A New Approach to Obtaining Nano-Sized Graphene Oxide for Biomedical Applications.

Graphene oxide (GO) is one of the most exciting and widely used materials. A new method of nanographene oxide (n-GO) formation is presented. The described unique sequence of ultrasonication in dimethyl sulfoxide solution allows us to obtain different sizes of n-GO sheets by controlling the timing of the cutting and re-aggregation processes. The obtained n-GO exhibits only minor spectral changes, mainly due to the formation of S-containing surface groups; thus, it can be concluded that the material is not reduced during the process. Maintaining the initial oxygen functionalities together with the required nano-size (down to 200 nm) and high homogeneity are beneficial for extensive applications of n-GO. Moreover, we prove that the obtained material is evidently biocompatible. The calculated half-maximal effective concentration (EC50) increases by 5-fold, i.e., from 50 to 250 µg/mL, when GO is converted to n-GO. As a consequence, the new n-GO neither disturbs blood flow even in the narrowest capillaries nor triggers a toxic influence in surrounding cells. Thus, it can be a serious candidate for drugs and biomolecule carriers administered systemically.

Fabrication of Nanopores Polylactic Acid Microtubes by Core-Sheath Electrospinning for Capillary Vascularization.

There has been substantial progress in tissue engineering of biological substitutes for medical applications. One of the major challenges in development of complex tissues is the difficulty of creating vascular networks for engineered constructs. The diameter of current artificial vascular channels is usually at millimeter or submillimeter level, while human capillaries are about 5 to 10 µm in diameter. In this paper, a novel core-sheath electrospinning process was adopted to fabricate nanoporous microtubes to mimic the structure of fenestrated capillary vessels. A mixture of polylactic acid (PLA) and polyethylene glycol (PEO) was used as the sheath solution and PEO was used as the core solution. The microtubes were observed under a scanning electron microscope and the images were analyzed by ImageJ. The diameter of the microtubes ranged from 1-8 microns. The diameter of the nanopores ranged from 100 to 800 nm. The statistical analysis showed that the microtube diameter was significantly influenced by the PEO ratio in the sheath solution, pump rate, and the viscosity gradient between the sheath and the core solution. The electrospun microtubes with nanoscale pores highly resemble human fenestrated capillaries. Therefore, the nanoporous microtubes have great potential to support vascularization in engineered tissues.

Aging of the Vascular System and Neural Diseases.

Vertebrates have acquired complex high-order functions facilitated by the dispersion of vascular and neural networks to every corner of the body. Blood vessels deliver oxygen and nutrients to all cells and provide essential transport systems for removing waste products. For these functions, tissue vascularization must be spatiotemporally appropriate. Recent studies revealed that blood vessels create a tissue-specific niche, thus attracting attention as biologically active sites for tissue development. Each capillary network is critical for maintaining proper brain function because age-related and disease-related impairment of cognitive function is associated with the loss or diminishment of brain capillaries. This review article highlights how structural and functional alterations in the brain vessels may change with age and neurogenerative diseases. Capillaries are also responsible for filtering toxic byproducts, providing an appropriate vascular environment for neuronal function. Accumulation of amyloid ß is a key event in Alzheimer's disease pathogenesis. Recent studies have focused on associations reported between Alzheimer's disease and vascular aging. Furthermore, the glymphatic system and meningeal lymphatic systems contribute to a functional unit for clearance of amyloid ß from the brain from the central nervous system into the cervical lymph nodes. This review article will also focus on recent advances in stem cell therapies that aim at repopulation or regeneration of a degenerating vascular system for neural diseases.

Do Direct Bypasses Really Resolve Capillary Vessels in Moyamoya Disease? Delayed Hemorrhage Potentially Relevant to Direct Bypasses: A Pathological Investigation.

OBJECTIVE: Moyamoya disease is a chronic but progressive obliterative cerebrovascular disease of bilateral internal carotid arteries (ICAs) causing hemorrhagic or ischemic cerebral strokes. Surgical revascularization has the potential for resolving the capillary vessels, but the effect on the occlusive ICA and the moyamoya vessels after a direct bypass remains unclear. PATIENT: A 2-year-old girl with a history of repeated transient ischemic attacks and direct bypasses but demonstrating improvement and associated anomaly is reported. A year and a half later, after a bilateral revascularization, an intracerebral capsulized hematoma growth was identified, and it was removed surgically. Neovascularization including many microvessels similar to capillary telangiectasia were identified by pathological investigation despite the reduction of moyamoya vessels on the repeated angiograms after the revascularization surgeries. In the present case, proliferation of capillary vessels was clearly confirmed by direct bypasses. CONCLUSION: There is no doubt that direct bypasses prevent further ischemic stroke by improving cerebral blood flow. However, they may result in failure in reducing the load of moyamoya vessels, albeit decreasing the potential risk of hemorrhagic strokes.

