| 1. |
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| 2. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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A microfluidics-based method for culturing osteoblasts on biomimetic hydroxyapatite
- 2021
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Ingår i: Acta Biomaterialia. - : Elsevier. - 1742-7061 .- 1878-7568. ; 127, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- The reliability of conventional cell culture studies to evaluate biomaterials is often questioned, as in vitro outcomes may contradict results obtained through in vivo assays. Microfluidics technology has the potential to reproduce complex physiological conditions by allowing for fine control of microscale features such as cell confinement and flow rate. Having a continuous flow during cell culture is especially advantageous for bioactive biomaterials such as calcium-deficient hydroxyapatite (HA), which may otherwise alter medium composition and jeopardize cell viability, potentially producing false negative results in vitro. In this work, HA was integrated into a microfluidics-based platform (HA-on-chip) and the effect of varied flow rates (2, 8 and 14 µl/min, corresponding to 0.002, 0.008 and 0.014 dyn/cm2, respectively) was evaluated. A HA sample placed in a well plate (HA-static) was included as a control. While substantial calcium depletion and phosphate release occurred in static conditions, the concentration of ions in HA-on-chip samples remained similar to those of fresh medium, particularly at higher flow rates. Pre-osteoblast-like cells (MC3T3-E1) exhibited a significantly higher degree of proliferation on HA-on-chip (8 μl/min flow rate) as compared to HA-static. However, cell differentiation, analysed by alkaline phosphatase (ALP) activity, showed low values in both conditions. This study indicates that cells respond differently when cultured on HA under flow compared to static conditions, which indicates the need for more physiologically relevant methods to increase the predictive value of in vitro studies used to evaluate biomaterials.
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| 3. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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A Universal Microfluidic Platform for In Vitro Biomaterial Evaluation
- 2022
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Conventionally, the biological properties of biomaterials are evaluated using well plates. Although being a standardized method, it is static in terms of fluid flow and is far from the physiological conditions found in vivo. This work presents a versatile microfluidic system that allows for integration of different biomaterials (ceramic, metals and polymers) under dynamic conditions.METHODS: The Universal Biomaterial-on-Chip (UBOC) consisted of two separate 3D printed (Polylactic acid, Ultimaker 2+) structures: the upper layer which contains the channel through which medium can flow (Fig1A) and the bottom layer that holds and secures the biomaterial in place (Fig 1B). A glass coverslip was taped to the upper layer to tightly seal the channel. Subsequently, an oval Polydimethylsiloxane (PDMS) gasket (l=10mm,w=7mm, h=0.8mm) was inserted into the periphery of the channel in the upper layer. Furthermore, magnets (Ø=12mm, h=3mm) were glued on both sides of the bottom layer. To close the channel, two magnets were placed on the upper layer, causing attraction to the magnets in the bottom layer. The gasket would then directly interface with the biomaterial inside the bottom layer, creating a leak-free channel on its surface. MC3T3-E1 pre-osteoblasts were seeded in the UBOC platform (50,000 cells/cm2) on calcium-deficient hydroxyapatite (HA) (Ø=15mm) and clinical grade titanium (Ti) (Ø=12mm). The cells were cultured for a period of 5 days at a flow rate of 2 μl/min using supplemented MEM-α medium (Hyclone, 10% FBS, 1% Pen-Strep). On day 5, the cells were stained on-chip with Live/Dead stain (Calcein, Propidium Iodide and Hoechst) and subsequently imaged.RESULTS: HA and Ti samples were successfully integrated into the UBOC. Cells cultured on-chip displayed a high degree of viability and confluence on day 5 of culture on both HA and Ti substrates (Fig 2).DISCUSSION & CONCLUSIONS: UBOC presents the possibility for flexible in vitro biomaterial analysis as it allows for easy incorporation of flow to conventional cell culture regimes in a low-cost manner. Via this method,cells can be cultured on the biomaterial with exposure to fluid flow and controlled shear-stress. The platform is compatible with standard characterization methods, such as imaging and biochemical cell analysis. In addition, since the system is designed to be opened and closed, the biomaterial could be easily accessed, harvested and transferred to a regular tissue culture vessel,enabling standard off-chip biochemical assays and protocols to be performed for further analysis.
