Optoakustische Bildgebungsverfahren: vom Prinzip zur klinischen Anwendung

Hintergrund und Ziele Die optoakustische Bildgebung beschreibt die Methodik mittels Laser-gestützter Gewebeanregung Bildinformationen aus resultierenden Schall- bzw. Druckwellen zu erzeugen. Die Kombination aus „Licht und Schall“ ermöglicht eine vergleichsweise hohe Tiefeneindringung bei gleichzeitig hochauflösender und spezifischer Darstellung von Gewebestandteilen. Optoakustik kann nicht als einheitliches Verfahren verstanden werden, sondern ermöglicht Bildgebung über ein sehr breites Einsatzgebiet. Derzeit fehlen für diese Methode häufig noch dezidierte klinisch relevante Fragestellung als auch standardisierte Untersuchungsbedingungen. Ziel dieser Arbeit war zu zeigen, in welchen Einsatzgebieten, vom Tiermodell bis zum Menschen, sich diese neuartigen Bildgebungsinformation nutzen lassen und wie dies mit Veränderungen in den Zielgeweben als auch klinischen Merkmalen korreliert. Methoden Für die Versuche in Tiermodellen als auch die klinischen Studien im Rahmen dieser Arbeit wurde auf mehrere verschiedene optoakustische Technologien zurückgegriffen. Es erfolgte eine hochauflösende Darstellung von Gefäßen in einem Tiermodell für die chronische Nierenerkrankung. Hierfür wurde die Raster-scanning Optoaocustic Mesoscopy (RSOM) verwendet, um über die Detektion von Hämoglobin das Gefäßnetzwerk in den explanierten Mäusenieren sichtbar zu machen. Die Ergebnisse der Bildgebung wurden hierfür mit dem vorliegenden Genotyp und der Histologie bzw. Immunhistochemie verglichen. Im nächsten Schritt erfolgte eine Studie an gesunden Probanden, um die Fehlanfälligkeit von Optoakustischer Bildgebung im klinischen Szenario genauer zu untersuchen. Unter der Nutzung eines tomographischen Verfahrens, der Multispektrale Optoakustische Tomographie (MSOT) wurden n=10 gesunde Probanden im Alter von 25.7+/-4.4 Jahren prospektiv untersucht und damit n=1920 Datensätze geniert. Die Fehlanfälligkeit und Messungenauigkeit wurden mittels semi-automatischer Analyse der Daten genauer bestimmt. Die erzielten Ergebnisse waren Grundlage um mittels optoakustischen Signalen die Krankheitslast bei einer seltenen kindlichen Muskelerkrankung darzustellen. Hierfür wurden n=10 Patienten mit einer spinalen Muskelatrophie (SMA) (Alter: 8.7+/-4.3) und n=10 gesunde Kontrollen (9.0+/-3.7) prospektiv untersucht. Ergebnisse und Beobachtungen Mittels RSOM-basierter Detektion gelang die Darstellung von Gefäßnetzwerk in den explanierten Mausnieren. Bei männlichen Tieren mit einer chronischen Nierenerkrankung waren die Nieren im Vergleich nicht betroffenen Mäusen kleiner und wiesen eine geringere absolute Vaskularisierung auf. Bei weiblichen Mäusen fanden sich keine Unterschiede. Die Ergebnisse deuten auf eine größere Nierenmasse bei männlichen Mäusen mit konsekutiv höherer absoluter Gefäßfläche hin. Immunhistochemischen Färbungen für Endomucin (Kappilaren) und SM-Actin (Arteriolen) bestätigten eine deutlich verminderte Gefäßdichte im genetisch veränderten Tier. In der klinischen Anwendung bestätigte sich an gesunden Probanden durch die Ermittlung von 13 Einzelwellenlängen (single wavelength, SWL) zwischen 660-1210nm und 5 berechneten MSOT Parametern (deoxygeniertes/oxygeniertes/totales Hämoglobin, Kollagen und Lipid) eine exzellente Intrarater-Reproduzierbarkeit (Intraclass Correlation Coefficient, ICC, SWL: 0.82–0.92; MSOT-parameter: 0.72−0.92) und Interrater-Reproduzierbarkeit (SWL: 0.79−0.87; MSOT-parameter: 0.78−0.86) mit Ausnahme des Parameters Lipid (0.56). Zusätzlich konnte die Stabilität des Verfahrens auch über einen Zeitraum von 14 Tagen bestätigt werden. Das MSOT Verfahren zeigte an Patienten mit SMA, dass insbesondere Veränderungen im 800nm Signal, dem isosbestischen Punkt für Hemoglobin, detektiert und klinisch genutzt werden konnten. Diese Signale entsprachen am ehesten der Strukltur einer degenertierten Muskelstruktur im Sinn einer „mottenfraas“-artigen Degeneration. Die quantitativen Signalinternsitäten korrelierten dabei mit standardisierten klinischen Testverfahren und dem klinischen Grad der Krankheitsausprägung. Schlussfolgerungen und Diskussion Die Arbeit zeigt, dass optoakustische Verfahren sehr präzise Gewebeinformationen gewinnen können. Einerseits ermöglichen diese im Tiermodell hochauflösende, feinstrukturelle Informationen, während sich im klinischen Einsatz Informationen aus relevanten Tiefen gewinnen lassen. Die Technologie liefert in der klinischen Applikation stabile und reproduzierbare Resultate, sodass diese auch klinisch relevante Prozesse wie das Ausmaß einer Muskeldegeneration in der SMA abbilden kann. Die vorliegenden Ergebnisse können als Ausgangspunkt für die weitere klinische Translation genutzt werden

