Today there is an increasing clinical demand and expectation of patients for biomaterials, which underscores the importance of discovering the correlations between biomaterials and biological systems, especially blood. When an artificial material makes contact with blood, the first event is a rapid adsorption of plasma protein on the material surface, on top of which the innate immune system is triggered, with potentially detrimental consequences. The work presented in this thesis, reported in four papers, was designed to investigate complications associated with (a) biomaterial-induced immune systems, including activation mechanisms and crosstalk between cascades on the biomaterial surface, and with (b) clinical investigations. In Paper I and Paper II, a series of studies led to the development of a direct prediction of the subsequent biological events based on the pattern of initially bound proteins. A reciprocal relationship was demonstrated between activation of the contact system and the complement system when they were induced on artificial material surfaces. Based on these studies, a robust and simple method for biocompatibility testing was proposed and validated, yielding high specificity and sensitivity when compared to today’s gold standard. Paper III investigated biomaterial-induced activation of complement and leukocytes in dialysis treatment-related conditions. The results suggested that citrate is more biocompatible than the conventionally used acetate. This reduction in activation could be further enhanced with higher citrate concentrations, suggesting that dialysis fluid containing citrate is a promising alternative to acetate dialysis fluid. Paper IV investigated complement initiation mechanisms with clinical implications. An experimental system was set up to revisit the initiation of the complement alternative pathway, and correlations were found between chaotropic or nucleophilic agents and iC3 generation under physiologically relevant conditions. A clinical study of hepatic encephalopathy patients indicated a direct correlation between elevated plasma ammonia and iC3 formation, as well as with complement activation in vivo.  Taken together, these studies have provided a model for a robust biomaterial test and have investigated biomaterial-induced complications in the fluid phase in clinically related conditions; furthermore, the basic mechanisms of complement activation have been dissected in relation to disease symptoms. Keywords: Complement system, contact system, blood, biomaterials, biocompatibility, in vitro screening, iC3, dialysis

The goal for this thesis was to apply electrospun biomimetic coatings on implantable glucose biosensors and test their efficacy as mass-transport limiting and tissue engineering membranes, with special focus on achieving reliable and long sensing life-time for biosensors when implanted in the body. The 3D structure of electrospun membranes provides the unique combination of extensively interconnected pores, large pore volumes and mechanical strength, which are anticipated to improving sensor sensitivity. Their structure also mimics the 3D architecture of natural extracellular matrix (ECM), which is exploited to engineer tissue responses to implants. A versatile vertical electrospinning setup was built in our workshop and used to electrospin single polymer - Selectophore™ polyurethane (PU) and two polymer (coaxial) – PU and gelatin (Ge) fibre membranes. Extensive studies involving optimization of electrospinning parameters (namely solvents, polymer solution concentration, applied electric potential, polymer solution feed flow rate, distance between spinneret and collector) were carried out to obtain electrospun membranes having tailorable fibre diameters, pore sizes and thickness. The morphology (scanning electron microscopy (SEM) and optical microscopy), fibre diameter (SEM), porosity (bubble point and gravimetry methods), hydrophilicity (contact angle), solute diffusion (biodialyzer) and uniaxial mechanical properties (tensile tester) were used to characterize certain shortlisted electrospun membranes. Static and dynamic collector configurations for electrospinning fibres directly on sensor surface were optimized of which the dynamic collections system helped achieve snugly fit membranes of uniform thickness on the entire surface of the sensor. The biocompatibility and the in vivo functional efficacy of electrospun membranes off and on glucose biosensors were evaluated in rat subcutaneous implantation model. Linear increase in thickness of electrospun membranes with increasing electrospinning time was observed. Further, the smaller the fibre diameter, smaller was the pore size and higher was the fibre density (predicted), the hydrophilicity and the mechanical strength. Very thin membranes showed zero-order (Fickian diffusion exponent ‘n’ ~ 1) permeability for glucose transport. Increasing membrane thickness lowered ‘n’ value through non-Fickian towards Fickian (‘n’ = 0.5) diffusion. Thin electrospun PU membranes (~10 μm thick) did not affect, while thicknesses between 20 and 140 μm all decreased sensitivity of glucose biosensor by about 20%. PU core - Ge shell coaxial fibre membranes caused decrease in ex vivo sensitivity by up to 40%. The membranes with sub-micron to micron sized pore sizes functioned as mass-transport limiting membranes; but were not permeable to host cells when implanted in the body. However, PU-Ge coaxial fibre membranes, having <2 μm pore sizes, were infiltrated with fibroblasts and deposition of collagen in their pores. Such tissue response prevented the formation of dense fibrous capsule around the implants, which helped improve the in vivo sensor sensitivity. To conclude, this study demonstrated that electrospun membrane having tailorable fibre diameters, porosity and thickness, while having mechanical strength similar to the natural soft tissues can be spun directly on sensor surfaces. The membranes can function as mass-transport limiting membranes, while causing minimal or no effect on sensor sensitivity. With the added bioactive Ge surfaces, evidence from this study indicates that reliable long-term in vivo sensor function can be achieved.

