Dental and orthopaedic implants are currently the solutions of choice for teeth and joint replacements with success rates continually improving, but they still have undesirable failure rates in patients who are compromised by disease or age, and who in many cases are the ones most in need. The success of titanium (Ti) implants depends on their ability to osseointegrate with the surrounding bone and this, in turn, is greatly dependent on the surface characteristics of the device. Advancements in surface analysis and surface modification techniques have improved the biological performance of metallic implants by mimicking the hierarchical structure of bone associated with regular bone remodeling. In this process, damaged bone is resorbed by osteoclasts, which produce resorption lacunae containing high microroughness generated after mineral dissolution under the ruffled border, as well as superimposed nanoscale features created by the collagen fibers left at the surface. Indeed, increasing Ti surface roughness at the micro and sub-microscale level has been shown to increase osteoblast differentiation in vitro, increase bone-to-implant contact in vivo, and accelerate healing times clinically. Recently, the clinical application of surface nanomodification of implants has been evaluated. Still, most clinically-available devices remain smooth at the nanoscale and fundamental questions remain to be elucidated about the effect of nanoroughness on the initial response of osteoblast lineage cells. Another property that could be used to control osteoblast development and the process of osseointegration is the electrical surface charge of implants. The presence of endogenous electrical signals in bone has been implicated in the processes of bone remodeling and repair. The existence of these native signals has prompted the use of external electrical stimulation to enhance bone growth in cases of fractures with delayed union or nonunion, with several in vitro and in vivo reports confirming its beneficial effects on bone formation. However, the use of electrical stimulation on Ti implants to enhance osseointegration is less understood, in part because of the lack of in vitro models that truly represent the in vivo environment. In addition, an aspect that has not been thoroughly examined is the electrical implication of implant corrosion and its effect on the surrounding tissue. Implants are exposed to extreme conditions in the body such as high pH during inflammation, and cyclic loads. These circumstances may lead to corrosion events that generate large electrochemical currents and potentials, and may cause abnormal cell and tissue responses that could be partly responsible for complications such as aseptic loosening of implants. Consequently, Ti implants with tailored surface characteristics such as nanotopography and electrical polarization, could promote bone healing and osseointegration to ensure successful outcomes for patients by mimicking the biological environment of bone without the use of systemic drugs. The objective of this thesis is to understand how surface nanostructural and electrical characteristics of Ti and Ti alloy surfaces may affect osteoblast lineage cell response in vitro for normal tissue regeneration and repair. Our central hypothesis is that combined micro/nanostructured surfaces, as well as direct stimulation of Ti surfaces with fixed direct current (DC) potentials, can enhance osteoblast differentiation.

Stable single-unit recordings from the nervous system using microelectrode arrays can have significant implications for the treatment of a wide variety of sensory and movement disorders. However, the long-term performance of the implanted neural electrodes is compromised by the formation of glial scar around these devices, which is a typical consequence of the inflammatory tissue reaction to implantation-induced injury in the CNS. The glial scar is inhibitory to neurons and forms a barrier between the electrode and neurons in the surrounding brain tissue. Therefore, to maintain long-term recording stability, reactive gliosis and other inflammatory processes around the electrode need to be minimized. This work has succeeded in the development of neural electrode coatings that are capable of sustained release of anti-inflammatory agents while not adversely affecting the electrical performance of the electrodes. The effects of coating methods, initial drug loadings on release kinetics were investigated to optimize the coatings. The physical properties of the coatings and the bioactivity of released anti-inflammatory agents were characterized. The effect of the coatings on the electrical property of the electrodes was tested. Two candidate anti-inflammatory agents were screened by evaluating their anti-inflammatory potency in vitro. Finally, neural electrodes coated with the anti-inflammatory coatings were implanted into rat brains to assess the anti-inflammatory potential of the coatings in vivo. This work represents a promising approach to attenuate astroglial scar around the implanted silicon neural electrodes, and may provide a promising strategy to improve the long-term recording stability of silicon neural electrodes.

Biomimetic materials that recapitulate the complex mechanical and biochemical cues in load-bearing tissues are of significant interest in regenerative medicine and tissue engineering applications. Several investigators have endeavored to not only emulate the mechanical properties of the vasculature, but to also mimic the biologic responsiveness of the blood vessel in creating vascular substitutes. Previous studies in our lab generated the elastin-like protein polymer LysB10, which was designed with the capability of physical and chemical crosslinks, and was shown to display a range of elastomeric properties that more closely matched those of the native artery. While extensive validation of the mechanical properties of elastin-mimetic polymers has demonstrated their functionality in a number of tissue engineering applications, limited cell growth on the surfaces of the polymers has motivated further optimization for biological interaction. Recent biologically-inspired surface strategies have focused on functionalizing material surfaces with extracellular matrix molecules and bioactive motifs in order to encourage integrin-mediated cellular responses that trigger precise intracellular signaling processes, while limiting nonspecific biomaterial interactions. Consequently, this dissertation addresses three approaches to modulating cellular behavior on elastin-mimetic analogs with the goal of promoting vascular wall healing and tissue regeneration: genetic engineering of elastin-like protein polymers (ELPs) with cell-binding domains, biofunctionalization of elastin-like protein polymers via chemoselective ligation of bioactive ligands, and incorporation of matrix protein fibronectin for engineering of cell-seeded multilamellar collagen-reinforced elastin-like constructs. The synthesis of recombinant elastin-like protein polymers that integrate biologic functions of the extracellular matrix provides a novel design strategy for generating clinically durable vascular substitutes. Ultimately, the synthesis of model protein networks provides new insights into the relationship between molecular architecture, biomimetic ligand presentation, and associated cellular responses at the cell-material interface. Understanding how each of these design parameters affects cell response will contribute significantly to the rational engineering of bioactive materials. Potential applications for polymer blends with enhanced mechanical and biological properties include surface coatings on vascular grafts and stents, as well as composite materials for tissue engineered scaffolds and vascular substitutes.

