Des matériaux sandwichs fabriqués sans colle époxy on été conçu pour réduire les contraintes mécaniques, ou “stress shielding”, entre l’os environnant et l’implant. Le titane (Ti) et le polyméthacrylate de méthyle (PMMA) sont les matériaux les plus utilisés dans les applications biomédicales, et on été choisi comme composants de base. Pour cela, on a élaboré des interfaces Ti/polymère dans lesquelles le métal et le polymère sont liés par une liaison covalente; cette couche de polymère permettra ultérieurement l’adhésion entre le métal et une feuille de polymère qui constituera le cœur du sandwich. Dans ce but, une stratégie en trois étapes permettant d’obtenir une fonctionnalisation de la surface du titane a été développé. Tout d’abord, la surface du Ti a été activée chimiquement; ensuite un initiateur de polymérisation y a été greffé de façon covalente. Enfin, la croissance des chaines polymères a été obtenue en utilisant une polymérisation par transfert d’atomes à partir de l’initiateur (SI-ATRP). Les sandwichs ont été préparés en insérant une feuille de polymère entre les deux feuilles de Ti recouvertes de polymère greffé et en pressant les trois composants à une température supérieure à celle de la transition vitreuse du polymère. / A procedure aimed at designing innovative epoxy resin-free sandwich materials (i.e., layered structure composed of two metal skin and a polymer core) able to reduce stress-shielding effect at the implant/bone interface was developed. For this purpose, titanium (Ti) and poly methymethacrilate (PMMA), the most extensively materials used for biomedical applications, were employed. In particular, surface-confined PMMA layers were proposed as adhesives to stick a PMMA foil (used as core of the structure) on the metallic Ti skin sheets exploiting the miscibility between the tethered polymer chains (previously grown on the Ti) and those of an adhering PMMA foil.To this purpose, a three steps strategy based on a suitable functionalization of Ti surface was developed. First of all, a chemical activation of Ti surface was performed. Then, a “grafting from” method was used to immobilize a polymerization initiator on the activated Ti surface. Finally, the polymer chains were grown from the initiator-modified surfaces using a surface initiation atom transfer radical polymerization (SI-ATRP). Biocompatible Ti/PMMA/Ti sandwiches were then prepared by hot-pressing, inserting between the two PMMA-coated Ti surfaces a thick PMMA foil.

Due to its strength, flexibility, and biocompatibility, spider silk is a highly appealing material for applications in the medical field. Unfortunately, natural spider silk is difficult to obtain in large quantities because spiders are territorial and cannibalistic, making them impractical to farm. Synthetic spider silk proteins produced by transgenic hosts such as bacteria and goats have made it possible to obtain the quantities of spider silk needed to study it more fully and to investigate its potential uses. The spider silk proteins produced in our laboratory do not have an optimal purification method to remove all of the non-biocompatible contaminants and have not previously been tested for their biocompatibility. The first focus of this dissertation was to create goat cells that can be used to create new goats. These new goats will produce proteins that can be purified more efficiently and more completely. The second focus of this dissertation was to perform biocompatibility tests on goat-derived spider silk proteins. Prior to performing any biocompatibility tests, a method was established for removing endotoxins – an impurity that causes an immune response in the body – from the proteins. This work has shed light on areas for improvement in the silk protein purification process and laid groundwork for the production of new goat-derived proteins. These steps will help make it possible for synthetic spider silk to progress further toward becoming a viable biomaterial.