Cardiovascular disease is the leading cause of death in the United States with approximately 49% of the cardiovascular related deaths attributed to coronary heart disease (CHD). CHD is the accumulation of plaque resulting in the narrowing of the vessel lumen and a decrease in blood flow to the downstream heart muscle. In order to restore blood flow, arterial by-pass procedures can be undertaken. However, the patient's own arteries/veins may not be suitable for use as a vessel replacement, and synthetic grafts lack the compliancy and durability needed for these small diameter locations (<5 mm). Therefore, the goal of this research is to develop a nanofibrous material that can be used in vascular applications such as this. In this study, we fabricate coaxial electrospun nanofibers with gelatin in the shell and polyvinyl alcohol (PVA) in the core using 1 Gelatin: 1 PVA and 3 Gelatin: 1 PVA mass ratios. Gelatin, derived from collagen, is highly bioactive while PVA, a synthetic polymer, has appealing mechanical properties. Therefore, by combining these materials in a core-shell structure, we hypothesize that the resulting nanofibers will have enhanced mechanical properties, cellular growth and migration, as well as minimal platelet deposition and activation compared to scaffolds composed solely of gelatin or PVA. First, the coaxial scaffolds exhibited an enhanced Young's modulus and ultimate strength compared to scaffolds composed of PVA or gelatin alone. Endothelial cells had high proliferation and migration on the coaxial electrospun scaffolds with higher migration seen on the stiffer, coaxial scaffolds. The smooth muscle cells had less proliferation and lower migration rates on the coaxial scaffolds than the endothelial cells. Using a modified prothrombinase assay, the coaxial scaffolds had minimal platelet activation. Lastly, when pre-seeding the coaxial scaffolds with endothelial cells or smooth muscle cells, the platelet deposition decreased in comparison to platelet deposition with no cell pre-seeding. Overall, the 1 Gel: 1 PVA coaxial scaffolds promoted endothelial cell growth and migration, minimized smooth muscle cell growth and migration, and had minimal platelet activation. Therefore, the 1 Gel: 1 PVA coaxial nanofibers are an intriguing material for use in vascular applications.

No description available.

The purpose of this research was to investigate the surface modifications that take place during the machining of NiTi SMA and Ti-6Al-4V with micro-EDM. This was done by creating an array of blind holes and micro-patterns on both work-pieces. To analyze the machined surface and investigate the results, scanning electron microscope (SEM), energy dispersive X- ray spectroscopy (EDS) and X-ray diffraction (XRD) techniques were employed. In addition, the effects of various operating parameters on the machining performance was studied to identify the optimum parameters for micro-EDM of NiTi SMA and Ti-6Al-4V. Recently, aerospace and biomedical industries have placed a high demand on nonconventional machining processes, which can be used to machine high strength and hardto- cut materials such as Titanium alloys, Shape Memory Alloys (SMA) and Super Alloys. Electrical Discharge Machining (EDM) is one of the non-traditional technologies that remove materials from the workpiece through a series of electrical sparks that occur between the workpiece and cutting tool with the presence of dielectric liquid. Obtaining smooth and defect-free surfaces on both workpieces was one of the challenges due to the re-solidified debris on the machined surface. The experimental results showed that there was significant amount of re-casting and formation of resolidification of debris on the Ti surface after machining. On the other hand, the surface generated in NiTi SMA were comparatively smoother with lesser amount of resolidified debris on the surface. By analyzing the results from XRD and EDS, some elements of electrode and dielectric materials such as Tungsten, Carbon and Oxygen were observed on NiTi and Ti surface after machining. In the study of effect of operating parameters, it was found that the voltage, capacitance and tool rotational speed had significant effect on machining time. The machining time was reduced by increasing the voltage, capacitance and tool rotational speed. The machining time was found to be comparatively higher for machining NiTi SMA than Ti alloy. Comparing all the parameters, the voltage of 60 V, capacitance of 1000 PF, and tool rotational speed of 3500 RPM were selected as optimum parameters for this study. Although signs of tool electrode wear and debris particles on the machined surface were observed for both workpieces during the micro-EDM process, Ti alloy and NiTi SMA could be machined successfully using the micro-EDM process.

