Molecular imaging and therapy directed at the neovasculature in pathologies

We have discussed the impact of molecular imaging on clinical and preclinical medicine. We have presented the potential problems of delivering the effective therapeutic dose and the properties that can help contribute to the drug efficacy. The rationale for the design of new antiangiogenic agents that can be used for imaging and therapy was presented. Finally, results from imaging and targeted nanoparticle based therapies were presented. In vivo imaging of angiogenic tumors using anti-alpha(v)beta3 -targeted polymerized vesicles composed of the murine antibody LM609 attached to NPs labeled with the MR contrast agent gadolinium in the V2 carcinoma model in rabbits. MRI studies using this targeted contrast agent revealed large areas of alpha(v)beta3 integrin expression in tumor-associated vasculature that conventional MRIs failed to show. Other investigators have used microemulsions conjugated to an antibody targeted against alpha(v)beta as imaging agents. These materials also show contrast enhancement of tumor vasculature undergoing angiogenesis. Other markers, such as the PECAM-1 (CD-31), VCAM-1 (CD54) and VEGF receptor (flk-1), have been shown to be upregulated on tumor endothelium and associated with angiogenesis but have not been used in imaging studies. Furthermore, by modification of the NPs, we were able to use this imaging agent as an antiangiogenic gene delivery system. The results from these studies are very promising and are being further pursued.     

Electrochemotherapy: transition from laboratory to the clinic

Although electroporation in the past has mainly been used as a research tool, recent work has demonstrated its potential for clinical applications. Some of the areas explored include electrochemotherapy (ECT), which utilizes electroporation as a means for delivering chemotherapeutic agents directly into tumor cells, encapsulation of drugs or genes into cells for their use as carrier systems, transdermal delivery of drugs or genes, gene therapy, and delivery of drugs or genes with an electroporation catheter. This article discusses the principles of ECT as a method of treating cancer, the requirements and development of electronic and electromechanical hardware for ECT, and it presents data for both in-vivo animal studies and clinical applications, especially for subcutaneous tumors. It is concluded that ECT has shown promise in treating a variety of cancers in humans. The basic principles are reasonably well understood. A good start has been made in the development of the necessary hardware to generate and apply the needed electric fields. As the human genome project progresses in identifying gene-based diseases and their possible cures, the same hardware system used for ECT can also be used for electrogene therapy. As ECT-based therapy becomes more widely recognized, it will offer an additional treatment modality and increased hope for cancer patients.     

Nonautologous gene therapy with implantable devices

Treatment of human diseases with gene therapy is a technological break through that has been touted to be the “ultimate medicine”. A potentially more cost-effective method of gene therapy is to use universal cell lines engineered to secrete therapeutic products that are suitable for implantation in all patients requiring the same product replacement. To avoid immune rejection, these nonautologous donor cells can be protected within immuno-isolation devices such as alginate-fabricated microcapsules. This article documents the early development and current status of nonautologous somatic gene therapy, combining biomaterial with genetic engineering to develop a new direction of research. Topics covered include: questions in gene therapy; nonautologous somatic gene therapeutics; the expression of recombinant gene products in immuno-isolation devices; the delivery of recombinant gene products with encapsulated cells in vivo; and animal models of human genetic diseases     

Energy-Based Diagnostic and Treatment Techniques

In living systems, numerous biochemical reactions take place, including energy and entropy variations. Understanding how energy flows and interacts with the surrounding tissues may provide some insights into tumor initiation and development and, thus, lay the foundation for early cancer diagnosis and treatment using energy-based technologies. For example, previous research showed that the internal temperature of breast cancer was 2?3 C higher than that of normal tissue mainly due to the higher metabolic rate and local blood perfusion [1]?[3]. This has been the biological basis for noninvasive breast cancer detection using infrared thermal imaging techniques. Also tumor cells and neo-vasculature were found to be more sensitive to temperature than normal vessels, providing the possibility of thermally targeted drug delivery for tumor therapy [4]?[10]. Thermal treatment     

High-voltage, electric field-driven micro/nanofabrication for polymeric drug delivery systems

