Statische und dynamische Magnetfelder für die Nanopartikel-basierte zielgerichtete Wirkstofffreisetzung

Although medicine has made great progress in the last centuries and decades, it is still facing basic challenges that make doctors fail to efficiently and successfully treat the continuously emerging diseases and ailments due to ageing, industrialization, pollution and resulting biological mutations. In this context, the systemic chemotherapeutic treatment of cancer seems to be one of the most fitting examples for the wide gap between the usually followed medical approach and the theoretically optimal solution. Extrapolating from in vitro experiments and mouse models to humans, treating children as “miniaturized” adults when analyzing therapeutic effects, estimating drug doses based on relatively coarse processes like up scaling on weight, volume or area, and flooding the human body with drugs to solely achieve a minimal effect at the ailment site are just few examples for improvement needs in medical methods. One of the most promising approaches intended to bring more specificity and precision into the therapeutic toolbox is the directed delivery of drugs, already prophesized and described one hundred years ago by the German immunologist and Nobel Laureate in Medicine (1908) Paul Ehrlich (1854-1915) as the “magic bullet” principle. It is a visionary medical method in which active agents -such as drugs or antibodies- are guided within the human body and brought to bind directly and exclusively to their biological target. This approach was triggered and has been remarkably promoted by the introduction and continuous development of nano-sized medical systems since the 1950s, and is expected to experience a real breakthrough by the clinical validation of the so called “Magnetic Drug Targeting”. According to this technique, magnetically active nanoparticles are coated with a therapeutically active biomaterial and guided through external magnetic fields in the natural transport pathways of the body, then retained and concentrated at target sites where the biologically active load is set free. The delivered dose is augmented, side effects are lowered and the overall therapeutic efficiency is enhanced. Especially for cancer treatment, the magnetically guided drug delivery represents a huge potential. In fact, conventional chemotherapy methods are used systemically and succeed in best cases in delivering only a fractional amount of the drug to the target sites, while the rest is absorbed by the healthy tissue of the treated body. This is so inefficient that dose levels of about 50 to 100-fold those of conventional doses need to be administered to achieve cures of cancer cells (T. A. Connors 1995). As a result, blood filtering and trafficking organs, such as the liver, the kidneys, the spleen and most importantly the heart, are the direct victims of the highly toxic substances used in chemotherapy. Even the apparently more gentle approach of applying the maximum tolerated dose at defined intervals -in order to avoid toxicity- can unintentionally lead to a chemoresistance of the tumor (C. Damyanov 2009). These shortcomings of the chemical therapy further aggravate the fact that cancer is still the worldwide deadliest disease, with an upward trend. For instance, around 25 % of all registered death cases in the European Union are reported by the World Health Organization to be caused by tumors. Despite the development of advanced anti-cancer medicine, it still remains a difficult challenge to keep costs at an affordable level. For that reason, new and more efficient cancer treatment methods with higher success rates and lower side effects and costs are urgently needed and would help physicians cope with an ever ageing world population. In this work, we report improvements achieved in the understanding and control of the magnetically targeted drug delivery, mainly realized by the consideration of time issues and the investigation of dynamic magnetic fields. New approaches to assess the magnetic behavior of nanoparticles in suspensions as well as an advanced examination of the lung drug targeting and the mechanisms of cellular drug uptake after successful localized delivery represent the major achievements compiled in this manuscript. The registered improvements are an important contribution to the further development of the idea of directed therapies promoted by the emerging