Multi-contrast Photoacoustic Microscopy

Photoacoustic microscopy is a hybrid imaging modality with high spatial resolution, moderate imaging depth, excellent imaging contrast and functional imaging capability. Taking full advantage of this powerful weapon, we have investigated different anatomical, functional, flow dynamic and metabolic parameter measurements using photoacoustic microscopy. Specifically, Evans-blue dye was used to enhance photoacoustic microscopy of capillaries; label-free transverse and axial blood flow was measured based on bandwidth broadening and time shift of the photoacoustic signals; metabolic rate of oxygen was quantified in vivo from all the five parameters measured by photoacoustic microcopy; whole cross-sectional imaging of small intestine was achieved on a double-illumination photoacoustic microscopy with extended depth of focus and imaging depth; hemodynamic imaging was performed on a MEMS-mirror enhanced photoacoustic microscopy with a cross-sectional imaging rate of 400 Hz. As a maturing imaging technique, PAM is expected to find new applications in both fundamental life science and clinical practice

Imaging Inflammation - From Whole Body Imaging to Cellular Resolution

Imaging techniques have evolved impressively lately, allowing whole new concepts like multimodal imaging, personal medicine, theranostic therapies, and molecular imaging to increase general awareness of possiblities of imaging to medicine field. Here, we have collected the selected (3D) imaging modalities and evaluated the recent findings on preclinical and clinical inflammation imaging. The focus has been on the feasibility of imaging to aid in inflammation precision medicine, and the key challenges and opportunities of the imaging modalities are presented. Some examples of the current usage in clinics/close to clinics have been brought out as an example. This review evaluates the future prospects of the imaging technologies for clinical applications in precision medicine from the pre-clinical development point of view

Nanosensors for In-vivo Opto-Chemical Imaging of Sodium Ions

Honors (Bachelor's)ChemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/120630/1/wulzhang.pd

Optical imaging in vivo with a focus on paediatric disease: technical progress, current preclinical and clinical applications and future perspectives

To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue

Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood–brain barrier: mechanisms of brain clearing

The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood–brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels. We first demonstrate successful application of optical coherence tomography (OCT) for imaging of the lymphatic vessels in the meninges after opening of the BBB, which might be a new useful strategy for noninvasive analysis of lymphatic drainage in daily clinical practice. Also, we give information about the depth and size of the meningeal lymphatic vessels in mice. These new fundamental data with the applied focus on the OCT shed light on the mechanisms of brain clearance and the role of lymphatic drainage in these processes that could serve as an informative platform for a development of therapy and diagnostics of diseases associated with injuries of the BBB such as stroke, brain trauma, glioma, depression, or Alzheimer disease

Developing multi-modal imaging agents for stem cell tracking

Clinical trials using stem cells as a regenerative therapy or a delivery vehicle for anti-cancer agents have been increasing but the outcomes are highly variable. In vivo imaging of stem cell delivery to target organs will help improve their therapeutic efficacy. However, a single imaging modality cannot provide the complete answer. The work in this thesis aims to develop a multi-modal imaging approach to overcome the limitations of each modality. To understand the distribution pattern of transplanted stem cells in vivo, luciferase expressing adipocyte derived mesenchymal stem cells (ADSCs) were labelled with novel bimodal (nuclear/magnetic resonance imaging) nanoparticles and the following hypotheses were tested; 1) that the distribution pattern of transplanted ADSCs would be different between venous and arterial routes, 2) that the arterial route would provide a more efficient way of delivering ADSC to tumours. In addition, ultrasound-guided renal artery injection was developed to improve stem cell delivery to kidney and the efficiency of this injection was assessed using photoacoustic and bioluminescence imaging. Moreover, the applicability of gold nanoparticles (GNP) as cell tracking agents was explored using multi-modal imaging. Results demonstrated the advantages of multi-modal imaging in assessing different cell distribution patterns after two systemic injections and confirmed that the arterial route was more efficient in delivering ADSCs to tumours. The assessment of cell localisation and viability in the kidney suggests that the level of cell engraftment improved after ultrasound-guided renal artery injection. Multi-modal imaging results indicated that GNPs are a promising cell tracking agent for computed tomography but further studies are required to define their specific applications. In conclusion, this work has demonstrated the successful application of multi-modal imaging for stem cell tracking in different organs. The findings from this thesis proved that combining the strengths of each modality can provide greater insight into cell migration and distribution

