The creation of efficient methods for manufacturing biotechnology drugs--many of which influence fundamental but complex cell behaviours, such as proliferation, migration and differentiation--is creating new opportunities for tissue repair. Many agents are potent and multifunctional; that is, they produce different effects within different tissues. Therefore, control of tissue concentration and spatial localization of delivery is essential for safety and effectiveness. Synthetic systems that can control agent delivery are particularly promising as materials for enhancing tissue regeneration. This review discusses the state of the art in controlled-release and microfluidic drug delivery technologies, and outlines their potential applications for tissue engineering.

Santisakultarm TP, Cornelius NR, Nishimura N, Schafer AI, Silver RT, Doerschuk PC, Olbricht WL, Schaffer CB. In vivo two-photon excited fluorescence microscopy reveals cardiac-and respiration-dependent pulsatile blood flow in cortical blood vessels in mice. Am J Physiol Heart Circ Physiol 302: H1367-H1377, 2012. First published January 20, 2012; doi:10.1152/ajpheart.00417.2011.-Subtle alterations in cerebral blood flow can impact the health and function of brain cells and are linked to cognitive decline and dementia. To understand hemodynamics in the three-dimensional vascular network of the cerebral cortex, we applied two-photon excited fluorescence microscopy to measure the motion of red blood cells (RBCs) in individual microvessels throughout the vascular hierarchy in anesthetized mice. To resolve heartbeat-and respirationdependent flow dynamics, we simultaneously recorded the electrocardiogram and respiratory waveform. We found that centerline RBC speed decreased with decreasing vessel diameter in arterioles, slowed further through the capillary bed, and then increased with increasing vessel diameter in venules. RBC flow was pulsatile in nearly all cortical vessels, including capillaries and venules. Heartbeat-induced speed modulation decreased through the vascular network, while the delay between heartbeat and the time of maximum speed increased. Capillary tube hematocrit was 0.21 and did not vary with centerline RBC speed or topological position. Spatial RBC flow profiles in surface vessels were blunted compared with a parabola and could be measured at vascular junctions. Finally, we observed a transient decrease in RBC speed in surface vessels before inspiration. In conclusion, we developed an approach to study detailed characteristics of RBC flow in the three-dimensional cortical vasculature, including quantification of fluctuations in centerline RBC speed due to cardiac and respiratory rhythms and flow profile measurements. These methods and the quantitative data on basal cerebral hemodynamics open the door to studies of the normal and diseased-state cerebral microcirculation. microcirculation; hemodynamics; intravital imaging; vessel bifurcation; brain THE COMPLEX, THREE-DIMENSIONAL (3-D) vascular architecture of the brain presents a challenge to studies of microvascular hemodynamics. Larger arterioles form a net at the cortical surface and give rise to penetrating arterioles that plunge into the brain and feed capillary networks, where most nutrient and metabolite exchange occurs (2). These capillaries coalesce into ascending venules, which return to the cortical surface and drain into larger surface venules (22). Several lines of evidence have suggested that even small changes in hemodynamics in the brain can have detrimental impacts on the health and function of neurons. Chronic diseases that alter the microcirculation, such as hypertension (24) and diabetes (7), are risk factors for dementia and have been linked to cognitive decline (33). Flow disruptions from hyperviscous blood in diseases such as...

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An experimental study is reported of the motion, deformation, and breakup of a synthetic capsule that is freely suspended in Couette flow. The capsule is a liquid drop surrounded by a thin polymeric membrane. The shape and orientation of the capsule are measured in steady flow and following the start-up of Couette flow. Results are compared with predictions of the small-deformation theory of Barthes-Biesel and co-workers. The data suggest that the capsule membrane is viscoelastic, and comparisons with theory yield values of the membrane elastic modulus and the membrane viscosity. The values of the elastic modulus of the capsule membrane deduced from the flow data are compared with independent measurements for the same capsule.When the flow-induced deformation becomes sufficiently large, the capsules break. Breakup begins at points on the membrane surface near the principal strain axis of the undisturbed flow. By examining the local deformation within the membrane, it is shown that breakup is correlated with local thinning of the membrane and is initiated at points where the thickness is a minimum.

Microhemorrhages are common in the aging brain, and their incidence is correlated with increased risk of neurodegenerative disease. Past work has shown that occlusion of individual cortical microvessels as well as large-scale hemorrhages can lead to degeneration of neurons and increased inflammation. Using two-photon excited fluorescence microscopy in anesthetized mice, we characterized the acute and chronic dynamics of vessel bleeding, tissue compression, blood flow change, neural degeneration, and inflammation following a microhemorrhage caused by rupturing a single penetrating arteriole with tightly-focused femtosecond laser pulses. We quantified the extravasation of red blood cells (RBCs) and blood plasma into the brain and determined that the bleeding was limited by clotting. The vascular bleeding formed a RBC-filled core that compressed the surrounding parenchymal tissue, but this compression was not sufficient to crush nearby brain capillaries, although blood flow speeds in these vessels was reduced by 20%. Imaging of cortical dendrites revealed no degeneration of the large-scale structure of the dendritic arbor up to 14 days after the microhemorrhage. Dendrites close to the RBC core were displaced by extravasating RBCs but began to relax back one day after the lesion. Finally, we observed a rapid inflammatory response characterized by morphology changes in microglia/macrophages up to 200 µm from the microhemorrhage as well as extension of cellular processes into the RBC core. This inflammation persisted over seven days. Taken together, our data suggest that a cortical microhemorrhage does not directly cause significant neural pathology but does trigger a sustained, local inflammatory response.