nanomedicine. This modern medicine is expected to provide techniques that can act on a cellular and even sub-cellular level, treating ailments with considerably more accuracy. Gradually, modern diagnostic and therapeutic techniques should elevate us slowly to the point where we can start thinking more in terms of real “regenerative” medicine. That means, we should be able to precisely and directly address pathologic tissues, save cells and organs, repair and heal them, rather than extinguish them.Mehr als hundert Jahre nach dem Tod von Paul Ehrlich, dem bedeutendsten deutschen Immunologen, verfolgt die "Nachwelt" noch mit großen Schritten eine seiner wichtigsten Visionen, die er während seiner Arbeiten zur Behandlung der Syphilis entwickelte: eine „Zauberkugel“ (magic bullet), die einen gegebenen krankmachenden Erreger gezielt abtöten kann. Ganz nach diesem noch -mehr denn je- aktuellen Prinzip, entwickeln Forscher heutzutage weltweit neue Methoden, um nicht nur Krankheitserreger, sondern auch befallene Gewebe, spezifisch zu behandeln. In den letzten Jahren entwickelte sich dadurch die Medizin von der konventionellen Anwendung, über die personalisierte Behandlung, wo die genetische Information eines jeden Patienten präventiv untersucht werden kann und die Ergebnisse zur Auswahl und Anpassung der Therapie-Art herangezogen werden, bis hin zur "Nanomedizin", einer neuen Ära der Arzneimittel-Konzipierung, -Synthese, -Dosierung und -Verabreichung, die Therapien auf zellulärer und sub-zellulärer Ebene ermöglichen sollte. Mediziner sind heutzutage weit entfernt von der Darstellung von Christian Friedrich Hebbel (18.03.1813 - 13.12.1863), dass "ein Arzt eine Aufgabe hat, als ob ein Mensch in einem dunklen Zimmer in einem Buche lesen sollte". Sie sind in der Lage, durch die Integration der Nanotechnologie im biomedizinischen Bereich, Gewebe und Zellen, die durchschnittliche Dimensionen von 10 µm haben, mit Nanosystemen im Submikrometer-Bereich zu adressieren und gezielt zu behandeln. In diesem Rahmen präsentiert sich das Magnetic Drug Targeting (MDT) als besonders wirksamer Therapie-Ansatz. Dabei werden Wirkstoff-beladene magnetische Nanopartikel über externe Magnetfelder im Körper geführt und an einem gegebenen Krankheitsort lokal angereichert. Die verabreichte Wirkdosis wird dadurch erhöht, Nebeneffekte minimiert. Besonders in der Krebsbekämpfung verspricht dieser Ansatz hohe Erfolgsquoten und eine Reduzierung der ohnehin enormen Chemo- und Radiotherapie-Kosten, die meistens einen bremsenden Effekt auf die Entwicklung und Verbreitung zahlreicher Behandlungsmethoden haben. An dieser Stelle sei daran erinnert, dass Krebs nach wie vor die weltweit wichtigste Todesursache ist, an der schätzungsweise 11.5 Millionen Weltbewohner im Jahre 2030 sterben werden, was einem Anstieg von 45% zum Jahre 2007 darstellt. Die zielgerichtete Arzneimittel-Applikation, zu Englisch "Directed Drug Delivery", soll hierfür Lösungen anbieten, die Tumore spezifisch angreifen und ausschalten können. Durch eine magnetische Lenkung und Anreicherung wird dieses Verfahren weiter optimiert. Die somit entstehende MDT-Methode eignet sich für Anwendungen in der Blutbahn, sowie in den Atemwegen von Patienten, mit entsprechenden Anpassungen. Entscheidend ist hierbei vor Allem das eingesetzte Magnetfeld, in Bezug auf Amplitude, Homogenität und Dynamik. In zahlreichen wissenschaftlichen Arbeiten, wurden bisher Erfolg versprechende Ergebnisse präsentiert, die überwiegend durch die Manipulation und Aufkonzentrierung von Nanopartikel-Wirkstoff-Komplexen mit statischen Magnetfeldern realisiert wurden. Eine hierzu komplementäre Betrachtung mit dynamischen Magnetfeldern wird in dieser Arbeit untersucht. Im Rahmen dieses Forschungsprojekts wurden Ansätze mit statischen und dynamischen Magnetfeldern zur Verbesserung des Magnetic Drug Targeting theoretisch überprüft, simulativ validiert und systemtechnisch umgesetzt. Nach einer ausführlichen Untersuchung der Nanopartikel-Eigenschaften, die den MDT-Effekt überhaupt ermöglichen und besonders beeinflussen, wurde der Anreicherungsprozess unter Magnetkraftwirkung modelliert und ein für Anwendungen in der Blutbahn optimiertes Magnetsystem simuliert, konstruiert und bei in-vivo-Versuchen eingesetzt. Dadurch konnte eine aktive und vor Allem reproduzierbare Retention von beladenen Nanopartikel-Komplexen in den Arterien und Venen der Rückenhaut einer Maus verzeichnet werden

