Sequentially suspended 3D bioprinting of multiple-layered vascular models with tunable geometries forin vitromodeling of arterial disorders initiation.

As the main precursor of arterial disorders, endothelial dysfunction preferentially occurs in regions of arteries prone to generating turbulent flow, particularly in branched regions of vasculatures. Although various diseased models have been engineered to investigate arterial pathology, producing a multiple-layered vascular model with branched geometries that can recapitulate the critical physiological environments of human arteries, such as intercellular communications and local turbulent flows, remains challenging. This study develops a sequentially suspended three-dimensional bioprinting (SSB) strategy and a visible-light-curable decellularized extracellular matrix bioink (abbreviated as 'VCD bioink') to construct a biomimetic human arterial model with tunable geometries. The engineered multiple-layered arterial models with compartmentalized vascular cells can exhibit physiological functionality and pathological performance under defined physiological flows specified by computational fluid dynamics simulation. Using different configurations of the vascular models, we investigated the independent and synergetic effects of cellular crosstalk and abnormal hemodynamics on the initiation of endothelial dysfunction, a hallmark event of arterial disorder. The results suggest that the arterial model constructed using the SSB strategy and VCD bioinks has promise in establishing diagnostic/analytic platforms for understanding the pathophysiology of human arterial disorders and relevant abnormalities, such as atherosclerosis, aneurysms, and ischemic diseases.

Retinal vessel diameters and microvascular abnormalities in patients with carotid stenosis before and 6 months after carotid endarterectomy: A prospective study.

PURPOSE: To assess retinal findings in patients with severe carotid stenosis (CS) before and after carotid endarterectomy (CEA) compared to those in controls. METHODS: This study is based on 70 patients (male 81%, mean age 69) scheduled for CEA in Helsinki University Hospital and 41 healthy nonmedicated controls (male 76%, mean age 68). Our examinations included fundus photographs. Semi-automated software (Vesselmap, Imedos) served for evaluation of central retinal arterial equivalent (CRAE) and venular equivalent (CRVE), and arterio-venous ratio (AVR) in both eyes. We assessed fundus photographs to subjectively grade microvascular abnormalities in the ipsilateral eyes including focal arteriolar narrowing and irregularities, arteriolar wall reflex, arterio-venous crossing signs and arteriolar and venular tortuosity in the macula. RESULTS: CRAE was similar in the ipsi-and contralateral eyes of our patients, and similar to that of the controls both pre- and postoperatively. Preoperatively, we observed higher CRVE in the patients' ipsilateral than in their contralateral eyes (222 vs. 217 µm, p = 0.009), and likewise higher than in controls' eyes (222 vs. 214 µm, p = 0.024). CRVE decreased postoperatively in the patients' ipsilateral eyes (222 vs. 217 µm, p = 0.037). Among the microvascular abnormalities, arteriolar and venular tortuosity in the macula showed higher grades in the patients than in the controls preoperatively (p = 0.035 and p = 0.043), but not postoperatively (p = 0.15 and p = 0.10). CONCLUSIONS: CRVE decreased after CEA, showing that venules constrict after the mechanical hindrance of blood flow is removed. Higher grades in arteriolar and venular tortuosity in the macula, a potential ocular biomarker of CS, subsided after CEA.

Comparative study of microvascular function: Forearm blood flow versus dynamic retinal vessel analysis.

OBJECTIVE: Recently, dynamic retinal vessel analysis (DVA) has gained interest for investigation of microvascular function but comparative measurements with standard methods like the forearm blood flow technique (FBF) are uncommon till now. METHODS: We recruited 23 high-risk cardiovascular patients (Risk) and 17 healthy persons (Ctrl). During the FBF experiment, postocclusive reactive hyperaemia (RH) as well as endothelium-dependent and independent vasodilation was measured by infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) into the brachial artery. The dynamic vessel analyzer was applied for measurement of the retinal arterial and venous response to flickering light during DVA and for determination of the central retinal arterial (CRAE) and venous equivalent (CRVE). RESULTS: Forearm blood flow technique was significantly attenuated in the patient group during postocclusive RH (p < .005). The increase of FBF in response to SNP did not differ significantly between the two groups (p = .09). In contrast, the FBF response to ACh was significantly blunted in the patient group (p < .05), indicating endothelial dysfunction. DVA did not detect any difference of retinal arterial (p = .68) or retinal venous (p = .93) vasodilation between both groups. The CRAE (p = .55) and CRVE (p = .83) did not differ significantly in either group. CONCLUSIONS: Forearm blood flow and DVA cannot be regarded as equivalent methods for testing of microvascular function. Possible explanations include differences in the vascular beds and vessel diameters examined as well as differences in the trigger mechanisms applied. Further studies are needed to define the role of DVA in this context.

Associations of cardiovascular risk factors and retinal vessel dimensions at present and their evolution over time in a healthy working population.

PURPOSE: The aim of this study was to investigate whether an association between retinal vessel diameters with blood pressure and other risk factors exists in a healthy working population and whether current risk factors can be used as predictors for retinal vessel changes over time. METHODS: Retinal photographs and medical data were obtained during a voluntary work health check in 2010 and 2013. The central retinal arterial equivalent (CRAE) and central retinal venular equivalent (CRVE) were assessed using a semi-automated software. Linear regression analysis was carried out to determine associations with systemic parameters and cardiovascular risk factors. RESULTS: A total of 1685 participants had gradable photographs and full medical data with a mean age of 44.8 years (SD: 10.2) and 80.8% being male; full data were obtained in both 2010 and 2013 for 365 participants allowing for longitudinal analysis. In the cross-sectional analysis, a mean CRAE of 171.2 ±18.3 µm and a mean CRVE 215.8 ± 18.6 µm were found. A significant negative association for CRAE was seen for age, mean arterial blood pressure (MABP), body mass index (BMI) and high-density lipoprotein (HDL), while triglycerides, spherical equivalent (SAE) and being a current smoker were positively associated. For CRVE age, MABP, HbA1c and HDL were negatively associated, while being female, low-density lipoprotein, white blood cell count, SAE and being a current smoker showed a positive association. The linear regression model for the cross-sectional analysis explained 31% and 21% of the variance of CRAE and CRVE, respectively. The longitudinal analysis showed a mean decrease of -1.6 µm (p = 0.04) for CRAE and -2.0 (p = 0.005) for CRVE within the three-year time frame. Linear regression analysis with longitudinal data showed a significant association for HDL and CRAE, while for other factors no statistically significant association between current risk factors and changes in CRAE and CRVE was observed. CONCLUSION: The width of both arterial and venous retinal vessels shows associations not only with arterial blood pressure but also with biochemical markers of cardiovascular risk. While such effects are partially established for elderly persons, our study results indicate that they apply also in a young population in working age with seemingly unimpaired health.