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This work describes the use of microfluidic technology and biomaterials in cancer research by mimicking the extracellular matrix (ECM) and development of drug delivery system. Initially, biomaterials such as Gelatin methacryloyl (GelMA) and collagen type I were combined to create a hydrogel composite able to mimic both healthy and cancerous ECM. The impact of the tumor microenvironment was analyzed by using the hydrogel inside of a pressurized microfluidic device and by tracking the movement of gold nanoparticles (GNPs). The GNPs showed a decrease in diffusion coefficient of 77% when analyzed in cancerous conditions. This investigation was further explored by analyzing the diffusion of charged GNPs in the same system, while also tracking cellular uptake. An inverse correlation between diffusion and cellular uptake was obtained for charged GNPs in breast cancer cells. Due to the tunable properties and biocompatibility of GelMA, this hydrogel was also employed in the development of pH-responsive drug delivery systems. Since GelMA contains a gelatin backbone, two responsive polymers (Polymers A and B) were synthesized. Microspheres of ~40 μm were fabricated in flow focusing microfluidic devices. Polymer A microspheres displayed a swelling increase of 167% in pH 6.0, while polymer B spheres showed a 296% swelling in pH 10. Considering the unique properties of the tumor microenvironment such as leaky vasculature and acid pH environment, polymer A was selected to be used in the production of nanocarriers. The behavior of this polymer in acidic environment illustrated its potential applicability as drug delivery systems to the tumor area. Polymer A nanogels displayed a uniform size of 74 ± 7 nm. Lastly, GNPs were added to the solution of polymer A, leading to the fabrication of GNPs-loaded nanogels, presenting a homogenous distribution of gold particles inside nanogels. / Graduate / 2023-07-05

Nanocrystalline hydroxyapatite (HAp) powder of size 10-20 nm was synthesized applying microwave radiation using calcium nitrate tetrahydrate and sodium phosphate dibasic anhydrous as the starting materials. Microwave power of 600 W and Ca/P ratio of 1.66 in the starting chemicals served as the major factors in the synthesis of nanocrystalline HAp powder. Phase composition and evolution were studied using X-ray diffraction (XRD) technique. Morphology, agglomeration and particle-size of the synthesized powder were studied using Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) techniques. Energy Dispersive Spectrum (EDS) was used to determine the elemental composition of the powder. Thermal properties were investigated using Thermogravimetric (TG) and Differential Thermal Analysis (DTA) and, Fourier Transform Infrared Spectroscopy (FTIR). As-synthesized HAP and TiO2 powder was uniaxially compacted into cylindrical pellets at a pressure of 78.69 MPa and sintered at high temperature to examine the effects of sintering on nano powder particles, densification behavior, phase evolution and mechanical properties. Phase evolution was studied using XRD whereas microstructure evolution was studied by SEM. To determine the mechanical properties Vickers hardness and biaxial flexural strength tests were performed. Biodegradability and biomechanical strength of nano-HAp and TiO2 samples sintered at high temperature was assessed in Simulated Body Fluid (SBF) having ionic concentration as that of human plasma. Biodegradation and change in mechanical properties of the sintered samples when kept in SBF and maintained in a dynamic condition were studied in terms of weight loss, change in Vickers hardness and biaxial flexural strength as a function of time. Highly crystalline HAp powder was achieved after microwave synthesis with average particle size in the range of 10-20 nm which was further confirmed by HR-TEM and SEM. Calcination of the synthesized powder at 500[degrees]C for 2 h increased the average particle size to 21 nm. EDS confirmed the elemental composition of the powder. FTIR analysis showed the presence of phosphate band which confirmed the presence of HAp at high temperature. TG analysis showed 23% weight-loss upon heating up to 1200[degrees]C, contributed by the removal of adsorbed and possible lattice water, decarboxylation of HAp or condensation of HPO42- releasing water. HAp along with [Beta]NaCaPO4 and Na3Ca6(PO4)5 was observed at 950[degrees]C, 1100[degrees]C and 1200[degrees]C. Density of HAp samples continued increasing with the increase in temperature from 1100[degrees]C to 1250[degrees]C and sintered density of 2.88 g/cc was obtained at 1250[degrees]C. Hardness and Biaxial strength of the HAp samples increased with temperature and maximum hardness value of 249.53 [plus or minus] 3.98 HV and biaxial flexural strength of 52.07 [plus or minus] 4.96 MPa were observed for samples sintered at 1250[degrees]C. Biaxial strength and hardness of TiO2 samples increased with temperature. Maximum biaxial flexural strength of 125.5 [plus or minus] 11.07 MPa and maximum hardness of 643.27 [plus or minus] 7.96 HV were observed for the TiO2 sample sintered at 1500[degrees]C which was much more than that of sintered HAp samples. Decrease in mass, hardness and biaxial strength of HAp samples sintered at 1250[degrees]C and TiO2 samples sintered at 1400[degrees]C showed biodegradation in SBF, maintained in a dynamic state, as a function of time. Increase in mass was observed for the HAp samples in SBF during the fourth week.