One of the major challenges in drug delivery is to provide an appropriate dosage of therapeutic agents at the right time to the right location. The therapeutic agents include small molecules, macromolecules, nanoparticles, and cells, whose sizes range from less than 0.5 nm to 20 mum. Major noninvasive routes of administration include oral, pulmonary, and transdermal drug delivery. Transport barriers associated with these drug delivery routes prevent the delivery of appropriate dosage of therapeutic agents to the right location. Size is one of the determining factors for drug delivery systems. Polymeric microstructured or nanostructured systems show a great potential to stabilize therapeutic agents and overcome transport barriers by controlling the size and surface properties. A high-voltage electric field can be imposed on a polymer liquid to form microcapsules, to produce nanoparticles through electrospray or electrostatic assembly and to fabricate nanofibers through electrospinning. The addition of an electric field results in charging the components of the system and the resulting electrostatic interactions. Because electrostatic forces become meaningful at the nanoscale, electrostatic technologies attractmuch attention in microfabrication or nanofabrication [1]. There are several recent review articles available for microencapsulation [2], [3], electrospray [4], and electrospinning [5]-[9]. However, very few have investigated connections among all these processes. The major objectives of this article are to discuss mechanisms behind these electrostatic processes and explore connections among these techniques that can lead to the design and fabrication of specific drug delivery systems using an electrostatic generator.     

Computational fluid dynamics

Variation in the individual airway geometry makes subject-specific models essential for the study of pulmonary air flow and drug delivery. Recent evidence also suggests that early exposure to environmental pollutants has chronic, adverse effects on lung development in children from the age of ten to 18 years [1]. Thus, the capability of predicting air flow and particle deposition in the subjectspecific breathing lungs is highly desirable for understanding the correlation between structure and function and for assessing individual differences in vulnerability to airborne pollutants. Furthermore, it has been demonstrated that a strong interaction exists between lung geometry and gas properties [2]. The interaction has major implications in determining gas delivery to and clearance from the lung periphery during ventilation imaging through X-ray computed tomography (CT) using xenon gas [3]-[5] or magnetic resonance imaging (MRI) using hyperpolarized helium gas [6]-[9]. Although there is a critical need to understand these geometry?property interactions, the current state of knowledge acquired from experiments is still far from revealing the true nature of their interplays. At the same time, three-dimensional (3-D) computational fluid dynamics (CFD) simulation of air flow for the entire lung geometry remains intractable because of constraints on imaging resolution and computational power. As a result, current 3-D CFD simulations of air flow are often restricted to a few generations of branching on a fixed mesh, and most studies are based on idealized Weibel airway models. With advances in imaging and computing technologies, anatomy coupled with functional measures (ventilation and perfusion) can now be obtained via CT imaging [10], [11]. These measures provide the detail needed to interrogate the utility of CFD in providing insights into subject-specific differences in regional lung function and the underlying mechanisms of pathologic developments     

BioMEMS devices for drug delivery

Successful therapeutic outcomes following the administration of drugs, including small molecules and large biomolecules, require not only the selection of a proper drug but also its delivery to the proper site of action, with proper temporal presentation. Drug delivery is an extremely broad area of research, as each molecule presents its own absorption, distribution, metabolism, excretion, and toxicology (ADMET) profile. Moreover, timing of drug release may affect the efficacy of a pharmacologic agent. Any means by which drug delivery can be actuated and controlled is, therefore, of interest, and there should be no surprise that microelectromechanical systems (MEMS) have received considerable attention over the past decade in the drug delivery field. The ability to generate two-dimensional (2-D) and three-dimensional (3-D) material constructs accurately and reproducibly using MEMS may lead to substantial advances over conventional drug delivery systems.     

Targeted imaging using ultrasound contrast agents

The applications of ultrasound contrast agents have recently expanded from blood pool enhancement to include passive targeting of physiological systems (in particular, the lymphatic and reticuloendothelial systems) and molecular imaging of factors expressed in angiogenesis, atherosclerosis, and inflammation. This article summarizes the progress made in targeted imaging using ultrasound with an emphasis on the opportunities this research provides for both clinical and research applications. We begin with a summary of current ultrasound contrast technology and then review the latest research in the use of targeted ultrasound contrast agents.     

A brief review of hardware for catheter tracking in magnetic resonance imaging.

Magnetic resonance imaging (MRI) has traditionally been used exclusively in a role for patient diagnosis. However, it is unlikely that this role is sufficient for its continued prominence in medical imaging. Instead, the more ambitious role in diagnosis and also therapy/intervention will occur as demand for minimally invasive procedures increases. Fortunately, with recent improvement in technical specifications and creative pulse sequence design, MRI systems can now provide high quality near-real-time images that facilitate a variety of image-guided procedures, many based around delivery via catheters. While X-ray opacity is not available as a means for detecting the progression of the catheter in MRI systems today, a variety of novel hardware devices have been designed and used for MRI catheter tracking. This report provides a brief review of some fundamental methods for catheter tracking in MRI.     

