In order to mimic the extracellular matrix for tissue engineering, recent research approaches often involve 3D printing or electrospinning of fibres to scaffolds as cell carrier material. Within this thesis, a micron fibre printing process, called melt electrospinning writing (MEW), combining both additive manufacturing and electrospinning, has been investigated and improved. Thus, a unique device was developed for accurate process control and manufacturing of high quality constructs. Thereby, different studies could be conducted in order to understand the electrohydrodynamic printing behaviour of different medically relevant thermoplastics as well as to characterise the influence of MEW on the resulting scaffold performance. For reproducible scaffold printing, a commonly occurring processing instability was investigated and defined as pulsing, or in extreme cases as long beading. Here, processing analysis could be performed with the aim to overcome those instabilities and prevent the resulting manufacturing issues. Two different biocompatible polymers were utilised for this study: poly(ε-caprolactone) (PCL) as the only material available for MEW until then and poly(2-ethyl-2-oxazoline) for the first time. A hypothesis including the dependency of pulsing regarding involved mass flows regulated by the feeding pressure and the electrical field strength could be presented. Further, a guide via fibre diameter quantification was established to assess and accomplish high quality printing of scaffolds for subsequent research tasks. By following a combined approach including small sized spinnerets, small flow rates and high field strengths, PCL fibres with submicron-sized fibre diameters (fØ = 817 ± 165 nm) were deposited to defined scaffolds. The resulting material characteristics could be investigated regarding molecular orientation and morphological aspects. Thereby, an alignment and isotropic crystallinity was observed that can be attributed to the distinct acceleration of the solidifying jet in the electrical field and by the collector uptake. Resulting submicron fibres formed accurate but mechanically sensitive structures requiring further preparation for a suitable use in cell biology. To overcome this handling issue, a coating procedure, by using hydrophilic and cross-linkable star-shaped molecules for preparing fibre adhesive but cell repellent collector surfaces, was used. Printing PCL fibre patterns below the critical translation speed (CTS) revealed the opportunity to manufacture sinusoidal shaped fibres analogously to those observed using purely viscous fluids falling on a moving belt. No significant influence of the high voltage field during MEW processing could be observed on the buckling phenomenon. A study on the sinusoidal geometry revealed increasing peak-to-peak values and decreasing wavelengths as a function of decreasing collector speeds sc between CTS > sc ≥ 2/3 CTS independent of feeding pressures. Resulting scaffolds printed at 100 %, 90 %, 80 % and 70 % of CTS exhibited significantly different tensile properties, foremost regarding Young’s moduli (E = 42 ± 7 MPa to 173 ± 22 MPa at 1 – 3 % strain). As known from literature, a changed morphology and mechanical environment can impact cell performance substantially leading to a new opportunity of tailoring TE scaffolds. Further, poly(L-lactide-co-ε-caprolactone-co-acryloyl carbonate) as well as poly(ε-caprolactone-co-acryloyl carbonate) (PCLAC) copolymers could be used for MEW printing. Those exhibit the opportunity for UV-initiated radical cross-linking in a post-processing step leading to significantly increased mechanical characteristics. Here, single fibres of the polymer composed of 90 mol.% CL and 10 mol.