Proof of concept of a multimodal intravital molecular imaging system for tumour transpathology investigation

Zhen Liu,Stephan Düwel,Tao Cheng,Sibylle I Ziegler,Rickmer Braren,Sung-Cheng Huang,Qian Wang,Kuangyu Shi,Christian Hundshammer,Markus Mittelhäuser,Franz Schilling,Ziying Jian,Benedikt Feuerecker,Markus Schwaiger,Katja Steiger,Sybille Reder,Geoffrey J Topping

doi:10.1007/s00259-021-05574-y

Abstract

BackgroundTranspathology highlights the interpretation of the underlying physiology behind molecular imaging. However, it remains challenging due to the discrepancies between in vivo and in vitro measurements and difficulties of precise co-registration between trans-scaled images. This study aims to develop a multimodal intravital molecular imaging (MIMI) system as a tool for in vivo tumour transpathology investigation.MethodsThe proposed MIMI system integrates high-resolution positron imaging, magnetic resonance imaging (MRI) and microscopic imaging on a dorsal skin window chamber on an athymic nude rat. The window chamber frame was designed to be compatible with multimodal imaging and its fiducial markers were customized for precise physical alignment among modalities. The co-registration accuracy was evaluated based on phantoms with thin catheters. For proof of concept, tumour models of the human colorectal adenocarcinoma cell line HT-29 were imaged. The tissue within the window chamber was sectioned, fixed and haematoxylin–eosin (HE) stained for comparison with multimodal in vivo imaging.ResultsThe final MIMI system had a maximum field of view (FOV) of 18 mm × 18 mm. Using the fiducial markers and the tubing phantom, the co-registration errors are 0.18 ± 0.27 mm between MRI and positron imaging, 0.19 ± 0.22 mm between positron imaging and microscopic imaging and 0.15 ± 0.27 mm between MRI and microscopic imaging. A pilot test demonstrated that the MIMI system provides an integrative visualization of the tumour anatomy, vasculatures and metabolism of the in vivo tumour microenvironment, which was consistent with ex vivo pathology.ConclusionsThe established multimodal intravital imaging system provided a co-registered in vivo platform for trans-scale and transparent investigation of the underlying pathology behind imaging, which has the potential to enhance the translation of molecular imaging.

Highlights

Transpathology is a new theory to summarize the endeavour of molecular imaging for deciphering underlying pathophysiology [1, 2], which consists of trans-scale, transparent and translational investigation of imaging signals (Fig. 1A)
The aim of this study is to establish a multimodal intravital molecular imaging (MIMI) system to support the investigation of transpathology (Fig. 1B)
Images from magnetic resonance imaging (MRI), positron imaging and fluorescence imaging were aligned via the fiducial markers

Summary

Introduction

Transpathology is a new theory to summarize the endeavour of molecular imaging for deciphering underlying pathophysiology [1, 2], which consists of trans-scale, transparent and translational investigation of imaging signals (Fig. 1A). Tissues need to be sampled or resected for the investigation by microscopy [3,4,5,6] These in vitro methods have been widely used in various applications, they are destructive and have limited ability to provide insight into in vivo dynamics [7]. Another crucial problem for the comparison between imaging and pathology is the co-registration of in vivo and ex vivo measurements. Conclusions The established multimodal intravital imaging system provided a co-registered in vivo platform for trans-scale and transparent investigation of the underlying pathology behind imaging, which has the potential to enhance the translation of molecular imaging

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Results

Discussion

Conclusion