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| 4. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Bone Cement Embedded in a Microfluidic Device
- 2018
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Konferensbidrag (refereegranskat)abstract
- Calcium phosphate cements (CPCs) have a great potential in the treatment of bone disorders due to their excellent biocompatibility. Although CPCs are promising when implanted in vivo, there is poor correlation between in vitro and in vivo studies. This could be because most conventional in vitro systems lack a 3D architecture, or dynamic conditions (i.e. a continuous refreshment stream). The aim of this work is to embed CPCs into a microfluidic system and evaluate ion and protein exchange at different flow rates.
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| 5. |
- Atif, Abdul Raouf, 1996-
(författare)
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Evaluation of Biological Biomaterial Properties using Microfluidic Systems
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite increased orthopedic biomaterial research activity over previous decades, relatively few novel biomaterials have made it to clinical use. This may partially be due to the inability of existing in vitro testing routines to sufficiently replicate the physiological environment, leading to potentially inaccurate assessments of a biomaterial’s therapeutic potential. To address this, mathematical modelling and microfluidic design principles were assessed as possible supportive strategies to better improve the informativity of in vitro testing approaches.Using principles of the Langmuir isotherm, a predictive computational model was constructed to capture the dynamics of protein and cell adhesion on a biomaterial surface, specifically on calcium-deficient hydroxyapatite, which is a synthetic biomaterial that is compositionally similar to the inorganic phase of the bone. The results demonstrated the success of the model at capturing the trends of the data, thereby indicating potential use as a predicative tool to assist with in vitro data interpretation.Furthermore, attempts were made to improve the in vitro environment towards better physiological relevancy via the introduction of microfluidics, which is method of precise fluid control in micron-sized channels. For instance, the use of microfluidics allows for cell culture under more tissue relevant length scales, as well as the provision of a continuous media flow, which facilitates nutrient delivery and activation of mechanosensitive pathways through shear stress. Through development of such “Biomaterial-on-chip” microfluidic platforms, a general increase in cell viability and proliferation was seen when cells were cultured under flow. The effect of flow on other parameters such as material-induced ionic exchange, immunogenicity and mechanotransduction was also tested using the platform. By the culmination of the thesis work, the Biomaterial-on-chip platform was designed with inherent standardization, allowing for the in vitro testing of different biomaterials of varying shapes and properties under the same conditions in the same platform. All in all, the main conclusion from this thesis work is that cell response can largely differ depending on the chosen culture conditions, which therefore necessities careful consideration of environmental parameters prior to the start of an in vitro biomaterial evaluation study.
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| 6. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Evaluation of Ionic Interactions of Bone Cement-on-Chip
- 2019
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Biomaterials are synthetic materials that can be incorporated into the body to replace an impaired physiological function. Apatite calcium phosphate cements (CPCs), used for bone regeneration, give calcium-deficient hydroxyapatite (CDHA) as an end-product after a dissolution-precipitation reaction during fabrication. CDHA has a tendency to uptake calcium and release phosphate into cell culture medium. Potentially, this leads to depletion of calcium ions in solution, which can be detrimental to cell survival. The aim of this work is to embed CDHA in a microfluidic system and evaluate ion exchange at different flow rates.METHODS: CPC paste was cast into a 0.8mm pocket within a Polydimethylsiloxane (PDMS, cured at 60°C for 2h) mould. CPCs were set in 0.9% w/v NaCl at 37°C for 10 days resulting in CDHA. The PDMS containing the CDHA was then bonded to glass, leaving a 0.5mm channel gap. Minimum Essential Media (MEM, 1ml) was pumped through the channel at low (2µl/min), medium (8µl/min) and high (14µl/min) flow rates. A CDHA disc (ø=15mm, h=2mm) was immersed in MEM (1ml) at static conditions (0µl/min) for 24h. Stock Media was taken as control. Calcium and phosphorus concentrations were analysed using Inductively Coupled Plasma Optical Emission Spectroscopy.RESULTS & CONCLUSIONS: CDHA was successfully embedded in a microfluidic chip (Fig. 1A). Observed [Ca] and [P] levels were closer to levels in stock MEM at higher flow rates (Fig. 1B). We anticipate that osteoblast viability will improve when grown under flow, as opposed to static conditions, due to continuous replenishment of cell medium.
