Essentials of Micro- and Nanofluidics


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Topics from this paper. Drug Delivery Systems Colloids. Citations Publications citing this paper. Reliable experimental setup to test the pressure modulation of Baerveldt Implant tubes for reducing post-operative hypotony Ajay Ramani. Exchange of stabilities in Couette flow between cylinders with Navier-slip conditions Isom H. Herron , Pablo Suarez. In , the economic cost of neurological diseases in Europe was estimated at between and billion euros Andlin-Sobocki et al. Research with models of brain disorders typically involves the use of rodents in vivo , which is time consuming, resource intensive, and arguably unethical because many animals are required for a single study Festing and Wilkinson, Moreover, rodent models may not accurately predict human disease and may lead to erroneous results i.

Various clinical researchers have highlighted this issue, showing that the initial physiological descriptions of animal models rarely encompass all of the desired human features, including how closely the model captures what is observed in patients. Consequently, such animal models are often inadequate for studying how a certain molecule affects various aspects of a disease Perrin, Thus, there is presently a great need for the development of better models to investigate the brain and its diseases.

In neurobiological research, microfluidic channels and various interconnected compartment geometries have been used to study axon guidance Francisco et al. Spatiotemporal investigations of electrophysiological function have also been performed on microelectrode arrays MEAs Ban et al. We recently introduced organ-on-a-chip technology, which yields miniaturized systems that support two- and three-dimensional 2D and 3D cell culture formats Frimat et al.

These on-chip low-volume culture systems can forward-engineer brain-like tissues as well as other organ features from a small number of human cells and simply rely on internal diffusion facilitated by the microfluidic approach Ronaldson-Bouchard and Vunjak-Novakovic, A lung-on-a-chip study demonstrated the use of stem cells assembled to provide an organotypic model resembling full organ structure rather than only mimicking certain aspects of organ function Huh et al.

Although this study is a fascinating development of our era, it had a basic science scope concerning disease modeling. Micro- and nanotechnologies have significantly contributed to the development of better human organ and disease models. However, to successfully engineer a brain-on-a-chip model, researchers must produce an in vitro model that accurately mimics critical cellular events observed in vivo. Therefore, to construct functional brain tissue within a miniaturized system, certain criteria must be met. Considering that brain disorders are the number one factor reducing quality of life in aging societies, we review the advances in and requirements of microsystems that mimic brain function.

First, we summarize the literature concerning the essential technical features involved in the design of brain-on-a-chip systems. Second, we address the clinical requirements of and medical need for brain-on-a-chip systems by reviewing previous applied studies.

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Finally, we argue that there is not only a clear need for brain-on-a-chip technology in biomedical research, but also, given the dedicated efforts of engineers to improve the performance of brain-on-a-chip devices as well as their high biological and clinical relevance, technological solutions can be achieved. As previously mentioned, a brain-on-a-chip is a micro-engineered chip platform that mimics the physiological microenvironment and tissue of a particular brain region.

In this section, we discuss detailed brain-on-a-chip design features and culture methods, including their applications to brain disease modeling. When designing brain models, cellular mass transport Yamada and Cukierman, is an essential aspect to consider to engineer the correct microenvironment for different cellular events Figure 1A. Various technologies exist that mainly attempt to mimic the in vivo microenvironment of the central nervous system CNS.

For example, electrophysiological recordings of neuronal tissues primarily rely on rodent brain slices Qi et al. Co-culture models with a glial cell layer overlaid by a second neuron layer have also been studied Viviani, To model the blood-brain barrier, transwell culture systems have been developed in which neurons and endothelial cells separated by a porous membrane can be grown and permeability assays as well as transendothelial electrical resistance TEER measurements can be performed Patabendige et al.

Dissociated rodent brain cells have also been used with the development of methods to isolate and re-aggregate 3D brain cell cultures Bart Schurink and Luttge, Moreover, neurospheres can be grown on low-adherence plastic plates and then replated onto an adhesive substrate, which supports the outgrowth of radial glia and migrating neurons Jensen and Parmar, Finally, using stem cell technology, neuronal tissue can spontaneously self-assemble into organoids Lancaster et al.

However, these methods are insufficient and too reductionist for disease modeling.

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Figure 1. A Microenvironmental factors affecting cell behavior. Numerous spatially and temporally changing microenvironmental aspects may affect how accurately a 3D model reflects cellular behavior in vivo. Conversely, cells center can actively modify their local microenvironment. Figure reprinted with permission, previously published in Cell, Yamada and Cukierman B Conventional methods for designing 3D in vitro models of the nervous system.

The first 3D in vitro models used rodent brain slices 1 or co-culture models consisting of neurons placed directly on top of a glial cell layer 2. Transwell culture models are also used to mimic the blood-brain barrier in vitro 3. Re-aggregating brain cell culture models can also be formed by the spontaneous re-aggregation of dissociated rodent brain cells 4.