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered

Translational Photoacoustic Tomography

Combining optical excitation and ultrasonic detection, photoacoustic tomography (PAT) offers deep imaging with high resolution. With optical excitation, PAT maintains the high contrast of optical imaging. Because of the low scattering of ultrasonic waves in tissue, PAT achieves high spatial resolution at depths. Several advantages make PAT suitable for clinical application, including its scalable penetration and resolution, high optical absorption contrast, fast imaging speed, and ability to perform spectral decomposition. Based on different image reconstruction mechanisms, PAT can be further divided into two embodiments: raster-scanning-based photoacoustic microscopy (PAM) and reconstruction-algorism-based photoacoustic computed tomography (PACT). This dissertation aims to advance the direction of translational PAT, including both PAM and PACT. In Chapter 1, I first explain the basic principles of PAM and PACT and then discuss in detail why they are suitable for translational studies. The chapter concludes with the motivation of my dissertation. Chapter 2 introduces my translational studies in PAM. I first improved the systems lateral resolution and imaging penetration depth by applying an optical clearing technique. With glycerol as an optical clearing agent, the imaging performance of optical resolution PAM (OR-PAM) was greatly enhanced both in vitro and in vivo. Then I applied PAM in quantifying concentrations of blood substances, including red blood cells (RBCs) and bilirubin, and studied related diseases, such as RBC aggregation and jaundice. After building a model to statistically analyze photoacoustic signals for absolute measurement of red blood cell count, I developed multi-wavelength decomposition algorithms and implemented multi-wavelength PA imaging to map bilirubin concentration. Chapter 3 describes studies of complex regional pain syndrome (CRPS) in patients with both OR-PAM and acoustic resolution PAM (AR-PAM). Blood vasculature and oxygen saturation (sO2) were imaged in eight adult patients with CRPS. Patients hands and cuticles were imaged both before and after stellate ganglion block (SGB) for comparison. For all patients, both vascular structure and sO2 could be assessed by PAM. In addition, more vessels and stronger signals were observed after SGB. The results show that PAM can help diagnose and monitor CRPS. Chapter 4 introduces my work on flow measurement both in mice and humans. It first discusses improving the flow measurement accuracy by a new technique cross-correlation-based flowmetry. This technique is based on OR-PAM and can effectively remove the particle size induced measurement error. I demonstrated this technique both in phantom and in vivo experiments in mice. To achieve flow measurement in the optical diffusive regime, I further developed two methods: saline-injection-based and cuffing-based flowmetries. The saline-injection-based method is especially pertinent to monitoring blood flow velocity in patients undergoing intravenous infusion, while the cuffing-based one is suitable for both patients and healthy people. Chapter 5 presents my work on brain imaging, including both mouse and human brains in vivo. To achieve deep mouse brain imaging, I first used a ring transducer array (5 MHz center frequency) with an acoustic reflector. Blood vessels from the bottom of the mouse brain could be imaged, and many key features were detected, such as diving vessels, the superior sagittal sinus, and the posterior cerebral artery. However, the image contrast was not high due to the poor spatial resolutions of the system. To improve the image quality, I later used a linear array system with a 21 MHz center frequency. By rotating the linear array, more striking images were acquired. For the human imaging project, I successfully imaged blood vessel phantoms through an adult human skull. Chapter 6 describes my work on melanoma imaging and depth measurement in patients. Two different systems were used in this project: a handheld AR-PAM system and a handheld linear array system. While the former is cheaper, the latter provides much faster imaging and a larger acceptance angle. With the array system, we successfully imaged melanomas in patients and achieved more accurate depth measurement than incisional biopsy in clinics