Femtosecond laser-induced microstructures on diamond for microfluidic sensing device applications

This paper reported a three-dimensional microfluidic channel structure, which was fabricated by Yb:YAG 1026?nm femtosecond laser irradiation on a single-crystalline diamond substrate. The femtosecond laser irradiation energy level was optimized at 100?kHz repetition rate with a sub-500 femtosecond pulse duration. The morphology and topography of the microfluidic channel were characterized by a scanning electron microscope and an atomic force microscope. Raman spectroscopy indicated that the irradiated area was covered by graphitic materials. By comparing the cross-sectional profiles before/after removing the graphitic materials, it could be deduced that the microfluidic channel has an average depth of ~410?nm with periodical ripples perpendicular to the irradiation direction. This work proves the feasibility of using ultra-fast laser inscription technology to fabricate microfluidic channels on biocompatible diamond substrates, which offers a great potential for biomedical sensing applications.

Optical in-fiber Bragg grating sensor systems for medical applications

Two in-fiber Bragg grating (FBG) temperature sensor systems for medical applications are demonstrated: (1) an FBG flow-directed thermodilution catheter based on interferometric detection of wavelength shift that is used for cardiac monitoring; and (2) an FBG sensor system with a tunable Fabry-Perot filter for in vivo temperature profiling in nuclear magnetic resonance (NMR) machines. Preliminary results show that the FBG sensor is in good agreement with electrical sensors that are widely used in practice. A field test shows that the FBG sensor system is suitable for in situ temperature profiling in NMR machines for medical applications.

Femtosecond laser-induced microstructures on diamond for microfluidic sensing devices applications

This paper reported a three-dimensional microfluidic channel structure, which was fabricated by Yb:YAG 1026?nm femtosecond laser irradiation on a single-crystalline diamond substrate. The femtosecond laser irradiation energy level was optimized at 100?kHz repetition rate with a sub-500 femtosecond pulse duration. The morphology and topography of the microfluidic channel were characterized by a scanning electron microscope and an atomic force microscope. Raman spectroscopy indicated that the irradiated area was covered by graphitic materials. By comparing the cross-sectional profiles before/after removing the graphitic materials, it could be deduced that the microfluidic channel has an average depth of ~410?nm with periodical ripples perpendicular to the irradiation direction. This work proves the feasibility of using ultra-fast laser inscription technology to fabricate microfluidic channels on biocompatible diamond substrates, which offers a great potential for biomedical sensing applications.

Classification of Biomedical Signals using the Dynamics of the False Nearest Neighbours (DFNN) Algorithm

* This study was supported in part by the Natural Sciences and Engineering Research Council of Canada, and by the Gastrointestinal Motility Laboratory (University of Alberta Hospitals) in Edmonton, Alberta, Canada.

Multipurpose portable system for environmental, industrial, and medical applications

This dissertation is about the research carried on developing an MPS (Multipurpose Portable System) which consists of an instrument and many accessories. The instrument is portable, hand-held, and rechargeable battery operated, and it measures temperature, absorbance, and concentration of samples by using optical principles. The system also performs auxiliary functions like incubation and mixing. This system can be used in environmental, industrial, and medical applications. ^ Research emphasis is on system modularity, easy configuration, accuracy of measurements, power management schemes, reliability, low cost, computer interface, and networking. The instrument can send the data to a computer for data analysis and presentation, or to a printer. ^ This dissertation includes the presentation of a full working system. This involved integration of hardware and firmware for the micro-controller in assembly language, software in C and other application modules. ^ The instrument contains the Optics, Transimpedance Amplifiers, Voltage-to-Frequency Converters, LCD display, Lamp Driver, Battery Charger, Battery Manager, Timer, Interface Port, and Micro-controller. ^ The accessories are a Printer, Data Acquisition Adapter (to transfer the measurements to a computer via the Printer Port and expand the Analog/Digital conversion capability), Car Plug Adapter, and AC Transformer. This system has been fully evaluated for fault tolerance and the schemes will also be presented. ^