The Tissue Engineering Research Lab at California Polytechnic State University, San Luis Obispo focuses on creating tissue-engineered blood vessel mimics (BVMs) for use in preclinical testing of vascular devices. These BVMs are composed of electrospun scaffolds made of an assortment of polymers that are seeded with different cell types. This integration of polymers with cells leads to the need for biocompatibility testing of the polymer scaffolds. Many of the lab’s newest scaffolds have not been fully characterized for biologic interactions. Therefore, the first aim of this thesis developed methods for in vitro cytotoxicity testing of polymers used in the fabrication of BVMs. This included cytotoxicity testing using direct contact and elution-based methods, along with fluorescent staining to visualize the scaffold effects on cells. The second aim of this thesis implemented the newly developed cytotoxicity protocols to evaluate the biocompatibility of existing polymers, ePTFE and PLGA, used in the tissue engineering lab. The results demonstrated that ePTFE and PLGA were noncytotoxic to cells. The third aim of this thesis evaluated the biocompatibility of novel polymers used to fabricate BVMs: PLGA with salt, PLLA, and PCL. Elution-based methods concluded that PLGA with salt, PLLA, and PCL were noncytotoxic to cells; however, the direct contact method illustrated PLGA with salt and PCL were mildly cytotoxic at 24 and 48 hours. Potential causes of this variability include the addition of salt to PLGA, dissolving PCL in dichloromethane, inadequate sample sizing, and the inherent differences between the test methods. Overall, this thesis developed and implemented methods to evaluate the biocompatibility of polymer scaffolds used in the BVM model, and found that ePTFE, PLGA, and PLLA scaffold materials were biocompatible and could be implemented in future BVM setups without concerns. Meanwhile, PLGA with salt and PCL’s toxicity was mild enough to urge future cytotoxicity testing on PLGA with salt and PCL before further use in the lab.

3D bioprinting is an emerging field with the potential to reform the process of organ transplantation. The ability to 3D print new organs and tissues would supplement the organ donor shortage and decrease the risk associated with organ rejection. One of the current areas of research focuses on printing cells using hydrogels composed of methacrylated compounds as a scaffolding. One of the chemical means of crosslinking the hydrogels is using the photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) to crosslink with light. The 3D bioprinter in the lab currently has an attachment for a 365nm lamp, however this is cytotoxic to cells. A 405nm laser was designed to mount on the hot tool of the BioAssemblyBot by Advanced Solutions and flash at a specific frequency when sent a signal from the bioprinter. This tool was then tested to determine effective flash frequencies for crosslinking hydrogels.

yes / Breast reconstruction is the opportunity that provides the chance of having breast after undergoing surgical removal of the breast tissue due to cancer-related surgery. However, this varies on the stage of the cancer diagnosis and the procedure undertaken. There are many regenerative medicine methods that provide several initiatives and direct solutions to problems such as the development of “bioactive tissue,” which can regenerate adipose tissues with similar normal functions and structures. There have been several studies which have previously explored for the improvement of breast reconstruction including different variations of biomaterials, different fabrication and processing techniques, cells as well as growth factors which enable bioengineers and tissue engineers to reconstruct a suitable breast for patients with breast cancer. Many factors such as shape, proper volume, mechanical properties have been studies but very scattered with not adequate solutions for existing patients worldwide. This review article aims to cover recent advances in biomaterials, which can be used for reconstruction of breasts as well as looking at the various factors that might lead to individuals needing reconstruction and the materials that are available. The focus would be to look at the various biomaterials that are available to use for reconstruction, their properties, and their structural integrity.