% AC showed a considerable maximum tensile strength of σmax = 53 ± 16 MPa. Furthermore, sinusoidal meanders made of PCLAC yielded a specific tensile stress-strain characteristic mimicking the qualitative behaviour of tendons or ligaments. Cell viability by L929 murine fibroblasts and live/dead staining with human mesenchymal stem cells revealed a promising biomaterial behaviour pointing out MEW printed PCLAC scaffolds as promising choice for medical repair of load-bearing soft tissue. Indeed, one apparent drawback, the small throughput similar to other AM methods, may still prevent MEW’s industrial application yet. However, ongoing research focusses on enlargement of manufacturing speed with the clear perspective of relevant improvement. Thereby, the utilisation of large spinneret sizes may enable printing of high volume rates, while downsizing the resulting fibre diameter via electrical field and mechanical stretching by the collector uptake. Using this approach, limitations of FDM by small nozzle sizes could be overcome. Thinking visionary, such printing devices could be placed in hospitals for patient-specific printing-on-demand therapies one day. Taking the evolved high deposition precision combined with the unique small fibre diameter sizes into account, technical processing of high performance membranes, filters or functional surface finishes also stands to reason. / Um biomimetische extrazelluläre Matrices für das Tissue Engineering herzustellen, bedienen sich aktuelle Forschungsansätze oftmals der Produktion von Faser-Konstrukten durch additive Fertigung oder Elektrospinn-Verfahren. Das sogenannte Melt Electrospinning Writing (MEW) kombiniert Vorteile beider Techniken und weist dadurch ein hohes Applikationspotential auf. Daher bestand das Ziel der vorliegenden Arbeit in der Weiterentwicklung und Erforschung des MEW. Für diesen Zweck wurde eine neuartige Forschungsanlage konzipiert und gebaut, welche mit einzigartiger Verfahrenspräzision und Prozesskontrolle die Fertigung von hochqualitativen Konstrukten ermöglichte. Auf Basis dessen konnten die durchgeführten Studien das Verständnis des elektrohydrodynamischen Druckvorgangs und der untersuchten Prozessparameter vertiefen und letztendlich zur Ausweitung des Verfahrens auf neue medizinisch relevante Thermoplaste beitragen. Um eine reproduzierbare Herstellung von Scaffolds zu ermöglichen, wurde eine häufig auftretende Prozessinstabilität erforscht und als pulsing, oder in stark ausgeprägten Fällen als long beading, klassifiziert. Durch Prozessanalyse konnte zudem eine Methode zur Vermeidung dieser Instabilität entwickelt werden. Dafür wurden zwei unterschiedliche biokompatible Polymere verwendet: Poly(ε-Caprolacton) (PCL) als bis dahin einziger verfügbarer MEW Werkstoff, sowie erstmalig Poly(2-Ethyl-2-Oxazolin). Die aufgestellte Hypothese umfasst eine universelle Abhängigkeit der pulsing Instabilität zu involvierten Massenströmen, welche durch Anpassung des angelegten Prozessdruckes und der elektrischen Feldstärke reguliert werden kann. Um ein optimales Prozessergebnis für nachfolgende Forschungsarbeiten zu erzielen, wurde zusätzlich ein Leitfaden zur quantitativen Bewertung des Grades der Instabilität bereitgestellt. Durch Kombination kleiner Spinndüsen, kleiner Schmelze-Flussraten und hoher elektrischen Feldstärken, konnten erstmalig PCL Fasern mit sub-mikron Durchmessern (fØ = 817 ± 165 nm) zu präzisen Scaffolds verarbeitet werden. Diese wurden anschließend durch materialwissenschaftliche Analytik charakterisiert. Dabei wurde eine molekulare Vorzugsorientierung und isotrope Kristallausrichtung entlang der Faser beobachtet, welche durch den hohen Verstreckungsgrad des erstarrenden Polymerstrahls erklärt werden konnte. Resultierende sub-mikron Fasern konnten zwar für einen akkuraten Druckvorgang verwendet werden, jedoch erwiesen sich die Strukturen als instabil und daher nicht geeignet für die Handhabung bei Zellkulturstudien. Aus diesem Grund wurde ein Beschichtungsansatz mittels hydrophilen und vernetzbaren Sternmolekülen für Substratflächen herangezogen. Während solche modifizierten Oberflächen bekanntermaßen Zelladhäsion verhindern, konnten gedruckte sub-mikron Scaffolds auf der Oberfläche haften und so für biologische Studien verwendet werden. Durch das gezielte Ablegen von Fasern unterhalb der kritischen Translationsgeschwindigkeit (CTS) des Kollektors, konnten sinusförmige Faserstrukturen erzeugt werden. Analog zu rein viskosen Fluiden, welche durch ein bewegliches Band aufgesammelt werden, schien dieser Vorgang dem sogenannten