Yes / High-throughput manufacturing of transdermal microneedle arrays poses a significant challenge due to the high precision and number of features that need to be produced and the requirement of multi-step processing methods for achieving challenging micro-features. To address this challenge, we report a flexible and cost-effective process chain for transdermal microneedle array manufacture that includes mould production using laser machining and replication of thermoplastic microneedles via micro-injection moulding (micromoulding). The process chain also incorporates an in-line manufacturing data monitoring capability where the variability in the quality of microneedle arrays can be determined in a production run using captured data. Optical imaging and machine vision technologies are also implemented to create a quality inspection system that allows rapid evaluation of key quality indicators. The work presents the capability of laser machining as a cost-effective method for making microneedle moulds and micro-injection moulding of thermoplastic microneedle arrays as a highly-suitable manufacturing technique for large-scale production with low marginal cost. / This research work was undertaken in the context of MICRO-MAN project (“Process Fingerprint for Zero-defect Net-shapeMICROMANufacturing”, http://www.microman.mek.dtu.dk/).MICROMAN is a European Training Network supported byHorizon 2020, the EU Framework Programme for Research andInnovation (Project ID: 674801). This research has also receivedfunding and support from two other Horizon 2020 projects:HIMALAIA (Grant agreement No. 766871) and Laser4Fun (GA no.675063).

The emergence of microneedle (MN) technologies offers a route for a pain free, straightforward and efficient way of transdermal drug delivery, but technological barriers still exist which pose significant challenges for manufacture of MN systems with high volume outputs at low cost. The main aim of this research was to develop new ways for MN manufacture primarily using micro-injection moulding processes with high performance engineering thermoplastics. During the moulding process these polymeric melts will be subjected to extreme stress and temperature gradients and detailed material characterisation combined with in-line monitoring is desirable to optimise the moulding parameters and will help in achieving sharp microneedles with acceptable quality. Hence high shear rheology of these selected materials was performed at wall shear rates carried out in excess of 107 s-1 over a range of temperatures to predict the flow behaviour of polymer melts at such high shear strain rates. This information was fed into injection moulding simulation software tools (Moldflow) to assist the MN production process design. The optimal design was then used to produce a full 3D solid model of the injection mould and mould insert. Furthermore various design of experiments were conducted considering input parameters such as injection pressure, injection speed, melt temperature, filling time and mould cavity temperature. Response variables including product quality and data acquired from the cavity pressure and temperature transducers were used to optimise the manufacturing process. The moulded MNs were geometrically assessed using a range of characterisation techniques such as atomic force microscopy, confocal microscopy and scanning electron microscopy. An attempt to make hollow MNs was performed and encountered many challenges like partial cavity filling and part ejection during processing. Studies were carried out to understand the problem and identified the major problem was in tool design and improvements to the moulding tool design were recommended. Plasma treatment and mechanical abrasion were employed to increase the surface energy of the moulded polymer surfaces with the aim of enhancing protein adsorption. Sample surface structures before and after treatment were studied using AFM and surface energies have been obtained using contact angle measurement and calculated using Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness resulting in better adsorption and release of BSA. To assist design-optimisation and to assess performance, a greater understanding of MN penetration behaviour is required. Contact stiffness, failure strength and creep behaviour were measured during compression tests of MN against a steel surface, and in-vitro penetration of MNs into porcine skin. The MN penetration process into porcine skin was imaged using optical coherence tomography. Finally, a finite element model of skin was established to understand the effect of tip geometry on penetration. The output of findings from this research will provide proof of concept level development and understanding of mechanisms of MN penetration and failure, facilitating design improvements for micro-injection moulded polymeric MNs.

Yes / Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy of micro-injection moulded microneedles and its influence on drug delivery. Microneedles of polyether ether ketone and polycarbonate and have been manufactured using micro-injection moulding and samples from each production batch have been subsequently subjected to a range of plasma treatment. These samples were coated with bovine serum albumin to study the protein adsorption on these treated polymer surfaces. Sample surfaces structures, before and after treatment, were studied using atomic force microscope and surface energies have been obtained using contact angle measurement and calculated using the Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness of the microneedles resulting in better adsorption and release of BSA.