Low temperature co-fired ceramic (LTCC) electronic packaging materials are applied for their electrical and mechanical properties, high reliability, chemical stability and ease of fabrication. Three dimensional features can also be prepared allowing integration of microfluidic channels and cavities inside LTCC modules. Mechanical, optical, electrical, microfluidic functions have been realized in single LTCC modules. For these reasons LTCC is attractive for biomedical microfluidics and Lab-on-a-Chip systems. However, commercial LTCC systems, optimized for microelectrics applications, have unknown cytocompatibility, and are not compatible with common surface functionalization chemistries. The first goal of this work is to develop biocompatible LTCC materials for biomedical applications. In the current work, two different biocompatible LTCC substrate materials are conceived, formulated and evaluated. Both materials are based from well-known and widely utilized biocompatible materials. The biocompatibilities of the developed LTCC materials for in-vitro applications are studied by cytotoxicity assays, including culturing endothelial cells (EC) both in LTCC leachate and directly on the LTCC substrates. The results demonstrate the developed LTCC materials are biocompatible for in-vitro biological applications involving EC. The second goal of this work is to develop functional capabilities in LTCC microfluidic systems suitable for in-vitro and biomedical applications. One proposed application is the evaluation of oxygen tension and oxidative stress in perfusion cell culture and bioreactors. A Clark-type oxygen sensor is successfully integrated with LTCC technique in this work. In the current work, a solid state proton conductive electrolyte is used to integrate an oxygen sensor into the LTCC. The measurement of oxygen concentration in Clark-type oxygen sensor is based on the electrochemical reaction between working electrode and counter electrode. Cyclic voltammetry and chronoamperometry are measured to determine the electrochemical properties of oxygen reduction in the LTCC based oxygen sensor. The reduction current showed a linear relationship with oxygen concentration. In addition, LTCC sensor exhibits rapid response and sensitivity in the physiological range 1─9 mg/L. The fabricated devices have the capabilities to regulate oxygen supply and determination of local dissolved oxygen concentration in the proposed applications including perfusion cell culture and biological assays.

Note: / as hip and knee prosthesis, orthopaedic fixations and coronary stents. The definition of a material's biocompatibility necessitates meeting a number of criteria, including high corrosion resistance and desirable interactions of the material's surface with biological species, such as cells, platelets, and serum proteins. SSs offer acceptable resistance to uniform (general) corrosion when used as materials of construction in sorne industrial applications, which is due to the formation of a thin passive oxide film on their surface. [...] / Les aciers inoxydables (AI) 316-L sont fréquemment utilisés dans le domaine biomédical. Par exemple, nous les retrouvons dans les prothèses de hanche et de genou, dans les fixatures orthopédiques et dans les prothèse vasculaires. Pour qu'un matériel soit biocompatible, il doit avoir une résistence élevée à la corrosion. De plus, la surface du matériel doit avoir des intéractions favorables avec les différentes espèces biologiques c'est-à-dire les cellules.[...]

Mica based glass - ceramics have been produced by subjecting the glasses in the SiO2 , Al2O3 , CaO , MgO, K2O , and F system to a controlled heat treatment called crystallization. TiO2 was added into the batch in the amount of 1 wt% of the glass as nucleating agent. B2O3 additions in the amounts of 1, 2, 4 and 8 wt% of the glass have been made in the batch to see and evaluate the effects of B2O3 additions on the texture of the mica glass ceramics. Crystallization was accomplished in two steps, nucleation and crystal growth. Nucleation temperature was 650 &amp / #61616 / C. Crystal growth temperatures were 850 and 1000 &amp / #61616 / C. The time for holding the specimens at the temperatures was 8 hours. The X-Ray diffraction analysis revealed that resultant glass ceramics possessed not only synthetic fluormica crystals called phlogopite which provide machinability, but also wollastonite crystals which provide biocompatibility. The scanning electron microscopy examinations have indicated that the amount and distribution of the crystalline phases varied as a function of B2O3 content and heat treatment schedule applied.

