Unlocking the Hidden Depths: Multi-Modal Integration of Imaging Mass Spectrometry-Based and Molecular Imaging Techniques

AbstractMultimodal imaging (MMI) has emerged as a powerful tool in clinical research, combining different imaging modes to acquire comprehensive information and enabling scientists and surgeons to study tissue identification, localization, metabolic activity, and molecular discovery, thus aiding in disease progression analysis. While multimodal instruments are gaining popularity, challenges such as non-standardized characteristics, custom software, inadequate commercial support, and integration issues with other instruments need to be addressed. The field of multimodal imaging or multiplexed imaging allows for simultaneous signal reproduction from multiple imaging strategies. Intraoperatively, MMI can be integrated into frameless stereotactic surgery. Recent developments in medical imaging modalities such as magnetic resonance imaging (MRI), and Positron Emission Topography (PET) have brought new perspectives to multimodal imaging, enabling early cancer detection, molecular tracking, and real-time progression monitoring. Despite the evidence supporting the role of MMI in surgical decision-making, there is a need for comprehensive studies to validate and perform integration at the intersection of multiple imaging technologies. They were integrating mass spectrometry-based technologies (e.g., imaging mass spectrometry (IMS), imaging mass cytometry (IMC), and Ion mobility mass spectrometry ((IM-IM) with medical imaging modalities, offering promising avenues for molecular discovery and clinical applications. This review emphasizes the potential of multi-omics approaches in tissue mapping using MMI integrated into desorption electrospray ionization (DESI) and matrix-assisted laser desorption ionization (MALDI), allowing for sequential analyses of the same section. By addressing existing knowledge gaps, this review encourages future research endeavors toward multi-omics approaches, providing a roadmap for future research and enhancing the value of MMI in molecular pathology for diagnosis.Keywords: Imaging mass spectrometrymagnetic resonance spectroscopymatrix-assisted laser desorptionmatrix-assisted laser desorption electrospray ionizationmultimodal imagingmetabolic imagingpositron emission tomographyvirtual multimodality Ethical compliance statementThis manuscript was written through the contributions of all authors, each of whom has approved the final version of the manuscript. The manuscript outline and its content have been meticulously designed and authored by Behnaz Akbari. The section on future perspectives is authored by Behnaz Akbari, who has fervently emphasized the significance of innovative essence of multi modal imaging (MMI) work associated with imaging mass spectrometry (IMS). The section of MRI authored by Dr. Janet Hope Sherman and the section of HALO products authored by Dr. Bertrand Russell Huber. There are figures credited to Hyperfine and those figures are the only role Hyperfine contributed. We would like to appreciate Solita Marie Wilson (Ph. D candidate) from Purdue University for her feedback.No datasets were generated or analyzed in this study; thus, data sharing is not applicable. The authors have no conflict of interest. This work did not involve human subjects, and therefore, no Institutional Review Board (IRB) applications or approval notices from the American Political Science Association (APSA)'s Principles and Guidance for Human Subjects Research and the American Association of Public Opinion Research (AAPOR)'s Code of Ethics are required.