Procédé de moulage par injection de poudres est constitué de quatre étapes principales: la préparation des matières premières, moulage par injection, le déliantage et le frittage. Cette thèse présente les recherches sur deux aspects principaux: la micro-injection et frittage par micro -ondes. Les contributions principaux peuvent être conclues dans les quatre aspects suivants: Modification et complément de l'algorithme précédent pour la simulation du procédé de moulage par injection; L'évaluation et la mise en œuvre de l'effet de tension de surface en simulation pour micro-injection; Micro-ondes expériences de frittage de compacts basés sur l'acier inoxydable 17-4PH; Réalisation de la simulation de frittage à micro-ondes avec couplage de la multi-physique, y compris le chauffage à micro-ondes classique, le transfert de chaleur, et le supplément de modèle pour la densification de frittage de la poudre compacté / Powder Injection molding process consists off our main stages: feedstock preparation, injection molding, debinding and sintering. The thesis presents the research on two main aspects: micro injectionmolding and microwave sintering. The main contributions can be concluded in thefollowing four aspects: Modification and supplement of previous algorithm for the simulation ofinjection molding process; Evaluation and implementation of surface tension effect in simulation for micro injection; Microwave sintering experiments of compacts based on 17-4PH stainles ssteel; Realization of the microwave sintering simulation with the coupling of multi-physics,including the classic microwave heating, heat transfer, and the supplement of model for sintering densification of powder impacts

This thesis focuses on the use of a design of experiment approach to examine the significance of process factors and interactions on the fabrication of micro- textured surfaces. The micro-textured surfaces examined contain pillar and hole features ranging from 80 – 2 micrometers in diameter. The processes examined are the deep reactive ion etching of silicon wafers for the production of silicon mould inserts and the micro-injection moulding of polypropylene, high density polyethylene and 316LS stainless steel replicate samples of the silicon mould insert. During the deep reactive ion etching of the silicon wafers the design of experiment approach was used to determine the significant of platen power, C4F8 gas flow and switching times to the presence of pillar undercut of 10 x 10, 5 x 5 and 2 x 2 micrometer pillars. Undercuts occur when the pillar base has a smaller cross-section than the apex of the pillar. Switching times was found to be the only statistically significant parameter for both 10 x 10 and 5 x 5 micrometer pillars. The design of experiment approach is used in the micro-injection moulding of polypropylene, high density polyethylene and 316LS stainless steel replicates to examine the significance of mould temperature, cooling time, holding pressure and injection speed on the part and buffer mass of the produce samples, the height and width of pillar on the replicate surfaces and the variation of the replicated pillars height and width from the original silicon mould insert. Examination of the high density polyethylene replicates found that mould temperature was the most significant factor regarding pillar dimensions (and variation from the silicon mould insert) across the range of pillar sizes. Upon examination of the polypropylene replicates it was found that the factor of most significance on pillar dimensions varied across the different pillar sizes. Holding pressure was identified as the most significant factor with regards to the 53 x 29 and 19 x 80 micrometer pillars. Injection speed was found to be most significant for the 25 x 25 and 19 x 29 micrometer pillars. Cooling time was found to be most significant with regards to the 30 x 10, 25 x 10, 20 x 10 and 15 x 10 micrometer pillars. While ii mould temperature was found to be most significant for the 20 x 20, 15 x 15 and 10 x 30 micrometer pillars. The interaction between mould temperature and injection speed was also found to be the most significant factor with regards to the 43 x 29 and 25 x 30 micrometer pillars. Examination of the 316LS replicates found that mould temperature was the most significant factor regarding pillar dimensions for 80 x 80 and 19 x 80 micrometer pillars. While holding pressure was found to be most significant to the 29 x 29 micrometer pillars and injection speed was identified as most significant to the 53 x 80 micrometer pillars. The samples produced during the design of experiment investigations were then used to examine the effect of surface texturing on droplet behaviour. Droplet contact angles were examined on polypropylene, high density polyethylene and silicon samples structured with 10 – 2 micrometer pillar. Initial droplet contact angles were found to be higher on the polypropylene samples than the high density polyethylene or silicon samples. With the lowest initial contact angles being found for the silicon inserts. Droplet ‘channelling’ and evaporation were examined on silicon, polypropylene, high density polyethylene and 316LS samples structured with micro-channel surface pillars and holes ranging from 80 – 2 micrometer in diameter. Contact pinning of the droplet to the surface via the three- phase contact-line was noted during observations of droplet ‘channelling’. This pinning effect was observed at all sample tilt angles (30 - 90 o ). With regards to droplet evaporation, the droplets were noted to evaporate evenly (with no or limited contact pinning) on all unstructured surfaces and the surfaces structured with hole features. On the surfaces structured with pillar features, the droplets appeared too evaporated along the surface gradient from the smallest pillars to the largest.

