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

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 prevascularization 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 mM and 500 mM 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 mM DMOG-NPSNPs.In fibrin-based tube formation assays,100 mM DMOG-NPSNPs had inhibitory effects whereas 50 mM 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 prevascularization of tissue-engineered constructs.Further studies will evaluate their effect in hydrogels under perfusion.

“Ferrero-like”nanoparticles knotted injectable hydrogels to initially scavenge ROS and lastingly promote vascularization in infarcted hearts

Myocardial infarction(MI)exhibits a complicated and ever-accelerated pathological change involving excessive reactive oxygen species(ROS)and the up-regulation of pro-inflammatory cytokines in the initial stage,and a permanently inadequate blood supply.Herein,an injectable hydrogel fabricated by nanoparticles(NPs)knotted thiolated hyaluronic acid(HA-SH)was reported to reverse the hostile microenvironment and rebuild the heart functions after MI.Inspired by the composite shell-core structure of Ferrero chocolate sphere,a mimetic nanocarrier was designed to consist of the hydrophobic dimethyloxalylglycine(DMOG)NPs core and a thick polydopamine(PDA)shell formed by the self-polymerization of dopamine embedded with watersoluble drug epigallocatechin-3-gallate(EGCG)throughπ-πinteractions.The resulted"Ferrero-like"NPs exhibited a"three-inone"capacity,namely loading two distinct drugs,elimination of ROS,and serving a crosslinker to knot HA-SH."Ferrero-like"NPs and HA-SH could rapidly form a hydrogel that exhibited a stable mechanical property,high capability to capture ROS,and programmed release of EGCG and DMOG.Four weeks after deploying the"Ferrero-like"NPs knotted hydrogels into rat infarcted hearts,the ejection fraction(EF)increased by 23.7%,and the infarct size decreased by 21.1%,and the fibrotic area reduced by 24.4%.The outcomes of immunofluorescence staining and reverse transcription-polymerase chain reaction(RTPCR)demonstrated a down-regulation of inflammatory factors(tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interferon-γ(IFN-γ)),up-regulation of vascular related growth factors(hypoxia inducible factor-1α(HIF-1α),vascular endothelial growth factor A(VEGFA),von Willebrand factor(vWF),angiopoietin-1(Ang-1))and cardiac-related m RNAs(gap junction protein(Cx43),Cadherin 2).All in all,in this report,a very simple approach to intertemporally address the intricate and ongoing pathological changes after MI by injecting"Ferrero-like"NPs knotted hydrogels is developed to reverse hostile microenvironment,with an ability to scavenge ROS,down-regulate pro-inflammation factors in the first stage,and promote angiogenesis in a long term,thereby contributing to a significant improvement of heart functions.