M.K. Ghatkesar
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1
Plasma Underetching of Suspended Silicon Nitride Membranes
Process Optimisation of SF6 ICP-RIE for Suspended Photonic Crystal Membranes
Suspended silicon nitride membranes are promising structures for ultra-light photonic applications, including photonic crystal membranes for future lightsail concepts. These membranes require a combination of low mass, optical functionality and mechanical stability. A major fabrication challenge is the final release step: the silicon substrate must be removed sufficiently to suspend the membrane, while the thin silicon nitride layer must remain intact. This thesis investigated (cryogenic) SF6 inductively coupled plasma reactive ion etching (ICP-RIE) as a dry-release method for silicon underetching beneath patterned silicon nitride membranes.
...
Suspended silicon nitride membranes are promising structures for ultra-light photonic applications, including photonic crystal membranes for future lightsail concepts. These membranes require a combination of low mass, optical functionality and mechanical stability. A major fabrication challenge is the final release step: the silicon substrate must be removed sufficiently to suspend the membrane, while the thin silicon nitride layer must remain intact. This thesis investigated (cryogenic) SF6 inductively coupled plasma reactive ion etching (ICP-RIE) as a dry-release method for silicon underetching beneath patterned silicon nitride membranes.
Introduction and Objectives: Macrophages are crucial cells in the foreign body response and subsequent tissue regeneration following biomaterial implantation, yet quantitative data describing their morphological and mechanical characteristics remain limited, particularly for human macrophage models. The absence of standardized reference values complicates the interpretation of macrophage responses in biomaterial research and hinders comparisons between studies. The objective of this study was to establish a reproducible Atomic Force Microscopy (AFM)-based protocol for the characterization of live THP-1-derived macrophages and use it to obtain quantitative baseline data on the morphology, elasticity, and viscoelastic behavior of M0 and M1 macrophages cultured under standard conditions. By generating a reference dataset under controlled experimental conditions, this work can provide a foundation for evaluating how biomaterial properties influence macrophage behaviors.
Methods: Human THP-1 monocytes were differentiated into macrophages and subsequently polarized into the pro-inflammatory M1. M0 and M1 macrophages were seeded in Petri dishes and cultured for three days prior to analysis. Morphological and mechanical characterization was performed on live cells under physiological conditions (37 °C) using Atomic Force Microscopy (AFM). Quantitative Imaging mode was employed to obtain high-resolution topographical images and apparent Young's modulus maps, enabling assessment of cell area, height, and stiffness. Viscoelastic properties were evaluated by AFM microrheology using frequency-dependent oscillatory indentation measurements.
Results: This study established a standardized AFM-based protocol for the quantitative characterization of live THP-1-derived macrophage morphology and mechanics, enabling the measurement of macrophages of different subtypes. Quantitative AFM analysis and complementary optical microscopy demonstrated substantial morphological heterogeneity within both macrophage populations. Irregular morphologies predominantly characterized M0 macrophages, whereas M1 macrophages exhibited a greater proportion of elongated cell shapes. Morphological subgroup analysis revealed that elongated cells consistently occupied smaller projected areas and had lower cell heights than round cells. Three-dimensional AFM reconstructions further revealed membrane roughness, cytoplasmic protrusions, and complex topographical features that were not readily detectable by conventional optical microscopy.
Mechanical characterization showed pronounced heterogeneity in apparent Young’s modulus both within and between individual cells. Elasticity maps consistently showed lower stiffness in nuclear regions than in the surrounding cytoplasm. Mean apparent Young’s modulus values were 1.27 ± 0.62 kPa for M0 macrophages and 1.43 ± 0.70 kPa for M1 macrophages, with no statistically significant difference observed between the two activation states. Frequency-dependent rheological measurements revealed similar viscoelastic behavior for both phenotypes. At lower frequencies, macrophages exhibited predominantly elastic behavior, whereas at higher frequencies, a gradual shift toward viscous dominance occurred. Overall, the results indicate that although morphological distributions differed between M0 and M1 macrophages, substantial heterogeneity existed within each population, and no single mechanical parameter was sufficient to clearly distinguish activation states. The quantitative morphological and mechanical dataset generated in this study provides a reference for future investigations of macrophage–biomaterial interactions and may contribute to the development of immune-informed biomaterial design. Future work should integrate advanced imaging techniques, optimized AFM probes, and physiologically relevant culture systems to further elucidate the relationship between cytoskeletal organization, cell mechanics, and macrophage phenotype.
...
Methods: Human THP-1 monocytes were differentiated into macrophages and subsequently polarized into the pro-inflammatory M1. M0 and M1 macrophages were seeded in Petri dishes and cultured for three days prior to analysis. Morphological and mechanical characterization was performed on live cells under physiological conditions (37 °C) using Atomic Force Microscopy (AFM). Quantitative Imaging mode was employed to obtain high-resolution topographical images and apparent Young's modulus maps, enabling assessment of cell area, height, and stiffness. Viscoelastic properties were evaluated by AFM microrheology using frequency-dependent oscillatory indentation measurements.
Results: This study established a standardized AFM-based protocol for the quantitative characterization of live THP-1-derived macrophage morphology and mechanics, enabling the measurement of macrophages of different subtypes. Quantitative AFM analysis and complementary optical microscopy demonstrated substantial morphological heterogeneity within both macrophage populations. Irregular morphologies predominantly characterized M0 macrophages, whereas M1 macrophages exhibited a greater proportion of elongated cell shapes. Morphological subgroup analysis revealed that elongated cells consistently occupied smaller projected areas and had lower cell heights than round cells. Three-dimensional AFM reconstructions further revealed membrane roughness, cytoplasmic protrusions, and complex topographical features that were not readily detectable by conventional optical microscopy.
Mechanical characterization showed pronounced heterogeneity in apparent Young’s modulus both within and between individual cells. Elasticity maps consistently showed lower stiffness in nuclear regions than in the surrounding cytoplasm. Mean apparent Young’s modulus values were 1.27 ± 0.62 kPa for M0 macrophages and 1.43 ± 0.70 kPa for M1 macrophages, with no statistically significant difference observed between the two activation states. Frequency-dependent rheological measurements revealed similar viscoelastic behavior for both phenotypes. At lower frequencies, macrophages exhibited predominantly elastic behavior, whereas at higher frequencies, a gradual shift toward viscous dominance occurred. Overall, the results indicate that although morphological distributions differed between M0 and M1 macrophages, substantial heterogeneity existed within each population, and no single mechanical parameter was sufficient to clearly distinguish activation states. The quantitative morphological and mechanical dataset generated in this study provides a reference for future investigations of macrophage–biomaterial interactions and may contribute to the development of immune-informed biomaterial design. Future work should integrate advanced imaging techniques, optimized AFM probes, and physiologically relevant culture systems to further elucidate the relationship between cytoskeletal organization, cell mechanics, and macrophage phenotype.
...
Introduction and Objectives: Macrophages are crucial cells in the foreign body response and subsequent tissue regeneration following biomaterial implantation, yet quantitative data describing their morphological and mechanical characteristics remain limited, particularly for human macrophage models. The absence of standardized reference values complicates the interpretation of macrophage responses in biomaterial research and hinders comparisons between studies. The objective of this study was to establish a reproducible Atomic Force Microscopy (AFM)-based protocol for the characterization of live THP-1-derived macrophages and use it to obtain quantitative baseline data on the morphology, elasticity, and viscoelastic behavior of M0 and M1 macrophages cultured under standard conditions. By generating a reference dataset under controlled experimental conditions, this work can provide a foundation for evaluating how biomaterial properties influence macrophage behaviors.
Methods: Human THP-1 monocytes were differentiated into macrophages and subsequently polarized into the pro-inflammatory M1. M0 and M1 macrophages were seeded in Petri dishes and cultured for three days prior to analysis. Morphological and mechanical characterization was performed on live cells under physiological conditions (37 °C) using Atomic Force Microscopy (AFM). Quantitative Imaging mode was employed to obtain high-resolution topographical images and apparent Young's modulus maps, enabling assessment of cell area, height, and stiffness. Viscoelastic properties were evaluated by AFM microrheology using frequency-dependent oscillatory indentation measurements.
Results: This study established a standardized AFM-based protocol for the quantitative characterization of live THP-1-derived macrophage morphology and mechanics, enabling the measurement of macrophages of different subtypes. Quantitative AFM analysis and complementary optical microscopy demonstrated substantial morphological heterogeneity within both macrophage populations. Irregular morphologies predominantly characterized M0 macrophages, whereas M1 macrophages exhibited a greater proportion of elongated cell shapes. Morphological subgroup analysis revealed that elongated cells consistently occupied smaller projected areas and had lower cell heights than round cells. Three-dimensional AFM reconstructions further revealed membrane roughness, cytoplasmic protrusions, and complex topographical features that were not readily detectable by conventional optical microscopy.
Mechanical characterization showed pronounced heterogeneity in apparent Young’s modulus both within and between individual cells. Elasticity maps consistently showed lower stiffness in nuclear regions than in the surrounding cytoplasm. Mean apparent Young’s modulus values were 1.27 ± 0.62 kPa for M0 macrophages and 1.43 ± 0.70 kPa for M1 macrophages, with no statistically significant difference observed between the two activation states. Frequency-dependent rheological measurements revealed similar viscoelastic behavior for both phenotypes. At lower frequencies, macrophages exhibited predominantly elastic behavior, whereas at higher frequencies, a gradual shift toward viscous dominance occurred. Overall, the results indicate that although morphological distributions differed between M0 and M1 macrophages, substantial heterogeneity existed within each population, and no single mechanical parameter was sufficient to clearly distinguish activation states. The quantitative morphological and mechanical dataset generated in this study provides a reference for future investigations of macrophage–biomaterial interactions and may contribute to the development of immune-informed biomaterial design. Future work should integrate advanced imaging techniques, optimized AFM probes, and physiologically relevant culture systems to further elucidate the relationship between cytoskeletal organization, cell mechanics, and macrophage phenotype.