Stabilization of troponin I for applications in clinical chemistry and forensic medicine. Cardiac troponin I: A time of death marker

Cardiac troponin I (cTnI) is one of the most useful serum marker test for the determination of myocardial infarction (MI). The first commercial assay of cTnI was released for medical use in the United States and Europe in 1995. It is useful in determining if the source of chest pains, whose etiology may be unknown, is cardiac related. Cardiac TnI is released into the bloodstream following myocardial necrosis (cardiac cell death) as a result of an infarct (heart attack). In this research project the utility of cardiac troponin I as a potential marker for the determination of time of death is investigated. The approach of this research is not to investigate cTnI degradation in serum/plasma, but to investigate the proteolytic breakdown of this protein in heart tissue postmortem. If our hypothesis is correct, cTnI might show a distinctive temporal degradation profile after death. This temporal profile may have potential as a time of death marker in forensic medicine. The field of time of death markers has lagged behind the great advances in technology since the late 1850's. Today medical examiners are using rudimentary time of death markers that offer limited reliability in the medico-legal arena. Cardiac TnI must be stabilized in order to avoid further degradation by proteases in the extraction process. Chemically derivatized magnetic microparticles were covalently linked to anti-cTnI monoclonal antibodies. A charge capture approach was also used to eliminate the antibody from the magnetic microparticles given the negative charge on the microparticles. The magnetic microparticles were used to extract cTnI from heart tissue homogenate for further bio-analysis. Cardiac TnI was eluted from the beads with a buffer and analyzed. This technique exploits banding pattern on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by a western blot transfer to polyvinylidene fluoride (PVDF) paper for probing with anti-cTnI monoclonal antibodies. Bovine hearts were used as a model to establish the relationship of time of death and concentration/band-pattern given its homology to human cardiac TnI. The final concept feasibility was tested with human heart samples from cadavers with known time of death. ^

A research platform for artificial neural networks with applications in pediatric epilepsy

This dissertation established a state-of-the-art programming tool for designing and training artificial neural networks (ANNs) and showed its applicability to brain research. The developed tool, called NeuralStudio, allows users without programming skills to conduct studies based on ANNs in a powerful and very user friendly interface. A series of unique features has been implemented in NeuralStudio, such as ROC analysis, cross-validation, network averaging, topology optimization, and optimization of the activation function’s slopes. It also included a Support Vector Machines module for comparison purposes. Once the tool was fully developed, it was applied to two studies in brain research. In the first study, the goal was to create and train an ANN to detect epileptic seizures from subdural EEG. This analysis involved extracting features from the spectral power in the gamma frequencies. In the second application, a unique method was devised to link EEG recordings to epileptic and nonepileptic subjects. The contribution of this method consisted of developing a descriptor matrix that can be used to represent any EEG file regarding its duration and the number of electrodes. The first study showed that the inter-electrode mean of the spectral power in the gamma frequencies and its duration above a specific threshold performs better than the other frequencies in seizure detection, exhibiting an accuracy of 95.90%, a sensitivity of 92.59%, and a specificity of 96.84%. The second study yielded that Hjorth’s parameter activity is sufficient to accurately relate EEG to epileptic and non-epileptic subjects. After testing, accuracy, sensitivity and specificity of the classifier were all above 0.9667. Statistical tests measured the superiority of activity at over 99.99 % certainty. It was demonstrated that (1) the spectral power in the gamma frequencies is highly effective in locating seizures from EEG and (2) activity can be used to link EEG recordings to epileptic and non-epileptic subjects. These two studies required high computational load and could be addressed thanks to NeuralStudio. From a medical perspective, both methods proved the merits of NeuralStudio in brain research applications. For its outstanding features, NeuralStudio has been recently awarded a patent (US patent No. 7502763).