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| 7. |
- Atif, Abdul-Raouf, 1996-, et al.
(författare)
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Experimental Characterization and Mathematical Modeling of the Adsorption of Proteins and Cells on Biomimetic Hydroxyapatite
- 2022
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 7:1, s. 908-920
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Tidskriftsartikel (refereegranskat)abstract
- Biomaterial development is a long process consisting of multiple stages of design and evaluation within the context of both in vitro and in vivo testing. To streamline this process, mathematical and computational modeling displays potential as a tool for rapid biomaterial characterization, enabling the prediction of optimal physicochemical parameters. In this work, a Langmuir isotherm-based model was used to describe protein and cell adhesion on a biomimetic hydroxyapatite surface, both independently and in a one-way coupled system. The results indicated that increased protein surface coverage leads to improved cell adhesion and spread, with maximal protein coverage occurring within 48 h. In addition, the Langmuir model displayed a good fit with the experimental data. Overall, computational modeling is an exciting avenue that may lead to savings in terms of time and cost during the biomaterial development process.
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| 8. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Influence of flow in the adhesion and proliferation of cells on hydroxyapatite integrated in a microscale culture
- 2021
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Synthetic biomaterials, such as calcium phosphate cements (CPCs), are a promising alternative to autologous bone to enhance bone regeneration. Calcium-deficient hydroxyapatite (CDHA), the end-product of apatite cements, matches the inorganic phase of the bone and exhibits excellent biocompatibility in vivo [1]. However, in vitro, CDHA uptakes calcium ions (Ca2+) from cell culture medium [2], causing detrimental effects on cell activity and function [3]. The aim of this work was to integrate CDHA into a microfluidic chip that provides continued culture medium supply, and to evaluate cell adhesion and proliferation as compared to standard well plates.METHODS:CDHA was integrated in a polydimethylsiloxane (PDMS)-glass microfluidic chip (CDHA-on-chip). PDMS was cured in a 3D-printed mould at 60°C for 2h. α-tricalcium phosphate was mixed with 2.5% w/v Na2HPO4(aq) (liquid-to-powder of 0.65 ml/g) and the CPC was cast within a PDMS pocket. The CPC was immersed in an aqueous solution at 37°C for 10 days to ensure full transformation to CDHA. Through plasma treatment, a glass slide was bonded to the PDMS holding the CDHA, thus forming a 0.5mm channel above the CDHA. CDHA samples were pre-incubated for 24h in minimum essential media (MEM) supplemented with 10% FBS and 1% penicillin-streptomycin (sMEM). Pre-osteoblasts (MC3T3-E1) were seeded at 50,000 cells/cm2 and after a cell adhesion period of 2h, flow was applied for 72h through the chip at different rates: 2, 8 and 14 μl/min. A static (0 μl/min) chip condition was included, where sMEM was manually replaced every 24h. CDHA discs (⌀=6mm, h=2mm) placed in a 96-well plate were used as a standard static control (200 μl sMEM replaced every 24h). At 6h and 72h, the cells were stained with a calcein, propidium iodide and Hoechst triple-stain to assess their adhesion and proliferation, respectively. In a separate experiment, sMEM was flown through the chips for 24h at the aforementioned flow rates, and Ca2+ concentration was quantified via inductively coupled plasma-optical emission spectroscopy (ICP-OES). As control, sMEM in contact with CDHA discs for 24h was evaluated.RESULTS:A larger number of cells adhered on the CDHA-on-chip under flow as opposed to both static CDHA-on-chip and CDHA disc in a well plate. Differences in cell adhesion between the flow conditions were negligible. Cell proliferation at 72h was significantly increased under flow compared to CDHA disc samples (Fig.1A). Static CDHA-on-chip showed almost no viable cells. 2 and 8 μl/min flow conditions showed the greatest cell counts, followed by the 14 μl/min flow condition. At higher flow rates, Ca2+ concentrations were closer to in fresh medium (Fig.1B)DISCUSSION & CONCLUSIONS:The static CDHA-on-chip and disc samples displayed a low degree of cell adhesion and proliferation, which seemed to indicate that ionic exchange led to detrimental cell behaviour. Cells displayed the greatest degree of adhesion and proliferation at a flow rate of 2 and 8 μl/min, probably due to more optimal Ca2+ concentrations. At 14 μl/min, the degree of cell adhesion and proliferation decreased, which could be ascribed to adverse effects of shear stress.