Methods: Human THP-1 monocytes were differentiated into macrophages and subsequently polarized into the pro-inflammatory M1. M0 and M1 macrophages were seeded in Petri dishes and cultured for three days prior to analysis. Morphological and mechanical characterization was performed on live cells under physiological conditions (37 °C) using Atomic Force Microscopy (AFM). Quantitative Imaging mode was employed to obtain high-resolution topographical images and apparent Young's modulus maps, enabling assessment of cell area, height, and stiffness. Viscoelastic properties were evaluated by AFM microrheology using frequency-dependent oscillatory indentation measurements.
Results: This study established a standardized AFM-based protocol for the quantitative characterization of live THP-1-derived macrophage morphology and mechanics, enabling the measurement of macrophages of different subtypes. Quantitative AFM analysis and complementary optical microscopy demonstrated substantial morphological heterogeneity within both macrophage populations. Irregular morphologies predominantly characterized M0 macrophages, whereas M1 macrophages exhibited a greater proportion of elongated cell shapes. Morphological subgroup analysis revealed that elongated cells consistently occupied smaller projected areas and had lower cell heights than round cells. Three-dimensional AFM reconstructions further revealed membrane roughness, cytoplasmic protrusions, and complex topographical features that were not readily detectable by conventional optical microscopy.
Mechanical characterization showed pronounced heterogeneity in apparent Young’s modulus both within and between individual cells. Elasticity maps consistently showed lower stiffness in nuclear regions than in the surrounding cytoplasm. Mean apparent Young’s modulus values were 1.27 ± 0.62 kPa for M0 macrophages and 1.43 ± 0.70 kPa for M1 macrophages, with no statistically significant difference observed between the two activation states. Frequency-dependent rheological measurements revealed similar viscoelastic behavior for both phenotypes. At lower frequencies, macrophages exhibited predominantly elastic behavior, whereas at higher frequencies, a gradual shift toward viscous dominance occurred. Overall, the results indicate that although morphological distributions differed between M0 and M1 macrophages, substantial heterogeneity existed within each population, and no single mechanical parameter was sufficient to clearly distinguish activation states. The quantitative morphological and mechanical dataset generated in this study provides a reference for future investigations of macrophage–biomaterial interactions and may contribute to the development of immune-informed biomaterial design. Future work should integrate advanced imaging techniques, optimized AFM probes, and physiologically relevant culture systems to further elucidate the relationship between cytoskeletal organization, cell mechanics, and macrophage phenotype.
This thesis investigates whether a wafer-defined circular blade can realise a mechanically robust cutting edge at thin-film thickness scale and perform first material removal under rotation. The concept uses a silicon annulus carrying a deposited film. Selective substrate removal near the outer perimeter releases a circumferential overhang whose thickness defines the nominal kerf scale, while overhang length governs achievable cutting depth. The work is structured around four challenges: reaching the minimum cutting-edge speed with acceptable run-out, fabricating annular blade blanks, selectively underetching the rim while preserving mounting geometry, and integrating the system to demonstrate cutting.
A practical spindle operating envelope was established in which the blade reached the minimum target speed while operational displacement remained predominantly rotation-synchronous and below the realised overhang range used for survival and engagement trials. LS-Precess femtosecond-laser cutting enabled repeatable fabrication of 525 µm-thick silicon annular blanks, and a lid–base sacrificial masking concept enabled selective SF₆ underetching and controlled release of SiO₂ rims while preserving hub-bore integrity when the lid remained intact. In the integrated demonstration, released SiO₂ rims survived operation at and above target speed and produced a continuous kerf in rigid ABS under incremental approach at N = 17.7 kRPM, with measured trench depths of 11.72 µm to 14.71 µm and a central kerf width of ~46 µm.
The main limitations are that rigid cutting was attributable primarily to the rear-side ~10 µm rim, sustained controlled engagement of the front-side ~4 µm ultra-thin rim remains unproven, and circumferentially continuous ultra-thin a-SiC edges were not reliably achieved within the present process window. ...
A practical spindle operating envelope was established in which the blade reached the minimum target speed while operational displacement remained predominantly rotation-synchronous and below the realised overhang range used for survival and engagement trials. LS-Precess femtosecond-laser cutting enabled repeatable fabrication of 525 µm-thick silicon annular blanks, and a lid–base sacrificial masking concept enabled selective SF₆ underetching and controlled release of SiO₂ rims while preserving hub-bore integrity when the lid remained intact. In the integrated demonstration, released SiO₂ rims survived operation at and above target speed and produced a continuous kerf in rigid ABS under incremental approach at N = 17.7 kRPM, with measured trench depths of 11.72 µm to 14.71 µm and a central kerf width of ~46 µm.
The main limitations are that rigid cutting was attributable primarily to the rear-side ~10 µm rim, sustained controlled engagement of the front-side ~4 µm ultra-thin rim remains unproven, and circumferentially continuous ultra-thin a-SiC edges were not reliably achieved within the present process window. ...
This thesis investigates whether a wafer-defined circular blade can realise a mechanically robust cutting edge at thin-film thickness scale and perform first material removal under rotation. The concept uses a silicon annulus carrying a deposited film. Selective substrate removal near the outer perimeter releases a circumferential overhang whose thickness defines the nominal kerf scale, while overhang length governs achievable cutting depth. The work is structured around four challenges: reaching the minimum cutting-edge speed with acceptable run-out, fabricating annular blade blanks, selectively underetching the rim while preserving mounting geometry, and integrating the system to demonstrate cutting.
A practical spindle operating envelope was established in which the blade reached the minimum target speed while operational displacement remained predominantly rotation-synchronous and below the realised overhang range used for survival and engagement trials. LS-Precess femtosecond-laser cutting enabled repeatable fabrication of 525 µm-thick silicon annular blanks, and a lid–base sacrificial masking concept enabled selective SF₆ underetching and controlled release of SiO₂ rims while preserving hub-bore integrity when the lid remained intact. In the integrated demonstration, released SiO₂ rims survived operation at and above target speed and produced a continuous kerf in rigid ABS under incremental approach at N = 17.7 kRPM, with measured trench depths of 11.72 µm to 14.71 µm and a central kerf width of ~46 µm.
The main limitations are that rigid cutting was attributable primarily to the rear-side ~10 µm rim, sustained controlled engagement of the front-side ~4 µm ultra-thin rim remains unproven, and circumferentially continuous ultra-thin a-SiC edges were not reliably achieved within the present process window.
A practical spindle operating envelope was established in which the blade reached the minimum target speed while operational displacement remained predominantly rotation-synchronous and below the realised overhang range used for survival and engagement trials. LS-Precess femtosecond-laser cutting enabled repeatable fabrication of 525 µm-thick silicon annular blanks, and a lid–base sacrificial masking concept enabled selective SF₆ underetching and controlled release of SiO₂ rims while preserving hub-bore integrity when the lid remained intact. In the integrated demonstration, released SiO₂ rims survived operation at and above target speed and produced a continuous kerf in rigid ABS under incremental approach at N = 17.7 kRPM, with measured trench depths of 11.72 µm to 14.71 µm and a central kerf width of ~46 µm.
The main limitations are that rigid cutting was attributable primarily to the rear-side ~10 µm rim, sustained controlled engagement of the front-side ~4 µm ultra-thin rim remains unproven, and circumferentially continuous ultra-thin a-SiC edges were not reliably achieved within the present process window.
Master thesis
(2026)
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C.D. Peels, T. Baardemans, R. Groen, E.L. Fratila-Apachitei, R.P. Tas, M.K. Ghatkesar
Understanding the interaction between osteoblasts and osteoclasts is essential to accurately model human bone regeneration. However, most existing co-culture models rely on primary or animal-derived cells, which limits their reproducibility and human-specific relevance. To address this, this thesis establishes a fully human 3D in vitro model using iPSC-derived osteoblasts and osteoclasts seeded on triphasic calcium phosphate scaffolds. This offers a scalable and physiologically relevant platfrom for bone research in human cell lines. Osteoblasts were generated using a monolayer approach involving mesoderm specification and mesenchymal differentiation, while osteoclast precursors were derived through embryoid body formation and myeloid induction. Two macrophage conditions were compared, with or without IL-3 supplementation, to investigate their effect on osteoclastogenesis. Multinucleated, TRAP-positive osteoclasts formed only in the IL-3 condition, although the low expression of late-stage markers may indicate incomplete maturation. Co-culture with macrophages slightly upregulated early osteogenic genes but suppressed late-stage markers, likely due to inflammatory signaling. Additionally, OPG/RANKL ratio and cytokine profiles revealed that IL-3 modulated both osteoclast development and osteoblast behavior. Despite limitations, such as qPCR inconsistencies, GFP-related staining interference, and limited maturation, this model demonstrates the feasibility of using iPSCs to replicate key aspects of human bone remodeling in vitro. It highlights IL-3 as a key modulator of osteoclastogenesis and demonstrates the potential of a reproducible and human-specific model for studying bone cell crosstalk. Future work should extend culture duration, incorporate functional assays, and further explore the molecular mechanisms underlying IL-3-mediated osteoclastogenesis.