The Relationship between Fluorescein Angiography Leakage after Infliximab Therapy and Relapse of Ocular Inflammatory Attacks in Ocular Behçet's Disease Patients.

Purpose: To clarify the relationship between fluorescein angiography (FA) leakage after infliximab therapy and ocular attack relapse in patients with ocular Behçet's disease (BD). Methods: Patients with ocular BD were divided into two groups based on the presence (Group 1) or absence (Group 2) of ocular attacks after IFX therapy. FA leakage was evaluated by FA score in each of the optic discs, macula, large retinal vessels, and capillary vessels. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the relationship between FA score after IFX therapy and ocular attack relapse. Results: The areas under the curves obtained from the ROC curve of optic disc score and capillary vessels score after IFX therapy were 0.867 (95% confidence interval [CI]: 0.788-0.946) and 0.788 (95% CI: 0.649-0.927), respectively. Conclusions: FA leakage in the optic disc and capillary vessels after IFX therapy was strongly related to ocular attack relapse.

Hemorrhage Caused by Snake Venom Metalloproteinases: A Journey of Discovery and Understanding.

The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration.

Evaluación de la microcirculación sublingual en un paciente en shock séptico / Sublingual microcirculation asessment in a patient with septic shock

Introduction: Septic shock involves a complicated network of circulatory, inflammatory and metabolic disturbances,leading to cellular energetic disruption. Microcirculatory alterations are frequently observed in septic shock, being characteristic the presence of weak microcirculatory units and heterogeneous microcircu-latory flow. Clinical case: A female patient, two months of age, with a pulmonary process-originated septic shock is presented. The description of microcirculation alterations at 24, 72 and 120 hrs was performed while the patient underwent therapy. A MicroScan®, (MicroVision Medical, Amsterdam, Holland) was utilised on the sublingual area. The patient received ventilation support, reanimation fluids, vasoactive drugs and antibiotics. The patient presented low proportion of perfused capillary vessels, low ratio of microcirculatory flow and a high heterogeneity in flow in the first measurement, all of them independant from systemic hemodynamics and disoxia indicators. These severe alterations improved progressively at 72 and 120 hrs of therapy. Discussion: Microcirculatory alterations and its time evolution may be a tool for dynamic diagnostic and severity staging assesment in septic shock. Further studies should assess microcirculation as a target for therapeutic intervention (microcirculatory resuscitation), being also of prognostic value for septic shock and severe sepsis in children.

Introducción: El shock séptico involucra una compleja red de alteraciones circulatorias, inflamatorias y metabólicas que conducen a una disrupción energética celular. En el shock séptico se observan frecuentemente alteraciones microcirculatorias, siendo característico la existencia de unidades microcirculatorias débiles y un flujo microcirculatorio heterogéneo. Caso clínico: Se presenta una paciente de dos meses de edad con shock séptico de foco pulmonar, en la que realizamos una descripción de las alteraciones microcirculatorias a las 24, 72 y 120 h durante su tratamiento. Se utilizó MicroScan®, (MicroVision Medical, Amsterdam, Holanda) en el área sublingual. La paciente recibió soporte ventilatorio, fluidos de reanimación, drogas vasoactivas y antibióticos. En la medición inicial la paciente presentaba una baja proporción de capilares perfundidos, un bajo índice de flujo microcirculatorio y una alta heterogeneidad de flujo, todas ellas con independencia de la hemodinamia sistémica e indicadores de disoxia. Estas alteraciones graves mejoraron progresivamente a las 72 y 120 h de tratamiento. Discusión: Las alteraciones microcirculatorias y su evolución temporal pueden ser una herramienta diagnóstica dinámica y de estratificación de gravedad en estados de shock séptico. En estudios futuros la microcirculación deberá ser evaluada como un objetivo de intervención terapéutica (resucitación microcirculatoria) presentando a su vez un rol pronóstico en el shock séptico y sepsis grave en niños.