Optoacoustic Imaging in Inflammation.

Optoacoustic or photoacoustic imaging (OAI/PAI) is a technology which enables non-invasive visualization of laser-illuminated tissue by the detection of acoustic signals. The combination of "light in" and "sound out" offers unprecedented scalability with a high penetration depth and resolution. The wide range of biomedical applications makes this technology a versatile tool for preclinical and clinical research. Particularly when imaging inflammation, the technology offers advantages over current clinical methods to diagnose, stage, and monitor physiological and pathophysiological processes. This review discusses the clinical perspective of using OAI in the context of imaging inflammation as well as in current and emerging translational applications

The influence of the optical properties on the determination of capillary diameters

Various clinically applicable scores and indices are available to help identify the state of a microcirculatory disorder in a patient. Several of these methods, however, leave room for interpretation and only provide clues for diagnosis. Thus, a measurement method that allows a reliable detection of impending or manifest circulatory malfunctions would be of great value. In this context, the optical and non-invasive method of shifted position-diffuse reflectance imaging (SP-DRI) was developed. It allows to determine the capillary diameter and thus to assess the state of the microcirculation. The aim of the present study is to investigate how the quantification of capillary diameters by SP-DRI behaves in different individuals, i.e. for a wide range of optical properties. For this, within Monte-Carlo simulations all optical properties (seven skin layers, hemoglobin) were randomly varied following a Gaussian distribution. An important finding from the present investigation is that SP-DRI works when the optical properties are chosen randomly. Furthermore, it is shown that appropriate data analysis allows calibration-free absolute quantification of the capillary diameter across individuals using SP-DRI. This underpins the potential of SP-DRI to serve as an early alert system for the onset of microcirculatory associated diseases

Routine Surveillance of SARS-CoV-2 Serostatus in Pediatrics Allows Monitoring of Humoral Response

The occurrence of SARS-CoV-2 infections during the pandemic was mainly based on PCR testing of symptomatic patients. However, with new variants, vaccinations, and the changing of the clinical disease severity, knowledge about general immunity is elusive. For public health systems, timely knowledge of these conditions is essential, but it is particularly scarce for the pediatric population. Therefore, in this study, we wanted to investigate the spike and nucleocapsid seroprevalence in pediatric patients using routine residual blood tests collected during the pandemic. This prospective observational study was conducted over seven one-month periods. Herein, the latest four time periods (November 2021, January 2022, March 2022, and May 2022) are depicted. Each patient of a tertiary-care center in Germany was anonymized after collection of clinical diagnosis (ICD-10) and then routinely tested for the respective spike and nucleocapsid SARS-CoV-2 antibody titer. A total of 3235 blood samples from four time periods were included. Spike seroprevalence rose from 37.6% to 51.9% to 70.5% to 85.1% and nucleocapsid seroprevalence from 11.6% to 17.0% to 36.7% to 58.1% in May 2022. In detail, significant changes in seroprevalence between age groups but not between sex or diagnosis groups were found. Quantitative measures revealed rising spike and constant nucleocapsid antibody levels over the pandemic with a half-life of 102 days for spike and 45 days for nucleocapsid antibodies. Routine laboratory assessment of SARS-CoV-2 in residual blood specimens of pediatric hospitals enables monitoring of the seroprevalence and may allow inferences about general immunity in this cohort.</jats:p