Preparation,Characterization, and Property of Chitosan/Polyethylene Oxide Electrospun Nanofibrous Membrane for Controlled Drug Release

Composite nanofibrous membranes of chitosan (CS) and polyethylene oxide (PEO) were prepared by electrospinning, which can be used as wound dressing scaffolds for controlled drug loading and release. Besides, 5-Fluorouracil (5-FU) which had been successfully electrospun into nanofibers was employed as a model of antitumor drug to electrospin within the nanofibrous membranes. The properties of the membranes were characterized by the means, such as SEM, AFM, FTIR spectra, XRD and DSC. Furthermore, this thesis investigates the drug releasing profile from the CS/PEO electrospun nanofibrous membrane. According to investigations, it is showed that when the composite nanofibrous membranes were decomposing, the drugs on the scaffolds were released, which was related to the molecular weight of polymers, the mass ratio of CS/PEO, different total concentrations of polymers and the variation of pH value of in solution. This reversible pH-responsive property of the drug delivery system will regulate the drug release of anticancer therapy in the organism. Therefore, possible mechanisms of controlled drug release were anticipated. Supplemental materials are available for this article. Go to the publisher's online edition of Integrated Ferroelectrics to view the free supplemental file.     

Engineering strategies for drug delivery

A drug is a molecule that changes physiological functions when absorbed into the cells or tissues of a living organism. It can be used to treat, cure, prevent, or diagnose diseases or to enhance physical or mental health. However, the discovery of a drug is an expensive, long, and challenging process. It can take 15 years for a big pharmaceutical company to spend more than US$500 million for developing a new drug. Despite the high cost, many drugs themselves can only provide the human being with modest desired effects. Moreover, almost all drugs can cause side effects when they act in the body. Therefore, there is a clear need to maximize the efficacy of a drug and simultaneously reduce its side effects. To achieve this goal, it is necessary to find a way to help drugs to primarily reach the target area of the body (e.g., solid tumors). Drug delivery is the right discipline for studying methods for administering drugs in a safe and efficient manner. The success of this discipline relies on different expertises from chemists, biologists, and engineers. In this special issue of IEEE Engineering in Medicine and Biology Magazine, we will particularly illustrate the significance of engineering knowledge in drug delivery through a collection of six articles from experts in the field.     

Enhancement of power system dynamic performance through an on-line self-tuning adaptive SVC controller

Static VAr compensators (SVC) are used for voltage control of long distance bulk power transmission lines. By using a supplemental control loop an SVC can also be used to improve the dynamic and transient stability of a power system. Use of a self-tuning adaptive control algorithm as a supplementary controller for the SVC is presented in this article. The control derived is based on a pole-shifting technique employing a predicted plant model. Simulation studies on a simple power system model showed rapid convergence of the estimated plant parameters with an extremely good damping profile. The controller has been tested for ranges of operating conditions and for various disturbances. The effectiveness of the adaptive damping controller was also evaluated through an ‘optimized’ PI controller.     

Transdermal drug delivery by localized intervention

Oral and needle-based administration of drugs have long been accepted as a simple, convenient, and inexpensive mode of drug delivery However, the systemic delivery of drugs degrades the compound during its passage through the low pH environment of the gastrointestinal (GI) tract. Also, these methods are not suited for the delivery of new and highly complex drugs. In addition, other concerns such as protection from needle-prick injuries, need for sustained delivery, and relief for needle-phobic patients have risen sharply. Several alternatives have been developed in the past few decades. These include pulmonary, transmucosal, transdermal, and buccal routes of delivery. These methods provide the advantages of local and minimally invasive delivery and are suited for the delivery of specific drugs.     

磁性纳米颗粒及其在生物医学领域中的应用

磁性纳米颗粒因其独特的超顺磁性质和纳米特性,在生物医学领域得到了日益广泛的应用。本文系统评述了磁性纳米颗粒的制备方法、表面改性及其在生物分离、靶向热疗、靶向给药以及核磁共振成像等生物医学领域中的应用,并对其应用前景进行了展望。     

A Cantilever Sensor With an Integrated Optical Readout for Detection of Enzymatically Produced Homocysteine

Microcantilever sensors have been recognized as a promising sensor platform for various chemical and biological applications. One of their major limitations is that the measurement of cantilever displacement typically involves elaborate off-chip setups with free-space optics. An improved device, known as the optical cantilever, has been proposed recently to eliminate the external optics. The response of the optical cantilever is measured on-chip through integrated waveguides. However, this method has been previously demonstrated only for devices operating in air, whereas most chemical and biological samples are in solution state. We present the first optical cantilever capable of operation in liquid. We test it with the detection of homocysteine with a minimal concentration of 10 $mu$M. The minimal measurable cantilever displacement and surface stress are 5 nm and 1 mN/m, respectively. The presented device will be used in studies of a homocysteine-producing bacterial pathway for the purpose of drug discovery. It can also be extended to various other chemical- or biological-sensing applications by selecting an appropriate surface coating.      