buckling zu unterliegen und daher phänomenologisch nicht oder nur geringfügig vom elektrischen Feld abhängig zu sein. Zudem konnte eine durchgeführte Studie die direkte Abhängigkeit der Fasergeometrie mit der Kollektorbewegung belegen. Unabhängig vom Prozessdruck, führte eine verminderte Kollektorgeschwindigkeit sc in den Grenzen CTS > sc ≥ 2/3 CTS zu erhöhten Amplituden bzw. Spitze-zu-Spitze Werten und verkürzten Wellenlängen. Durch das kontrollierte Ablegen der Fasern bei Geschwindigkeiten von 100 %, 90 % 80 % und 70 % CTS konnten zudem Scaffolds mit unterschiedlichen mechanischen Eigenschaften hergestellt werden. Speziell der Zugmodul wurde dadurch etwa um eine halbe Größenordnung moduliert (Es = 42 ± 7 MPa bis 173 ± 22 MPa bei 1 – 3 % Dehnung). Dies ist in Kombination mit der Strukturierung für maßgeschneiderte TE Scaffolds von großem Interesse, da zelluläre Systeme sensibel auf ihre Umgebung reagieren können. Des Weiteren wurden Poly(L-Lactid-co-ε-Caprolacton-co-Acryloylcarbonat) und Poly(ε-Caprolacton-co-Acryloylcarbonat) (PCLAC) Copolymere hinsichtlich deren MEW Verarbeitbarkeit untersucht. Solche Kunststoffe können nach dem Druckvorgang mit UV-Strahlung radikalisch vernetzt werden und dadurch deutlich erhöhte mechanische Eigenschaften ausbilden. Für Fasern aus 90 mol.% CL und 10 mol.% AC wurden beispielsweise maximale Zugfestigkeiten von σmax = 53 ± 16 MPa ermittelt. MEW gedruckte sinusförmige Faserstrukturen aus PCLAC wiesen darüber hinaus ein biomimetisches Spannungs-Dehnung-Verhalten auf, vergleichbar zu Sehnen- und Ligamentgewebe. Eine Untersuchung der Zellviabilität von L929 murinen Fibroblasten im Eluattest, sowie eine lebend/tot-Färbung von humanen mesenchymalen Stammzellen auf den Scaffolds, ergab vielversprechende Resultate und damit ein relevantes Anwendungspotential solcher Strukturen als Implantat. Neben genannten Vorteilen, weist MEW als Verfahren bislang allerdings geringe Produktionsgeschwindigkeiten auf. Diese sind daher in den Fokus aktueller Forschungsvorhaben gerückt. Einen Ansatz hierfür bieten Spinndüsen mit hohem Innendurchmesser und erhöhter Austragsrate, wobei die optimierte elektrische Feldstärke, sowie ein Verstrecken durch die Kollektorbewegung, zu den erwünschten dünnen Fasern führen können. Dadurch kann die abwärtslimitierte Düsengröße des FDM Verfahrens überwunden werden. Visionär gedacht, könnte eine solche Anlage direkt in Krankenhäusern zur Fertigung von patienten- und defektspezifischen Implantaten eingesetzt werden. Darüber hinaus ermöglicht die hohe Präzision, zusammen mit dem Drucken von Mikro-Fasern, einen technischen Einsatz zur Herstellung von Membranen, Filtern oder funktionalen Oberflächenbeschichtungen.

3D printing, also known as ”additive manufacturing”, indicates a set of fabrication techniques that build objects by adding material, typically layer by layer. The main advantages of 3D printing are unlimited shapes and geometry, fast prototyping, and cost-effective small scale production. Two-photon lithography (TPL) is a laserbased 3D printing technique with submicron resolution, that can be used to create miniaturized structures. One of the most compelling applications of TPL is the 3D printing of miniaturized optical elements with unprecedented complexity, small-scale and precision. This could be potentially beneficial in biophotonics, a multidisciplinary research field in which light-based techniques are used to study biological processes. My research has been aimed at demonstrating novel applications of 3D printing based on TPL to different biophotonic applications. In particular, here we show 3D printed micro-optical structures that enhance and/or enable novel functions in advanced biophotonics methods as two-photon microendoscopy, optical trapping and Stimulated Raman Scattering microscopy. Remarkably, the micro-optical structures presented in this thesis enable the implementation of advanced techniques in existing or simpler microscopy setups with little to no modification to the original setup. This possibility is essentially allowed by the unique miniaturization and in-situ 3D printing capabilities offered by TPL.