Cardiovascular diseases are currently the leading cause of death globally. Progression of the disease affects the composition and function of the heart and in many cases subsequently results in heart failure over time where a heart transplant is vital. Therefore, there is a need for medical treatments to stop the progression of the disease. Hydrogels as a biomaterial have been investigated for this purpose, but most known research to date has focused on their bioactive properties. Since a part of the disease progression is affected by the mechanical differences between myocardial tissue and the collagen the body replaces the loss of viable myocardium with after myocardial infarction, this thesis conducted a novel approach of comparing a thiol functionalized collagen hydrogel with a healthy left ventricle in terms of viscoelastic properties for tissue-bulking application. Swelling tests showed that the gel did not swell significantly over time during incubation in phosphate buffer and even if self-healing of the gel after subjection to ultrasound radiation could not be proven and previously used methods to obtain mechanical stiffness of a tissue (compression tests) could not be utilized for soft materials such as hydrogels, the material is of great interest as a candidate for tissue bulking purposes. The gel showed viscoelastic properties similar to the healthy left ventricle and was injectable, to be administrated in a minimally invasive manner, indicating that the material could act as a tissue-bulking agent. This project has developed a new approach to evaluating hydrogels as a biomaterial by comparing it to the viscoelastic characterization of the intended application tissue.

The field of implantology is centred around interfacial interactions with the surrounding bone tissue. Assessing the suitability of novel engineering materials as implants for clinical application follows a preliminary workflow that can be simplified into three main stages: (i) implant design, (ii) in vitro compatibility, and (iii) in vivo compatibility. This thesis is subdivided to mirror each of these three themes, with a specific focus on the multiscale features of the implant itself as well as appositional bone tissue. In Chapter 3, a biomimetic approach to generate porous metallic implants is presented, using preferential seeding in a 3D Voronoi tessellation to create struts within a porous scaffold that mirror the trabecular orientation in human bone tissue. In Chapter 4, cytocompatible succinate-alginate films are generated to promote the in vitro activity of osteoblast-like cells and endothelial cells using a methodology that could be replicated to coat the interior and exterior of porous metals. In Chapter 5, two types of porous implants with graded and uniform pore size are implanted into rabbit tibiae to characterize the biological process of osseointegration into porous scaffolds. In Chapter 6, these same scaffolds are probed with high-resolution 2D and 3D methods using scanning transmission electron microscopy (STEM) and the first-ever application of plasma focused ion beam (PFIB) serial sectioning to observe structural motifs in biomineralization at the implant interface in 3D. This thesis provides new knowledge, synthesis techniques, and development of characterization tools for bone-interfacing implants, specifically including a means to: (i) provide novel biomaterial design strategies for additive manufacturing; (ii) synthesize coatings that are compatible with additively manufactured surfaces; (iii) improve our understanding of mineralization process in newly formed bone, with the ultimate goal of improving the osseointegration of implants. / Thesis / Doctor of Philosophy (PhD) / Metallic implants are widely used in dental and orthopedic applications but can be prone to failure or incomplete integration with bone tissue due to a breakdown at the bone-implant interface as defined by clinical standards. In order to improve the ability of the implant to anchor itself into the surrounding bone tissue, it is possible to use novel three-dimensional (3D) printing approaches to produce porous metals with an increased area for direct bone-implant contact. This thesis examines strategies to design porous implants that better mimic the structure of human bone, possible coating materials to accelerate early bone growth at the implant interface, and the microscale-to-nanoscale origins of bone formation within the interior of porous materials.