Hydroxyapatite-nanotube composites and coatings for orthopedic applications

Hydroxyapatite (HA) has received wide attention in orthopedics, due to its biocompatibility and osseointegration ability. Despite these advantages, the brittle nature and low fracture toughness of HA often results in rapid wear and premature fracture of implant. Hence, there is a need to improve the fracture toughness and wear resistance of HA without compromising its biocompatibility. ^ The aim of the current research is to explore the potential of nanotubes as reinforcement to HA for orthopedic implants. HA- 4 wt.% carbon nanotube (CNT) composites and coatings are synthesized by spark plasma sintering and plasma spraying respectively, and investigated for their mechanical, tribological and biological behavior. CNT reinforcement improves the fracture toughness (>90%) and wear resistance (>66%) of HA for coating and free standing composites. CNTs have demonstrated a positive influence on the proliferation, differentiation and matrix mineralization activities of osteoblasts, during in-vitro biocompatibility studies. In-vivo exposure of HA-CNT coated titanium implant in animal model (rat) shows excellent histocompatibility and neobone integration on the implant surface. The improved osseointegration due to presence of CNTs in HA is quantified by the adhesion strength measurement of single osteoblast using nano-scratch technique. ^ Considering the ongoing debate about cytotoxicity of CNTs in the literature, the present study also suggests boron nitride nanotube (BNNT) as an alternative reinforcement. BNNT with the similar elastic modulus and strength as CNT, were added to HA. The resulting composite having 4 wt.% BNNTs improved the fracture toughness (∼85%) and wear resistance (∼75%) of HA in the similar range as HA-CNT composites. BNNTs were found to be non-cytotoxic for osteoblasts and macrophages. In-vitro evaluation shows positive role of BNNT in osteoblast proliferation and viability. Apatite formability of BNNT surface in ∼4 days establishes its osseointegration ability.^

Vacuum brazing of alumina ceramic to titanium for biomedical implants using pure gold as the filler metal

One of the many promising applications of metal/ceramic joining is in biomedical implantable devices. This work is focused on vacuum brazing of C.P titanium to 96% alumina ceramic using pure gold as the filler metal. A novel method of brazing is developed where resistance heating of C.P titanium is done inside a thermal evaporator using a Ta heating electrode. The design of electrode is optimized using Ansys resistive heating simulations. The materials chosen in this study are biocompatible and have prior history in implantable devices approved by FDA. This research is part of Boston Retinal implant project to make a biocompatible implantable device (www.bostonretina.org). ^ Pure gold braze has been used in the construction of single terminal feedthrough in low density hermetic packages utilizing a single platinum pin brazed to an alumina or sapphire ceramic donut (brazed to a titanium case or ferrule for many years in implantable pacemakers. Pure gold (99.99%) brazing of 96% alumina ceramic with CP titanium has been performed and evaluated in this dissertation. Brazing has been done by using electrical resistance heating. The 96% alumina ceramic disk was manufactured by high temperature cofired ceramic (HTCC) processing while the Ti ferrule and gold performs were purchased from outside. Hermetic joints having leak rate of the order of 1.6 × 10-8 atm-cc/ sec on a helium leak detector were measured. ^ Alumina ceramics made by HTCC processing were centreless grounded utilizing 800 grit diamond wheel to provide a smooth surface for sputtering of a thin film of Nb. Since pure alumina demonstrates no adhesion or wetting to gold, an adhesion layer must be used on the alumina surface. Niobium (Nb), Tantalum (Ta) and Tungsten (W) were chosen for evaluation since all are refractory (less dissolution into molten gold), all form stable oxides (necessary for adhesion to alumina) and all are readily thin film deposited as metals. Wetting studies are also performed to determine the wetting angle of pure gold to Ti, Ta, Nb and W substrates. Nano tribological scratch testing of thin film of Nb (which demonstrated the best wetting properties towards gold) on polished 96% alumina ceramic is performed to determine the adhesion strength of thin film to the substrate. The wetting studies also determined the thickness of the intermetallic compounds layers formed between Ti and gold, reaction microstructure and the dissolution of the metal into the molten gold.^

