Sequential ultrasound molecular imaging for noninvasive identification and assessment of non-alcoholic steatohepatitis in mouse models

Background and objective:Noninvasive non-alcoholic steatohepatitis(NASH)assessment is a clinical challenge to the management of non-alcoholic fatty liver disease.We aim to develop diagnostic models based on sequential ultrasound molecular imaging(USMI)for the noninvasive identification of NASH in mouse models.Methods:Animal experiments were approved by the Animal Ethics Committee of South China Agricultural University.Forty-nine C57BL/6 mice were divided into normal control,non-alcoholic fatty liver,NASH,and hepatitis groups.Sequential USMI was implemented using CD36-targeted microbubbles(MBs-CD36)and intercellular adhesion molecule-1(ICAM-1)-targeted microbubbles(MBs-ICAM-1)to visualize hepatic steatosis and inflammation.The targeting signal of USMI was quantified as the normalized intensity difference(NID)with the destruction-replenishment method.Correlation analysis was conducted between the NID-MBs-CD36 and pathological steatosis score and between the NID-MBsICAM-1 and pathological inflammation score.Finally,diagnostic models combining NID-MBs-CD36 with NID-MBs-ICAM-1 were established for NASH diagnosis.Results:MBs-CD36 and MBs-ICAM-1 were successfully prepared and used for sequential USMI in all mice.NID-MBs-CD36 values increased with the progression of steatosis,while NID-MBs-ICAM-1 values increased in parallel with the progression of inflammation.A strong positive correlation was identified between NID-MBs-CD36 and pathological steatosis grade(r_(s)=0.9078,P<0.0001)and between NIDMBs-ICAM-1 and pathological inflammation grade(r_(s)=0.9071,P<0.0001).Among various sequential USMI-based diagnostic models,the serial testing model showed high diagnostic performance in detecting NASH,with 95%sensitivity,97%specificity,95%positive predictive values,97%negative predictive values,and 96%accuracy.Conclusions:Sequential USMI using MBs-CD36 and MBs-ICAM-1 allows noninvasive grading of hepatic steatosis and inflammation.Sequential USMI-based diagnostic models hold great potential in the noninvasive identification of NASH.

Light and sound- emerging imaging techniques for inflammatory bowel disease

Patients with inflammatory bowel disease are known to have a high demand of recurrent evaluation for therapy and disease activity. Further, the risk of developing cancer during the disease progression is increasing from year to year. New, mostly non-radiant, quick to perform and quantitative methods are challenging, conventional endoscopy with biopsy as gold standard. Especially, new physical imaging approaches utilizing light and sound waves have facilitated the development of advanced functional and molecular modalities. Besides these advantages they hold the promise to predict personalized therapeutic responses and to spare frequent invasive procedures. Within this article we highlight their potential for initial diagnosis, assessment of disease activity and surveillance of cancer development in established techniques and recent advances such as wide-view full-spectrum endoscopy, chromoendoscopy, autofluorescence endoscopy, endocytoscopy, confocal laser endoscopy, multiphoton endoscopy, molecular imaging endoscopy, B-mode and Doppler ultrasound, contrast-enhanced ultrasound, ultrasound molecular imaging, and elastography.

Ultrasound contrast agents from microbubbles to biogenic gas vesicles

Microbubbles have been the earliest and most widely used ultrasound contrast agents by virtue of their unique features:such as non-toxicity,intravenous inject-ability,ability to cross the pulmonary capillary bed,and significant enhancement of echo signals for the duration of the examination,resulting in essential preclinical and clinical applications.The use of microbubbles functional-ized with targeting ligands to bind to specific targets in the bloodstream has further enabled ultrasound molecular imaging.Nevertheless,it is very challenging to utilize targeted microbubbles for molecular imaging of extra-vascular targets due to their size.A series of acoustic nanomaterials have been developed for breaking free from this constraint.Especially,biogenic gas vesicles,gas-filled protein nanostructures from microorganisms,were engineered as thefirst biomolecular ultrasound contrast agents,opening the door for more direct visual-ization of cellular and molecular function by ultrasound imaging.The ordered protein shell structure and unique gasfilling mechanism of biogenic gas vesicles endow them with excellent stability and attractive acoustic responses.What’s more,their genetic encodability enables them to act as acoustic reporter genes.This article reviews the upgrading progresses of ultrasound contrast agents from microbubbles to biogenic gas vesicles,and the opportu-nities and challenges for the commercial and clinical translation of the nascentfield of biomolecular ultrasound.