Chronic pulmonary disorders, marked by excessive extracellular matrix deposition (ECM) or fibrosis, are the most resistant to present clinical therapies resulting in prognoses of 50% life expectancy three years from diagnosis. Inadequacies of current treatments may be attributable to limitations in non-invasive therapeutic administration modalities. However, with the use of polyketal microparticles (PKMs), a novel drug delivery vehicle, a myriad of therapeutic schemes may be explored. Polyketals are a new polymeric family characterized by tissue biocompatibility, rapid hydrolysis, and benign degradation byproducts making it attuned for pulmonary applications. Potential treatments such as siRNA, oligo nucleotides, enzymes and other biomolecules can be encapsulated within PKMs and administered non-invasively via inhalation. For this study, we selected a model therapeutic peptide, Ac-SDKP, with established anti-fibrotic properties as the load for PKMs. For lung dysfunctions accompanied by fibrotic scarring, Ac-SDKP possesses promise in restoring the normal ECM framework. To assess PKMs viability as a pulmonary drug delivery vehicle three objectives were initially defined: 1) Synthesize particles possessing aerodynamic properties conducive for aerosolization 2) Optimization of the therapeutic load, Ac-SDKP, in PKMs to levels that will translate to clinical dosing concentrations, and 3) Determine the biocompatibility of the PKMs in the lung. Optimization of the Ac-SKDP loading within PKMs and size analysis revealed that a solid in oil in water double emulsion particle synthesis technique produced the most ideal microspheres. Based on previous reports, the loading efficiency attained, when locally dispensed, should reach clinical dosing requirements. Synthesized particles were compatible with aerosolization criteria; i.e., diameters below 3 μm and low polydispersities. In addition, we evaluated PKM tissue biocompatibility using a murine lung model. Examination of bronchoalveolar lavage fluid demonstrated only a slight inflammatory response to intratracheal particle injections of PKMs whereas PLGA, a commonly used biomaterial, elicited a significantly higher response. Histological assessment of the lungs following particle injection verified PKMs biocompatibility superiority. In conclusion, small-diameter PKMs are a suitable delivery system for pulmonary drug delivery, capable of delivering small peptide therapeutics and evading the local inflammatory response. The present work will enable expansion of therapeutic avenues capable of combating chronic lung disease.

The delivery of growth factors has been attempted for a number of different therapies. The approach of delivering therapeutic growth factors in a safe and efficient manner is difficult and certain criteria should be met. These criteria include: binding the appropriate growth factors, maintaining their bioactivity, and delivering these proteins with controllable release kinetics for an extended period of time. These criteria encompass a set of guidelines that hope to mimic in vivo biological events such as neovascularization. The central goal of this thesis is to meet these criteria by introducing a novel delivery strategy for growth factors using a biocompatible polycation and heparin. It was hypothesized that a polycation could interact with heparin to form a complex with the potential to deliver bioactive growth factors with an adaptable release. This hypothesis was tested by examining the release kinetics of bFGF from the complex and investigating whether the released bFGF maintained its bioactivity. The [polycation:heparin:bFGF] complex was formed by mixing the components in water, resulting in a precipitate. This precipitate was able to deliver bFGF with controllable release kinetics and the bioactivity of the released bFGF was higher than bolus bFGF and comparable to heparin stabilized bFGF. This system is expected to have the ability to bind and deliver numerous heparin-binding growth factors. In conclusion, the delivery system developed in this research provides a novel mechanism for controlled release of growth factors. This delivery strategy has met the criteria listed earlier and this research has laid the foundation for a successful delivery vehicle. Further, a biocompatible polycation was synthesized, which is a critical component of the delivery system. This polycation exhibited in vitro and in vivo biocompatibility that was orders of magnitude higher than existing polycations and has the potential to be very useful in a variety of biomedical applications. This design principle is also expected to serve as a platform for the synthesis of other biocompatible polycations.