Nanotechnology offers exciting opportunities and unprecedented compatibilities in manipulating chemical and biological materials at the atomic or molecular scale for the development of novel functional materials with enhanced capabilities. It plays a central role in the recent technological advances in biomedical technology, especially in the areas of disease diagnosis, drug design and drug delivery. In this review, we present the recent trend and challenges in the development of nanomaterials for biomedical applications with a special emphasis on the analysis of neurotransmitters. Neurotransmitters are the chemical messengers which transform information and signals all over the body. They play prime role in functioning of the central nervous system (CNS) and governs most of the metabolic functions including movement, pleasure, pain, mood, emotion, thinking, digestion, sleep, addiction, fear, anxiety and depression. Thus, development of high-performance and user-friendly analytical methods for ultra-sensitive detection of neurotransmitters remain a major challenge in modern biomedical analysis. Nanostructured materials are emerging as a powerful mean for diagnosis of CNS disorders because of their unique optical, size and surface characteristics. This review provides a brief outline on the basic concepts and recent advancements of nanotechnology for biomedical applications, especially in the analysis of neurotransmitters. A brief introduction to the nanomaterials, bionanotechnology and neurotransmitters is also included along with discussions on most of the patents published in these areas.
Tuesday, March 15, 2011
Haematology
Haematology is the long-awaited, revised and updated version of the original edition first published in 1999 as part of the highly respected 'Biomedical Sciences Explained' series. This time we have a new editor as Chris Pallister has been joined by Malcolm Watson, and the book has grown by over 130 pages. Initial impression is of a very nicely presented text with a clear, uniform style throughout and numerous boxes containing mainly historical and some explanatory annotations, which add a nice touch. All illustrations are greyscale but they work well.
All of the major headings that one would expect in a book of this kind are represented, with 20 chapters in total, starting with an initial introduction to blood and haemopoiesis, followed by substantial chapters covering red cells, a chapter covering non-malignant leucocyte disorders, seven chapters covering all major areas of haematological malignancy, and finally three chapters devoted to coagulation. Each chapter begins with clearly stated learning objectives.
Chapter 3 introduces us to the concepts of anaemia and the description of red cells. On page 43 we are told that the term 'hyperchromic' is not used, but in practice it sometimes is - spherocytes do lose their area of central pallor because they are no longer biconcave, but they are often smaller than normal red cells and have an increased haemoglobin concentration, and they do look darker upon microscopic examination. Even the suggested further reading (Bain) supports careful use of this term.
Chapter 4 provides sound coverage of the disorders of iron metabolism and the relationship between hepcidin and ferroportin that would not have been found in any book published in 1999.
All of the major headings that one would expect in a book of this kind are represented, with 20 chapters in total, starting with an initial introduction to blood and haemopoiesis, followed by substantial chapters covering red cells, a chapter covering non-malignant leucocyte disorders, seven chapters covering all major areas of haematological malignancy, and finally three chapters devoted to coagulation. Each chapter begins with clearly stated learning objectives.
Chapter 3 introduces us to the concepts of anaemia and the description of red cells. On page 43 we are told that the term 'hyperchromic' is not used, but in practice it sometimes is - spherocytes do lose their area of central pallor because they are no longer biconcave, but they are often smaller than normal red cells and have an increased haemoglobin concentration, and they do look darker upon microscopic examination. Even the suggested further reading (Bain) supports careful use of this term.
Chapter 4 provides sound coverage of the disorders of iron metabolism and the relationship between hepcidin and ferroportin that would not have been found in any book published in 1999.
Automatic skin tumour border detection for digital dermoscopy using a new digital image analysis scheme
Malignant melanoma and basal cell carcinoma are common skin tumours. For skin lesion classification it is necessary to determine and calculate different attributes such as exact location, size, shape and appearance. It has been noted that illumination, dermoscopic gel and features such as blood vessels, hair and skin lines can affect border detection. Thus, there is a need for approaches that minimise the effect of such features. This study aims to detect multiple borders from dermoscopy with increased sensitivity and specificity for the detection of early melanoma and other pigment lesions. An automated border detection method based on minimising geodesic active contour energy and incorporating homomorphic, median and anisotropic diffusion (AD) filtering, as well as top-hat watershed transformation is used. Extensive experiments on various skin lesions were conducted on real dermoscopic images and proved to enhance accurate border detection and improve the segmentation result by reducing the error rate from 12.42% to 7.23%. The results have validated the integrated enhancement of numerous lesion border detections with the noise removal algorithm which may contribute to skin cancer classification.