...
Understanding the interaction between osteoblasts and osteoclasts is essential to accurately model human bone regeneration. However, most existing co-culture models rely on primary or animal-derived cells, which limits their reproducibility and human-specific relevance. To address this, this thesis establishes a fully human 3D in vitro model using iPSC-derived osteoblasts and osteoclasts seeded on triphasic calcium phosphate scaffolds. This offers a scalable and physiologically relevant platfrom for bone research in human cell lines. Osteoblasts were generated using a monolayer approach involving mesoderm specification and mesenchymal differentiation, while osteoclast precursors were derived through embryoid body formation and myeloid induction. Two macrophage conditions were compared, with or without IL-3 supplementation, to investigate their effect on osteoclastogenesis. Multinucleated, TRAP-positive osteoclasts formed only in the IL-3 condition, although the low expression of late-stage markers may indicate incomplete maturation. Co-culture with macrophages slightly upregulated early osteogenic genes but suppressed late-stage markers, likely due to inflammatory signaling. Additionally, OPG/RANKL ratio and cytokine profiles revealed that IL-3 modulated both osteoclast development and osteoblast behavior. Despite limitations, such as qPCR inconsistencies, GFP-related staining interference, and limited maturation, this model demonstrates the feasibility of using iPSCs to replicate key aspects of human bone remodeling in vitro. It highlights IL-3 as a key modulator of osteoclastogenesis and demonstrates the potential of a reproducible and human-specific model for studying bone cell crosstalk. Future work should extend culture duration, incorporate functional assays, and further explore the molecular mechanisms underlying IL-3-mediated osteoclastogenesis.
There is demand for non-invasive, low-cost and accurate sap flow measurement in horticulture in order to optimize yield, heating and irrigation. The current state-of-the-art of sap flow technology and ultrasonic sensors do not fulfil this research gap. The novel concept for a non-invasive ultrasonic sensor for slow flow rates demonstrated by a TU Delft bachelor thesis group was a promising alternative solution. To find out if the novel concept could be developed in to a reliable alternative method for sap flow or slow flow rate measurement this thesis project sought to answer the following research question: What are the design sensitivities and parasitic sensitivities of the non-invasive ultrasonic flow sensors accuracy and how can the latter be mitigated. The experimental setup of the previous research was constructed and improved upon. A one-dimensional analytical model of the setup was composed to evaluate the contribution of the transducers oscillator dynamics to the output measurement. This research unfortunately found that the sensors seemingly high resolution to very small flow rates can be attributed to a consistent measurement error.
...
There is demand for non-invasive, low-cost and accurate sap flow measurement in horticulture in order to optimize yield, heating and irrigation. The current state-of-the-art of sap flow technology and ultrasonic sensors do not fulfil this research gap. The novel concept for a non-invasive ultrasonic sensor for slow flow rates demonstrated by a TU Delft bachelor thesis group was a promising alternative solution. To find out if the novel concept could be developed in to a reliable alternative method for sap flow or slow flow rate measurement this thesis project sought to answer the following research question: What are the design sensitivities and parasitic sensitivities of the non-invasive ultrasonic flow sensors accuracy and how can the latter be mitigated. The experimental setup of the previous research was constructed and improved upon. A one-dimensional analytical model of the setup was composed to evaluate the contribution of the transducers oscillator dynamics to the output measurement. This research unfortunately found that the sensors seemingly high resolution to very small flow rates can be attributed to a consistent measurement error.
Master thesis
(2025)
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N.V. de Haan, S. Pirola, I. Apachitei, P. Fanzio, M.K. Ghatkesar, A.M.S.E. Sharaf
Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia, making the study of small vessel hemodynamics vital for advancing diagnostic and therapeutic strategies. This research focuses on fabricating microfluidic devices that replicate the lateral lenticulostriate arteries (LSA) to validate computational flow models of small cerebral vessels. A key challenge in studying CSVD is the lack of experimental validation for computational fluid dynamics (CFD) models, which are widely used to simulate hemodynamics. To address this, additive masked Stereolithography (mSLA) was employed to fabricate a microfluidic model of the LSAs. The study explored the impact of orientation, exposure time, and layer height on the roundness and error of the intended area of printed micro-pores, to optimize the manufacturing of a microfluidic device. The smallest printed pore measured 270 μm in diameter. Pores printed at a larger angle as assessed from the build plate were more likely to remain open, but exhibited a larger decrease in area compared to smaller angles. A lower exposure time exhibited a larger pore area, whereas a larger layer height showed a decrease in area from intended. The layer height and angle did not influence the roundness, whereas an increase in exposure time decreased the roundness of the pores. Additionally, flow experiments were conducted using a 3D printed microfluidic device to compare empirical data with CFD and analytical simulations. The encountered resistance was larger for the experimental results (3.19 ⋅10^11 Pa⋅s/m^3) compared to the analytical result (1.96 ⋅10^11 Pa⋅s/m^3) and the computational result (1.90 ⋅10^11 Pa⋅s/m^3), likely due to deviation from the intended size. Finally, arterial microfluidic devices were printed and flow was induced to showcase their functionality. Achieving precise channel dimensions remains the primary challenge in mSLA printing due to cumulative dosage effects.
This research bridges the gap between computational modeling and experimental validation, providing a platform for studying cerebral microcirculation. The findings demonstrate the feasibility of using commercially available 3D-printed microfluidic devices to replicate small cerebral vessels. The outcomes of this study contribute to the advancement of vascular biomodeling, with implications for future clinical applications in stroke and neurovascular research.
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This research bridges the gap between computational modeling and experimental validation, providing a platform for studying cerebral microcirculation. The findings demonstrate the feasibility of using commercially available 3D-printed microfluidic devices to replicate small cerebral vessels. The outcomes of this study contribute to the advancement of vascular biomodeling, with implications for future clinical applications in stroke and neurovascular research.
...
Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia, making the study of small vessel hemodynamics vital for advancing diagnostic and therapeutic strategies. This research focuses on fabricating microfluidic devices that replicate the lateral lenticulostriate arteries (LSA) to validate computational flow models of small cerebral vessels. A key challenge in studying CSVD is the lack of experimental validation for computational fluid dynamics (CFD) models, which are widely used to simulate hemodynamics. To address this, additive masked Stereolithography (mSLA) was employed to fabricate a microfluidic model of the LSAs. The study explored the impact of orientation, exposure time, and layer height on the roundness and error of the intended area of printed micro-pores, to optimize the manufacturing of a microfluidic device. The smallest printed pore measured 270 μm in diameter. Pores printed at a larger angle as assessed from the build plate were more likely to remain open, but exhibited a larger decrease in area compared to smaller angles. A lower exposure time exhibited a larger pore area, whereas a larger layer height showed a decrease in area from intended. The layer height and angle did not influence the roundness, whereas an increase in exposure time decreased the roundness of the pores. Additionally, flow experiments were conducted using a 3D printed microfluidic device to compare empirical data with CFD and analytical simulations. The encountered resistance was larger for the experimental results (3.19 ⋅10^11 Pa⋅s/m^3) compared to the analytical result (1.96 ⋅10^11 Pa⋅s/m^3) and the computational result (1.90 ⋅10^11 Pa⋅s/m^3), likely due to deviation from the intended size. Finally, arterial microfluidic devices were printed and flow was induced to showcase their functionality. Achieving precise channel dimensions remains the primary challenge in mSLA printing due to cumulative dosage effects.
This research bridges the gap between computational modeling and experimental validation, providing a platform for studying cerebral microcirculation. The findings demonstrate the feasibility of using commercially available 3D-printed microfluidic devices to replicate small cerebral vessels. The outcomes of this study contribute to the advancement of vascular biomodeling, with implications for future clinical applications in stroke and neurovascular research.
This research bridges the gap between computational modeling and experimental validation, providing a platform for studying cerebral microcirculation. The findings demonstrate the feasibility of using commercially available 3D-printed microfluidic devices to replicate small cerebral vessels. The outcomes of this study contribute to the advancement of vascular biomodeling, with implications for future clinical applications in stroke and neurovascular research.
This study establishes an adhesive bonding strategy for the micro-assembly of optical components using UV-curable adhesives. The focus is on factors influencing adhesive shrinkage and alignment accuracy. Key findings reveal that higher UV intensity reduces both volumetric and linear shrinkage, while curing from below the substrate minimizes horizontal shifts on the to-be bonded optical components, eliminating the need for horizontal offset adjustments. The study highlights how variations in the distance between the substrate and component affect vertical shrinkage displacements and stresses the importance of precise adhesive volume control to enhance accurate shrinkage prediction. The developed shrinkage prediction model forecasts sub-micrometer accurate vertical component shrinkage compensations, validated through comprehensive parameter testing. To advance research toward more accurate shrinkage predictions and a deeper understanding of adhesive shrinkage behavior, future studies propose integrating multi-angle observation systems and expanding parameter testing. These efforts aim to refine prediction models and validate strategies in real-world applications, thereby enhancing the reliability and precision of optical systems across industrial and scientific domains.
...
