The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.

Dendritic cell (DC) migration into the draining lymph nodes is critical for T cell priming. Here, we show that magnetic resonance imaging (MRI) can be used to visualize DC migration in vivo. We combined clinically approved small particles of iron oxide (SPIO) with protamine sulfate to achieve efficient uptake by murine bone marrow-derived DC. SPIO-DC were largely unaltered and after injection into the footpads of mice, they migrated into the T cell areas of the draining lymph nodes, which could be visualized by MRI. Distinct MRI signal reduction patterns correlated with the detection of SPIO-DC mainly within Thy-1.2 + B220 -T cell areas, as confirmed by iron staining and immunohistology. Clear signal reduction patterns could still be observed with 1 Â 10 6 injected SPIO-DC at high resolution, resulting in the detection of about 2000 DC. Control injections of homing-incompetent SPIO-DC derived from CCR7 -/-mice or SPIO alone did not reach the T cell areas. Taken together, the results demonstrate that clinically approved contrast agents allow the non-invasive visualization of DC migration into the draining lymph node by MRI in vivo at high resolution. This protocol therefore also allows dynamic imaging of immune responses and MRI-based tracking of human DC in patients.

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Cerebral activation in response to sequences of temperature boosts at the hindpaw was observed in functional magnetic resonance imaging (fMRI) experiments in isoflurane anesthetized rats. Cingulate, retrosplenial, sensory-motor and insular cortex, medial and lateral posterior thalamic nuclei, pretectal area, hypothalamus and periaqueductal gray were the most consistently, often bilaterally activated regions. With the same experimental paradigm, activity changes in the brain following subcutaneous zymosan injection into one hindpaw were detected. These changes developed over time (up to 4 h) in parallel with the temporal development of hyperalgesia shown by a modified Hargreaves test, thus reflecting processes of peripheral and central sensitization. When the heat stimuli were applied to the inflamed paw, the hyperalgesia manifested itself as a volume increase of the activated areas and/or an enhanced functional blood oxygenation level dependent (BOLD) signal in all the above-mentioned brain regions. Enhanced BOLD signals were also observed in response to stimulation of the contralateral non-injected paw. They were significant in higher associative regions and more pronounced in output-related than in input-related brain structures. This indicates additional sensitization processes in the brain, which we named cerebral sensitization.Long lasting zymosan-induced hyperalgesia could be monitored with high resolution fMRI in rats under isoflurane anaesthesia. This technique may provide an effective method for testing new analgesics and studying structure specific pain processing.