Highly integrated and customizable systems have been a principal focus of development for parenteral and oral drug administration. Extensive work has been done to optimize drug efficacy via localized delivery and dosage control providing new ways for accomplishing targeted therapeutic effects. However, many challenges and opportunities for advancement remain. One promising research path is introducing novel microfabrication methods or engineering discoveries in concept realization, making devices more versatile and effective. Firstly, this dissertation focuses on designing and fabricating a miniaturized, 3D printed, wirelessly powered drug delivery system for biomedical applications. The drug delivery system is composed of an electrolytic micropump integrated into a 3D printed reservoir equipped with hollow microneedles. The electrolytic pump is composed of interdigitated electrodes and a bellows membrane. A simple and customizable manufacturing process is developed to fabricate miniaturized bellows membranes. To improve the integration of microneedles in microelectromechanical devices, a high-resolution 3D printing technique is implemented to produce a reservoir equipped with an array of hollow microneedles. Penetration tests of microneedles into a skin-like material confirm sufficient stability of microneedles. Furthermore, the microneedle arrays are used to pierce and deliver into mouse skin successfully. The assembled system (electrolytic micropump integrated into the 3D printed reservoir equipped with hollow microneedles) is actuated using inductive wireless powering. Secondly, this dissertation tackles one of the most challenging diseases, Coronary Artery Disease. Delivering a therapeutic agent directly to the inner wall of affected blood vessels can be a transformative step toward a better treatment option. To open the door for such an approach, a catheter delivery system is developed based on a conventional balloon catheter where a fluidic channel and microneedles are integrated on top of it. This enables precise and localized delivery of therapeutics directly into vessel walls. Ex vivo tests on rabbit aorta confirm the microneedles-upgraded balloon catheter’s performance on real tissue. This study shows that microneedles-upgraded balloon catheter is capable of localized and targeted drug delivery into artery walls. The fabrication process ensures a highly customizable solution that can be tailored to patient-specific requirements.

Indiana University-Purdue University Indianapolis (IUPUI) / One of the primary challenges faced in Additive Manufacturing (AM) is reducing the overall cost and printing time. A critical factor in cost and time reduction is post-processing of 3D printed (3DP) parts, which includes removing support structures. Support is needed to prevent the collapse of the part or certain areas under its own weight during the 3D printing process. Currently, the design of self-supported 3DP parts follows experimental trials. A trial and error process is needed to produce high quality parts by Fused Depositing Modeling (FDM). An example for a chamfer angle, is the common use of 45 degree angle in the AM process. Surfaces that are more flat show defects than inclined surfaces, and therefore a numerical model is needed. The model can predict the problematic areas at a print, reducing the experimental prints and providing a higher number of usable parts. Physical-based models have not been established due to the generally unknown properties of the material during the AM process. With simulations it is possible to simulate the part at different temperatures with a variety of other parameters that have influence on the behavior of the model. In this research, analytic calculations and physical tests are carried out to determine the material properties of the thermoplastic polymer Acrylonitrile - Butadiene - Styrene (ABS) for FDM at the time of extrusion. This means that the ABS is going to be extruded at 200C to 245C and is a viscus material during part construction. Using the results from the physical and analytical models, i.e., Timoshenko’s modified beam theory for micro structures, a numerical material model is established to simulate the filament deformation once it is deposited onto the part. Experiments were also used to find the threshold for different geometric specifications, which could then be applied to the numerical model to improve the accuracy of the simulation. The result of the nonlinear finite element analysis is compared to experiments to show the correlation between the prediction of deflection in simulation and the actual deflection measured in physical experiments. A case study was conducted using an application that optimizes topology of complex geometries. After modeling and simulating the optimized part, areas of defect and errors were determined in the simulation, then verified and and measured with actual 3D prints.