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Neurospheres can be generated and kept in low-adherence plastic plates 5 with secondary 3D cultures being produced by plating these neurospheres onto a planar adhesive substrate 6. Engineered neural tissue is generated by growing highly concentrated stem cell suspensions on a membrane floating at the air-liquid interface.

This tissue is polarized e. To a large extent, brain model advances have been limited due to a lack of controlled environments which recreate CNS microenvironment characteristics. The established cell culture models mimicking brain function are too simplistic, whereas more physiologically relevant approaches, such as the use of ex vivo brain slices or in vivo experiments, provide limited control and make information extraction difficult.

Therefore, advances in nano- and microfabrication technology have increased the developmental potential of brain-on-a-chip devices Figures 2A—D ; Park et al. These advances include microfluidic platforms that have been engineered for different neuroscience research needs, such as greater visualization Lu et al. The development of compartmental culturing platform for primary neurons, which combines microfluidics with surface patterning Figure 2 , has allowed for real-time monitoring of axons Zhao et al. Another important platform is the transwell assay, which enables the study of organ membrane function Jang et al.

The development of microfabrication methods yielding novel platforms for complex tissue constructs, such as the blood brain barrier BBB , has received considerable attention Banks, Figure 2. Dendrites grow into the microgrooves of microfluidic chambers. A Schematic of a microfluidic chamber.

C Dendritic length within microgrooves as a function of days in culture. Figure reprinted with permission, previously published in Neuron, Taylor et al. Figure reprinted with permission, previously published in Lab on a Chip, Dinh et al. These platform technology advances have enabled the production of various brain structures, including the cerebral cortical layers, which were engineered by intercalating neuron-hydrogel layers with plain hydrogel layers Figure 3A ; Kunze et al.

These engineered cortical layers exhibited different synaptic densities per layer as well as chemical gradients of growth factors Cheng et al. In addition, neurospheroids, which are 3D non-hydrogel-based brain models, have also been developed Choi et al. Choi et al. More detailed 3D brain models have also attempted to include the BBB using microfluidic approaches.

The BBB is a 3D multicellular structure of the brain which regulates the passage of molecules from the blood to the brain and has profound implications for modeling disease responses to drugs Vandenhaute et al. In BBB models, intersecting microfluidic channels are separated by a porous polycarbonate membrane upon which endothelial cells vascular and astrocytes brain are cultured on opposite sides, which essentially mimics the BBB Griep et al. Alternatively, a hollow fiber-like design i.

These models have elucidated how drugs or toxins can breach the BBB and enter the brain microenvironment. Another brain model platform combines 3D cell cultures or samples with MEA systems, which allows for real-time electrical readouts of cells as well as the identification of electrical signatures associated with neurotoxicity Pancrazio et al. Moreover, a system has been established that allows for 3D perfusion by using an active 3D microscaffold system with fluid perfusion for culturing in vitro neuronal networks Rowe et al.

Figure 3. A Three-dimensional layers of the cerebral cortex, which were engineered using intercalating neuron-hydrogel layers. This drawing illustrates the layered structure of the 3D neural cell culture. The hydrogel or cell-loaded hydrogel flow through four inlet, main, and outlet channels. The two inserts show the final microfluidic device fabricated using polydimethylsiloxane top insert and three devices placed in a Petri dish for incubation during cell culture bottom insert. Figure reprinted with permission, previously published in Biomaterials, Kunze et al.

B Three-dimensional microelectrode array for recording dissociated neuronal cultures. Figure reprinted with permission, previously published in Lab on a Chip, Musick et al. An alternative brain model that utilizes 3D culture involves the use of stem cell technology to engineer neural tissues which grow directly from neurospheres, yielding organoids Lancaster et al.

Although the aforementioned technologies allow for the development of brain-on-a-chip platforms, the cell sources used in such models must be carefully considered. Stem cell technology has been a giant-leap forward in the design of brain organoids; however, human induced pluripotent stem cells hiPSCs are an attractive alternative for on-chip brain modeling. HiPSCs have several advantages over immortalized neuronal cell lines or primary animal brain cells.

HiPSCs can be obtained from human somatic cells Takahashi et al. Moreover, hiPSCs can be cultured and differentiated into multiple brain cell types and are genetically matched with the patient Dolmetsch and Geschwind, HiPSCs differentiated into neural lineages allow for neurotoxicological or neurodevelopmental assays as well as the analysis of mature human neuronal networks by exploiting self-organization during neural differentiation. Kilic et al. This 3D multicellular on-chip environment enhanced chemotactic cue-induced human neural progenitor migration i.

A promising development in iPSC technology is the use of patient-derived iPSCs containing single mutations that lead to disease e. In such patients, the IKBKAP encoding gene contains a point mutation that is directly correlated with the loss of autonomic and sensory neurons. Through healthy vs. Neurodegenerative diseases and disorders, such as Parkinson's disease PD and Alzheimer's disease AD , lead to the destruction or degradation of synaptic connections, whereas neurological diseases, such as epilepsy, are thought to be related to dysfunctional network responses.