The emergence of microneedle (MN) technologies offers a route for a pain free, straightforward and efficient way of transdermal drug delivery, but technological barriers still exist which pose significant challenges for manufacture of MN systems with high volume outputs at low cost. The main aim of this research was to develop new ways for MN manufacture primarily using micro-injection moulding processes with high performance engineering thermoplastics. During the moulding process these polymeric melts will be subjected to extreme stress and temperature gradients and detailed material characterisation combined with in-line monitoring is desirable to optimise the moulding parameters and will help in achieving sharp microneedles with acceptable quality. Hence high shear rheology of these selected materials was performed at wall shear rates carried out in excess of 107 s-1 over a range of temperatures to predict the flow behaviour of polymer melts at such high shear strain rates. This information was fed into injection moulding simulation software tools (Moldflow) to assist the MN production process design. The optimal design was then used to produce a full 3D solid model of the injection mould and mould insert. Furthermore various design of experiments were conducted considering input parameters such as injection pressure, injection speed, melt temperature, filling time and mould cavity temperature. Response variables including product quality and data acquired from the cavity pressure and temperature transducers were used to optimise the manufacturing process. The moulded MNs were geometrically assessed using a range of characterisation techniques such as atomic force microscopy, confocal microscopy and scanning electron microscopy. An attempt to make hollow MNs was performed and encountered many challenges like partial cavity filling and part ejection during processing. Studies were carried out to understand the problem and identified the major problem was in tool design and improvements to the moulding tool design were recommended. Plasma treatment and mechanical abrasion were employed to increase the surface energy of the moulded polymer surfaces with the aim of enhancing protein adsorption. Sample surface structures before and after treatment were studied using AFM and surface energies have been obtained using contact angle measurement and calculated using Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness resulting in better adsorption and release of BSA. To assist design-optimisation and to assess performance, a greater understanding of MN penetration behaviour is required. Contact stiffness, failure strength and creep behaviour were measured during compression tests of MN against a steel surface, and in-vitro penetration of MNs into porcine skin. The MN penetration process into porcine skin was imaged using optical coherence tomography. Finally, a finite element model of skin was established to understand the effect of tip geometry on penetration. The output of findings from this research will provide proof of concept level development and understanding of mechanisms of MN penetration and failure, facilitating design improvements for micro-injection moulded polymeric MNs.

Bacteria are known to adhere to surfaces, which allows for the formation of biofilms, possibly causing a surge in hospital-offset infections, perilous diseases, and in some cases, death. Although certain bacteria are present in the natural flora of the human skin, some present extreme clinical significance due to the ability to transmit and adhere, and can be resistant to antibiotics. They also evolve over time to survive in harsh environmental conditions. Current research reveals that design of plastic surfaces containing submicron structures, is becoming a popular approach to tackle issues concerning infection transmission, with inspiration being derived from biomimetics and self-cleaning surfaces, such as the surface of a gecko skin, and the hydrophobic wax layer of forest leaves. Main barriers to adoption include that these surfaces alone are difficult to manufacture on 3D products, expensive to fabricate on a large scale and do not last long when subjected to environmental wear. Replication of nano-scale ridges was carried out using micro-injection, and the various samples were characterised using a range of tools to determine physical and biomechanical parameters. The sample surfaces were then cultured with the pathogenic bacterium Staphylococcus aureus under several environmental conditions, and the results were statistically analysed to reveal that anti-fouling LIPSS (laser induced periodic surface structures) ridges perform better to reduce bacteria cell-substrate adhesion, when compared to flat surfaces, or surfaces containing dual structures (anti-fouling ridges combined with anti-wear walls). It was therefore demonstrated that nanotextured polymeric surfaces with hydrophobic characteristics have exceptional non-fouling properties, preventing S. aureus, a very significant bacterial strain, from initial adhesion, a critical primary mechanism in its ability to proliferate. Collectively, the findings of this study strongly support the literature, suggesting that the bacteria struggle to adhere onto polymeric topography with increased water contact angles and simple nanostructures. However, the addition of certain anti-wear micro-features increased bacterial adhesion, reducing the efficacy of the non-fouling nanostructures from preventing biofilm formation.

This research work investigates the development and application of process fingerprinting for conventional micro-injection moulding and ultrasonic micro injection moulding manufacturing of microneedle arrays for drug delivery. The process fingerprinting method covers in-depth analysis, interrogation and selection of certain process data features and correlation of these features with product fingerprints which are defined by the geometrical outcomes of the microneedle arrays in micro scale. The method was developed using the data collected using extensive sensor technologies attached to the conventional and ultrasonic micromoulding machines. Moreover, a machine vision based microneedle product evaluation apparatus is presented. Micromachining capabilities of different processes is also assessed and presented where state-of-the-art laser machining was used for microneedle tool manufacturing in the work. By using process fingerprinting procedures, conventional and ultrasonic micromoulding processes has been characterised thoroughly and aspects of the process that is affecting the part quality was also addressed for microneedle manufacturing. It was found that polymer structure is of paramount importance in obtaining sufficient microneedle replication. An amorphous polymer have been found to be more suitable for conventional moulding whereas semi-crystalline materials performed better in ultrasonic micromoulding. In-line captured micromoulding process data for conventional and ultrasonic moulding provided detailed insight of machine dynamics and understanding. Linear correlations between process fingerprints and micro replication efficiency of the microneedles have been presented for both micromoulding technologies. The in-line process monitoring and product quality evaluation procedures presented in this work for micro-injection moulding techniques will pave ways for zero-defect micromanufacturing of miniature products towards Industry 4.0.

