Carbon monoxide-releasing Vehicle CO@TPyP-FeMOFs modulating macrophages phenotype in inflammatory wound healing.

Healing of chronic wounds has been critically limited by prolonged inflammation. Carbon monoxide (CO) is a biologically active molecule with high potential based on its efficacy in modulating inflammation, promoting wound healing and tissue remodeling. Strategies to use CO as a gaseous drug to chronic wounds have emerged, but controlling the sustained release of CO at the wound site remains a major challenge. In this work, a porphyrin-Fe based metal organic frameworks, TPyP-FeMOFs was prepared. The synthesized TPyP-FeMOFs was high-temperature vacuum activated (AcTPyP-FeMOFs) and AcTPyP-FeMOFs had a relatively high Fe (II) content. CO sorption isotherms showed that AcTPyP-FeMOFs chemisorbed CO and thus CO release was sustained and prolonged. In vitro evaluation results showed that CO@TPyP-FeMOFs reduced the inflammatory level of lipopolysaccharide (LPS) activated macrophages, polarized macrophages to M2 anti-inflammatory phenotype, and promoted the proliferation of fibroblasts by altering the pathological microenvironment. In vivo study confirmed CO@TPyP-FeMOFs promoted healing in a LPS model of delayed cutaneous wound repair and reduced macrophages and neutrophils recruitment. Both in vitro and in vivo studies verified that CO@TPyP-FeMOFs acted on macrophages by modulating phenotype and inflammatory factor expression. Thus, CO release targeting macrophages and pathological microenvironment modulation presented a promising strategy for wound healing.

Reducing Endogenous Labile Zn May Help to Reduce Smooth Muscle Cell Injury around Vascular Stents.

Vascular stent service involves complex service environments and performance requirements, among which the histocompatibility of the stent could seriously affect the therapeutic effect. In the pathology of vascular disease, the thin fiber cap is easily ruptured, exposing the necrotic core below, and triggering a series of dangerous biochemical reactions. In contrast, the thin neointima, considered an essential structure growing on the stent, may evolve into vulnerable plaque structures due to lesions induced by the stent. Therefore, the reduction of necrosis around the stent below the thin neointima is indispensable. In this work, different cell model experiments suggested that the content of endogenous labile Zn positively correlated with cell injury. Zinquin-Zn fluorescence experiments and zinc ion channels research suggested that the change in the content of endogenous labile Zn in smooth muscle cells is affected by different stent coatings. The content of endogenous labile Zn in cells negatively correlated with cell viability. Animal experiments indirectly verified the increase in endogenous labile Zn by detecting the expression of Zn regulatory protein (metallothionein) in the necrotic tissues. Reducing the content of endogenous labile Zn may favor a reduction in smooth muscle cell injury and necrosis. This biochemical mechanism is effective in improving the therapeutic effect of vascular stents.

Selective endothelialization and alleviation of neointimal hyperplasia by functionalizing the Ti-O surface with l-selenocystine and KREDVC.

Due to their relatively good biocompatibility and inactivity, titanium oxide films (Ti-O) are used in the coating of coronary stents, which reduces metal corrosion, slows metal ion release, and improves endothelial cell (EC) compatibility. Here, we report further functionalizing Ti-O with biological cues for selective endothelialization. Selenocystine with an l- or a d-enantiomer was first immobilized on the Ti-O film via polydopamine to generate nitric oxide (NO) endogenously, which inhibited smooth muscle cell (SMC) proliferation, followed by the grafting of a functional KREDVC peptide to induce EC adhesion. The synergistic effects of the immobilized KREDVC, surface chirality, and NO generation on selective endothelialization were investigated. The results showed that the surface chirality of the l-enantiomer and KREDVC grafting significantly enhanced the attachment and growth of ECs compared to SMCs. An in vivo study showed von Willebrand factor expression was increased and neointimal hyperplasia was significantly decreased in samples with l-selenocystine immobilization and KREDVC grafting. In summary, these findings provide new insights on the surface modification of cardiovascular implants with selective endothelialization.

Immobilization of nano Cu-MOFs with polydopamine coating for adaptable gasotransmitter generation and copper ion delivery on cardiovascular stents.

In-stent restenosis is worsened by thrombosis, acute inflammation, and uncontrollable smooth muscle cells (SMCs) proliferation at the early stage of implantation. Tailoring the stent surface can inhibit thrombosis, intimal hyperplasia, and accelerate re-endothelialization. In situ nitric oxide (NO) generation is considered as a promising method to improve anti-coagulation and anti-hyperplasia abilities. Copper based metal organic frameworks showed great potential as catalysts for NO generation, and copper ion (Cu2+) was demonstrated to promote endothelial cells (ECs) growth. Herein, by using polydopamine as the linker and coating matrix, nanoscale copper-based metal organic frameworks (nano Cu-MOFs) were immobilized onto the titanium surface for simultaneous nitric oxide (NO) catalytic generation and Cu2+ delivery. The nano Cu-MOFs-immobilized coating exhibited desirable NO release and adaptable Cu2+ delivery. Such coating inhibited platelet aggregation and activation via NO-cGMP signaling pathway, and significantly reduced thrombosis in an ex vivo extracorporeal circulation model. NO release and Cu2+ delivery showed synergetic effect to promote EC proliferation. Moreover, SMCs and macrophage proliferation was suppressed by the nano Cu-MOFs-immobilized coating, thereby reducing neointimal hyperplasia in vivo. Overall, this biocompatible coating is convenient for the surface modification of cardiovascular stents and effectively prevents the late stent thrombosis and in-stent restenosis associated with stent implantation.