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Chemically induced hypoxia by dimethyloxalylglycine (DMOG)-loaded nanoporous silica nanoparticles supports endothelial tube formation by sustained VEGF release from adipose tissue-derived stem cells.

ABSTRACT: Inadequate vascularization leading to insufficient oxygen and nutrient supply in deeper layers of bioartificial tissues remains a limitation in current tissue engineering approaches to which pre-vascularization offers a promising solution. Hypoxia triggering pre-vascularization by enhanced vascular endothelial growth factor (VEGF) expression can be induced chemically by dimethyloxalylglycine (DMOG). Nanoporous silica nanoparticles (NPSNPs, or mesoporous silica nanoparticles, MSNs) enable sustained delivery of molecules and potentially release DMOG allowing a durable capillarization of a construct. Here we evaluated the effects of soluble DMOG and DMOG-loaded NPSNPs on VEGF secretion of adipose tissue-derived stem cells (ASC) and on tube formation by human umbilical vein endothelial cells (HUVEC)-ASC co-cultures. Repeated doses of 100 µM and 500 µM soluble DMOG on ASC resulted in 3- to 7-fold increased VEGF levels on day 9 (P < 0.0001). Same doses of DMOG-NPSNPs enhanced VEGF secretion 7.7-fold (P < 0.0001) which could be maintained until day 12 with 500 µM DMOG-NPSNPs. In fibrin-based tube formation assays, 100 µM DMOG-NPSNPs had inhibitory effects whereas 50 µM significantly increased tube length, area and number of junctions transiently for 4 days. Thus, DMOG-NPSNPs supported endothelial tube formation by upregulated VEGF secretion from ASC and thus display a promising tool for pre-vascularization of tissue-engineered constructs. Further studies will evaluate their effect in hydrogels under perfusion.

SUBMITTER: Zippusch S

PROVIDER: S-EPMC8363767 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Biomaterials, once inserted in the oral cavity, become immediately covered by a layer of adsorbed proteins that consists mostly of salivary proteins but also of plasma proteins if the biomaterial is placed close to the gingival margin or if it becomes implanted into tissue and bone. It is often this protein layer, rather than the pristine biomaterial surface, that is subsequently encountered by colonizing bacteria or attaching tissue cells. Thus, to study this important initial protein adsorption from human saliva and serum and how it might be influenced through chemical modification of the biomaterial surface, we have measured the amount of protein adsorbed and analyzed the composition of the adsorbed protein layer using gel electrophoresis and western blotting. Here, we have developed an in vitro model system based on silica surfaces, chemically modified with 7 silane-based self-assembled monolayers that span a broad range of physicochemical properties, from hydrophilic to hydrophobic surfaces (water contact angles from 15° to 115°), low to high surface free energy (12 to 57 mN/m), and negative to positive surface charge (zeta potentials from -120 to +40 mV at physiologic pH). We found that the chemical surface functionalities exerted a substantial effect on the total amounts of proteins adsorbed; however, no linear correlation of the adsorbed amounts with the physicochemical surface parameters was observed. Only the adsorption behavior of a few singular protein components, from which physicochemical data are available, seems to follow physicochemical expectations. Examples are albumin in serum and lysozyme in saliva; in both, adsorption was favored on countercharged surfaces. We conclude from these findings that in complex biofluids such as saliva and serum, adsorption behavior is dominated by the overall protein-binding capacity of the surface rather than by specific physicochemical interactions of single protein entities with the surface.

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Chemically induced hypoxia by dimethyloxalylglycine (DMOG)-loaded nanoporous silica nanoparticles supports endothelial tube formation by sustained VEGF release from adipose tissue-derived stem cells.

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