Indiana University-Purdue University Indianapolis (IUPUI) / Material jetting (MJ) additive manufacturing (AM) has experienced an increased adoption in several industry areas and as well as research applications. One of MJ’s distinct benefits is the ability to print tunable composites, digital materials (DM) by carefully adjusting the ratio of droplets of heterogeneous base-polymeric inks. However, the lack of material information usable in computer simulations has hampered its acceptance in some end-use applications. For these materials to be used in Finite Element Analysis (FEA) simulations the mechanical properties of the DMs need to be characterized into usable material models. DMs printable with an MJ printer has a wide variety of materials properties, ranging from flexible silicone rubber to rigid Acrylonitrile Butadiene Styrene (ABS). Therefore, to cohesively express the mechanical behavior of the DMs it is necessary to utilize non-linear material models. The objective this research is to conduct physical testing to characterize the mechanical behavior of DMs printable with an MJ. Subsequently, to validate the effectiveness of the material models for multi-DM prints. Utilizing the newly characterized material models two use cases were investigated, with the goal of improving the performance of printed parts through simulation. In this study, an MJ printer was used to fabricate the test specimens as well as the components used in the use case studies. The study was focused on the family of six DMs printable from the mixture of the base polymers Tango Black+ (TB+) and Vero White+ (VW+). To characterize the mechanical properties of the materials a tensile test was conducted utilizing the KS-M6518 standard as a basis. The mechanical properties of the DMs were then fitted into four non-linear models and the results compared. The fitted models were, the Neo Hookean model, a two-parameter, three-parameter, and a five-parameter Mooney Rivlin model. To confidently use the material models for multi-DM prints FEA simulations need to validate the accuracy to which they can predict the deformation of the samples under load. To compare the results of the computer simulations and the physical test, strain maps for both results were analyzed. Four different test specimens were printed and tested. A baseline single material samples were compared to three multi-material samples with different embedded structures. The results confirmed the validity of the material models even when used for multi-DM prints. The recently characterized models are utilized in two use case studies which showcase the potential of DMs. The first use case was focused on printing multi-DM substrates for the use of stretchable electronics. The second use case investigated the benefits of utilizing multiple materials to create 3D conductive traces utilizing a new method, the “swollen-off” method. Both case studies showed the benefits of utilizing DMs as well as the applicability of the material models in predictive simulations.

Indiana University-Purdue University Indianapolis (IUPUI) / Extrusion-based 3D printing is one of the emerging additive manufacturing technologies used for printing a range of materials from metal to ceramics. In this process, the required material is extruded from the extruder in the form of a slurry. Zeolite and MOFs are mainly used for CO2 adsorption in the form of pellets and beads due to their good adsorptive property. Researchers are developing monoliths of Zeolite and MOFs and fabricate them using traditional extrusion and implement them in the gas adsorption applications as an option for beads and pellets by developing a monolithic structure. Previous research on Zeolite 13X and 5A have shown good structural and physical properties in monolith form. In this study, we developed slurry of two molecular sieve Zeolite 3A and 4A monoliths powders, mixing it with bentonite clay, methyl cellulose, and PVA as a binder. The slurry preparation was carried out at room temperature. Once the 3D printed samples are dried at room temperature, a sintering process was performed to increase mechanical strength. To be used in real-time applications, the 3D printed Zeolite sample need to have sufficient mechanical strength. The BET surface area test showed good results for Zeolite 13X compared to available literature. The surface area calculated for 3D printed Zeolite 13X was 767m2/g and available literature showed 498 m2/g for 3D printed Zeolite 13X. The microhardness values of 3D printed Zeolite samples were measured using a Vicker hardness tester. The hardness value of the 3D - printed Zeolite samples increased from 8.3 ± 2 to 12.5 ± 3 HV0.05 for Zeolite 13X, 3.3 ± 1 to 7.3 ± 1 HV0.05 for Zeolite 3A, 4.3 ± 2 to 7.5 ± 2 HV0.05 for Zeolite 4A, 7.4 ± 1 to 14.0 ± 0.5 HV0.05 for Zeolite 5A respectively. The SEM, EDS and XRD analysis was performed for 3D printed samples before and after sintering to evaluate their structural properties. The SEM analysis reveals that all 3D printed Zeolite samples retained their microstructure after slurry preparation and also after the sintering process. The porous nature of 3D printed Zeolite walls was retained after the sintering process. The EDS analysis showed that the composition of 3D printed Zeolite samples remained somewhat similar with minor variation for before and after sintering. The framework structure of Zeolite Type X for Zeolite 13X and Zeolite Type A for Zeolite 3A, 4A, 5A were in good shape after sintering as standard peak intensity points were retained. Zn-MOF74 was synthesized using solvothermal synthesis which is a well-established synthesis process used for the synthesis of MOFs. We also developed slurry for Zn-MOF-74 using bentonite clay and PVA as binders and printed small parts using hand printing.