KEY WORDS: Carcinoma, basal cell.
Dermoscopy.
Image processing, computer assisted.
Skin neoplasms.
Introduction
Skin cancer is one of the most common types of cancer1 among populations worldwide. Generally, skin cancer is divided into two groups, melanoma and non-melanoma. Malignant melanoma3 usually appears as an enlarged naevus with multiple shades of colours, and its border tends to be irregular and asymmetric with protrusions and indentations. This is a potentially fatal malignancy3 of the epidermal melanocyte which invades the dermis of the skin, and thus early detection is vital to the treatment process.
Basal cell carcinoma' is the most common form of cancer in the United States. According to the American Cancer Society, 75% of all skin cancers are basal cell carcinomas. It develops in the epidermis and grows slowly and painlessly. A new skin growth that bleeds easily or does not heal well may suggest basal cell carcinoma. The majority of such tumours occur on areas of skin regularly exposed to sunlight or other ultraviolet (UV) radiation.
KEY WORDS: Carcinoma, basal cell.
Dermoscopy.
Image processing, computer assisted.
Skin neoplasms.
Introduction
Skin cancer is one of the most common types of cancer1 among populations worldwide. Generally, skin cancer is divided into two groups, melanoma and non-melanoma. Malignant melanoma3 usually appears as an enlarged naevus with multiple shades of colours, and its border tends to be irregular and asymmetric with protrusions and indentations. This is a potentially fatal malignancy3 of the epidermal melanocyte which invades the dermis of the skin, and thus early detection is vital to the treatment process.
Basal cell carcinoma' is the most common form of cancer in the United States. According to the American Cancer Society, 75% of all skin cancers are basal cell carcinomas. It develops in the epidermis and grows slowly and painlessly. A new skin growth that bleeds easily or does not heal well may suggest basal cell carcinoma. The majority of such tumours occur on areas of skin regularly exposed to sunlight or other ultraviolet (UV) radiation.
Recent advances in biomedical applications of accelerator mass spectrometry
The development of biomedical AMS
The use of radioisotopes has a long history in biomedical science. Isotopic enrichment of xenobiotics with 14C is routinely used as a method of following their metabolic fate in both animals and humans, and a drug is typically synthesized such that the natural abundance of 14C is increased from the background level of 1.2 × 10-10% to 20% or even higher depending upon the compound. The low energy β-radioactivity is then used to track the radiolabeled compound and its metabolites in biological samples derived from laboratory animal or human studies. LSC has been generally used for a long time to detect, follow and quantitate levels of radiotracer in such studies. There are occasions, however, when the low sensitivity of LSC becomes experimentally limiting, while the technique of AMS has now changed the experimental paradigm because its extremely sensitive detection limit virtually removed the previous experimental barriers.The high sensitivity of AMS indeed affects experimental designs in several ways. First, the radioisotopic dose can be reduced to inconsequential levels of radiolysis, hazardous waste streams, and human subject exposure. Secondly, the chemical dose to a biological system, including humans of all ages and health status, is minimized to sub-physiological and sub-toxic doses. This allows a realistic analysis of the effects arising from low chemical doses. For example, children and women of child-bearing ages, who are important targets of increased health-related research, are suitable subjects at the low doses afforded by AMS [10,11], since the administration of such low levels of 14C are considered non-radioactive from a regulatory point of view. Finally, even if the sampled material needs fractionation to specific biomolecules prior to quantitation, the sample sizes are reduced to amounts that can be obtained from well-defined, and often non-invasive procedures.
For a practical AMS measurement, biological samples containing 0.2–5 mg of carbon must be converted to solid carbon (graphite or fullerene) using a two-step process [12]. In a quartz tube, and using excess copper oxide (CuO), the sample's biological carbon is oxidized to CO2. The CO2 is then reduced to solid carbon by both reduction with titanium hydride and zinc powder and catalyzation with either iron or cobalt. Because this process is independent of the chemical nature of the sample, it eliminates interference or suppression from other sample components. Therefore, AMS provides one piece of information about the sample of carbon measured: the precise 12C:14C ratio. In AMS, one measures the isotope ratio with respect to that of a well-known (external) standard in order to produce an absolute isotope concentration for the combusted sample [13,14]. With AMS, experimenters only need the fractional elemental abundance of the sample and the specific activity of the tracer compound in order to obtain, in the units most useful for interpretation, the concentration of the tracer in the sampled material. The mechanics of an AMS instrument, the mathematical conversions of the measured values to meaningful "Modern" values, and the comparisons with LSC are well reviewed in the literature [3,11,15-17].
