Foundation provides surgeons with 183,000 Euro in funding

FAU research group examines how the formation of blood vessels can be controlled

Over the next two years, a team of research scientists headed up by Prof. Dr. Raymund E. Horch, director of the University Hospital’s Plastic and Hand Surgery Clinic at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) is to receive over €180,000 from the Else Kröner Fresenius Foundation. This funding will support research into finding ways of controlling the formation of new blood vessels in artificial tissue in vivo – i.e. in living organisms. Principal applicant and project leader Dr. Oliver Bleiziffer, also from the Plastic and Hand Surgery Clinic, is hopeful that this research can lay the groundwork to finding a solution to a key problem in regenerative medicine: insufficient blood circulation in artificial tissue.

“Nowadays the cultivation of bioartificial tissue in a Petri dish isn’t a problem. In these dishes, bone, skin or muscle tissue is provided with nutrient solution and growth factors where it thrives”, explains Bleiziffer. However, the tissue engineer believes that transplanting artificial tissue into a living organism on a clinically relevant scale is what poses the greatest challenges. If the new tissue is not supplied with sufficient blood in the body it will die – rendering all efforts null and void. In order to ensure the tissue receives an adequate supply of blood, a sufficient amount of blood vessels and capillaries must permeate the tissue. And this is exactly what the Erlangen surgeons intend to research.

Thanks to the arteriovenous vessel loop (AV loop), the formation of new blood vessels in artificial tissue has been successfully stimulated in the past. “The advanced model of the AV loop, developed by our team has long since been established in Erlangen”, says co-applicant PD Dr. Ulrich Kneser. The vessel loop is embedded in a matrix of the “adhesive protein” fibrin which lends the artificial tissue shape and form. The fibrin matrix, in turn, is enriched with endothelial progenitor cells (EPCs) which play a key role in vessel formation (Fig. 1).

The matrix and vessel loop are surrounded by a sealable chamber made of Teflon, which – implanted into a living organism – is connected to the natural bloodstream at both ends of the AV Loop. The artificial tissue therefore grows sealed off in a type of bioreactor and is connected to an artery at one end of the loop and to a vein at the other end – which explains the term “AV loop” (Fig. 2).

The role of the aforementioned endothelial progenitor cells (EPCs) in new vessel formation in bioartificial tissue is now to become the core focus of the researchers’ project. These cells are made in the bone marrow and circulate in the bloodstream. They line the inner walls of blood vessels as differentiated endothelial cells. The EPCs have their vascularisation potential to thank for their crucial role in tissue engineering. Endothelial progenitor cells play a significant role in the budding of vessels in a pre-existing capillary system (angiogenisis) as well as in new vessel formation (vasculogenesis). And what makes them unique is that vascular wall progenitor cells are recruited when blood supply is inadequate at the oxygen deprived location. Here, growth factors and messengers are released which, in turn, trigger vascular budding. They differentiate during periods of oxygen deficiency, but also into mature endothelial cells and thus participate in the formation of new vessels – as if out of nowhere.

Dr. Oliver Bleiziffer has now decided to modulate the formation of new blood vessels by transplanting EPCs. In order to accelerate the formation of a vascular system, these EPCs can be provided with a pro-angeogenic (vascularisation promoting) transgene. In the preliminary stages, researchers were able to insert a growth-inhibiting transgene and thereby interfere with vascularisation.

Another area of interest to researchers is the role of hypoxia as a stimulant in vascularisation processes. Periods of oxygen deficiency result in the expression of a special transcription factor (Hypoxia Inducible Factor (HIF) – 1 alpha), which in turn activates a whole range of vascularisation promoting growth factors. This is the body’s attempt at counterbalancing incidences of oxygen deficiency. It is hoped that through the targeted triggering of hypoxia, the formation of new blood vessels can be experimentally stimulated in artificial tissue.

Innovative imaging and analysis methods should finally make it possible to evaluate the extent and density of vascularisation. This is possible with the help of fluorescence microscopy, histochemistry, morphometry, vascular casting, micro CT and, last but not least, electron microscopy.

Should the Erlangen researchers from the Plastic and Hand Surgery Clinic be successful, this would not only constitute an important contribution to tissue engineering but “cancer research could also greatly benefit from our findings as vascularisation does not only keep healthy tissue alive, but also plays a crucial role in tumour growth”, comments Bleiziffer.

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uni | media service | research No. 2/2012 on 11.1.2012