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The development of a fully integrated biomedical engineering programme (life sciences included from the start) is described. Details are provided about background, implementation, and didactic concept: design centred learning combined with courses. The curriculum has developed into a bachelor—master's programme with two different master's degrees: Master's Degree in Biomedical Engineering and Master's Degree in Medical Engineering. Recently, the programme has adopted semester programming, has included a major and minor in the bachelor's degree phase, and a true bachelor's degree final project. Details about the programme and data about where graduates find jobs are provided in this paper.

Leukocyte-endothelium interactions are diminished in tumors. It is reported here that, in a tumor-free in vivo model, angiogenic factors can down-regulate leukocyte adhesion to endothelium. Slow releasing pellets were loaded with either basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF) or vehicle alone and were placed in the scrotum of mice. After 3 days, a single intrascrotal injection of 1 microg/kg IL-1beta was given 4 h before vessels of the cremaster muscle were investigated for leukocyte rolling and adhesion by means of intravital microscopy. Exposure of normal tissue to either bFGF or VEGF resulted in markedly decreased levels of cytokine-induced leukocyte adhesion. Suppression of leukocyte rolling was not observed. Instead a moderate enhancement of rolling by VEGF was found. The observed differences could not be explained by differences in fluid dynamic parameters or systemic leukocyte counts. In conclusion, evidence is presented that, in vivo, angiogenic factors significantly reduce leukocyte adhesion, the final step preceding leukocyte infiltration. This observation may explain why tumors escape from immune surveillance.

1. To investigate the nature of sympathetic dysfunction in the pathogenesis of reflex sympathetic dystrophy, the microcirculatory vasoconstrictive responses to dependency were investigated in the skin of the hand of 76 reflex sympathetic dystrophy patients with unilateral disease by means of laser Doppler flowmetry (in perfusion units) and capillary microscopy. The patients were divided into three stages according to their perception of skin temperature (stage I in the case of a stationary warmth sensation, stage II in the case of an intermittent warmth and cold sensation, and stage III in the case of a stationary cold sensation). The vasoconstrictive responses were induced by lowering of the affected hand. 2. As compared to controls, the mainly sympathetically mediated vasoconstrictive response at thermoregulatory level of the skin microcirculation, as measured by laser Doppler flowmetry, was attenuated at stage I (1.82 versus 1.41, P < 0.05), stage II (1.82 versus 1.09, P < 0.0001) and stage III (1.82 versus 1.14, P < 0.01), suggesting the involvement of sympathetic denervation at all stages of the reflex sympathetic dystrophy syndrome. This sympathetic denervation may also account for the observed increase in thermoregulatory skin blood flow at stage I as compared to controls (152 versus 81, P < 0.01). 3. Since sympathetic denervation has been reported to cause increased sensitivity of vascular structures to catecholamines, the decrease in thermoregulatory skin blood flow at stages II (54 versus 81, P < 0.05) and III (31 versus 81, P < 0.05), both as compared to controls, may result from hypersensitivity to catecholamines of skin microvessels. 4. The sympathetically independent vasoconstrictive response at the nutritive level of skin microcirculation, as measured by capillary microscopy, was impaired only at stage III as compared to controls (1.04 versus 2.06, P < 0.05). This divergence in microvascular reactivity upon dependency of the nutritive and thermoregulatory subsystems also supports the hypothesis of sympathetic dysfunction. 5. The disturbed vasoconstrictive responses to dependency may give rise to raised capillary pressures, contributing to the formation of oedema. 6. These findings suggest that sympathetic denervation and consequent hypersensitivity to catecholamines play an important role in the pathophysiology of reflex sympathetic dystrophy.

Isovolemic haemodilution with plasma was performed in 36 newborn infants with polycythaemia 3 h after birth. Continuous wave Doppler ultrasonography was used to study the short and longer term influence of partial plasma exchange transfusion on cerebral blood flow velocity in both the anterior cerebral and mid cerebral arterial system up to 24 h after haemodilution. The study group consisted of 11 preterm infants, 12 term infants, and 13 small for date infants. After exchange transfusion peripheral venous haemotocrit decreased from 72.5% to 59.4%. In all experimental groups cerebral blood flow velocity (CBFV) before exchange transfution was significantly lower (18%–44%) than matched controls, and increased to control levels after exchange transfusion. CBFV improved most in preterm infants. After the transfusion the values were no different from the age-, weight-, sex-and parity-matched control groups, and they remained at this level during the next 24 h. No differences could be found between the anterior and mid-cerebral arterial system. When clinical symptoms were present, they subsided in all infants. In conclusion, partial plasma exchange transfusion has a favourable effect for at least 24 h on cerebral blood flow velocity in newborn infants with polycythaemia.