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| 9. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Modelling adsorption of proteins and cells on biomimetic hydroxyapatite
- 2021
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Calcium-deficient hydroxyapatite (CDHA), a biomaterial similar to the inorganic bone matrix, can be used in non-load bearing areas to promote bone regeneration. Upon implantation, CDHA is exposed to blood, leading to serum protein deposition on the surface and enabling cell attachment via membrane-bound receptors. In cell culture studies, biomaterials are often pre-incubated in serum supplemented medium to mimic this process. In this work, to study the extent the protein layer assists in cell adhesion, a Langmuir isotherm-based model for protein and cell adhesion kinetics was used.
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| 10. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Quantitative evaluation of osteoblast proliferation and differentiation on a biomaterial in a microfluidic device
- 2020
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionCalcium phosphate cements (CPCs) are able to transform into calcium deficient hydroxyapatite (CDHA), whose crystal size and chemistry closely matches that of the inorganic phase of bone [1]. CDHA readily uptakes calcium ions, and releases phosphate, when immersed in synthetic solutions that mimic physiological fluids [1]. While CPCs are able to enhance bone regeneration in defect sites located in non-load bearing areas, the ionic imbalance that arises from dissolution may also have detrimental effects on cell behavior and function. The purpose of this study was to culture cells on CDHA embedded in a microfluidic chip, under flow, to sustain optimal ionic concentrations, and subsequently evaluate cell proliferation and differentiation. MethodsCPC was cast into a polydimethylsiloxane (PDMS) pocket (h = 0.8 mm) and then set in a 0.9 % NaCl(aq) solution at 37°C for 10 days leading to conversion into CDHA. The CDHA embedded in PDMS were dried and bonded to glass via oxygen plasma treatment, resulting in chips with a 0.5 mm deep channel above the CDHA. In parallel, CDHA discs (⌀ = 6 mm) were set in Teflon molds for the same period of time. The CDHA chips and discs were sterilized with ethanol and pre-incubated with cell culture media overnight. MC3T3-E1 pre-osteoblasts (50,000 cells/cm2) were seeded on the CDHA, and allowed to adhere for 2 h, before initiating a flow of 8 µl/min. Cell proliferation (indirectly measured as the cytosolic lactate dehydrogenase (LDH) enzyme of cells previously adhered to the material) and cell differentiation (alkaline phosphatase activity normalized by total amount of protein) were quantified on day 1, 5 and 10. On day 10, cells were stained with Calcein, Propidium iodide (live/dead assay) and Hoechst (nucleus), and were imaged via fluorescence microscopy. ResultsThe fabrication of the CDHA-on-chip was successful (Fig 1A). There was a faster increase of osteoblast growth on the CDHA-on-chip (under flow) than on discs (static conditions). Specifically, between day 5 and 10, cell number on-chip increased a two-fold as compared to the insignificant change on discs (Fig 1B). Cells on-chip were observed confluent at day 10 (Fig 1C) and seemed to differentiate over time (not shown).ConclusionThe integrated hydroxyapatite platform is a potential alternative for standard in vitro analysis using well plates. Application of flow ameliorates media ionic imbalance, while also providing fresh nutrients and removing waste.