For the first time in 1990, sensitive and precise quantitation of 14C was applied to the analysis of biological samples containing enriched 14C-labeled carcinogens for toxicology and cancer studies by Turteltaub et al. [18]. Their research quantified chemical binding of the 14C-labeled carcinogens to DNA at the level of 1 binding in 1011 bases. The benefits of using AMS for the analysis of samples derived from radiotracer studies with humans soon became apparent, since AMS produces very specific quantitation with simple analysis [19]. Any isotope concentration greater than the known stable natural 14C background must arise from an introduced isotope label ("introduced" includes contamination, which must be carefully controlled and avoided). In the simplest experimental design, there is only one external radioactive source, perhaps a radiolabeled compound introduced into the biological system at a specific time. The isotope ratio of the isolated sample is then easily converted to the concentration of the labeled compound and its metabolites per g or ml of the analyte.
Not surprisingly, AMS has soon become a tool of choice for pharmacokinetic analyses [10,11,16]. All the metabolites of the compound that contain the labeled moiety can be directly quantified in chromatographic separations without resorting either to secondary standards or to prior knowledge of metabolic pathways. Although some fluorescent methods quantitate into the amol levels [20,21], they require derivatization procedures that are not suitable for in vivo tracing, create tracers that are not chemically equivalent, and are less general in applicability across many biological systems. Conversely, AMS is specific only to the labeled compound in any chemical or biological medium. Such specificity requires neither prior speciation nor the introduction of either molecular modifications or internal standards. With AMS, it is possible to conduct radiotracer studies in human with the administration of such low levels of 14C [10,11].
The most recent innovation using AMS technology is the so-called "microdosing" concept [10]. Choosing a drug for clinical trials from numerous candidates is very much a hit-and-miss business. Data are gathered from in vitro, in vivo, and in silico models in order to predict the drug's behavior in humans but such methods are probably only about 60% predictive. Presented with a choice of good candidates, it would be better to take them all into human subjects. This would, however, be prohibitively expensive, as each compound would require a significant package of toxicological safety testing. Alternatively, each candidate drug could be given to human volunteers at very low levels of a few tens, or at most a hundred μg. At these levels, only a limited toxicology package is required and in vivo human data can be acquired for candidate selection [22]. Only AMS has the required sensitivity to conduct such studies at the low μg level.
In this review, the recent development of AMS methods to the present day in biomedical/bioanalytical research where it is being strategically used with high precision (see Figure 2 for the major applications of AMS discussed here) will be followed.
A structural constitutive model considering angular dispersion and waviness of collagen fibres of rabbit facial veins
Constitutive modelling of vascular tissue has been a challenging area for several decades [1,2]. Structural constitutive models, in particular, attempt to integrate information on composition and structural arrangements of tissue to avoid ambiguities in material characterization. In this way, they offer an insight into the function, structure and mechanics of the principal wall components i.e. elastin, collagen and vascular smooth muscle cells. Structural constitutive models have been developed for a variety of tissues and tissue components including blood vessels [3-8], skin [9], pericardium [10], heart valves [11], tendons and ligaments [12], articular cartilage [13].
In blood vessels, collagen fibres appear in coiled and wavy bundles in their unloaded state [14,15] and the individual collagen fibres have a deviation from their mean orientations [16,17]. In the media, collagen fibres are strongly co-aligned [17]. Canham et al. [18] reported the angular standard deviation of fibres in the media as 5.2° in brain arteries and 5.6° in coronary arteries [18]. However, within the adventitia layer, collagen fibres have large angular dispersion [17]. A complete structural constitutive model for vascular collagen should incorporate both waviness and orientational distribution of fibres.