The sympathetic nervous system is one of the primary factors controlling vascular resistance. Vascular smooth muscle contraction by sympathetic stimulation is mediated primarily by alpha-adrenoceptors. In this study, we investigated the effects of different forms of adrenergic stimulation on simultaneously measured macro- and microcirculatory dynamics in the rat mesenteric vascular bed. Macrocirculatory effects were measured by means of registration of changes in mean arterial pressure (MAP) and blood flow feeding this tissue via a miniaturized Doppler flow probe around the superior mesenteric artery. Microvascular changes were measured at the level of A2 arterioles by means of intravital microscopic registration of arteriolar diameters and red blood cell velocity (RBC vel). Topical or intra-arterial application of noradrenaline caused a dose-dependent decrease in arteriolar diameter and RBC vel at doses that did not cause significant systemic effects. On the other hand, during intravenous application of noradrenaline or other vasopressor substances an increase in MAP and decrease in organ (Doppler) blood flow was not parallelled by a decrease in arteriolar diameter or RBC vel. In contrast, RBC vel increased in a dose-related manner, whereas arteriolar diameter only secondarily decreased to a small degree. Similar results were obtained when the sympathetic nervous system was activated by means of electrical stimulation of the posterior hypothalamus. These data indicate that adrenergic stimulation can elicit different vascular responses. The ultimate microvascular effect depends upon the way of stimulation or route of drug administration.

Abstract: A bidirectional optical (BDO) three-stage prism grating system has been developed to measure online direction and magnitude of red blood cell (RBC) velocities in the microcirculation. The paper describes a mathematical evaluation of the BDO system. The optical grating configuration was simulated in terms of a spatial filter. The input signal was the simulated spatial light distribution of a group of moving RBCs Three methods for estimating the mean frequency (fmean) of the signal corresponding to RBC velocity were evaluated on the criteria of accuracy and noise sensitivity. All underestimated the RBC velocity. The reference method calculates fmean from the power density spectrum. A zero-crossing counting technique and a method based on time differentiation underestimated the mean frequency by 141113 per cent (mean SD) and 0901 per cent, respectively. The zero-crossing counting technique was more sensitive to noise than both other methods. The reference method, operating in the frequency domain, is preferred, because the power density spectrum obtained can be corrected for filtering errors induced by higher-order passbands of the optical filter.

Houben A J H M, Slaaf D W, Huvers F C, de Leeuw P W, Nieuwenhuijzen Kruseman A C, Schaper N C. Diurnal variations in total forearm and skin microcirculatory blood flow in man. Scand J Clin Lab Invest 1994; 54: 161-168.The aim of the present study was to determine diurnal variations in total forearm and skin microcirculatory blood flow in healthy man. At six time points between 08.00 and 18.00 hours was measured: blood pressure, forearm blood flow (FBF; strain gauge plethysmography), skin thermoregulatory blood flow (LDF; laser-Doppler fluxmetry), and skin nutritive blood flow (CBV: Capillary Blood Cell Velocity; intravital capillary microscopy) in 15 healthy, fasting, and resting men. FBF increased gradually from 2.8 in the morning to 4.3 ml 100 ml min1 in the afternoon (p < 0.001). In contrast, LDF decreased, predominantly in the morning, from 18.3 at 09.00 hours to 13.1 at 12.00 hours and to 12.1 perfusion units at 17.30 hours (p < 0.001). However, performing the same protocol starting in the afternoon resulted in a similar initial decrease in LDF, suggesting an acclimatization phenomenon. Although not satistically significant, the decrease in CBV showed a similar pattern as compared to LDF. Blood pressure did not change. In conclusion, forearm blood flow increased during the day, probably due to diurnal variation in muscle flow. The initial decrease we observed in skin thermoregulatory blood flow is probably not related to diurnal variation but due to long-term acclimatization to the experimental conditions. These data suggest different regulatory mechanisms for the different vascular beds studied. Measurements of forearm blood flow should preferably be performed at the same time of day, and skin microcirculatory haemodynamic measurements should be performed after a standard period of acclimatization.