Accuracy of Length of Virtual Stents in Treatment of Intracranial Wide-Necked Aneurysms.

Background and purposePrecise stent deployment is important for successful treatment of intracranial aneurysms by stent-assisted coiling (SAC). We evaluated the accuracy of virtual stents generated using commercial stent planning software by comparing the length of virtual and actually deployed intracranial laser cut stents on three-dimensional digital subtraction angiography (3D-DSA) images.MethodsWe retrospectively analyzed the data of 75 consecutive cases of intracranial wide-necked aneurysms treated with the SAC technique using laser cut stents. Based on 3D-DSA images acquired by C-arm CT, stent sizing and placement were intraoperatively simulated by a commercial software application. The difference in length of the stents was estimated by measuring proximal discrepancies between the end points of the virtual and actually deployed stents on fused pre-procedural and post-procedural 3D-DSA images. Discrepancies between distal stent end points were manually minimized. The Kruskal-Wallis test was applied to test whether stent location, type, and length had an effect on difference in length between virtual and real stent.ResultsThe median difference in length between virtual and real stents was 1.58 mm with interquartile range 1.12-2.12 mm. There was no evidence for an effect of stent location (p = 0.23), stent type (p = 0.33), or stent length (p = 0.53) on difference in length between virtual and real stents.ConclusionsStent planning software allows 3D simulation of laser cut stents overlain on 3D-DSA images of vessels and may thus be useful for stent selection and deployment of laser cut stents during stent-assisted coiling of intracranial aneurysms

Combination of high-resolution cone beam computed tomography and metal artefact reduction software: a new image fusion technique for evaluating intracranial stent apposition after aneurysm treatment.

We introduce a new imaging technique to improve visualisation of stent apposition after endovascular treatment of brain aneurysms employing high-resolution cone beam CT and three-dimensional digital subtraction angiography. After performing a stent-assisted coil embolisation of brain aneurysm, the image datasets were processed with a metal artefact reduction software followed by the automated image fusion programmes. Two patients who underwent aneurysm coiling using a Neuroform stent were evaluated. The reconstructed 3D images showed a detailed structure of the stent struts and identified malappositions of the deployed stents. Case 1 showed good apposition on the outer curvature side of the carotid siphon, while the inner curvature side showed prominent malapposition. Case 2, with multiple aneurysms, showed good apposition on both outer and inner curvature sides, although inward prolapse of the struts was observed. This new imaging technique may help evaluate stent apposition after the endovascular aneurysm treatment

Accuracy of Length of Virtual Stents in Treatment of Intracranial Wide-Necked Aneurysms.