A brief review of hardware for catheter tracking in magnetic resonance imaging

Magnetic resonance imaging (MRI) has traditionally been used exclusively in a role for patient diagnosis. However, it is unlikely that this role is sufficient for its continued prominence in medical imaging. Instead, the more ambitious role in diagnosis and also therapy intervention will occur as demand for minimally invasive procedures increases. Fortunately, with recent improvement in technical specifications and creative pulse sequence design, MRI systems can now provide high quality near-real-time images that facilitate a variety of image-guided procedures, many based around delivery via catheters. While X-ray opacity is not available as a means for detecting the progression of the catheter in MRI systems today, a variety of novel hardware devices have been designed and used for MRI catheter tracking. This report provides a brief review of some fundamental methods for catheter tracking in MRI. Submitted at the ISMRM Hardware Workshop held 23–25 February 2001 in Cleveland, OH, USA.     

Clinical evaluation of ultra-high-field MRI for three-dimensional visualisation of tumour size in uveal melanoma patients,with direct relevance to treatment planning

Objectives

To assess the tumour dimensions in uveal melanoma patients using 7-T ocular MRI and compare these values with conventional ultrasound imaging to provide improved information for treatment options.

Materials and methods

Ten uveal melanoma patients were examined on a 7-T MRI system using a custom-built eye coil and dedicated 3D scan sequences to minimise eye-motion-induced image artefacts. The maximum tumour prominence was estimated from the three-dimensional images and compared with the standard clinical evaluation from 2D ultrasound images.

Results

The MRI protocols resulted in high-resolution motion-free images of the eye in which the tumour and surrounding tissues could clearly be discriminated. For eight of the ten patients the MR images showed a slightly different value of tumour prominence (average 1.0 mm difference) compared to the ultrasound measurements, which can be attributed to the oblique cuts through the tumour made by the ultrasound. For two of these patients the more accurate results from the MR images changed the treatment plan, with the smaller tumour dimensions making them eligible for eye-preserving therapy.

Conclusion

High-field ocular MRI can yield a more accurate measurement of the tumour dimensions than conventional ultrasound, which can result in significant changes in the prescribed treatment.

     

Sonophoretic Delivery for Contrast and Depth Improvement in Skin Optical Coherence Tomography

Our previous studies demonstrated the feasibility of using a sonophoretic delivery method to enhance skin light transmittance with topical application of optical clearing agents using spectroscopy. In this study, we examined the effect of ultrasound [surgeon-performed (SP)] on optical coherence tomography (OCT) imaging depth and contrast of in vitro and in vivo skin. Sixty percent glycerol (G) and SP with a frequency of 1 MHz and a power of 0.75 W over a 3 cm probe was simultaneously applied for 15 min. We find that 60% G/SP results in a twofold increase in achievable OCT imaging depth for in vitro porcine skin and induces 11% shrinkage of the skin. For in vivo human skin, OCT imaging depth and contrast is significantly improved within 30 min of treatment. Imaging depth is increased from 1.4 to 2 mm, and dermal vasculature is clearly visualized in the deeper tissue. OCT imaging of the skin treated with 60% glycerol shows little enhancement in contrast or imaging depth over 60 min. We first demonstrate the superb ability of sonophoretic delivery for in vivo human skin optical clearing, particularly in accelerating the clearing rate. The greater clearing efficiency of glycerol implemented with ultrasound may be attributed to more effective dehydration.     

CAD图平面坐标转换算法与VBA实现

当今,AutoCAD在设计施工与地形测绘中的应用已经相当的广泛,CAD图已经成为图形数据编辑和各种成果提交的主要形式。例如在施工放样桩位时,若工程桩施工图就是在其设计坐标系统下,则可以直接在图中"拾取"桩位坐标用于指导放样。但工程桩的图上坐标系统与其设计坐标系统往往并不一致,给设计和施工人员双方之间信息的共享带来了不便。本文以此为题,介绍了一种基于最小二乘的平面坐标转换算法,并针对该算法,给出CAD图坐标转换的VBA实现,最后结合一个施工放样工程桩的实际工程,验证了算法的可行性和软件在实际应用中的良好效果。