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US)

Purpose Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. Methods In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. Results Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73–0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. Conclusion An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma

Long-Term Experience of Arterio-Venous Fistula Surgery in Children on Hemodialysis

Background : Arterio-venous fistulas (AVF) are used as first-line access for hemodialysis (HD) in the pediatric population. The aim of this investigation was to describe a single-center experience in the creation of AVF, together with its patency in children. Methods : This single-center retrospective study included all patients aged ≤18 years with AVFs created between 1993 and 2023. The collected data included patients’ demographics, hemodialysis history, intraoperative data, and required reinterventions in order to determine the impact of these variables on primary, primary-assisted, and secondary patency. Results : Fifty-seven patients were analyzed with a median age of 15 years (range, 7–18 years). Fifty-four forearm and four upper arm fistulas were performed. The median follow-up was 6.9 years (range, 0–23 years). The primary failure rate was 10.5%. The primary patency rate was 67.6%, 53.6%, 51.4%, and 38.1% after 1, 3, 5, and 10 years; primary-assisted patency was 72.9%, 62.8%, 60.6%, and 41.5%; and secondary patency was 87.3%, 81.3%, 76.8%, and 66.6% after 1, 3, 5, and 10 years in the studied population. Conclusions : AVFs showed an acceptable rate of primary failure and excellent long-term patency. In this context, AVFs are an appropriate option for HD access, especially in pediatric patients.This research received no external funding

Metabolic and molecular imaging in inflammatory arthritis

It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively.Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation.Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.http://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100000781European Research Councilhttp://dx.doi.org/10.13039/501100001652Friedrich-Alexander-Universität Erlangen-Nürnberghttp://dx.doi.org/10.13039/501100010767Innovative Medicines Initiativehttp://dx.doi.org/10.13039/501100002347Bundesministerium für Bildung und Forschung2022 GRAPPA Pilot Research Gran

Precision of handheld multispectral optoacoustic tomography for muscle imaging

Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm–1210 nm and five MSOT-parameters (deoxygenated/oxygenated/ total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82–0.92; MSOT-parameter: 0.72 0.92) and interrater reproducibility (SWL: 0.79 0.87; MSOT-parameter: 0.78 0.86), with the exception for MSOTparameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation

Multispectral optoacoustic tomography for non-invasive disease phenotyping in pediatric spinal muscular atrophy patients

Proximal spinal muscular atrophy (SMA) is a rare progressive, life limiting genetic motor neuron disease. While promising causal therapies are available, meaningful prognostic biomarkers for therapeutic monitoring are missing. We demonstrate handheld Multispectral Optoacoustic Tomography (MSOT) as a novel non-invasive imaging approach to visualize and quantify muscle wasting in pediatric SMA. While MSOT signals were distributed homogeneously in muscles of healthy volunteers (HVs), SMA patients showed moth-eaten optoacoustic signal patterns. Further signal quantification revealed greatest differences between groups at the isosbestic point for hemoglobin (SWL 800 nm). The SWL 800 nm signal intensities further correlated with clinical phenotype tested by standard motor outcome measures. Therefore, handheld MSOT could enable non-invasive assessment of disease burden in SMA patients

A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.This article is published as Assi, Hisham, Rui Cao, Madhura Castelino, Ben Cox, Fiona J. Gilbert, Janek Gröhl, Kurinchi Gurusamy et al. "A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: from current barriers to future adoption." Photoacoustics (2023): 100539. doi: https://doi.org/10.1016/j.pacs.2023.100539. © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)