BACKGROUND AND PURPOSE: Precise stent deployment is important for successful treatment of intracranial aneurysms by stent-assisted coiling (SAC). We evaluated the accuracy of virtual stents generated using commercial stent planning software by comparing the length of virtual and actually deployed intracranial laser cut stents on three-dimensional digital subtraction angiography (3D-DSA) images. METHODS: We retrospectively analyzed the data of 75 consecutive cases of intracranial wide-necked aneurysms treated with the SAC technique using laser cut stents. Based on 3D-DSA images acquired by C-arm CT, stent sizing and placement were intraoperatively simulated by a commercial software application. The difference in length of the stents was estimated by measuring proximal discrepancies between the end points of the virtual and actually deployed stents on fused pre-procedural and post-procedural 3D-DSA images. Discrepancies between distal stent end points were manually minimized. The Kruskal-Wallis test was applied to test whether stent location, type, and length had an effect on difference in length between virtual and real stent. RESULTS: The median difference in length between virtual and real stents was 1.58 mm with interquartile range 1.12-2.12 mm. There was no evidence for an effect of stent location (p = 0.23), stent type (p = 0.33), or stent length (p = 0.53) on difference in length between virtual and real stents. CONCLUSIONS: Stent planning software allows 3D simulation of laser cut stents overlain on 3D-DSA images of vessels and may thus be useful for stent selection and deployment of laser cut stents during stent-assisted coiling of intracranial aneurysms

Accuracy of Length of Virtual Stents in Treatment of Intracranial Wide-Necked Aneurysms.

Background and purposePrecise stent deployment is important for successful treatment of intracranial aneurysms by stent-assisted coiling (SAC). We evaluated the accuracy of virtual stents generated using commercial stent planning software by comparing the length of virtual and actually deployed intracranial laser cut stents on three-dimensional digital subtraction angiography (3D-DSA) images.MethodsWe retrospectively analyzed the data of 75 consecutive cases of intracranial wide-necked aneurysms treated with the SAC technique using laser cut stents. Based on 3D-DSA images acquired by C-arm CT, stent sizing and placement were intraoperatively simulated by a commercial software application. The difference in length of the stents was estimated by measuring proximal discrepancies between the end points of the virtual and actually deployed stents on fused pre-procedural and post-procedural 3D-DSA images. Discrepancies between distal stent end points were manually minimized. The Kruskal-Wallis test was applied to test whether stent location, type, and length had an effect on difference in length between virtual and real stent.ResultsThe median difference in length between virtual and real stents was 1.58 mm with interquartile range 1.12-2.12 mm. There was no evidence for an effect of stent location (p = 0.23), stent type (p = 0.33), or stent length (p = 0.53) on difference in length between virtual and real stents.ConclusionsStent planning software allows 3D simulation of laser cut stents overlain on 3D-DSA images of vessels and may thus be useful for stent selection and deployment of laser cut stents during stent-assisted coiling of intracranial aneurysms

Time-resolved magnetic resonance angiography (TR-MRA) for the evaluation of post coiling aneurysms; A quantitative analysis of the residual aneurysm using full-width at half-maximum (FWHM) value.

Magnetic resonance image (MRI) is now widely used for imaging follow-up for post coiling brain aneurysms. However, the accuracy on the estimation of residual aneurysm, which is crucial for the retreatment planning, remains to be controversial. The purpose of this study is to evaluate a new post-processing technique that provides improved estimation of the residual aneurysm after coil embolization. One hundred aneurysms on 93 patients who underwent coil embolization for brain aneurysm were evaluated using the 1.5 Tesla time-resolved magnetic resonance angiography (TR-MRA) one year after the treatment. To minimize the inter-observer variability caused by the window level adjustment, an automatic post processing protocol using the full-width at half-maximum (FWHM) value was utilized. The result was then compared with that from the conventional cerebral angiography. Of the 97 aneurysms that underwent both TR-MRA and DSA, 23 (23.7%) showed residual neck / dome during follow-up. After window level adjustment, the size of the parent artery in the TR-MRA was consistent with that in the DSA. The reconstructed Volume Rendering images provided clear contours of the residual aneurysms and contributed to the understanding the configuration of residual aneurysm. The largest and the smallest diameter of the residual aneurysms was larger in the TR-MRA than in the DSA (8.05 vs. 7.72 mm, p = 0.0004; 4.99 vs. 4.19 mm, p = 0.007 respectively). The sensitivity, specificity, and positive and negative predictive values of TR-MRA compared to DSA were 100%, 97%, 73%, and 100%, respectively. Using the FWHM value to optimize the window level adjustment, the size of the residual component observed in the TR-MRA was larger compared to that in the DSA whereas the size of neck and the parent artery showed consistency between the two modalities. This image processing technique can be used as an effective screening tool for evaluating residual component in post-coiling brain aneurysms

