Molecular imaging of inflammation - Current and emerging technologies for diagnosis and treatment

Inflammation is a key factor in multiple diseases including primary immune-mediated inflammatory diseases e.g. rheumatoid arthritis but also, less obviously, in many other common conditions, e.g. cardiovascular disease and diabetes. Together, chronic inflammatory diseases contribute to the majority of global morbidity and mortality. However, our understanding of the underlying processes by which the immune response is activated and sustained is limited by a lack of cellular and molecular information obtained in situ. Molecular imaging is the visualization, detection and quantification of molecules in the body. The ability to reveal information on inflammatory biomarkers, pathways and cells can improve disease diagnosis, guide and monitor therapeutic intervention and identify new targets for research. The optimum molecular imaging modality will possess high sensitivity and high resolution and be capable of non-invasive quantitative imaging of multiple disease biomarkers while maintaining an acceptable safety profile. The mainstays of current clinical imaging are computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US) and nuclear imaging such as positron emission tomography (PET). However, none of these have yet progressed to routine clinical use in the molecular imaging of inflammation, therefore new approaches are required to meet this goal. This review sets out the respective merits and limitations of both established and emerging imaging modalities as clinically useful molecular imaging tools in addition to potential theranostic applications

Advances in Nanomaterials in Biomedicine

Advances in Nanomaterials in Biomedicine” provided a platform for more than 110 researchers from different countries to present their latest investigations in various fields of nanotechnology, new methods and nanomaterials intended for medical applications. Modern achievements in the field of nanoparticle-based diagnostics, drug delivery and the use of various nanomaterials in the treatment of diseases are presented in 11 original articles. The published reviews provide a comprehensive analysis of the current information on the use of nanomedicine in the treatment and diagnosis of cancer and liver fibrosis, in the field of solid tissue engineering and in drug delivery systems

Engineered Nanomaterials for Targeted Imaging and Therapy

The early diagnosis of cancer can help direct the best treatment strategy and improve patients' survival. The unique and tunable properties of nanoparticles facilitate the development of diagnostic imaging tools for earlier diagnosis and disease staging, and they can provide fundamental information on the pathological process. Nanoparticle probes have demonstrated to have numerous advantages over single molecule-based contrast agents, such as tumor-targeted delivery via the enhanced permeability and retention (EPR) effect, prolonged systemic circulation times to enhance imaging contrast efficiency, and facile surface modification for specific applications. The first part of this dissertation focuses on the development of radiation- damaged nanodiamonds (DNDs), a type of carbon-based nanoparticles, for the detection of solid tumors using a photoacoustic (PA) imaging technique. In chapter 2 of this dissertation, DNDs are proposed as ideal optical contrast agents for PA imaging in biological tissues due to their low toxicity and high optical absorbance. A new DND with very high NIR absorption was synthesized by He+ ion beam irradiation. These DNDs produced a 71-fold higher PA signal on a molar basis than similarly dimensioned gold nanorods, which were considered the "gold" standard agent for PA contrast agents. In order to develop DNDs as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with PA imaging, in chapter 3, an anti- Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) was conjugated to the surface of PEGylated DNDs. PA images demonstrated that DNDs accumulate in orthotopic HER2 positive tumors and completely delineated the entire tumor within 10 hours. Chapters 4 and 5 of this dissertation describe the development of a hyaluronic acid (HA) polymeric nanoparticle to deliver drugs for the locoregional treatment of head and neck squamous cell carcinoma (HNSCC). In chapter 4, a HA-pyropheophorbide a (PPa) conjugate was synthesized. The anti-cancer efficacy was improved compared to the intravenously administered PPa molecules, and it was demonstrated that it could be useful for in vivo locoregional photodynamic therapy of HNSCC. In chapter 5, a pH- tunable delivery platform of platinum-based anti-cancer drug was designed and synthesized to improve the therapeutic index. The systemic toxicity of cisplatin was significantly reduced due to the pH-controlled release of the active forms of Pt species. In chapter 6, a lanthanum label was non-covalently conjugated to HA polymer to track the in vivo bio-distribution of HA in HNSCC tumors and organs that are responsible for the elimination of nanoparticles. In the last chapter, an enzymatic N-deacetylation method was applied in the modification on HA. New synthetic routs were explored to prepare HA derivatives for anti-cancer drug delivery to meet specific needs with retained HA characteristics