This study establishes an adhesive bonding strategy for the micro-assembly of optical components using UV-curable adhesives. The focus is on factors influencing adhesive shrinkage and alignment accuracy. Key findings reveal that higher UV intensity reduces both volumetric and linear shrinkage, while curing from below the substrate minimizes horizontal shifts on the to-be bonded optical components, eliminating the need for horizontal offset adjustments. The study highlights how variations in the distance between the substrate and component affect vertical shrinkage displacements and stresses the importance of precise adhesive volume control to enhance accurate shrinkage prediction. The developed shrinkage prediction model forecasts sub-micrometer accurate vertical component shrinkage compensations, validated through comprehensive parameter testing. To advance research toward more accurate shrinkage predictions and a deeper understanding of adhesive shrinkage behavior, future studies propose integrating multi-angle observation systems and expanding parameter testing. These efforts aim to refine prediction models and validate strategies in real-world applications, thereby enhancing the reliability and precision of optical systems across industrial and scientific domains.
The use of geometric anti-springs (GASs) in MEMS accelerometers can not only boost the sensitivity through the static balancing effect, it also introduces the capability to tune the stiffness post-manufacturing by adjusting the balancing force. This paper addresses the challenge of mechanically fine-tuning the stiffness to create the potential for compensating thermal drift of bias (TDB), whereas previous methods focused on doing so electrostatically. Due to the large effect of TDB on integration errors, creating this new method for compensation could help open up the way to more accurate inertial navigation by high-precision MEMS. As the basis of our research we used an existing accelerometer from Innoseis Sensor Technologies (version G6). Based on a theoretical analysis of the TDB, requirements were formulated and a design was developed through a combination of pseudo-rigid body and finite element modelling. By building a macro-scale prototype, we were able to validate our models. It can therefore be concluded that our design provides 8 additional compression steps ranging between 50 and 54 nm based on the model predictions. This proof-of-concept demonstrates to be a new tool in the design of future accelerometers with GASs.
...
The use of geometric anti-springs (GASs) in MEMS accelerometers can not only boost the sensitivity through the static balancing effect, it also introduces the capability to tune the stiffness post-manufacturing by adjusting the balancing force. This paper addresses the challenge of mechanically fine-tuning the stiffness to create the potential for compensating thermal drift of bias (TDB), whereas previous methods focused on doing so electrostatically. Due to the large effect of TDB on integration errors, creating this new method for compensation could help open up the way to more accurate inertial navigation by high-precision MEMS. As the basis of our research we used an existing accelerometer from Innoseis Sensor Technologies (version G6). Based on a theoretical analysis of the TDB, requirements were formulated and a design was developed through a combination of pseudo-rigid body and finite element modelling. By building a macro-scale prototype, we were able to validate our models. It can therefore be concluded that our design provides 8 additional compression steps ranging between 50 and 54 nm based on the model predictions. This proof-of-concept demonstrates to be a new tool in the design of future accelerometers with GASs.
Resolving the underlying mechanisms of complex brain functions and associated disorders remains a major challenge in neuroscience, largely due to the difficulty in mapping large-scale neural network dynamics with high temporal and spatial resolution. Multimodal neural platforms that integrate optical and electrical modalities offer a promising solution, with microelectrode arrays (MEAs) being particularly effective for capturing electrophysiological activity across multiple neurons at the cellular level. Graphene has emerged as a highly attractive material for such neural interfaces due to its unique combination of biophysical, electrical, mechanical, biological, and optical properties. However, current graphene-based electrodes face challenges, including the need for transferring pre-grown graphene layers, which causes reliability issues.
In this work, microelectrode arrays based on transfer-free multilayer graphene and PEDOT:PSS are developed, and their feasibility for in vitro neural activity detection is evaluated through a brain slice culture. Firstly, the design and fabrication of graphene-based MEAs (grMEA) on transparent substrates is presented, establishing optimized microfabrication procedures for the integration of transfer-free multilayer graphene technology on in vitro MEAs. Several electrode diameters, ranging from 10 μm to 500 μm, are included to accommodate different experimental requirements and test the limits of the technology. Second, the combination of graphene and PEDOT:PSS conductive polymer is explored to overcome the fundamental limitations associated with graphene electrodes, such as high impedance at small electrode sizes, without compromising the optical transparency. A technique to integrate patterned PEDOT:PSS polymer coating on the electrodes to form graphene/PEDOT:PSS microelectrodes
(grppMEA) is developed.
The electrochemical performance, including charge storage capacity (CSC) and impedance properties, of the grMEA and grppMEA devices are evaluated. Obtained results, comparable with state-of-the-art neural interfaces, show that the PEDOT:PSS coating increases CSC values more than the double and substantially reduces the impedance by 10-20 times (e.g., from 247 kΩ to 13 kΩ for 50 μm diameter electrodes). This demonstrates the potential of the devices for efficient electrical coupling with neural tissue. Additionally, the volumetric capacitance of grppMEA electrodes was found to be 55.7 F/cm3, highlighting the volumetric ionic-electronic interaction coming from the PEDOT:PSS film, a feature absent in metal electrodes.
A custom-made interface that effectively connects the MEA devices to specific recording systems is developed to enable the acquisition of neural signals. The electrophysiological recording capabilities of the grMEA and grppMEA devices were subsequently evaluated through in vitro cerebellar brain slice cultures. Acute recordings of spontaneous activity and spike pattern characteristics of Purkinje cells and other neurons have been successfully obtained. The obtained signal-to-noise ratio values, ∼ 30 dB, demonstrate the great recording potential of the proposed MEAs. Overall, the results presented in this work demonstrate that transfer-free multilayer graphene MEA technology, especially when combined with PEDOT:PSS, overcomes the current limitations and offers the possibility for high-density recordings with single-cell resolution. ...
In this work, microelectrode arrays based on transfer-free multilayer graphene and PEDOT:PSS are developed, and their feasibility for in vitro neural activity detection is evaluated through a brain slice culture. Firstly, the design and fabrication of graphene-based MEAs (grMEA) on transparent substrates is presented, establishing optimized microfabrication procedures for the integration of transfer-free multilayer graphene technology on in vitro MEAs. Several electrode diameters, ranging from 10 μm to 500 μm, are included to accommodate different experimental requirements and test the limits of the technology. Second, the combination of graphene and PEDOT:PSS conductive polymer is explored to overcome the fundamental limitations associated with graphene electrodes, such as high impedance at small electrode sizes, without compromising the optical transparency. A technique to integrate patterned PEDOT:PSS polymer coating on the electrodes to form graphene/PEDOT:PSS microelectrodes
(grppMEA) is developed.
The electrochemical performance, including charge storage capacity (CSC) and impedance properties, of the grMEA and grppMEA devices are evaluated. Obtained results, comparable with state-of-the-art neural interfaces, show that the PEDOT:PSS coating increases CSC values more than the double and substantially reduces the impedance by 10-20 times (e.g., from 247 kΩ to 13 kΩ for 50 μm diameter electrodes). This demonstrates the potential of the devices for efficient electrical coupling with neural tissue. Additionally, the volumetric capacitance of grppMEA electrodes was found to be 55.7 F/cm3, highlighting the volumetric ionic-electronic interaction coming from the PEDOT:PSS film, a feature absent in metal electrodes.
A custom-made interface that effectively connects the MEA devices to specific recording systems is developed to enable the acquisition of neural signals. The electrophysiological recording capabilities of the grMEA and grppMEA devices were subsequently evaluated through in vitro cerebellar brain slice cultures. Acute recordings of spontaneous activity and spike pattern characteristics of Purkinje cells and other neurons have been successfully obtained. The obtained signal-to-noise ratio values, ∼ 30 dB, demonstrate the great recording potential of the proposed MEAs. Overall, the results presented in this work demonstrate that transfer-free multilayer graphene MEA technology, especially when combined with PEDOT:PSS, overcomes the current limitations and offers the possibility for high-density recordings with single-cell resolution. ...
Resolving the underlying mechanisms of complex brain functions and associated disorders remains a major challenge in neuroscience, largely due to the difficulty in mapping large-scale neural network dynamics with high temporal and spatial resolution. Multimodal neural platforms that integrate optical and electrical modalities offer a promising solution, with microelectrode arrays (MEAs) being particularly effective for capturing electrophysiological activity across multiple neurons at the cellular level. Graphene has emerged as a highly attractive material for such neural interfaces due to its unique combination of biophysical, electrical, mechanical, biological, and optical properties. However, current graphene-based electrodes face challenges, including the need for transferring pre-grown graphene layers, which causes reliability issues.
In this work, microelectrode arrays based on transfer-free multilayer graphene and PEDOT:PSS are developed, and their feasibility for in vitro neural activity detection is evaluated through a brain slice culture. Firstly, the design and fabrication of graphene-based MEAs (grMEA) on transparent substrates is presented, establishing optimized microfabrication procedures for the integration of transfer-free multilayer graphene technology on in vitro MEAs. Several electrode diameters, ranging from 10 μm to 500 μm, are included to accommodate different experimental requirements and test the limits of the technology. Second, the combination of graphene and PEDOT:PSS conductive polymer is explored to overcome the fundamental limitations associated with graphene electrodes, such as high impedance at small electrode sizes, without compromising the optical transparency. A technique to integrate patterned PEDOT:PSS polymer coating on the electrodes to form graphene/PEDOT:PSS microelectrodes
(grppMEA) is developed.
The electrochemical performance, including charge storage capacity (CSC) and impedance properties, of the grMEA and grppMEA devices are evaluated. Obtained results, comparable with state-of-the-art neural interfaces, show that the PEDOT:PSS coating increases CSC values more than the double and substantially reduces the impedance by 10-20 times (e.g., from 247 kΩ to 13 kΩ for 50 μm diameter electrodes). This demonstrates the potential of the devices for efficient electrical coupling with neural tissue. Additionally, the volumetric capacitance of grppMEA electrodes was found to be 55.7 F/cm3, highlighting the volumetric ionic-electronic interaction coming from the PEDOT:PSS film, a feature absent in metal electrodes.