1. Skin microcirculation was investigated in 12 asymptomatic subjects and 76 patients, grouped according to their ankle-to-brachial systolic blood pressure index, in order to evaluate to what extent posturally induced microvascular constriction is dependent on the stage of leg ischaemia at different local skin temperatures. 2. Skin microcirculation was assessed in the supine and sitting position by using laser Doppler fluxmetry at unheated skin temperature and at 36°C, and transcutaneous oximetry at 37°C and 44°C. 3. Skin perfusion and oxygenation diminished with decreasing ankle-to-brachial systolic blood pressure index. In healthy control subjects, perfusion and oxygenation were reduced when changing from the supine to the sitting position, but were enhanced in patients with severe leg ischaemia (ankle-to-brachial systolic blood pressure < 30%), indicating disturbed posturally induced vasoconstriction. 4. Increasing the local skin temperature resulted in a higher perfusion and masked the posturally induced vasoconstriction in healthy subjects. In patients with severe leg ischaemia, however, perfusion was unaltered by the temperature increase, apparently because the microvessels were already maximally dilated. The induction of reactive hyperaemia produced no additional increase in perfusion or oxygenation. 5. It is concluded that posturally induced microvascular constriction in the skin is disturbed in patients with severe leg ischaemia (ankle-to-brachial systolic blood pressure index < 30%). Disturbed microvascular constriction upon dependency was also seen in healthy subjects after local skin heating. This suggests that posturally induced vasoconstriction is mainly regulated by local mechanisms.

Transcutaneous oximetry (TcpO₂) performed at 37 and 44° on the dorsum of the foot and capillary microscopy of the nailfold of the big toe were applied to 85 patients with various (including asymptomatic) stages of lower limb ischemia to appreciate the relationship between (disturbances in) capillary perfusion and skin oxygen tension. In mildly diseased patients, capillary perfusion as measured by direct observation, was preserved. In critically ischemic patients in the supine position, red blood cell-perfused capillary density was reduced. Nutritive perfusion was severely reduced and showed an absent reactive hyperemia after a 1-min arterial occlusion. Also, postural vasoconstrictive activity was reduced, TcpO₂ measured at 37° was very low already in mildly diseased patients, illustrating the poor oxygen diffusion toward the skin. At 44°, TcpO₂ was severely reduced in critically ischemic patients. Reactive hyperemic response and postural vasoconstriction were suppressed, due to local heating of the skin. Measurement of the TcpO₂ has limitations in the assessment of nutritive perfusion, as opposed to capillary microscopy, since it is an indirect measure of skin perfusion, not necessarily derived from capillaries only. The obligatory local skin heating impairs physiological studies as to hyperemic reserve capacity or postural constriction mechanisms. Thus, transcutaneous oximetry is a poor method of characterizing pathophysiological mechanisms occurring in skin nutritive microcirculation. However, capillary microscopy and transcutaneous oximetry can give additive information as to the severity of peripheral ischemia. Peak red blood cell velocity during reactive hyperemia using capillary microscopy and the resting TcpO₂ at 44°, both measured in the supine position, appeared to be valuable microcirculatory parameters in detecting critical limb ischemia. Copyright 1995, 1999 Academic Press

Animal studies suggest that hyperglycaemia directly affects local blood flow and vascular reactivity. We studied the effects of 7 h of local forearm hyperglycaemia, on forearm (muscle) and skin microcirculatory blood flow in 12 healthy men. Furthermore, the effects of this local hyperglycaemia on forearm vasoreactivity to noradrenaline were studied. Using the perfused forearm technique, a local hyperglycaemia of approximately 16 mmol/l was induced by continuous intraarterial infusion of 5% glucose. All subjects received both glucose and placebo (0.9% NaCl) infusions on two different occasions, in random order and blinded for the subjects. Forearm (muscle) blood flow and vascular reactivity to noradrenaline were measured using venous occlusion plethysmography. Skin microcirculatory blood flow was evaluated using intravital capillary microscopy (nutritive blood flow) and laser-Doppler fluxmetry (thermoregulatory blood flow). Measurements were performed at baseline, after 4 h, and after 7 h of intraarterial glucose or placebo infusion. During local glucose infusion there was a slight increase in the levels of insulin, C-peptide, systemic glucose, and blood pressure, compared to the placebo experiments. No differences were observed in forearm blood flow and laser-Doppler flux ratio (infused: contralateral arm), as well as in capillary blood cell velocity between glucose and placebo experiments. Noradrenaline produced similar reductions in forearm blood flow ratio during glucose and placebo experiments. We conclude that in contrast to animal studies, local hyperglycaemia (≈ 16 mmol/1) for 7 h does not affect forearm macro and microcirculatory blood flow or vascular reactivity to noradrenaline in man.

The effect of ketanserin on macrocirculatory and microcirculatory blood flow was investigated in a placebo-controlled, double-blind trial in 11 patients suffering from intermittent claudication using Doppler velocimetry and intravital skin capillary microscopy, respectively.