Development and Validation of Mechatronic Systems for Image-Guided Needle Interventions and Point-of-Care Breast Cancer Screening with Ultrasound (2D and 3D) and Positron Emission Mammography

The successful intervention of breast cancer relies on effective early detection and definitive diagnosis. While conventional screening mammography has substantially reduced breast cancer-related mortalities, substantial challenges persist in women with dense breasts. Additionally, complex interrelated risk factors and healthcare disparities contribute to breast cancer-related inequities, which restrict accessibility, impose cost constraints, and reduce inclusivity to high-quality healthcare. These limitations predominantly stem from the inadequate sensitivity and clinical utility of currently available approaches in increased-risk populations, including those with dense breasts, underserved and vulnerable populations. This PhD dissertation aims to describe the development and validation of alternative, cost-effective, robust, and high-resolution systems for point-of-care (POC) breast cancer screening and image-guided needle interventions. Specifically, 2D and 3D ultrasound (US) and positron emission mammography (PEM) were employed to improve detection, independent of breast density, in conjunction with mechatronic and automated approaches for accurate image acquisition and precise interventional workflow. First, a mechatronic guidance system for US-guided biopsy under high-resolution PEM localization was developed to improve spatial sampling of early-stage breast cancers. Validation and phantom studies showed accurate needle positioning and 3D spatial sampling under simulated PEM localization. Subsequently, a whole-breast spatially-tracked 3DUS system for point-of-care screening was developed, optimized, and validated within a clinically-relevant workspace and healthy volunteer studies. To improve robust image acquisition and adaptability to diverse patient populations, an alternative, cost-effective, portable, and patient-dedicated 3D automated breast (AB) US system for point-of-care screening was developed. Validation showed accurate geometric reconstruction, feasible clinical workflow, and proof-of-concept utility across healthy volunteers and acquisition conditions. Lastly, an orthogonal acquisition and 3D complementary breast (CB) US generation approach were described and experimentally validated to improve spatial resolution uniformity by recovering poor out-of-plane resolution. These systems developed and described throughout this dissertation show promise as alternative, cost-effective, robust, and high-resolution approaches for improving early detection and definitive diagnosis. Consequently, these contributions may advance breast cancer-related equities and improve outcomes in increased-risk populations and limited-resource settings

PRELIMINARY FINDINGS OF A POTENZIATED PIEZOSURGERGICAL DEVICE AT THE RABBIT SKULL

The number of available ultrasonic osteotomes has remarkably increased. In vitro and in vivo studies have revealed differences between conventional osteotomes, such as rotating or sawing devices, and ultrasound-supported osteotomes (Piezosurgery®) regarding the micromorphology and roughness values of osteotomized bone surfaces. Objective: the present study compares the micro-morphologies and roughness values of osteotomized bone surfaces after the application of rotating and sawing devices, Piezosurgery Medical® and Piezosurgery Medical New Generation Powerful Handpiece. Methods: Fresh, standard-sized bony samples were taken from a rabbit skull using the following osteotomes: rotating and sawing devices, Piezosurgery Medical® and a Piezosurgery Medical New Generation Powerful Handpiece. The required duration of time for each osteotomy was recorded. Micromorphologies and roughness values to characterize the bone surfaces following the different osteotomy methods were described. The prepared surfaces were examined via light microscopy, environmental surface electron microscopy (ESEM), transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM) and atomic force microscopy. The selective cutting of mineralized tissues while preserving adjacent soft tissue (dura mater and nervous tissue) was studied. Bone necrosis of the osteotomy sites and the vitality of the osteocytes near the sectional plane were investigated, as well as the proportion of apoptosis or cell degeneration. Results and Conclusions: The potential positive effects on bone healing and reossification associated with different devices were evaluated and the comparative analysis among the different devices used was performed, in order to determine the best osteotomes to be employed during cranio-facial surgery