An assessment of novel biodegradable magnesium alloys for endovascular biomaterial applications

Magnesium alloys have been widely explored as potential biomaterials, but several limitations to using these materials have prevented their widespread use, such as uncontrollable degradation kinetics which alter their mechanical properties. In an attempt to further the applicability of magnesium and its alloys for biomedical purposes, two novel magnesium alloys Mg-Zn-Cu and Mg-Zn-Se were developed with the expectation of improving upon the unfavorable qualities shown by similar magnesium based materials that have previously been explored. The overall performance of these novel magnesium alloys has been assessesed in three distinct phases of research: 1) analysing the mechanical properties of the as-cast magnesium alloys, 2) evaluating the biocompatibility of the as-cast magnesium alloys through the use of in-vitro cellular studies, and 3) profiling the degradation kinetics of the as-cast magnesium alloys through the use of electrochemical potentiodynamic polarization techqnique as well as gravimetric weight-loss methods. As compared to currently available shape memory alloys and degradable as-cast alloys, these experimental alloys possess superior as-cast mechanical properties with elongation at failure values of 12% and 13% for the Mg-Zn-Se and Mg-Zn-Se alloys, respectively. This is substantially higher than other as-cast magnesium alloys that have elongation at failure values that range from 7-10%. Biocompatibility tests revealed that both the Mg-Zn-Se and Mg-Zn-Cu alloys exhibit low cytotoxicity levels which are suitable for biomaterial applications. Gravimetric and electrochemical testing was indicative of the weight loss and initial corrosion behavior of the alloys once immersed within a simulated body fluid. The development of these novel as-cast magnesium alloys provide an advancement to the field of degradable metallic materials, while experimental results indicate their potential as cost-effective medical devices.^

Acoustic Manipulation and Alignment of Particles for Applications in Separation, Micro-Templating, and Device Fabrication

This dissertation studies the manipulation of particles using acoustic stimulation for applications in microfluidics and templating of devices. The term particle is used here to denote any solid, liquid or gaseous material that has properties, which are distinct from the fluid in which it is suspended. Manipulation means to take over the movements of the particles and to position them in specified locations. Using devices, microfabricated out of silicon, the behavior of particles under the acoustic stimulation was studied with the main purpose of aligning the particles at either low-pressure zones, known as the nodes or high-pressure zones, known as anti-nodes. By aligning particles at the nodes in a flow system, these particles can be focused at the center or walls of a microchannel in order to ultimately separate them. These separations are of high scientific importance, especially in the biomedical domain, since acoustopheresis provides a unique approach to separate based on density and compressibility, unparalleled by other techniques. The study of controlling and aligning the particles in various geometries and configurations was successfully achieved by controlling the acoustic waves. Apart from their use in flow systems, a stationary suspended-particle device was developed to provide controllable light transmittance based on acoustic stimuli. Using a glass compartment and a carbon-particle suspension in an organic solvent, the device responded to acoustic stimulation by aligning the particles. The alignment of light-absorbing carbon particles afforded an increase in visible light transmittance as high as 84.5%, and it was controlled by adjusting the frequency and amplitude of the acoustic wave. The device also demonstrated alignment memory rendering it energy-efficient. A similar device for suspended-particles in a monomer enabled the development of electrically conductive films. These films were based on networks of conductive particles. Elastomers doped with conductive metal particles were rendered surface conductive at particle loadings as low as 1% by weight using acoustic focusing. The resulting films were flexible and had transparencies exceeding 80% in the visible spectrum (400-800 nm) These films had electrical bulk conductivities exceeding 50 S/cm.