A custom-made interface that effectively connects the MEA devices to specific recording systems is developed to enable the acquisition of neural signals. The electrophysiological recording capabilities of the grMEA and grppMEA devices were subsequently evaluated through in vitro cerebellar brain slice cultures. Acute recordings of spontaneous activity and spike pattern characteristics of Purkinje cells and other neurons have been successfully obtained. The obtained signal-to-noise ratio values, ∼ 30 dB, demonstrate the great recording potential of the proposed MEAs. Overall, the results presented in this work demonstrate that transfer-free multilayer graphene MEA technology, especially when combined with PEDOT:PSS, overcomes the current limitations and offers the possibility for high-density recordings with single-cell resolution.
In this work, microelectrode arrays based on transfer-free multilayer graphene and PEDOT:PSS are developed, and their feasibility for in vitro neural activity detection is evaluated through a brain slice culture. Firstly, the design and fabrication of graphene-based MEAs (grMEA) on transparent substrates is presented, establishing optimized microfabrication procedures for the integration of transfer-free multilayer graphene technology on in vitro MEAs. Several electrode diameters, ranging from 10 μm to 500 μm, are included to accommodate different experimental requirements and test the limits of the technology. Second, the combination of graphene and PEDOT:PSS conductive polymer is explored to overcome the fundamental limitations associated with graphene electrodes, such as high impedance at small electrode sizes, without compromising the optical transparency. A technique to integrate patterned PEDOT:PSS polymer coating on the electrodes to form graphene/PEDOT:PSS microelectrodes
(grppMEA) is developed.
The electrochemical performance, including charge storage capacity (CSC) and impedance properties, of the grMEA and grppMEA devices are evaluated. Obtained results, comparable with state-of-the-art neural interfaces, show that the PEDOT:PSS coating increases CSC values more than the double and substantially reduces the impedance by 10-20 times (e.g., from 247 kΩ to 13 kΩ for 50 μm diameter electrodes). This demonstrates the potential of the devices for efficient electrical coupling with neural tissue. Additionally, the volumetric capacitance of grppMEA electrodes was found to be 55.7 F/cm3, highlighting the volumetric ionic-electronic interaction coming from the PEDOT:PSS film, a feature absent in metal electrodes.
A custom-made interface that effectively connects the MEA devices to specific recording systems is developed to enable the acquisition of neural signals. The electrophysiological recording capabilities of the grMEA and grppMEA devices were subsequently evaluated through in vitro cerebellar brain slice cultures. Acute recordings of spontaneous activity and spike pattern characteristics of Purkinje cells and other neurons have been successfully obtained. The obtained signal-to-noise ratio values, ∼ 30 dB, demonstrate the great recording potential of the proposed MEAs. Overall, the results presented in this work demonstrate that transfer-free multilayer graphene MEA technology, especially when combined with PEDOT:PSS, overcomes the current limitations and offers the possibility for high-density recordings with single-cell resolution.
Master thesis
(2023)
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V.D. Struijk, F. Alijani, A. Japaridze, I.E. Roslon, M.K. Ghatkesar, D.S.W. Tam
Life at low-Reynolds numbers regime is intriguing. Single motile bacteria are known to exhibit erratic behaviour; they swim in what is known as a random walk, alternating between periods of swimming straight and abrupt moments of re-orientation. Yet in dense populations, cells of E.coli have been reported to exhibit weak synchronization and self-organize into collective oscillatory motion patterns. However, the origin of this rhythmic behaviour remains largely unknown. Here, we present a method of inducing self-sustained oscillations over minute timescales in single E.coli cells by trapping them in circular microcavities. By engineering the size of these microwells, we show that the velocity of single E.coli can be tuned between speeds ranging from a few to 20 um/s. Furthermore, we show that by connecting the microwells via on-chip channels, E.coli tend to coordinate their motion through hydrodynamic interaction and exhibit collective dynamics. Using analytical modeling, we extract the coupling strength and design the channels to mediate synchronized oscillation between two bacterial oscillators. Our work not only advances our understanding of the collective dynamics of swarming bacteria but also provides the first evidence for single-cell bacterial oscillators, paving the way to using micro-organism-inspired oscillations in applications as varied as antibiotic screening, scientific computing and micro-swimmers.
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Life at low-Reynolds numbers regime is intriguing. Single motile bacteria are known to exhibit erratic behaviour; they swim in what is known as a random walk, alternating between periods of swimming straight and abrupt moments of re-orientation. Yet in dense populations, cells of E.coli have been reported to exhibit weak synchronization and self-organize into collective oscillatory motion patterns. However, the origin of this rhythmic behaviour remains largely unknown. Here, we present a method of inducing self-sustained oscillations over minute timescales in single E.coli cells by trapping them in circular microcavities. By engineering the size of these microwells, we show that the velocity of single E.coli can be tuned between speeds ranging from a few to 20 um/s. Furthermore, we show that by connecting the microwells via on-chip channels, E.coli tend to coordinate their motion through hydrodynamic interaction and exhibit collective dynamics. Using analytical modeling, we extract the coupling strength and design the channels to mediate synchronized oscillation between two bacterial oscillators. Our work not only advances our understanding of the collective dynamics of swarming bacteria but also provides the first evidence for single-cell bacterial oscillators, paving the way to using micro-organism-inspired oscillations in applications as varied as antibiotic screening, scientific computing and micro-swimmers.
Small satellites require efficient propulsion systems for attitude and orbit control. This thesis focuses on the development and characterization of two distinct types of micro-resistojet thrusters, namely Vaporizing Liquid Micro-resistojet (VLM) and Low Pressure Micro-resistojet (LPM). Both concepts are developed at TU Delft and are designed to use water as a propellant, conforming to launch-safety, simplicity, and cost-effectiveness criteria.
In VLM, liquid water is vaporized and accelerated through a convergent-divergent nozzle. In contrast, LPM operates by reducing water vapor pressure to below 300 Pa and then accelerating it through expansion slots under a rarefied flow regime. Both types of thrusters are built on Micro-Electro-Mechanical Systems (MEMS) chips to accommodate the size constraints of nano- and pico-satellites.
The thesis introduces refined designs for both VLM and LPM thrusters. Specifically, the VLM design features an optimized nozzle shape and improved inlet flow, while the redesigned LPM assembly is more space-efficient. These modifications increase the thrust-to-size ratio for both thruster types.
The thesis presents a fabrication process for these thrusters, employing an anodic bonded silicon-glass wafer stack with a capped microfluidic channel. Fabrication was executed at the EKL lab, using a simplified manufacturing process that is detailed within the report.
Post-fabrication, the thrusters underwent mechanical and electrical characterization. The results indicate incremental improvements in both design performance and manufacturability. The new VLM design yielded a 15% increase in thrust efficiency, while the new LPM assembly reduced the occupied volume by 30%.
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In VLM, liquid water is vaporized and accelerated through a convergent-divergent nozzle. In contrast, LPM operates by reducing water vapor pressure to below 300 Pa and then accelerating it through expansion slots under a rarefied flow regime. Both types of thrusters are built on Micro-Electro-Mechanical Systems (MEMS) chips to accommodate the size constraints of nano- and pico-satellites.
The thesis introduces refined designs for both VLM and LPM thrusters. Specifically, the VLM design features an optimized nozzle shape and improved inlet flow, while the redesigned LPM assembly is more space-efficient. These modifications increase the thrust-to-size ratio for both thruster types.
The thesis presents a fabrication process for these thrusters, employing an anodic bonded silicon-glass wafer stack with a capped microfluidic channel. Fabrication was executed at the EKL lab, using a simplified manufacturing process that is detailed within the report.
Post-fabrication, the thrusters underwent mechanical and electrical characterization. The results indicate incremental improvements in both design performance and manufacturability. The new VLM design yielded a 15% increase in thrust efficiency, while the new LPM assembly reduced the occupied volume by 30%.
...
Small satellites require efficient propulsion systems for attitude and orbit control. This thesis focuses on the development and characterization of two distinct types of micro-resistojet thrusters, namely Vaporizing Liquid Micro-resistojet (VLM) and Low Pressure Micro-resistojet (LPM). Both concepts are developed at TU Delft and are designed to use water as a propellant, conforming to launch-safety, simplicity, and cost-effectiveness criteria.
In VLM, liquid water is vaporized and accelerated through a convergent-divergent nozzle. In contrast, LPM operates by reducing water vapor pressure to below 300 Pa and then accelerating it through expansion slots under a rarefied flow regime. Both types of thrusters are built on Micro-Electro-Mechanical Systems (MEMS) chips to accommodate the size constraints of nano- and pico-satellites.
The thesis introduces refined designs for both VLM and LPM thrusters. Specifically, the VLM design features an optimized nozzle shape and improved inlet flow, while the redesigned LPM assembly is more space-efficient. These modifications increase the thrust-to-size ratio for both thruster types.
The thesis presents a fabrication process for these thrusters, employing an anodic bonded silicon-glass wafer stack with a capped microfluidic channel. Fabrication was executed at the EKL lab, using a simplified manufacturing process that is detailed within the report.
Post-fabrication, the thrusters underwent mechanical and electrical characterization. The results indicate incremental improvements in both design performance and manufacturability. The new VLM design yielded a 15% increase in thrust efficiency, while the new LPM assembly reduced the occupied volume by 30%.
