Abstract
There is continual demand for animal models that allow a quantitative assessment of angiogenic properties of biomaterials, therapies, and pharmaceuticals. In its simplest form, this is done by subcutaneous material implantation and subsequent vessel counting which usually omits spatial data. We have refined an implantation model and paired it with a computational analytic routine which outputs not only vessel count but also vessel density, distribution, and vessel penetration depth, that relies on a centric vessel as a reference point. We have successfully validated our model by characterizing the angiogenic potential of a fibrin matrix in conjunction with recombinant human vascular endothelial growth factor (rhVEGF165). The inferior epigastric vascular pedicles of rats were sheathed with silicone tubes, which were subsequently filled with 0.2 ml of fibrin and different doses of rhVEGF165, centrically embedding the vessels. Over 4 weeks, tissue samples were harvested and subsequently immunohistologically stained and computationally analyzed. The model was able to detect variations over the angiogenic potentials of growth factor spiked fibrin matrices. Adding 20 ng of rhVEGF165 resulted in a significant increase in vasculature while 200 ng of rhVEGF165 did not improve vascular growth. Vascularized tissue volume increased during the first week and vascular density increased during the second week. Total vessel count increased significantly and exhibited a peak after 2 weeks which was followed by a resorption of vasculature by week 4. In summary, a simple implantation model to study in vivo vascularization with only a minimal workload attached was enhanced to include morphologic data of the emerging vascular tree.
Highlights
The ability to understand and manipulate angiogenic processes has become a key element of many therapeutic approaches
We aim to facilitate the assessment of angiogenic properties of biomaterials and growth factors in conjunction with a characterization of the resulting vascularization, based on a spatial analysis of basic histologic slices, that results in an array of morphological read out parameters that provide a comprehensive representation of newly formed vasculature
The study design consisted of two parts: first, four groups of N = 10 samples were set up to study the angiogenic effect of recombinant human vascular endothelial growth factor (PeproTech, Rocky Hill, NJ, USA) inside a fibrin matrix after a time period of 4 weeks
Summary
The ability to understand and manipulate angiogenic processes has become a key element of many therapeutic approaches. The emerging vasculature may be tracked via techniques of varying technical complexity These include in vivo perfusion with casting agents and subsequent scanning electron microscopy (Polykandriotis et al, 2008) of the resulting corrosion casts, magnetic resonance angiography (Polykandriotis et al, 2008), photoacoustic imaging (Meiburger et al, 2016), or in vivo perfusion with radiopaque contrast agents and ex vivo computer tomography scans (Sider et al, 2010). The goal of this study was to combine an implantation based model of angiogenesis (Cronin et al, 2004; Rophael et al, 2007; Tilkorn et al, 2012; Lilja et al, 2013) that is time and work efficient with a computational analysis of manually marked vessels This provides insight into the morphology of newly developed vascular structures that goes beyond simple vessel counting and does not require sophisticated technical equipment. We aim to facilitate the assessment of angiogenic properties of biomaterials and growth factors in conjunction with a characterization of the resulting vascularization, based on a spatial analysis of basic histologic slices, that results in an array of morphological read out parameters that provide a comprehensive representation of newly formed vasculature
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