Development of Swept Source Optical Coherence Tomography and Adaptive Optics Scanning Laser Ophthalmoscopy: Improved Imaging Speed and Handheld Applications

Optical coherence tomography (OCT) is a noninvasive three-dimensional interferometric imaging technique capable of achieving micrometer scale resolution. It is now a standard of care in ophthalmology, where it is used to improve the accuracy of early diagnosis, to better understand the source of pathophysiology, and to monitor disease progression and response to therapy. In particular, retinal imaging has been the most prevalent clinical application of OCT, but researchers and companies alike are developing OCT systems for cardiology, dermatology, dentistry, and many other medical and industrial applications.

Adaptive optics (AO) is a technique used to reduce monochromatic aberrations in optical instruments. It is used in astronomical telescopes, laser communications, high-power lasers, retinal imaging, optical fabrication and microscopy to improve system performance. Scanning laser ophthalmoscopy (SLO) is a noninvasive confocal imaging technique that produces high contrast two-dimensional retinal images. AO is combined with SLO (AOSLO) to compensate for the wavefront distortions caused by the optics of the eye, providing the ability to visualize the living retina with cellular resolution. AOSLO has shown great promise to advance the understanding of the etiology of retinal diseases on a cellular level.

Broadly, we endeavor to enhance the vision outcome of ophthalmic patients through improved diagnostics and personalized therapy. Toward this end, the objective of the work presented herein was the development of advanced techniques for increasing the imaging speed, reducing the form factor, and broadening the versatility of OCT and AOSLO. Despite our focus on applications in ophthalmology, the techniques developed could be applied to other medical and industrial applications. In this dissertation, a technique to quadruple the imaging speed of OCT was developed. This technique was demonstrated by imaging the retinas of healthy human subjects. A handheld, dual depth OCT system was developed. This system enabled sequential imaging of the anterior segment and retina of human eyes. Finally, handheld SLO/OCT systems were developed, culminating in the design of a handheld AOSLO system. This system has the potential to provide cellular level imaging of the human retina, resolving even the most densely packed foveal cones.

Biologically Inspired Design of Protein-Silica Hybrid Nanoparticles for Drug Delivery Applications

The design and application of effective drug carriers is a fundamental concern in the delivery of therapeutics for the treatment of cancer and other vexing health problems. Traditionally utilized chemotherapeutics are limited in efficacy due to poor bioavailability as a result of their size and solubility as well as significant deleterious effects to healthy tissue through their inability to preferentially target pathological cells and tissues, especially in treatment of cancer. Thus, a major effort in the development of nanoscopic drug delivery vehicles for cancer treatment has focused on exploiting the inherent differences in tumor physiology and limiting the exposure of drugs to non-tumorous tissue, which is commonly achieved by encapsulation of chemotherapeutics within macromolecular or supramolecular carriers that incorporate targeting ligands and that enable controlled release. The overall aim of this work is to engineer a hybrid nanomaterial system comprised of protein and silica and to characterize its potential as an encapsulating drug carrier. The synthesis of silica, an attractive nanomaterial component because it is both biocompatible as well as structurally and chemically stable, within this system is catalyzed by self-assembled elastin-like polypeptide (ELP) micelles that incorporate of a class of biologically-inspired, silica-promoting peptides, silaffins. Furthermore, this methodology produces near-monodisperse, hybrid inorganic/micellar materials under mild reaction conditions such as temperature, pH and solvent. This work studies this material system along three avenues: 1) proof-of-concept silicification (i.e. the formation and deposition of silica upon organic materials) of ELP micellar templates, 2) encapsulation and pH-triggered release of small, hydrophobic chemotherapeutics, and 3) selective silicification of templates to potentiate retention of peptide targeting ability.

Laser-Driven Ion Accelerators: State of the Art and Applications

Laser-plasma based accelerators of protons and heavier ions are a source of potential interest for several applications, including in the biomedical area. While the potential future use in cancer hadrontherapy acts as a strong aspirational motivation for this research field, radiobiology employing laser-driven ion bursts is alreadyan active field of research. Here we give a summary of the state of the art in laser driven ion acceleration, of the main challenges currently faced by the research inthis field and of some of the current and future strategies for overcoming them.