Verification of porous loss model for assessment of flow diverters

Recently neurointerventional treatments using flow diverters (FDs) have been introduced and increasingly performed. However, complications (non-occluded and ruptured aneurysms after the treatment) have been reported. To assess the effects of FDs to the blood flow, Computational Fluid Dynamics (CFD) have been performed. In the approach using FDs geometries, higher machine specifications are required because of the larger number of computational elements due to the large scale difference between the size of the flow diverter's struts and the aneurysms. As an alternative method, we validate the applicability of the porous model approach for patient-specific CFD. Two patients treated with FDs are analyzed. The results show that, in both cases, inflow rate into the aneurysms, velocity in the aneurysm and wall shear stress at the aneurysm surface are underestimated. However, pressure at the aneurysm surface are in good agreement between both models.10 page(s

Time-resolved magnetic resonance angiography (TR-MRA) for the evaluation of post coiling aneurysms; A quantitative analysis of the residual aneurysm using full-width at half-maximum (FWHM) value.

Magnetic resonance image (MRI) is now widely used for imaging follow-up for post coiling brain aneurysms. However, the accuracy on the estimation of residual aneurysm, which is crucial for the retreatment planning, remains to be controversial. The purpose of this study is to evaluate a new post-processing technique that provides improved estimation of the residual aneurysm after coil embolization. One hundred aneurysms on 93 patients who underwent coil embolization for brain aneurysm were evaluated using the 1.5 Tesla time-resolved magnetic resonance angiography (TR-MRA) one year after the treatment. To minimize the inter-observer variability caused by the window level adjustment, an automatic post processing protocol using the full-width at half-maximum (FWHM) value was utilized. The result was then compared with that from the conventional cerebral angiography. Of the 97 aneurysms that underwent both TR-MRA and DSA, 23 (23.7%) showed residual neck / dome during follow-up. After window level adjustment, the size of the parent artery in the TR-MRA was consistent with that in the DSA. The reconstructed Volume Rendering images provided clear contours of the residual aneurysms and contributed to the understanding the configuration of residual aneurysm. The largest and the smallest diameter of the residual aneurysms was larger in the TR-MRA than in the DSA (8.05 vs. 7.72 mm, p = 0.0004; 4.99 vs. 4.19 mm, p = 0.007 respectively). The sensitivity, specificity, and positive and negative predictive values of TR-MRA compared to DSA were 100%, 97%, 73%, and 100%, respectively. Using the FWHM value to optimize the window level adjustment, the size of the residual component observed in the TR-MRA was larger compared to that in the DSA whereas the size of neck and the parent artery showed consistency between the two modalities. This image processing technique can be used as an effective screening tool for evaluating residual component in post-coiling brain aneurysms

Combination of high-resolution cone beam computed tomography and metal artefact reduction software: a new image fusion technique for evaluating intracranial stent apposition after aneurysm treatment.

We introduce a new imaging technique to improve visualisation of stent apposition after endovascular treatment of brain aneurysms employing high-resolution cone beam CT and three-dimensional digital subtraction angiography. After performing a stent-assisted coil embolisation of brain aneurysm, the image datasets were processed with a metal artefact reduction software followed by the automated image fusion programmes. Two patients who underwent aneurysm coiling using a Neuroform stent were evaluated. The reconstructed 3D images showed a detailed structure of the stent struts and identified malappositions of the deployed stents. Case 1 showed good apposition on the outer curvature side of the carotid siphon, while the inner curvature side showed prominent malapposition. Case 2, with multiple aneurysms, showed good apposition on both outer and inner curvature sides, although inward prolapse of the struts was observed. This new imaging technique may help evaluate stent apposition after the endovascular aneurysm treatment