In VLM, liquid water is vaporized and accelerated through a convergent-divergent nozzle. In contrast, LPM operates by reducing water vapor pressure to below 300 Pa and then accelerating it through expansion slots under a rarefied flow regime. Both types of thrusters are built on Micro-Electro-Mechanical Systems (MEMS) chips to accommodate the size constraints of nano- and pico-satellites.
The thesis introduces refined designs for both VLM and LPM thrusters. Specifically, the VLM design features an optimized nozzle shape and improved inlet flow, while the redesigned LPM assembly is more space-efficient. These modifications increase the thrust-to-size ratio for both thruster types.
The thesis presents a fabrication process for these thrusters, employing an anodic bonded silicon-glass wafer stack with a capped microfluidic channel. Fabrication was executed at the EKL lab, using a simplified manufacturing process that is detailed within the report.
Post-fabrication, the thrusters underwent mechanical and electrical characterization. The results indicate incremental improvements in both design performance and manufacturability. The new VLM design yielded a 15% increase in thrust efficiency, while the new LPM assembly reduced the occupied volume by 30%.
Proteins play a key role in many biological processes and are thus useful indicators of health and disease states. Since the size of proteins is few hundred nanometers, it is necessary to explore new techniques to manipulate and 'read' them. This thesis aims to identify and build a platform that enables sub-micron bead manipulation, which will be used to actively deliver the biomolecules attached to the beads to the single-molecule sensor. During this process, accurate positioning, speed control, and multiplexing of the beads need to be solved to give high-resolution and high-throughput sequencing capabilities. We identify surface acoustics wave (SAW) devices as powerful tools to achieve both beads transport and massively parallel manipulation. Our hypothesis is that we can increase the efficiency and precision of bead capture and manipulation by using SAW devices combined with a microcavity layer. In this master thesis, we fabricate the SAW device with an average 2 $\mu m$ thick film, and there are cavity arrays on the film. In addition, we investigate the performance of trapping sub-micron objects during the actuation. Further more, we discuss few challenges found through the experiments and provide possible solutions for them. At last, this thesis is concluded by discussing the work been done and providing suggestions for future experiments.
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Proteins play a key role in many biological processes and are thus useful indicators of health and disease states. Since the size of proteins is few hundred nanometers, it is necessary to explore new techniques to manipulate and 'read' them. This thesis aims to identify and build a platform that enables sub-micron bead manipulation, which will be used to actively deliver the biomolecules attached to the beads to the single-molecule sensor. During this process, accurate positioning, speed control, and multiplexing of the beads need to be solved to give high-resolution and high-throughput sequencing capabilities. We identify surface acoustics wave (SAW) devices as powerful tools to achieve both beads transport and massively parallel manipulation. Our hypothesis is that we can increase the efficiency and precision of bead capture and manipulation by using SAW devices combined with a microcavity layer. In this master thesis, we fabricate the SAW device with an average 2 $\mu m$ thick film, and there are cavity arrays on the film. In addition, we investigate the performance of trapping sub-micron objects during the actuation. Further more, we discuss few challenges found through the experiments and provide possible solutions for them. At last, this thesis is concluded by discussing the work been done and providing suggestions for future experiments.
Toward 3D printed suspended microchannel resonators
A study on damping and mass resolution of 3D printed microbeam resonators
Biosensing properties like mass, density and stiffness on a single cell level can help diagnose diseases. Mass sensing of cells and subcellular components is typically performed with resonant microstructures. Recently such microstructures were fabricated using an emerging 3D printing technique called two-photon polymerization (2PP) contrary to conventional lithography-based fabrication. The suspended microchannel resonator (SMR) is such a resonant microstructure with an embedded fluidic channel for buoyant mass sensing, which has not yet been fabricated using 2PP. This work aims to 3D print an SMR with a sufficient mass resolution to detect the buoyant mass of E. Coli bacteria (175 fg in water). It was realized by first characterizing the damping in 3D printed polymer microbeam resonators for a better understanding of dominating damping sources. Followed by maximizing their quality factor and fabricating a prototype 3D-printed SMR. The characterized devices set a record-breaking standard for damping of polymer microbeam resonators: Cantilevers and bridges approached quality factors of 1000 and tensile stressed narrow bridges achieved a quality factor of 1819. These polymer resonators were dominated by bulk friction damping, but still had a mass resolution advantage over similar silicon-based devices when working in lower quality factor (Q < 1000) conditions, due to the low mass density of the polymer. Subsequently, prototypes of the suspended microchannel resonator were fabricated with multi-scale 3D printing containing a plug-and-play connection to fluidics and measurement equipment. Their theoretical mass resolution was estimated to be ≤ 60 fg, which is sensitive enough to detect E. Coli bacteria and compete with conventional fabricated SMRs. This paves the path towards actual biosensing 3D printed SMRs with the capabilities of lithography-based fabricated devices but with additional design and fabrication flexibility.
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Biosensing properties like mass, density and stiffness on a single cell level can help diagnose diseases. Mass sensing of cells and subcellular components is typically performed with resonant microstructures. Recently such microstructures were fabricated using an emerging 3D printing technique called two-photon polymerization (2PP) contrary to conventional lithography-based fabrication. The suspended microchannel resonator (SMR) is such a resonant microstructure with an embedded fluidic channel for buoyant mass sensing, which has not yet been fabricated using 2PP. This work aims to 3D print an SMR with a sufficient mass resolution to detect the buoyant mass of E. Coli bacteria (175 fg in water). It was realized by first characterizing the damping in 3D printed polymer microbeam resonators for a better understanding of dominating damping sources. Followed by maximizing their quality factor and fabricating a prototype 3D-printed SMR. The characterized devices set a record-breaking standard for damping of polymer microbeam resonators: Cantilevers and bridges approached quality factors of 1000 and tensile stressed narrow bridges achieved a quality factor of 1819. These polymer resonators were dominated by bulk friction damping, but still had a mass resolution advantage over similar silicon-based devices when working in lower quality factor (Q < 1000) conditions, due to the low mass density of the polymer. Subsequently, prototypes of the suspended microchannel resonator were fabricated with multi-scale 3D printing containing a plug-and-play connection to fluidics and measurement equipment. Their theoretical mass resolution was estimated to be ≤ 60 fg, which is sensitive enough to detect E. Coli bacteria and compete with conventional fabricated SMRs. This paves the path towards actual biosensing 3D printed SMRs with the capabilities of lithography-based fabricated devices but with additional design and fabrication flexibility.
In connection with growing in applications of nanoparticles in various industrial sectors such as cosmetics and pharmaceuticals, the demand for in-line identification and characterization of nanoparticles suspended in fluids has increased. In addition to that, nanoparticles in general and nanoplastics in particular, can easily contaminate air and water resources, resulting in human health risks. Among available techniques, suspended microchannel resonators can respond to the characterization demands in terms of mass detection and concentration of nanoparticles in fluids. This technique is based on changes in resonance frequency of the suspended microchannel due to flowing of nanoparticles through the suspended hollow cantilever. In this project we aimed to characterise TUDelft made suspended microchannel resonators in terms of mass limit detection and speed of detection. We found that the lowest resolved mass can be detected by the second bending mode. This was 0.11 fg and0.38 fg using an empty and a water-filled resonator respectively, for a system bandwidth of 1000 Hz that corresponds to a system settling time of 0.37 ms. We also managed to measure a buoyant mass of 21.2 fg which is an equivalent gold nanoparticle of 130 nm in diameter, during one of the attempts to detect suspended gold nanoparticles in deionized water.
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In connection with growing in applications of nanoparticles in various industrial sectors such as cosmetics and pharmaceuticals, the demand for in-line identification and characterization of nanoparticles suspended in fluids has increased. In addition to that, nanoparticles in general and nanoplastics in particular, can easily contaminate air and water resources, resulting in human health risks. Among available techniques, suspended microchannel resonators can respond to the characterization demands in terms of mass detection and concentration of nanoparticles in fluids. This technique is based on changes in resonance frequency of the suspended microchannel due to flowing of nanoparticles through the suspended hollow cantilever. In this project we aimed to characterise TUDelft made suspended microchannel resonators in terms of mass limit detection and speed of detection. We found that the lowest resolved mass can be detected by the second bending mode. This was 0.11 fg and0.38 fg using an empty and a water-filled resonator respectively, for a system bandwidth of 1000 Hz that corresponds to a system settling time of 0.37 ms. We also managed to measure a buoyant mass of 21.2 fg which is an equivalent gold nanoparticle of 130 nm in diameter, during one of the attempts to detect suspended gold nanoparticles in deionized water.
Master thesis
(2021)
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B. Roos, A. Accardo, M.K. Ghatkesar, A.M.S.E. Sharaf, Raissa Timmerman, Jeffrey Bajramovic
Microglia, the resident macrophages of the central nervous system, are key players in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. These cells represent promising cellular targets for therapeutic intervention, therefore a detailed cellular biological knowledge of microglia is of paramount importance. Current microglia in vitro cell culture models are limited in their ability to recapitulate in vivo microglia in terms of gene expression and cell morphology. There is growing evidence that mimicking the cellular environment of microglia in the central nervous system will contribute to a more physiologically accurate culture model. Three-dimensional geometries, and physical and biochemical cues similar to the brain’s extracellular matrix, are necessary to create a 3D biomimetic in vitro environment, as microglia cells can sense these environmental cues through mechanosensing. In this thesis, the effect of two-photon polymerized 2.5D and 3D microstructures on microglia morphology and phenotype was studied through quantitative and qualitative cell analysis. Also, an attempt was made to create in vitro ramified microglia that resemble in vivo microglia from a morphological point of view, by con-trolling the effective shear modulus through dimensional optimization of compliant micro-and nanopillars. It was found that culturing microglia especially on nanopillars enabled an increase of the ramified pheno-type and a more complex (i.e. more ramifications) cell morphology as compared to microglia cultured onflat fused silica substrates. Furthermore, we report that microglia cultured on 3D structures exhibit similarphenotypes observed in the 2D and 2.5D cultures, and were more resemblingin vivomicroglia in terms of3D cell morphology.
