization mimicking age related macular degeneration, cancer, tumors, and atherosclerosis in a short period of time that does not require expensive equipment and minimizes collateral damage to the subject. It would also be desirable to develop a method for inducing neovascularization to accelerate wound healing. The limitations of the prior art are overcome by the present invention as described below.
USPTO Backgrounds
USPTO Backgrounds