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The purpose of this master’s thesis was to, by the use of nanotechnology, improve material properties of the biomedical polymer Optim™, used as the insulation of pacemaker leads. Improved material properties are required to reduce the extent of fibrous encapsulation of the leads. Today, laser ablation is used to be able to remove the pacemaker lead because of the fibrous tissue, which can cause the lead to adhere to vascular structures. Consequently, the laser ablation results in risks of damaging cardiovascular structures. Moreover, improved material properties are needed to reduce the friction at the surface and enhance the wear resistance. Large wearing occurs between the lead and the titanium pacemaker shell as well as lead against lead and the wearing can result in a damaged insulation, which in turn might result in removal of the device. To achieve these improved material properties a hierarchically micro- and nanostructured and superhydrophobic surface was fabricated and to enhance the wear resistance, nanocomposites with 1 wt % and 5 wt % added hydroxyapatite nanoparticles were fabricated. The surface structures were fabricated via hot embossing and plasma treatment and were characterised with atomic force microscopy, environment scanning electron microscopy and with contact angle measurements. To evaluate the biological response to the surfaces, adsorption of radioisotope labelled human serum albumin proteins and adhesion of the human fibroblast cell line MRC-5 were studied. The results show that a superhydrophobic surface, with contact angle as high as 170.0 ± 0.4 °, can be fabricated via hierarchically micro- and nanostructures on an Optim™ surface. The fabricated surface is more protein resistant and cell resistant compared to a smooth surface. The nanocomposites fabricated, especially the one with 5 wt % nanoparticles added, show an enhanced abrasive wear resistance compared to Optim™ without added nanoparticles. In conclusion, a hierarchically micro- and nanostructured superhydrophobic surface of the pacemaker lead seems promising for reducing the extent of fibrous encapsulation and by fabricating a nanocomposite, the abrasive wear damage of the lead insulation can be reduced.

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Cell-based therapeutic strategies are becoming increasingly popular in treating many diseases that historically have been challenging to treat. Strategies involving injections of healthy cells into damaged tissues have benefits over current transplantation and drug strategies because they eliminate the need for long term use of immunosuppressing drugs and reduce the issues of limited availabilities of tissue donors. However, there are still major issues with current cell-based strategies, including limited cell engraftment and retention at the site of injury. Recent studies show that a very limited number of cells are retained at the site of injection, but therapeutic effects as still observed. Examples include improved cardiac function when cells are used to treat myocardial infarctions, improvements are observed for treating retinal degenerative diseases, and increased bone formation in bone regeneration strategies, as well as improvements for many other disease treatments. Encapsulating cells in hydrogel microcapsules has been shown to increase cell retention significantly, as well as protect the cells from any unwanted, negative immune responses from the host. However, previous studies showed that long-term retention of encapsulated cells is still reduced due to cell escape or egress from the hydrogel microcapsules. Once escaped, these cells are free floating, and surrounding vasculature and blood flow clear the cells from the site quickly. The proposed strategy of reducing cellular clearance is through modifying the encapsulation material with cell binding domains, specifically by adding a peptide sequence of arginine, glycine, and aspartate (RGD). These binding sites allow the cells to adhere to the outside of the microcapsules after they have escaped. Attachment to the microcapsules means the egressed cells are not free floating and therefore will not be cleared away from the site of injury as easily, therefore leading to long-term retention at the site of injury. Long-term retention is believed to increase efficacy of these cell-based treatments. Cellular attachment to hydrogel microcapsules was investigated by encapsulating cells in regular agarose and in RGD-modified agarose. Encapsulation was conducted using a microfluidic device to create uniform, monodisperse agarose microcapsules containing cells. These encapsulated cells were then studied using timepoint fluorescence microscopy to determine cell viability, microcapsule occupancy, cell escape from microcapsules and cellular adhesion onto the microcapsules. These quantities were assessed at three timepoints after encapsulation - 2 h, 24 h, and 48 h - to investigate whether cell behaviour was changing with time. Different environmental conditions were investigated as well, to imitate different cellular environments that may affect cell adhesion to a material. Samples were studied in cell culture treated dishes as well as poly(2-hydroxyethyl methacrylate) (pHEMA) coated dishes to simulate environments in which cells can adhere to surrounding surfaces, and environments in which adhesion is inhibited. The results presented here show that RGD-modified encapsulation material does increase cell attachment to the outside of microcapsules. I show that this cellular behaviour occurs with multiple cell types, including therapeutically relevant cells such as explant derived cardiac stem cells, and human umbilical vein endothelial cells. Cells behave quite differently in regular, unmodified agarose, where almost no cell attachment is observed. I show that this novel biomaterial does not negatively impact viability of encapsulated cells, and can be used inside semi-automated, scalable microfluidic devices for cell encapsulation. The research presented here shows promise for eliminating some of the limitations currently observed in many cell-based therapeutic strategies and it is hypothesized that the use of this novel biomaterial for cell encapsulation will lead to increased therapeutic effects in vivo due to increasing cellular retention at the site of injury.