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Microglia, the resident macrophages of the central nervous system, are key players in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. These cells represent promising cellular targets for therapeutic intervention, therefore a detailed cellular biological knowledge of microglia is of paramount importance. Current microglia in vitro cell culture models are limited in their ability to recapitulate in vivo microglia in terms of gene expression and cell morphology. There is growing evidence that mimicking the cellular environment of microglia in the central nervous system will contribute to a more physiologically accurate culture model. Three-dimensional geometries, and physical and biochemical cues similar to the brain’s extracellular matrix, are necessary to create a 3D biomimetic in vitro environment, as microglia cells can sense these environmental cues through mechanosensing. In this thesis, the effect of two-photon polymerized 2.5D and 3D microstructures on microglia morphology and phenotype was studied through quantitative and qualitative cell analysis. Also, an attempt was made to create in vitro ramified microglia that resemble in vivo microglia from a morphological point of view, by con-trolling the effective shear modulus through dimensional optimization of compliant micro-and nanopillars. It was found that culturing microglia especially on nanopillars enabled an increase of the ramified pheno-type and a more complex (i.e. more ramifications) cell morphology as compared to microglia cultured onflat fused silica substrates. Furthermore, we report that microglia cultured on 3D structures exhibit similarphenotypes observed in the 2D and 2.5D cultures, and were more resemblingin vivomicroglia in terms of3D cell morphology.
Design of a valveless organ-on-chip micropump
A new take on on-chip actuation for organ-on-chip devices
In the last few years organ-on-chip (OoC) has been emerging as a new method for more reliable research to screen the effects of new drugs on the body. This is a novel technology mimicking the in vivo environment of tissue cells, making it a more suitable candidate for experimentation than traditional 2D cell cultures. However, in order to ensure smooth and swift implementation of this technique, some issues must be addressed first. One of these issues concerns perfusion: most OoC devices require external equipment to provide the necessary dynamic flow that makes the OoC unique, so that cells experience continuous fluid shear and are perfused sufficiently. In this thesis a model of an on-chip electro-polymeric pump is designed for application on an OoC. From a background study the design aims are defined: a membrane actuated pump with a nozzle-diffuser channel providing pump action. The membrane is made from ionic polymer-metal composite (IPMC), a material that deforms under electric current which is produced at TU Delft with the intention to use it in OoC applications. Its low voltage operating range and its biocompatibility make it an excellent candidate for this. Furthermore, the nozzle-diffuser elements avoid the need for moving elements inside the channel, instead providing pump action based on a pressure gradient over the nozzle elements. Finally, three design aims are defined, being: high flowrate, high flow pulse and low flow rate and pulse applications, corresponding to various needs in the OoC field. A base model is designed using COMSOL Multiphysics software, using similar devices described in literature. The model consists of a combination of solid mechanics (for membrane movement), fluid mechanics (for flow movement) and a fluid-structure interaction module to combine the two. This model is then tested for a range of parameters, first independently and later in pairs. General conclusions drawn from these simulations include: - Between the membrane displacement and -frequency (which can both be varied after fabrication), the membrane displacement magnitude affects the output more significantly than actuation frequency - The membrane width is positively correlated with flow rate output and pulse amplitude - The channel depth is positively correlated with flow rate output, but only if the membrane displacement scales along with it - A long slender nozzle yields lower flow output than a short, squat nozzle - The results from this model are consistent with nozzle-diffuser theory, stating that nozzle resistance and membrane movement affect the flow most significantly. This leads to three designs according to the three application wishes expressed earlier. The pump is designed such that it can be manufactured on a silicon wafer using electronics cleanroom equipment. The combination with the process developed for IPMC provides a novel pumping mechanism that has the potential to fully integrate an important aspect of an OoC on-chip, greatly increasing user friendliness and allowing for wider implementation of this technology.
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In the last few years organ-on-chip (OoC) has been emerging as a new method for more reliable research to screen the effects of new drugs on the body. This is a novel technology mimicking the in vivo environment of tissue cells, making it a more suitable candidate for experimentation than traditional 2D cell cultures. However, in order to ensure smooth and swift implementation of this technique, some issues must be addressed first. One of these issues concerns perfusion: most OoC devices require external equipment to provide the necessary dynamic flow that makes the OoC unique, so that cells experience continuous fluid shear and are perfused sufficiently. In this thesis a model of an on-chip electro-polymeric pump is designed for application on an OoC. From a background study the design aims are defined: a membrane actuated pump with a nozzle-diffuser channel providing pump action. The membrane is made from ionic polymer-metal composite (IPMC), a material that deforms under electric current which is produced at TU Delft with the intention to use it in OoC applications. Its low voltage operating range and its biocompatibility make it an excellent candidate for this. Furthermore, the nozzle-diffuser elements avoid the need for moving elements inside the channel, instead providing pump action based on a pressure gradient over the nozzle elements. Finally, three design aims are defined, being: high flowrate, high flow pulse and low flow rate and pulse applications, corresponding to various needs in the OoC field. A base model is designed using COMSOL Multiphysics software, using similar devices described in literature. The model consists of a combination of solid mechanics (for membrane movement), fluid mechanics (for flow movement) and a fluid-structure interaction module to combine the two. This model is then tested for a range of parameters, first independently and later in pairs. General conclusions drawn from these simulations include: - Between the membrane displacement and -frequency (which can both be varied after fabrication), the membrane displacement magnitude affects the output more significantly than actuation frequency - The membrane width is positively correlated with flow rate output and pulse amplitude - The channel depth is positively correlated with flow rate output, but only if the membrane displacement scales along with it - A long slender nozzle yields lower flow output than a short, squat nozzle - The results from this model are consistent with nozzle-diffuser theory, stating that nozzle resistance and membrane movement affect the flow most significantly. This leads to three designs according to the three application wishes expressed earlier. The pump is designed such that it can be manufactured on a silicon wafer using electronics cleanroom equipment. The combination with the process developed for IPMC provides a novel pumping mechanism that has the potential to fully integrate an important aspect of an OoC on-chip, greatly increasing user friendliness and allowing for wider implementation of this technology.
Cell behavior in vitro can be regulated by mechanical stimulation. Cytostretch is an Organ-on-Chip (OOC) platform that allows cyclic stretching tissue in culture. Its pneumatic actuation can hinder it from microfluidic systems integration. A dielectric elastomer actuator (DEA) was developed and fabricated in this thesis for Cytostretch as an alternative actuation method. The DEA consists of a suspended polymer membrane sandwiched between electrodes, which can induce out-of-plane motion when a voltage is applied. The functionality of the design was proved in numerical analysis. A complete process flow was developed and partly implemented for the wafer-scale microfabrication of this innovative actuator. The top electrodes of the device were fabricated by depositing and patterning titanium nitride with stress buffering layers. The quality of the electrodes was examined and wrinkles were found at corners of certain etching patterns. The angle of the corner and spacing between corners were proposed to be two factors influencing the wrinkle formation. This work paves the way to the successful integration of DEAs for mechanical stimulation of cell tissues within OOC platforms.
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Cell behavior in vitro can be regulated by mechanical stimulation. Cytostretch is an Organ-on-Chip (OOC) platform that allows cyclic stretching tissue in culture. Its pneumatic actuation can hinder it from microfluidic systems integration. A dielectric elastomer actuator (DEA) was developed and fabricated in this thesis for Cytostretch as an alternative actuation method. The DEA consists of a suspended polymer membrane sandwiched between electrodes, which can induce out-of-plane motion when a voltage is applied. The functionality of the design was proved in numerical analysis. A complete process flow was developed and partly implemented for the wafer-scale microfabrication of this innovative actuator. The top electrodes of the device were fabricated by depositing and patterning titanium nitride with stress buffering layers. The quality of the electrodes was examined and wrinkles were found at corners of certain etching patterns. The angle of the corner and spacing between corners were proposed to be two factors influencing the wrinkle formation. This work paves the way to the successful integration of DEAs for mechanical stimulation of cell tissues within OOC platforms.