Perhaps the most complete framework for structural modelling of fibrous tissue has been presented by Lanir et al. [19-21]. In this framework, the total strain energy function (SEF) is assumed to be a result of the collective contribution of the individual fibres linked with tensor transformations from the fibre coordinates to the global tissue coordinates. A number of previous studies have followed this approach and have incorporated waviness [22,23] or orientational distribution of collagen fibres [10,11,24], to study the effects of collagen micro-organization on the macroscopic behaviour of vascular tissue. Other studies have followed a different approach and involved the use of invariants [22,23,25]. Yet, to the best of our knowledge, currently, there is no structure-based SEF for the vascular wall, which includes both waviness and angular distribution of collagen fibres and which has been verified using standard inflation-extension tests. We have therefore set as goals of this study to, first, extend our previously developed model [22,23] to include both waviness and angular distribution of collagen fibres, second, to perform a parametric study to analyze the effects of orientational distribution parameters on the macro-mechanical behaviour of the vascular tissue and, third, to assess the suitability and importance of including fibres' orientational distribution by applying the model to experimental data from inflation-extension tests.
In blood vessels, collagen fibres appear in coiled and wavy bundles in their unloaded state [14,15] and the individual collagen fibres have a deviation from their mean orientations [16,17]. In the media, collagen fibres are strongly co-aligned [17]. Canham et al. [18] reported the angular standard deviation of fibres in the media as 5.2° in brain arteries and 5.6° in coronary arteries [18]. However, within the adventitia layer, collagen fibres have large angular dispersion [17]. A complete structural constitutive model for vascular collagen should incorporate both waviness and orientational distribution of fibres.
Perhaps the most complete framework for structural modelling of fibrous tissue has been presented by Lanir et al. [19-21]. In this framework, the total strain energy function (SEF) is assumed to be a result of the collective contribution of the individual fibres linked with tensor transformations from the fibre coordinates to the global tissue coordinates. A number of previous studies have followed this approach and have incorporated waviness [22,23] or orientational distribution of collagen fibres [10,11,24], to study the effects of collagen micro-organization on the macroscopic behaviour of vascular tissue. Other studies have followed a different approach and involved the use of invariants [22,23,25]. Yet, to the best of our knowledge, currently, there is no structure-based SEF for the vascular wall, which includes both waviness and angular distribution of collagen fibres and which has been verified using standard inflation-extension tests. We have therefore set as goals of this study to, first, extend our previously developed model [22,23] to include both waviness and angular distribution of collagen fibres, second, to perform a parametric study to analyze the effects of orientational distribution parameters on the macro-mechanical behaviour of the vascular tissue and, third, to assess the suitability and importance of including fibres' orientational distribution by applying the model to experimental data from inflation-extension tests.
Dispensing pico to nanolitre of a natural hydrogel by laser-assisted bioprinting
Bioprinting techniques are emerging as potential instruments for the multidisciplinary field of tissue engineering and regenerative medicine. The possibility to arrange multiple cell types in a computer-controlled 3 D manner may substantially improve our understanding about complex cell-cell and cell-environment interaction. Among all bioprinting techniques [1-3], laser-assisted bioprinting (LaBP) approaches based on laser-induced forward transfer were demonstrated to possess additional benefits: (i) tiny amounts of different hydrogels with a wide range of rheological characteristics can be printed in a controlled and precise way [4-8], which is important for the realisation of 3 D cell-hydrogel constructs mimicking various stiffnesses of native tissues; (ii) any desired cell amount ranging from single [9] to dozens of cells [10] can be printed without observable damage to pheno- and genotype [7,9-12]; and (iii) the printing speed (number of droplets per second) depends mainly on the pulse repetition rate of the applied laser. Printing speed of 5000 droplets per second was recently demonstrated [4], which enables fast generation of large cell constructs.
