Michael Reinhardt

Ultrasound derived imaging and quantification of cell adhesion molecules in experimental autoimmune encephalomyelitis (EAE) by Sensitive Particle Acoustic Quantification (SPAQ).

Molecular imaging requires, not only the identification of an appropriate marker, but also its quantitative analysis. We used the Sensitive Particle Acoustic Quantification (SPAQ) technology - a novel ultrasound technique - for detection and quantification of cell adhesion molecules in isolated tissue and in live animals. By conjugating gas-filled microparticles (MPs) with antibodies to intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), we were able to depict and quantify ICAM-1 and VCAM-1 in isolated brain and spinal cord from rats with autoimmune encephalomyelitis (EAE), an established inflammatory disease model of human multiple sclerosis (MS). Depiction and quantification of specific MPs were also feasible in living animals with AT-EAE with similar results. After treatment with methylprednisolone, the measured number of targeted anti-ICAM-1 and VCAM-1-MPs was significantly lower (P<0.01) compared to untreated animals demonstrating the high sensitivity of this imaging technique. Depending on the antibody linked to the surface of the MPs, the technique can be used to quantify the expression of any accessible antigen expressed on the luminal surface of endothelial cells and is therefore a promising tool for the non-invasive and dynamic assessment of disease-related molecules.

Acoustic behaviour of current ultrasound contrast agents.

A general law gives the approximate change in signal level obtained in a particular imaging mode when a suitable contrast agent is added. It also shows that reduction of background signals is essential to overcome limitations found mainly in conventional (linear) ultrasound contrast imaging. Contrast agents contain stabilized microbubbles with very helpful non-linear properties. Acoustic methods for non-destructive and destructive testing of microbubbles are briefly discussed. In the main part, the linear and non-linear acoustic behaviour of various types of contrast agent are described. The latter is useful for new applications in diagnostic ultrasound.

Temporal pattern of ICAM-I mediated regulatory T cell recruitment to sites of inflammation in adoptive transfer model of multiple sclerosis.

Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development.

Possible target specific molecular imaging with ultrasound contrast agents

ZusammenfassungIn der modernen Medizin besteht ein zunehmendes Interesse an der Abbildung zellulärer und molekularer Vorgänge. Aktuell werden bereits verschiedene bildgebende Verfahren mit dem Ziel einer molekularen Bildgebung in der biomedizinischen Forschung getestet. Neben radionuklidgestützten Methoden gewinnt hierbei die Sonographie an zunehmender Bedeutung. Dies wird insbesondere durch die Entwicklung neuer, zielgerichteter (Target-spezifischer) Kontrastmittel und verbesserter Messverfahren ermöglicht. Target-spezifische Ultraschallkontrastmittel (USKM) lassen sich selbst in kleinsten Mengen anhand eines charakteristischen Signals im Gewebe detektieren. In verschiedenen Untersuchungen mit spezifischen USKM konnte bereits die generelle Machbarkeit molekularer sonographischer Bildgebung gezeigt werden. Diese Übersichtsarbeit beschreibt verschiedene Einsatzmöglichkeiten Target-spezifischer USKM und fasst erste Erfahrungen aus ihrer präklinischen Anwendung zusammen.AbstractNon-invasive molecular imaging technologies provide researchers with the opportunity to study cellular and molecular processes. Among different imaging technologies, ultrasound based molecular imaging methods are also of interest, since the use of ultrasound contrast agents allows specific and sensitive depiction of molecular targets. Recent studies are encouraging and have demonstrated the feasibility of ultrasound based molecular imaging. This review summarizes current experiences and recent preclinical studies with target-specific ultrasound contrast agents.Non-invasive molecular imaging technologies provide researchers with the opportunity to study cellular and molecular processes. Among different imaging technologies, ultrasound based molecular imaging methods are also of interest, since the use of ultrasound contrast agents allows specific and sensitive depiction of molecular targets. Recent studies are encouraging and have demonstrated the feasibility of ultrasound based molecular imaging. This review summarizes current experiences and recent preclinical studies with target-specific ultrasound contrast agents.