Master thesis
(2019)
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Lorenzo Kunkels, Amir Zadpoor, Lidy Fratila-Apachitei, Kees Hagen, Peter-Leon Hagedoorn, Khashayar Modaresifar, Murali Ghatkesar, Caroline Paul
Patients with orthopaedic implants often experience implant-associated infections (IAI), one of the most prominent causes for implant failure. IAIs are caused by pathogens adhering to the implant surface. One method to prevent IAIs is through the use of surface topography modifications. Cellular behaviour has been shown to be influenced by substrate surface topographies. Ideally, a topography that can simultaneously kill bacteria and promote osseointegration is desirable. In previous research, proved-to-be-bactericidal nanopillars of ~180 nm in height and ~80 nm in diameter were fabricated at 170 nm interspace, resulting in a bactericidal efficiency of 36 ± 5% for Staphylococcus aureus (S. aureus). The current research aimed to enhance this bactericidal efficiency by producing nanopatterns with different interspace distances and introducing disorder, while keeping the same nanopillar dimensions. The patterns have been produced by using electron beam induced deposition (EBID) at 100, 170, 300 and 500 nm interspacing. A disordered version of the 170, 300 and 500 nm samples was included with 45, 110 and 210 nm disorder distance, respectively. In order to keep the nanopillar dimensions consistent, EBID parameters were systematically optimised. The nanopatterns were interfaced with S. aureus cells and the bactericidal efficiencies were determined by counting the number of healthy, deformed and dead bacterial cells. For the ordered 100, 170, 300 and 500 nm interspace nanopatterns, bactericidal efficiencies of 62.3 ± 23.1%, 45.0 ± 31.4%, 8.6 ± 4.2% and 3.7 ± 2.3% were found, respectively. For the disordered 170, 300 and 500 nm interspace nanopatterns, bactericidal efficiencies of 45.9 ± 29.2%, 14.7 ± 7.2% and 12.7 ± 9.8% were found, respectively. These results showed a significantly higher bactericidal effect on lower-interspace nanopatterns. Disordered nanopatterns showed only slightly higher bactericidal efficiencies when compared to the ordered nanopatterns. This data indicated that bactericidal efficiencies could be increased relative to the previous nanopattern design. The findings of this research aid in developing antibacterial nanopatterns that are capable of killing gram-positive bacteria and support the path to prevention of IAIs.
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Patients with orthopaedic implants often experience implant-associated infections (IAI), one of the most prominent causes for implant failure. IAIs are caused by pathogens adhering to the implant surface. One method to prevent IAIs is through the use of surface topography modifications. Cellular behaviour has been shown to be influenced by substrate surface topographies. Ideally, a topography that can simultaneously kill bacteria and promote osseointegration is desirable. In previous research, proved-to-be-bactericidal nanopillars of ~180 nm in height and ~80 nm in diameter were fabricated at 170 nm interspace, resulting in a bactericidal efficiency of 36 ± 5% for Staphylococcus aureus (S. aureus). The current research aimed to enhance this bactericidal efficiency by producing nanopatterns with different interspace distances and introducing disorder, while keeping the same nanopillar dimensions. The patterns have been produced by using electron beam induced deposition (EBID) at 100, 170, 300 and 500 nm interspacing. A disordered version of the 170, 300 and 500 nm samples was included with 45, 110 and 210 nm disorder distance, respectively. In order to keep the nanopillar dimensions consistent, EBID parameters were systematically optimised. The nanopatterns were interfaced with S. aureus cells and the bactericidal efficiencies were determined by counting the number of healthy, deformed and dead bacterial cells. For the ordered 100, 170, 300 and 500 nm interspace nanopatterns, bactericidal efficiencies of 62.3 ± 23.1%, 45.0 ± 31.4%, 8.6 ± 4.2% and 3.7 ± 2.3% were found, respectively. For the disordered 170, 300 and 500 nm interspace nanopatterns, bactericidal efficiencies of 45.9 ± 29.2%, 14.7 ± 7.2% and 12.7 ± 9.8% were found, respectively. These results showed a significantly higher bactericidal effect on lower-interspace nanopatterns. Disordered nanopatterns showed only slightly higher bactericidal efficiencies when compared to the ordered nanopatterns. This data indicated that bactericidal efficiencies could be increased relative to the previous nanopattern design. The findings of this research aid in developing antibacterial nanopatterns that are capable of killing gram-positive bacteria and support the path to prevention of IAIs.
Master thesis
(2019)
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Xuanmin He, Sander den Hoedt, Jo Spronck, Murali Ghatkesar, Hassan Hossein Nia Kani
The Nobel Prize in Chemistry in 2017 went to the development of cryo-electron microscopy, which contributed to the discovery of new cells and viruses, the diagnosis of unknown diseases, the mapping of human genomes and the manufacturing of semiconductors. Cryo Correlative light and electron microscopy (Cryo-CLEM), is the combination of using fluorescence microscopy and cryo-electron microscopy to image cryo-immobilized bio-samples. These samples (at a temperature lower than −165ᵒC), require critical conditions in preparation and preservation to prevent contamination and heating which have a negative influence on the imaging results. In the current sample transfer workflow, almost 90% of the samples transferred end up being wasted due to the unideal protection and transfer gap. Therefore, an integrated high-vacuum sample transfer system which fits the interfaces of CLEM devices and actively protects the samples from heating and contamination in transfer has been designed to conquer the problems, ensure better imaging results, and increase the process yield. COMSOL simulations on its thermal and mechanical behaviors have been carried out to theoretically verify and iterate the design. The new transfer system provides a cheaper, faster, easier, more contamination-free, more temperature-stable, more user-friendly workflow that can increase the yield of sample transfer from 10% to 90%.
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The Nobel Prize in Chemistry in 2017 went to the development of cryo-electron microscopy, which contributed to the discovery of new cells and viruses, the diagnosis of unknown diseases, the mapping of human genomes and the manufacturing of semiconductors. Cryo Correlative light and electron microscopy (Cryo-CLEM), is the combination of using fluorescence microscopy and cryo-electron microscopy to image cryo-immobilized bio-samples. These samples (at a temperature lower than −165ᵒC), require critical conditions in preparation and preservation to prevent contamination and heating which have a negative influence on the imaging results. In the current sample transfer workflow, almost 90% of the samples transferred end up being wasted due to the unideal protection and transfer gap. Therefore, an integrated high-vacuum sample transfer system which fits the interfaces of CLEM devices and actively protects the samples from heating and contamination in transfer has been designed to conquer the problems, ensure better imaging results, and increase the process yield. COMSOL simulations on its thermal and mechanical behaviors have been carried out to theoretically verify and iterate the design. The new transfer system provides a cheaper, faster, easier, more contamination-free, more temperature-stable, more user-friendly workflow that can increase the yield of sample transfer from 10% to 90%.
Diamagnetically Levitated Resonant Mass Sensor
Master of Science Thesis
Master thesis
(2019)
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Nimit Kothari, Peter Steeneken, Farbod Alijani, Murali Ghatkesar, Sten Vollebregt
In the past few decades, there has been a growing demand for low-cost disposable sensors to be utilized in hazardous and toxic environments such as high temperature and chemically aggressive environments, which can lead to irreversible damage to the sensor. Moreover, by cost reduction, they become more attractive for utilization in developing countries, where the research of new biomedical technologies has been restricted due to a decentralized healthcare system, lack of infrastructure and shortage of investment. This research focuses on developing a low-cost, disposable and easy to use mass sensor utilizing diamagnetic levitation. Diamagnetic levitation is the only stable form of levitation at room temperature and does not require external sources of energy, feedback loops or cooling for stable levitation. It is a low cost, easy to use, disposable sensor that makes it suitable for potential point-of-care applications. The sensor consists of a pyrolytic graphite plate that levitates above a checkerboard arrangement of permanent magnets with alternating magnetization. The system is actuated using electromagnetic excitation and the material properties of the sample are extracted by conducting a multi-modal analysis of the resonance frequencies and mode shapes; measured using a laser Doppler vibrometer (LDV). An opto-electronic phase lock loop utilizing the LDV is used to bring the levitating pyrolytic graphite into sustained mechanical oscillation controlled by a PID controller. The experimental mass sensitivity is measured by analysing the frequency shift associated with the placement of glass beads. The frequency stability is measured by computing the Allan deviation and the experimental precision of mass sensor is then computed. The results show that the precision of a diamagnetically levitated resonant mass sensors decreases with the decrease of the size of the levitating oscillator. The precision of a levitating oscillator of side length 2mm and thickness 0.08mm is found to be 14.4pg at a gate time of 0.1s for an instantaneous change in frequency.
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In the past few decades, there has been a growing demand for low-cost disposable sensors to be utilized in hazardous and toxic environments such as high temperature and chemically aggressive environments, which can lead to irreversible damage to the sensor. Moreover, by cost reduction, they become more attractive for utilization in developing countries, where the research of new biomedical technologies has been restricted due to a decentralized healthcare system, lack of infrastructure and shortage of investment. This research focuses on developing a low-cost, disposable and easy to use mass sensor utilizing diamagnetic levitation. Diamagnetic levitation is the only stable form of levitation at room temperature and does not require external sources of energy, feedback loops or cooling for stable levitation. It is a low cost, easy to use, disposable sensor that makes it suitable for potential point-of-care applications. The sensor consists of a pyrolytic graphite plate that levitates above a checkerboard arrangement of permanent magnets with alternating magnetization. The system is actuated using electromagnetic excitation and the material properties of the sample are extracted by conducting a multi-modal analysis of the resonance frequencies and mode shapes; measured using a laser Doppler vibrometer (LDV). An opto-electronic phase lock loop utilizing the LDV is used to bring the levitating pyrolytic graphite into sustained mechanical oscillation controlled by a PID controller. The experimental mass sensitivity is measured by analysing the frequency shift associated with the placement of glass beads. The frequency stability is measured by computing the Allan deviation and the experimental precision of mass sensor is then computed. The results show that the precision of a diamagnetically levitated resonant mass sensors decreases with the decrease of the size of the levitating oscillator. The precision of a levitating oscillator of side length 2mm and thickness 0.08mm is found to be 14.4pg at a gate time of 0.1s for an instantaneous change in frequency.