Due to their unique structure and flexible choice of materials, electrospun degradable and biocompatible polymer fibres are considered to be extremely suitable for biomedical applications such as tissue engineering and drug delivery, either on their own or integrated within composites. Conventional electrospun fibre composites are typically based on non-woven mats and therefore limited to simple-curved geometries (films, membranes, etc.). For aqueous composites such as hydrogels, the hydrophobicity of the materials sometimes prohibits fibres to be easily integrated or distributed in these composites. In this thesis, a review on the topic is firstly presented in Chapter 2, introducing and discussing engineering of electrospun fibre as well as their biomedical applications. In Chapter 3, electrospun polylactide (PLA) fibres reinforced poly(trimethylene carbonate) (PTMC) composites are prepared. The composites are loaded with both continuous and short PLA fibres, achieving significant mechanical enhancement and offering opportunities to produce composites conveniently using liquid formulations. Chapter 4 presents the development of shape memory polymer composites based on a combination of PLA fibres and a PTMC matrix. By loading different amounts of short fibres with different aspect ratios or by using plasticisers, the shape memory behaviour is modulated; and composites of more complex geometries are produced. In Chapter 5, PTMC-PLA fibre composites are made into drug release system. Dexamethasone-loaded PLA fibres are integrated into a PTMC matrix, showing sustained drug release and stimulating stem cell osteogenic differentiation. This concept gives promise to loading various drugs into photo-crosslinked structures without denaturation. In Chapter 6, electrospun PLA fibres are functionalized by amphiphilic block copolymer polylactide-block-poly[2-(dimethylamino)ethyl methacrylate] (PLA-b-PDMAEMA) for the development of carboxymethylcellulose composites hydrogels. Functionalization of PLA fibres not only allows for easy integration and dispersion into the hydrogel, but also enhances the interfacial bonding between fibre and hydrogel. In the last chapter (Chapter 7), some conclusions are drawn and future works are discussed.

Electrospinning has provided the opportunity to create extracellular matrix (ECM) mimicking scaffolds for the development of tissue-engineered constructs. Within Professor Kristen Cardinal’s Blood Vessel Mimic (BVM) Lab, at Cal Poly, there exists a constant demand for innovation and the expansion of polymer types and electrospinning capabilities for its BVM model. Along these lines, the BVM Lab has recently acquired two new electrospinning systems: the Spinbox, a commercially graded electrospinning system, and the Learn-By-Doing system, which was part of a recently completed thesis conducted by Jason Provol. Additionally, recently published literature has demonstrated polyvinyl alcohol (PVA) as a viable option for creating electrospun scaffolds in the nanometer range. These findings prompt interest in investigating this polymer type due to its potential for producing extremely thin fiber diameters. Therefore, the overall objective of this thesis was to enhance the electrospinning capabilities of the BVM Lab through the utilization of the water-soluble polymer, PVA and to comprehensively compare the three available electrospinning systems within the BVM Lab, for novel tissue engineering or classroom applications. The work performed in this thesis was structured around three main Aims. The first Aim of this thesis was to demonstrate the feasibility of using PVA to create flatsheet scaffolds using the Spinbox system. To achieve this, different PVA types with varying degrees of hydrolysis (DH) and molecular weight (MW) were spun to determine the most suitable PVA formulation. These experiments revealed that PVA with low DH and ultra-high MW was the most suitable for electrospinning. Subsequently, a formal Design of Experiments (DOE) was conducted to determine an effective parameter combination for Spinbox flatsheets. The DOE yielded a parameter combination with a voltage of 27 kV, a flow rate of 0.50 ml/hr, a gap distance of 17 cm, and a weight percentage of 10%. The selection of a PVA formulation with appropriate parameters in Aim 1 established the groundwork for accomplishing the objectives of Aim 2. Aim 2 sought to extend PVA’s electrospinning utility to other collector geometries across all three of the BVM lab’s electrospinning systems, while also comparing the usability, safety, and adjustability of each system relative to one another. This was the first time all 3 systems were directly compared. The results from Aim 2 demonstrated the reproducibility of tubular scaffolds on both the Custom and Spinbox systems, featuring nanoscale fibrous scaffolds, as well as on the LBD system with flatsheets. Furthermore, a qualitative comparison of the systems indicated that the Spinbox exhibited the highest degree of adjustability and safety among the electrospinners, albeit with the lowest relative degree of usability. Conversely, the LBD system demonstrated the highest usability or intuitiveness, while also being the most hazardous and least adjustable of the systems. The Custom system ranked in the middle for all three metrics. Finally, the successful creation of tubular PVA scaffolds led to Aim 3 of this thesis, which focused on evaluating the potential of PVA scaffolds in a bioreactor environment for research applications and devising an accessible classroom PVA protocol for teaching applications. To accomplish this final aim, the scaffolds produced in Aim 2 were characterized and evaluated based on their solubility in cell-media. Additionally, methods for enhancing water-resistance through methanol cross-linking were explored and assessed. The results indicated that cross-linking PVA with methanol could enhance water resistance, but additional treatment would be necessary for PVA to serve as a standalone vascular scaffold in BVMs. However, a PVA Lab protocol was successfully developed to facilitate classroom education, providing a tangible and immediately impactful outcome of this thesis.

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