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| 11. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Universal Biomaterial-on-Chip : a versatile platform for evaluating cellular responses on diverse biomaterial substrates
- 2024
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Ingår i: Journal of materials science. Materials in medicine. - : Springer. - 0957-4530 .- 1573-4838. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- Microfluidics has emerged as a promising approach for assessing cellular behavior in vitro, providing more physiologically relevant cell culture environments with dynamic flow and shear stresses. This study introduces the Universal Biomaterial-on-Chip (UBoC) device, which enables the evaluation of cell response on diverse biomaterial substrates in a 3D-printed microfluidic device. The UBoC platform offers mechanical stimulation of the cells and monitoring of their response on diverse biomaterials, enabling qualitative and quantitative in vitro analysis both on- and off-chip. Cell adhesion and proliferation were assessed to evaluate the biocompatibility of materials with different physical properties, while mechanical stimulation was performed to investigate shear-dependent calcium signaling in pre-osteoblasts. Moreover, the applicability of the UBoC platform in creating more complex in vitro models by culturing multiple cell types was demonstrated, establishing a dynamic multicellular environment to investigate cellular interfaces and their significance in biological processes. Overall, the UBoC presents an adaptable tool for in vitro evaluation of cellular behavior, offering opportunities for studying various biomaterials and cell interactions in microfluidic environments.
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| 12. |
- Atif, Abdul Raouf, 1996-, et al.
(författare)
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Universal Biomaterial-on-Chip: A modular platform for flexible biomaterial integration and versatile quantitative assessment
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A requirement for clinical approval is verification of a biomaterial’s functionality and biocompatibility. However, discrepancies between in vitro and in vivo evaluations have been reported, possibly due in part to a lack of physiological relevance of typical in vitro culture set-ups. We introduce a Universal Biomaterial-on-Chip (UBoC), which is a microfluidics device that allows integration of biomaterials with varied shapes and properties and subsequent evaluation of in vitro performance under design considerations that resemble physiological conditions. In addition, UBoC operates with multifunctional modalities such as continuous perfusion, shear stress mechanostimulation and cell co-culture. The device is constructed using simple 3D printing and microfabrication techniques and its cell culture area resembles a 96-well plate (0.32 cm2). Successful cell adhesion and proliferation was observed on-chip on different materials (hydroxyapatite, titanium and fibrin) using fluorescence microscopy. Furthermore, device applicability for mechanostimulation was demonstrated through shear stimulation, where sensitivity of pre-osteoblasts to flow was captured via live Ca2+ imaging. Finally, the modularity of the UBoC platform for on-chip co-culture experiments was established after simple modifications of on-board fluidic arrangements. Overall, the UBoC presents a useful tool that augments existing in vitro testing strategies and enables thorough comparisons between biomaterials in tunable culture conditions.
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| 13. |
- Carter, Sarah-Sophia, 1994-, et al.
(författare)
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A microfluidic-based approach to investigate the inflammatory response of macrophages to pristine and drug-loaded nanostructured hydroxyapatite
- 2022
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Ingår i: Materials Today Bio. - : Elsevier. - 2590-0064. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- The in vitro biological characterization of biomaterials is largely based on static cell cultures. However, for highly reactive biomaterials such as calcium-deficient hydroxyapatite (CDHA), this static environment has limitations. Drastic alterations in the ionic composition of the cell culture medium can negatively affect cell behavior, which can lead to misleading results or data that is difficult to interpret. This challenge could be addressed by a microfluidics-based approach (i.e. on-chip), which offers the opportunity to provide a continuous flow of cell culture medium and a potentially more physiologically relevant microenvironment. The aim of this work was to explore microfluidic technology for its potential to characterize CDHA, particularly in the context of inflammation. Two different CDHA substrates (chemically identical, but varying in microstructure) were integrated on-chip and subsequently evaluated. We demonstrated that the on-chip environment can avoid drastic ionic alterations and increase protein sorption, which was reflected in cell studies with RAW 264.7 macrophages. The cells grown on-chip showed a high cell viability and enhanced proliferation compared to cells maintained under static conditions. Whereas no clear differences in the secretion of tumor necrosis factor alpha (TNF-α) were found, variations in cell morphology suggested a more anti-inflammatory environment on-chip. In the second part of this study, the CDHA substrates were loaded with the drug Trolox. We showed that it is possible to characterize drug release on-chip and moreover demonstrated that Trolox affects the TNF-α secretion and morphology of RAW 264.7 cells. Overall, these results highlight the potential of microfluidics to evaluate (bioactive) biomaterials, both in pristine form and when drug-loaded. This is of particular interest for the latter case, as it allows the biological characterization and assessment of drug release to take place under the same dynamic in vitro environment.