Already demonstrated biological applications reflect the flexibility of this laser printing technique, for instance: (1) generation and differentiation of 3 D stem cell grafts [13], which can be used as in vitro tissue models for the screening of drug effects; (2) assembly of cellular micro arrays of single [11] and multiple [14] cell types for systematic studies of fundamental aspects of cell-cell and cell-environment interaction; (3) computer-controlled seeding of 3 D scaffolds with multiple cell types [15]; and (4) in vivo bioprinting of nano-hydroxyapatite [16]. The principal laser-assisted bioprinting setup (see Figure 1) consists of a pulsed laser source and two positioning systems on which a donor-slide coated with an energy-absorbing material layer carrying the cell-hydrogel compound, and a collector-slide receiving the printed biological material are located. In brief, laser pulses are focussed through the donor-slide onto the gold layer which is evaporated locally at the focal point. This rapid energy deposition leads to the generation of a jet dynamic [17] resulting in the deposition of a tiny hydrogel volume on the collector-slide. Control of the printed volume is a key issue and great efforts have been made to understand the relationship between the printed volume and the processing parameters [5,6,8,18]. Providing a deeper understanding of this relationship is crucial in order to make the printed volume with embedded cells more predictable, and to enable theoretical simulation of cell-cell interaction, cell-extracellular matrix interaction and signalling pathways [12]. However, the whole jet generation process is not completely understood. Moreover, recent studies mainly used glycerol-based fluids to investigate the effects of the laser fluence and fluid properties on the droplet volume [5,8,18] instead of fluids based on fibrin-precursors, which are widely used for bioprinting of different cell types
Already demonstrated biological applications reflect the flexibility of this laser printing technique, for instance: (1) generation and differentiation of 3 D stem cell grafts [13], which can be used as in vitro tissue models for the screening of drug effects; (2) assembly of cellular micro arrays of single [11] and multiple [14] cell types for systematic studies of fundamental aspects of cell-cell and cell-environment interaction; (3) computer-controlled seeding of 3 D scaffolds with multiple cell types [15]; and (4) in vivo bioprinting of nano-hydroxyapatite [16]. The principal laser-assisted bioprinting setup (see Figure 1) consists of a pulsed laser source and two positioning systems on which a donor-slide coated with an energy-absorbing material layer carrying the cell-hydrogel compound, and a collector-slide receiving the printed biological material are located. In brief, laser pulses are focussed through the donor-slide onto the gold layer which is evaporated locally at the focal point. This rapid energy deposition leads to the generation of a jet dynamic [17] resulting in the deposition of a tiny hydrogel volume on the collector-slide. Control of the printed volume is a key issue and great efforts have been made to understand the relationship between the printed volume and the processing parameters [5,6,8,18]. Providing a deeper understanding of this relationship is crucial in order to make the printed volume with embedded cells more predictable, and to enable theoretical simulation of cell-cell interaction, cell-extracellular matrix interaction and signalling pathways [12]. However, the whole jet generation process is not completely understood. Moreover, recent studies mainly used glycerol-based fluids to investigate the effects of the laser fluence and fluid properties on the droplet volume [5,8,18] instead of fluids based on fibrin-precursors, which are widely used for bioprinting of different cell types
Recent developments in biomedical optics
- The rapid growth in laser and photonic technology has resulted in new tools being proposed and developed for use in the medical and biological sciences. Specifically, a discipline known as biomedical optics has emerged which is providing a broad variety of optical techniques and instruments for diagnostic, therapeutic and basic science applications. New laser sources, detectors and measurement techniques are yielding powerful new methods for the study of diseases on all scales, from single molecules, to specific tissues and whole organs. For example, novel laser microscopes permit spectroscopic and force measurements to be performed on single protein molecules; new optical devices provide information on molecular dynamics and structure to perform `optical biopsy' non-invasively and almost instantaneously; and optical coherence tomography and diffuse optical tomography allow visualization of specific tissues and organs. Using genetic promoters to derive luciferase expression, bioluminescence methods can generate molecular light switches, which serve as functional indicator lights reporting cellular conditions and responses in living animals. This technique could allow rapid assessment of and response to the effects of anti-tumour drugs, antibiotics, or antiviral drugs. This issue of Physics in Medicine and Biology highlights recent research in biomedical optics, and is based on invited contributions to the International Conference on Advanced Laser Technology (Focused on Biomedical Optics) held at Cranfield University at Silsoe on 19--23 September 2003. This meeting included sessions devoted to: diffuse optical imaging and spectroscopy; optical coherence tomography and coherent domain techniques; optical sensing and applications in life science; microscopic, spectroscopic and opto-acoustic imaging; therapeutic and diagnostic applications; and laser interaction with organic and inorganic materials. Twenty-one papers are included in this special issue. The first paper gives an overview on the current status of scanning laser ophthalmoscopy and its role in bioscience and medicine, while the second paper describes the current problems in tissue engineering and the potential role for optical coherence tomography. The following seven papers present and discuss latest developments in infrared spectroscopy and diffuse optical tomography for medical diagnostics. Eight further papers report recent advances in optical coherence tomography, covering new and evolving methods and instrumentation, theoretical and numerical modelling, and its clinical applications. The remaining papers cover miscellaneous topics in biomedical optics, including new developments in opto-acoustic imaging techniques, laser speckle imaging of blood flow in microcirculations, and potential of hollow-core photonic-crystal fibres for laser dentistry. We thank all the authors for their valuable contributions and their prompt responses to reviewers' comments. We are also very grateful to the reviewers for their hard work and their considerable efforts to meet tight deadlines.
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