Thanks to pioneering scientists and clinicians, prosthetic devices that are controlled by intra-cortical electrodes recording one's 'thoughts' are a reality today, and no longer merely in the realm of science fiction. However, widespread clinical use of implanted electrodes is hampered by a lack of reliability in chronic recordings, independent of the type of electrodes used. The dominant hypothesis has been that astroglial scar electrically impedes the electrodes. However, recent studies suggest that the impedance changes associated with the astroglial scar are not high enough to interfere significantly impair neural recordings. Furthermore, there is a time delay between when scar electrically stabilizes and when neural recordings fail (typically >1 month lag), suggesting that scar, per se, does not cause chronic recording unreliability. In this study, an alternative hypothesis was tested in a rat model, namely, that chronic inflammation surrounding microelectrodes causes a local neurodegenerative state. Chronic inflammation was varied in three ways: 1) stab wound control, 2) age-matched control, and 3) inter-shank spacing of a multishank electrode. The results of this study suggest that chronic inflammation, as indicated by activated microglia and reactive astrocytes, is correlated with local neurodegeneration, marked by neuron cell death and dendritic loss. Surprisingly, axonal pathology in the form of hyperphosphorylation of the protein Tau (the hallmark of many tauopathies, including Alzheimer's Disease) was also observed in the immediate vicinity of microelectrodes implanted for 16 weeks. Additionally, work is presented on a fast, non-invasive method to monitor the astrocytic response to intra-cortical electrodes using electrical impedance spectroscopy. This work provides a non-invasive monitoring tool for inflammation, albeit an indirect one, and fills a gap which has slowed the development of strategies to control the inflammatory tissue response surrounding microelectrodes and thereby improve the reliability of chronic neural recordings. The results of these experiments have significance for the field of neuroengineering, because a more accurate understanding of why recordings fail is integral to engineering reliable solutions for integrating brain tissue with microelectrode arrays.

CNPq / Este trabalho apresenta o estudo de um método para a determinação da posição e orientação de uma bobina implantável em relação à bobina transmissora localizada externamente ao paciente. No aspecto elétrico, conhecer a posição e orientação da bobina implantada permite um maior domínio sobre o posicionamento do enlace e, consequentemente, das características de eficiência e potência entregue ao secundário, i.e. ao IMD. Já no aspecto clínico, detectar e determinar a posição da bobina implantável e, se possível, do IMD, pode auxiliar na determinação de possíveis movimentações do dispositivo na região implantada que podem influenciar o seu desempenho. Neste sentido, realizou-se análises teóricas a cerca da indutância mútua, do coeficiente de acoplamento magnético e de sistemas de transferência de energia sem fio (WPT) a duas bobinas. Por meio do modelo matemático implementado no software Matlab e o projeto experimental de sistemas de WPT a duas bobinas, avaliou-se a influência de desalinhamentos laterais e angulares sobre o acoplamento magnético. A partir das características observadas, descreveu-se os procedimentos necessários para estimar a posição e orientação relativa da bobina do dispositivo implantável apenas mensurando os parâmetros elétricos do primário. Em uma avaliação preliminar, por meio de testes virtuais, observou-se um erro médio e incerteza padrão na determinação da posição relativa de 2,4 mm e 1,1 mm, respectivamente, que se comparada às dimensões das bobinas (40 mm de diâmetro para bobina externa e 5,5 mm para a bobina implantável) indicam uma exatidão adequada. Para a determinação do ângulo relativo o método também apresentou resultados promissores, uma vez que o erro médio foi de 7º e a incerteza padrão obtida de 8,2º. Desta forma, o método estudado possibilita o desenvolvimento de equipamentos para determinação da posição e orientação relativa de uma bobina implantável mensurando apenas a corrente no primário, sem a necessidade de circuitos adicionais no IMD ou a utilização de equipamentos de imagem médicos. / This paper presents the study of a method for determining the implanted coil position and orientation relative to the transmitter coil externally located to the patient. In the electrical aspect, knowing the implanted coil position and orientation allows greater control over the placement of the link and thus the efficiency of features and power delivered to the secondary, i.e. the IMD. In the clinical aspect, detect and determine the implantable coil position, if possible, the IMD can assist in determining possible device movements in the implanted area that can influence their performance. In this sense, a theoretical analysis about the mutual inductance, the magnetic coupling coefficient and two coils wireless power transfer (WPT) systems was realized. Through mathematical model implemented in Matlab and experimental design of two coil WPT systems, the influence of lateral and angular misalignment on the magnetic coupling was assessed. From the observed characteristics, was described the necessary procedures to estimate the relative position and orientation of the implantable device coil only measuring the primary electrical parameters. In a preliminary evaluation, through virtual testing, there was an average error and standard deviation in determining the relative position of 2.4 mm and 1.1 mm, respectively, compared to the dimensions of the coils (40 mm diameter to external coil and 5.5 mm for implantable coil) indicate adequate accuracy. To the relative angle the method also yielded promising results, since the average error was 7° and the standard deviation obtained 8.2°. Thus, the method studied enables the development of equipment for determining the implanted coil relative position and orientation measuring only the primary current without the need for additional circuitry in IMD or the use of medical imaging equipment.