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| 14. |
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| 15. |
- Carter, Sarah-Sophia, 1994-, et al.
(författare)
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PDMS leaching and its implications for on-chip studies focusing on bone regeneration applications
- 2020
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Ingår i: Organs-on-a-Chip. - : Elsevier. - 2666-1020. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Polydimethylsiloxane (PDMS) is among the most widely used materials for organ-on-chip systems. Despite itsmultiple beneficial characteristics from an engineering point of view, there is a concern about the effect of PDMSon the cells cultured in such devices. The aim of this study was to enhance the understanding of the effect of PDMSon cellular behavior in a context relevant for on-chip studies. The focus was put on an indirect effect of PDMS,namely leaching of uncrosslinked oligomers, particularly for bone regeneration applications. PDMS-based chipswere prepared and analyzed for the potential release of PDMS oligomers within the microfluidic channel whenkept at different flow rates. Leaching of uncrosslinked oligomers from PDMS was quantified as silicon concen-tration by inductively coupled plasma - optical emission spectrometry and further confirmed by mass spec-trometry. Subsequently, PDMS-leached media, with a silicon concentration matching the on-chip experiment,were prepared to study cell proliferation and osteogenic differentiation of MC3T3-E1 pre-osteoblasts and humanmesenchymal stem cells. The silicon concentration initially detected in the media was inversely proportional tothe tested flow rates and decreased to control levels within 52 h. In addition, by curing the material overnightinstead of 2 h, regardless of the curing temperature (65 and 80 C), a large reduction in silicon concentration wasfound, indicating the importance of the PDMS curing parameters. Furthermore, it was shown that PDMS oligo-mers enhanced the differentiation of MC3T3-E1 pre-osteoblasts, this being a cell type dependent effect as nochanges in cell differentiation were observed for human mesenchymal stem cells. Overall, this study illustrates theimportance of optimization steps when using PDMS devices for biological studies, in particular PDMS curingconditions and extensive washing steps prior to an experiment.
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| 17. |
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| 18. |
- Wu, Lulu, et al.
(författare)
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Microfluidic system with integrated nanocellulose cell culture substrate to study alignment of human umbilical vein endothelial cells in relation to external physical cues
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In this work, aligned cationic cellulose nanofibrils (c-CNF) were integrated into a microfluidic channel to guide cell attachment of human umbilical vein endothelial cells (HUVECs) and the effect of different mechanical cues on cell orientation was investigated. The on-chip cultured cells were exposed to external stimuli by the c-CNF topography and a fluid flow-induced shear stress, either separately or combined. Fluorescent images of the c-CNF pattern stained with calcofluor white and HUVECs stained for F-actin fibers and cell nuclei were obtained and used to quantify orientation of the CNFs, the F-actin fibers and the cell nuclei together with the eccentricity of the nuclei. Compared to the control, where the cells were cultured on a smooth surface in static conditions, cells cultured on the c-CNF pattern alone showed a clear alignment to the underlying microtopography. Cells cultured on a smooth surface responded slightly to the external mechanical stimuli indicating that the cell orientation was more strongly affected by c-CNF topography than the shear stress. With these results, we established a platform that can de-couple external mechanical stimuli originating from surface topography and shear stress to increase our understanding of how cells react to these factors when cultured in microfluidic in vitro systems.
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