Near-infrared light-driven multifunctional metal ion(Cu^(2+))-loaded polydopamine nanomotors for therapeutic angiogenesis in critical limb ischemia

Most of the current nanomedicine-based treatments for critical limb ischemia(CLI)only aim at promoting angiogenesis,ignoring the negative influence on the therapeutic effects caused by the complex pathological micro-environment of ischemic tissue.Herein,near-infrared(NIR)light-driven metal ion(Cu^(2+))-loaded polydopamine(PDA)nanomotors(JMPN@Cu^(2+))is designed and prepared.Due to the good antioxidant and anti-inflammatory activities of PDA,JMPN@Cu^(2+)exhibits excellent biocompatibility and significantly improves the ischemic micro-environment.Additionally,based on superior photothermal conversion effect and jellyfish-like structure,the nanomotors are quickly propelled under NIR laser with low energy intensity to acquire the ability of movement and facilitate intracellular uptake of JMPN@Cu^(2+)by endothelial cells,resulting in the enhanced pro-angiogenic effect of Cu^(2+).Moreover,in vivo experimental findings show that JMPN@Cu^(2+)combined with NIR irradiation can successfully accelerate blood flow recovery and improve muscle repair.Taking these results together,this kind of nanomotor can promote angiogenesis along with ischemic micro-environment amelioration,holding great potential applications for the treatment of limb ischemia.

Engineering microparticles based on solidified stem cell secretome with an augmented pro-angiogenic factor portfolio for therapeutic angiogenesis

Tissue (re)vascularization strategies face various challenges, as therapeutic cells do not survive long enough in situ, while the administration of pro-angiogenic factors is hampered by fast clearance and insufficient ability to emulate complex spatiotemporal signaling. Here, we propose to address these limitations by engineering a functional biomaterial capable of capturing and concentrating the pro-angiogenic activities of mesenchymal stem cells (MSCs). In particular, dextran sulfate, a high molecular weight sulfated glucose polymer, supplemented to MSC cul-tures, interacts with MSC-derived extracellular matrix (ECM) components and facilitates their co-assembly and accumulation in the pericellular space. Upon decellularization, the resulting dextran sulfate-ECM hybrid material can be processed into MIcroparticles of SOlidified Secretome (MIPSOS). The insoluble format of MIPSOS protects protein components from degradation, while facilitating their sustained release. Proteomic analysis demonstrates that MIPSOS are highly enriched in pro-angiogenic factors, resulting in an enhanced pro-angiogenic bioactivity when compared to naïve MSC-derived ECM (cECM). Consequently, intravital microscopy of full-thickness skin wounds treated with MIPSOS demonstrates accelerated revascularization and healing, far superior to the ther-apeutic potential of cECM. Hence, the microparticle-based solidified stem cell secretome provides a promising platform to address major limitations of current therapeutic angiogenesis approaches.

Therapeutic Angiogenesis:The Combination Point of Chinese and Western Medicine in Prevention and Treatment of Ischemic Heart Disease

At present, the conventional medicine and revascularization （including interventional treatment and coronary bypass surgery） in ischemic heart disease have limited the clinical efficacy on the progress of the left ventricular remodeling and heart failure after myocardial infarction, and the mortality accounts about 50% of cardiovascular diseases. With the potential role of repairing injured or necrotic myocardium and improving the blood supply in ischemic region, heart cell therapy and therapeutic angiogenesis have become new highlights in disease treatment and the field of cardiovascular new strategies for the prevention and treatment of complications of endstage ischemic heart diseases.

Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs

Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adeno- virus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we estab- lished a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were ran- domly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.