Möglichkeiten Target-spezifischer molekularer Bildgebung mit Ultraschallkontrastmitteln

ZusammenfassungIn der modernen Medizin besteht ein zunehmendes Interesse an der Abbildung zellulärer und molekularer Vorgänge. Aktuell werden bereits verschiedene bildgebende Verfahren mit dem Ziel einer molekularen Bildgebung in der biomedizinischen Forschung getestet. Neben radionuklidgestützten Methoden gewinnt hierbei die Sonographie an zunehmender Bedeutung. Dies wird insbesondere durch die Entwicklung neuer, zielgerichteter (Target-spezifischer) Kontrastmittel und verbesserter Messverfahren ermöglicht. Target-spezifische Ultraschallkontrastmittel (USKM) lassen sich selbst in kleinsten Mengen anhand eines charakteristischen Signals im Gewebe detektieren. In verschiedenen Untersuchungen mit spezifischen USKM konnte bereits die generelle Machbarkeit molekularer sonographischer Bildgebung gezeigt werden. Diese Übersichtsarbeit beschreibt verschiedene Einsatzmöglichkeiten Target-spezifischer USKM und fasst erste Erfahrungen aus ihrer präklinischen Anwendung zusammen.AbstractNon-invasive molecular imaging technologies provide researchers with the opportunity to study cellular and molecular processes. Among different imaging technologies, ultrasound based molecular imaging methods are also of interest, since the use of ultrasound contrast agents allows specific and sensitive depiction of molecular targets. Recent studies are encouraging and have demonstrated the feasibility of ultrasound based molecular imaging. This review summarizes current experiences and recent preclinical studies with target-specific ultrasound contrast agents.Non-invasive molecular imaging technologies provide researchers with the opportunity to study cellular and molecular processes. Among different imaging technologies, ultrasound based molecular imaging methods are also of interest, since the use of ultrasound contrast agents allows specific and sensitive depiction of molecular targets. Recent studies are encouraging and have demonstrated the feasibility of ultrasound based molecular imaging. This review summarizes current experiences and recent preclinical studies with target-specific ultrasound contrast agents.

Möglichkeiten Target-spezifischer molekularer Bildgebung mit Ultraschallkontrastmitteln@@@Possible target specific molecular imaging with ultrasound contrast agents

ZusammenfassungIn der modernen Medizin besteht ein zunehmendes Interesse an der Abbildung zellulärer und molekularer Vorgänge. Aktuell werden bereits verschiedene bildgebende Verfahren mit dem Ziel einer molekularen Bildgebung in der biomedizinischen Forschung getestet. Neben radionuklidgestützten Methoden gewinnt hierbei die Sonographie an zunehmender Bedeutung. Dies wird insbesondere durch die Entwicklung neuer, zielgerichteter (Target-spezifischer) Kontrastmittel und verbesserter Messverfahren ermöglicht. Target-spezifische Ultraschallkontrastmittel (USKM) lassen sich selbst in kleinsten Mengen anhand eines charakteristischen Signals im Gewebe detektieren. In verschiedenen Untersuchungen mit spezifischen USKM konnte bereits die generelle Machbarkeit molekularer sonographischer Bildgebung gezeigt werden. Diese Übersichtsarbeit beschreibt verschiedene Einsatzmöglichkeiten Target-spezifischer USKM und fasst erste Erfahrungen aus ihrer präklinischen Anwendung zusammen.AbstractNon-invasive molecular imaging technologies provide researchers with the opportunity to study cellular and molecular processes. Among different imaging technologies, ultrasound based molecular imaging methods are also of interest, since the use of ultrasound contrast agents allows specific and sensitive depiction of molecular targets. Recent studies are encouraging and have demonstrated the feasibility of ultrasound based molecular imaging. This review summarizes current experiences and recent preclinical studies with target-specific ultrasound contrast agents.Non-invasive molecular imaging technologies provide researchers with the opportunity to study cellular and molecular processes. Among different imaging technologies, ultrasound based molecular imaging methods are also of interest, since the use of ultrasound contrast agents allows specific and sensitive depiction of molecular targets. Recent studies are encouraging and have demonstrated the feasibility of ultrasound based molecular imaging. This review summarizes current experiences and recent preclinical studies with target-specific ultrasound contrast agents.

Nonlinear properties of microbubbles and applications to medical ultrasound imaging

Gas bubbles smaller than 10 μm dissolve within milliseconds even in gas‐saturated liquids, but coatings, etc. can prevent dissolution. These stabilized microbubbles serve as transpulmonary contrast agents. When only their linear properties are employed, physical laws limit the diagnostic potential to detection in large diameter vessels. Nonlinear acoustic properties of contrast agents permit very important additional applications. Nonlinearity arises from bubble pulsations, shell properties, finite amplitude waves, and electronic hardware. The first two sources can dominate, allowing new diagnostic imaging modes sufficiently sensitive to detect isolated microbubbles in vivo. Harmonic imaging modes detect 2nd harmonics of the transmit frequency, mainly from microbubbles. Acoustic Emission modes destroy bubble shells by one pulse of moderate amplitude. Consequently, the free bubbles respond strongly to this and other pulses before dissolving. Observed lifetimes of 1–20 ms are enough for harmonic or conventi...