Page 95 - Magnesium-based supports for stem cell therapy of vascular disease - Mónica Echeverry Rendón

PLASMA ELECTROLYTIC OXIDIZED MAGNESIUM ADVERSELY INFLUENCES VASCULAR CELLS TYPES BUT NOT MESENCHYMAL CELLS AND MONOCYTES
1. Introduction
Cardiovascular disease (CVD) is one of the prevalent globally public health problems that causes millions of deaths per year [1]. The worldwide increased general life expectancy comes at the cost of increased risk of disease or age- related cardiovascular complications[2][3]. Major CVD risk factors comprise adverse habits such as a sessile lifestyle, stress, smoking and high caloric nutrition. Major presentations of CVD, involve blood vessels with arterial lesions such as atherosclerosis and aneurysms [4][5]. To regain vascular integrity and architecture, metal stents and coils have been used successfully but over time, this may present long term complications such as vascular re-occlusion i.e. restenosis[6][7][8][9]. Throughout the history of the development of stents, different formulations have been evaluated that range from bare metal implants to drug-eluting stents and bioabsorbable vascular stents (BVAS) [10] [11][12]. Nevertheless, the self-expanding bare metal stent still is most commonly applied. These consist of nickel titanium alloys (Nitinol) or cobalt chromium alloys and are permanent, undegradable implants. Although implant failures have decreased with each technological next generation, the number of failures remains high in proportion to the affected population. Recently, biodegradable stents showed to be promising alternatives that did not have the adverse side effects of permanent metal stents [13]. These biodegradable stents are composed of polymers or ab- sorbable metals or their combination [14][15][16][17]. As metal, in particular magnesium (Mg) is increasingly stud- ied. Mg is an essential element for the body because Mg2+ ions are co-factors of several enzymes thus many physi- ological processes depend on Mg [18][19]. Mg is even more abundant than sodium or potassium in our body. One of the advantages to use Mg as material is its high biocompatibility. Despite this, metallic Mg has some limitations to be used as implant. In aqueous solution, Mg is highly reactive and this reaction comprises the (fast) alkalization of the surrounding area by formation of Mg(OH)2. Additionally, during this oxidation of Mg, hydrogen gas is released. This gas may accumulate in tissue and form highly cytotoxic gas pockets that inhibit wound healing and induce ne- crosis [20][21]. The fast degradation of Mg is, however, manageable e.g. via its use as alloys with other metals which improve the corrosion resistance of the materials [22][23][24]. A different approach to increase corrosion resistance is to oxidize the surface of Mg and generate a protective oxide-based coating. This can be achieved with plasma elec- trolytic oxidation (PEO) which is a low cost, simple and effective technique which employs an electrochemical cell in which Mg is used as anode and oxidized in a controlled way [25]. Via the regulation of voltage, current density, time and electrolyte solution composition, a protective layer of MgO/Mg(OH)2 is grown from the Mg. This layer is more chemically stable and thus decreases the rate of degradation of the underlying Mg[26][27][28][29].
Previous studies on implanted Mg, report that its degradation may cause its structure to collapse, which is unde- sirable if this occurs prior to the recovery of the tissue[30][31]. The restoration of the arterial wall after stenting could likely be accelerated by the local administration of therapeutic cells such as adipose tissue-derived (mesenchy- mal) stromal cells (ASC). These are pro-angiogenic and may also differentiate to contractile medial smooth muscle cells[32][33]. Therefore, loading of ASC onto surface-coated Mg stents might act as a double-edged sword: on the one hand, repair of the arterial wall is accelerated after balloon catheterization and stent placement, while on the other hand this will compensate for premature collapse to the integrity of Mg-based stents. The aim of our study was to develop and evaluate a temporal scaffold based on degradable anodized commercial pure magnesium (c.p Mg) loaded with regenerative cells, i.e. ASC, for future use in arteries with atherosclerotic lesions to restore blood flow. As a first approach, we studied the response of different cell types involved in the blood vessel context after exposure to released degradation compounds, i.e. leachables, of uncoated c.p Mg and c.p Mg surface-coated by PEO. Addition- ally, the influence of Mg was assessed on relevant biological functions where ASC.
2. Materials and methods
2.1 Materials and modifications
Chemically pure magnesium (c.p Mg) was processed into thin sections (10x10x1mm), polished with a series of up
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