No / A novel process chain for serial production of polymer-based devices incorporating both micro- and nano-scale features is proposed. The process chain is enabled by the use of Zr-based bulk metallic glasses (BMG) to achieve the necessary level of compatibility and complementarity between its component technologies. It integrates two different technologies, namely laser ablation and focused ion beam (FIB) milling for micro-structuring and sub-micron patterning, respectively, thus to fabricate inserts incorporating different length scale functional features. Two alternative laser sources, namely nano-second (NS) and pico-second (PS) lasers, were considered as potential candidates for the first step in this master-making process chain. The capabilities of the component technologies together with some issues associated with their integration were studied. To validate the replication performance of the produced masters, a Zr-based BMG insert was used to produce a small batch of micro-fluidic devices by micro-injection moulding. Furthermore, an experimental study was also carried out to determine whether it would be possible by NS laser ablation to structure the Zr-based BMG workpieces with a high surface integrity whilst retaining the BMG’s non-crystalline morphology. Collectively, it was demonstrated that the proposed process chain could be a viable fabrication route for mass production of polymer devices incorporating different length scale features.

Este trabalho analisou o processo de moldagem por injeção de micro elementos ópticos difrativos usinados em insertos de cobre eletrolítico com ferramenta de diamante com ponta única. Quatro tipos de microestruturas características foram selecionados neste estudo, a saber: lente anesférica, lente de Fresnel, grade de difração (blaze grating) e sensor de frente de onda. A análise da fidelidade de replicação foi feita considerando aspectos dimensionais micrométricos e nanométricos para a microestrutura e acabamento. Um perfilometro óptico e microscópio eletrônico de varredura foram utilizados para avaliar os insertos usinados e as características dos replicados. Uma ferramenta de diamante com geometria especial, com meio raio, foi usada para usinar as características de difração. As superfícies usinadas apresentaram baixo acabamento superficial, na faixa de 16 nm Rms. As simulações numéricas foram realizadas para avaliar o desempenho do processo de moldagem por injeção com polimetilmetacrilato (PMMA), e os resultados foram utilizados para orientar a injeção do polímero. Com base na simulações numéricas as temperaturas do molde e pressões de injeção foram variadas entre 85ºC/130°C e 70 bar/130 bar, respectivamente. A influência destes parâmetros no desempenho do processo de replicação foi analisada. A análise quantitativa da replicação foi feita através de um parâmetro denominado grau de replicação que define a relação entre a altura nominal da microestrutura do inserto e à altura da microestrutura na réplica de polímero. A grade de difração e o sensor de frente de onda apresentaram os melhores níveis de replicação: 98% e 99%, respectivamente. Os resultados experimentais mostraram que o processo de moldagem por injeção é uma técnica viável para replicar com alta qualidade microcaracterísticas de elementos ópticos de difração gerados por torneamento com ferramenta de diamante com ponta única. / This work investigated the injection molding process of micro diffractive optical elements machined on electrolytic copper inserts by single point diamond turning. Four types of microstructure features were selected in this study, namely: aspherical lens, Fresnel lens, blaze grating and the wavefront sensor. The replication fidelity was evaluated in terms of dimensional micrometric features found in the microstructure and the surface finish. An optical profiler and scanning electron microscopy were used to assess the machined inserts and the replicated features. A special geometry diamond tool with half radius was used to machine the diffraction features. The machined surfaces presented very low surface finish in the range of 16 nm Rms. Numerical simulations were carried out to evaluate the performance of the injection molding process with polymethylmethacrylate (PMMA), and the results were used to guide the polymer injection. Based on numerical simulations mold temperatures and injection pressures were varied between 85°C/130°C and 70 bar/130 bar, respectively. The influence of these parameters on performance of the replication process was assessed. The quantitative assessement of the replication was made by using a parameter called degree of replication which defines the ratio between the nominal height of the microstructure in the insert and the height of the microstructure in the polymer replica. The blaze grating and the wavefront sensor presented the best degrees of replication: 98% and 99%, respectively. The experimental results showed that injection molding process is a viable technique to replicate high quality micro features of optical diffraction elements generated by single point diamond turning.