Photoacoustic Molecular Imaging For Precise Analysis Of Brain Tissue Compositions And Diagnosis Of Cerebrovascular Diseases

Photoacoustic(PA)imaging is an emerging,nonionizing,noninvasive and nonradiative biomedical imaging modality.Taking advantages of rich optical contrast and deep penetration depth,this evolutional technique can be used for multiscale and multiftunctional visualization from organelles to organs,molecule to metabolism,anatomy to function with high specificity and sensitivity.With the unique ability to sense various endogenous chromophores,biomarkers or exogenous chromophores,PA molecular imaging empowers potential capabilities for exploring brain functions and mechanisms.In neuroscience,there is a urgent need for an accurate imaging technology that can monitor specific biomarkers and biochemical processes.Here,the potential applications of PA molecular imaging for accurate analysis of brain tissue compositions and diagnosis of cerebrovascular diseases with well designed near infrared contrasts are studied.This dissertation is described in the following four parts:1.In chapter 1,we systematically elucidate the basic principle of PA imaging,the main PA imaging embodiments,the latest development of PA imaging and its application for early-stage theranostics.At the same time,the traditional diagnostic techniques and challenges of brain diseases are studied.The potential applications of PA molecular imaging in the diagnosis of cerebrovascular diseases are introduced.Finally,the great prospects of PA molecular imaging for cerebrovascular diseases are highlighted.2.In chapter 2,the interaction and distribution of basic components in brain cells,such as lipids,protein,and DNA,plays a vital role in exploring function and structure of tissues,and pathological mechanisms of diseases in the brain.Different cellular components have different characteristic absorption spectra in different optical windows.A lab-made wide-band multispectral optical resolution photoacoustic microscope(wbmOR-PAM)has been developed for imaging of cellular components in brain tissues,which covers the wavelength ranging from ultraviolet region to short-wave infrared region.It was used to sense multiple cellular components of 300-?m-thick brain samples at multiwavelengths without repeated staining.At the same time,an efficient phospholipids fingerprint was found,which will push the study of phospholipid-related brain diseases.With multiple wavelengths,this emerging imaging technology will provide new insights in discovering more cellular components and exploring the pathological mechanism of brain diseases.3.In chapter 3,with the ability to map blood vessels and exogenous chromophorcs,PA molecular imaging was used to mornitor cerebral amyloid angiopathy(CAA).The characteristics of CAA is the deposition of amyloid beta(A?)plaque in the vascular walls of cortical arteries,and veins of the brain.A superb NIR croconium dye was well synthesized,which showed high affinity to cerebrovascular amyloid protein without coupling with any antibodies.This smart PA contrast labeled with radioactive 18F enabled hypersensitive NIR-I PA/positron emission tomography(PET)/fluorescence sensing of A? in the brain.Our results confirmed that PA/PET can be a valuable tool for accurate diagnosis and localization of cerebrovascular diseases with advanced mutifunctional dyes.4.In chapter 4,compared with traditional NIR-I PA imaging,NIR-? PA imaging with lower light attenuation and background interference,holds great potential in the diagnosis of deep brain gliomas.Brain glioma is the most common primary intracranial malignancy.Effective imaging methods and specific contrasts are very important for the identification of deep brain tumors.A mesoionic organic dye,which showed effective aggregation-induced absorption enhancement(AIAE)property when packaged in the Arg-Gly-Asp modified hepatitis B virus core protein,was discovered for deep PA imaging and showed 9-fold PA signal amplification in vivo.Here,high resolution PA molecular imaging combined with single photon emission computed tomography allowing for noninvasive imaging of brain gliomas in 5.9 mm deep will provide valuble tools for the accurate diagnosis of deep brain tumors.