Indiana University-Purdue University Indianapolis (IUPUI) / Metal 3D printing typically requires high energy laser or electron sources. Recently, 3D printing using metal filled filaments becomes available which uses PLA filaments filled with metal powders (such as copper, bronze, brass, and stainless steel). Although there are some studies on their printability, the detailed study of their sintering and characterizations is still missing. In this study, the research is focused on 3D printing of bronze filaments. Bronze is a popular metal for many important uses. The objectives of this research project are to study the optimal processing conditions (like printer settings, nozzle, and bed temperatures) to print bronze metal filament, develop the sintering conditions (temperature and duration), and characterization of the microstructure and mechanical properties of 3D printed specimens to produce strong specimens. The thesis includes three components: (1) 3D printing and sintering at selected conditions, following a design of experiment (DOE) principle; (2) microstructure and compositional characterizations; and (3) mechanical property characterization. The results show that it is feasible to print using bronze filaments using a typical FDM machine with optimized printing settings. XRD spectrums show that there is no effect of sintering temperature on the composition of the printed parts. SEM images illustrate the porous structure of the printed and sintered parts, suggesting the need to optimize the process to improve the density. The micro hardness and three-point bending tests show that the mechanical strengths are highly related to the sintering conditions. This study provides important information of applying the bronze filament in future engineering applications.

Indiana University-Purdue University Indianapolis (IUPUI) / In this work we developed paper spray mass spectrometry methods to obtain lower detection limits for pharmaceuticals and drugs of abuse. The second chapter investigates blood fractionation membranes for their ability to obtain lysis free plasma from whole blood without changing the drug concentration relative to centrifugation. We presented a device capable of obtaining and analyzing plasma samples from whole blood and obtaining quantitative results similar to traditional methods. In the third chapter the properties of the paper substrate are investigated systematically for their impacts on ionization efficiency and recovery in combination with the solvent choice. The fourth and fifth chapters detail a simple method for lowering detection limits using a method called paper strip extraction. In this method biofluids are wicked through either sesame seed oil or solid phase extraction powder on a paper strip to concentrate and preserve (in the case of THC) analytes out of biofluids. The use of 3D printing for rapid prototyping and how it potentially impacts paper spray MS sensitivity is outlined in the final chapter.

Indiana University-Purdue University Indianapolis (IUPUI) / Ceramics have been extensively used in aerospace, automotive, medical, and energy industries due to their unique combination of mechanical, thermal, and chemical properties. The objective of this thesis is to develop an extrusion based ceramic 3D printing process to digitally produce a casting mold. To achieve the objective, an in-house designed ceramic 3D printer was developed by converting a filament based plastic 3D printer. For mold making applications, zircon was selected because it is an ultra-high temperature ceramic with high toughness and good refractory properties. Additionally, alumina, bioglass, and zirconia slurries were formulated and used as the feedstock material for the ceramic 3D printer. The developed 3D printing system was used to demonstrate successful printing of special feature parts such as thin-walled high aspect ratio structures and biomimetically inspired complex structures. Also, proof of concept with regard to the application of 3D printing for producing zircon molds and casting of metal parts was also successfully demonstrated. To characterize the printed parts, microhardness test, scanning electron microscopy (SEM), and X-ray diffraction (XRD) analyses were conducted. The zircon samples showed an increase in hardness value with an initial increase in heat treatment temperature followed by a drop due to the development of porosity in the microstructure, caused by the decomposition of the binder. The peak hardness value for zircon was observed to be 101±10 HV0.2. Similarly, the microhardness values of the other 3D printed ceramic specimens were observed to increase from 37±3 to 112±5 HV0.2 for alumina, 23±5 to 35±1 HV0.2 for bioglass, and 22±5 to 31±3 HV0.2 for zirconia, before and after the heat-treatment process, respectively. Finally, a system model for the ceramic 3D printing system was developed through the application of the model-based systems engineering (MBSE) approach using the MagicGrid framework. Through the system engineering effort, a logical level solution architecture was modeled, which captured the different system requirements, the system behaviors, and the system functionalities. Also, a traceability matrix for the system from a very abstract logical level to the definition of physical requirements for the subsystems was demonstrated.

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