Although epilepsy-on-a-chip has not been established yet, brain-on-a-chip technology has been applied to PD and AD modeling. In the following sections, we discuss the main technical features of the brain-on-a-chip platforms utilized for these disease models. Therefore, some AD models have focused on modulating these proteins with respect to their influence on synapse formation and glial cell communication Hai et al.

Three-dimensional neuronal tissue models, including the aforementioned networked neurospheres Choi et al. Platforms and systems offering real-time analyses of neuronal activity, co-culturing, and chemotaxis gradients have been used to model AD. Tau protein hyperphosphorylation is a hallmark trait of AD Pascoal et al.

In another AD model study, microfluidic devices were used to demonstrate neuron-to-neuron wild-type tau protein transfer through trans-synaptic mechanisms Dujardin et al. More recently, an 3D on-chip AD model was proposed Park et al. This chip contained concave microwells for the formation of homogeneous 3D neurospheroids of a uniform size. Its osmotic micropump system was connected to the outlet to provide a continuous flow of medium. On the microfluidic chip, normal i. AD neurospheroids were cultured on the microfluidic chip under dynamic conditions with a flow of normal medium containing oxygen and nutrients for 7 d.

Compared with the normal model, the AD model had decreased cell viability and increased neural destruction and synaptic dysfunction, which are pathophysiological features of AD in vivo. Figure 4. Schematic diagram of a 3D Alzheimer's disease brain-on-a-chip with an interstitial level of flow.

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The chip contains a concave microwell array for the formation of homogeneous neurospheroids of a uniform size with 3D cytoarchitecture. The osmotic micropump system is connected to the outlet to provide a continuous flow of medium at the level of interstitial flow. Figure reprinted with permission, previously published in Lab on a Chip, Park et al. An on-chip PD model that allowed for monitoring of mitochondrial transport on single dopaminergic axons was also proposed Lu et al. This device consisted of two open chambers connected via microchannels in which axon growth was monitored and labeled mitochondria were visualized.

The device promoted oriented axon growth into a separate axonal compartment for analysis. Moreover, this device improved upon the culture of more sensitive neurons i.


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Although this work was limited to mitochondrial transport, vesicular transport, and microtubule fragmentation, which also contribute to dopaminergic fiber loss, could also be analyzed with this device. This is an important development because such studies are difficult to perform using traditional cell culture approaches and PD brain lesions are always associated with dopaminergic fiber loss.

To date, this device does not support co-culture or 3D cell cultures but instead uses microfluidics to align axons. This approach highlights the axonal degeneration mechanisms potentially underlying PD pathophysiology as well as those underlying other major neurodegenerative diseases. Another potential on-chip PD model using 3D phase-guided microfluidic cell culture bioreactors was recently developed as a personalized biomedical approach to PD Moreno et al.

These authors differentiated human neuroepithelial stem cells into dopaminergic neurons in microfluidic cell culture bioreactors and suggested that this platform could be used to study substantia nigra dopaminergic neuron degeneration, a hallmark of PD. Epilepsy is characterized by excessive synchronized electrical activity within the brain. MEAs in combination with brain slices have been the best technology used so far to monitor, study, and detect epileptic activity in vitro. This technology consists of rapid high-throughput static platforms used for drug discovery and toxicology studies.

In addition, MEAs coupled with microfluidics have been proposed to monitor neuronal network activity under different conditions and exposures Morin et al. These brain slice-based models can be used as chronic models of spontaneous hyperexcitability i. However, these models have questionable clinical relevance.

Given the recent advances combining brain-on-a-chip and iPSC technologies, epilepsy-on-a-chip may become a reality. Genetic factors play an important etiological role in epilepsy development. Although tremendous progress has been made with brain-on-a-chip technology and its applications, challenges remain with respect to the translational and clinical value of such systems.

To recreate the critical features of the in vivo human brain microenvironment, several factors must be addressed. First, advanced cell composition reflecting the type, ratio, and 3D architecture of cells within brain tissue must be achieved by incorporating stem cell technologies Lancaster et al.

Another important aspect of validating brain-on-a-chip models is to identify the functional readouts of the healthy or pathological states of these systems. As previously discussed, MEA-based electrophysiological measurements should be appropriate for 3D microphysiological cell culture systems. Alternatively, advanced neuroprobe microtechnologies Xie et al.

Progress in neuroprobe technology has been reviewed elsewhere Seymour et al. Despite the current limitations, most modern microscale platforms have already identified known pathological mechanisms and pathways; however, they have yet to contribute to novel therapeutic solutions. Thus, the clinical relevance of brain-on-a-chip technology remains limited; however, the pharmaceutical industry has started to examine these new technologies for drug discovery and testing.

Nonetheless, these systems show great promise in more closely representing the diseased human tissue microenvironment in vitro compared with standard tissue culture tests. Resolving the aforementioned critical features as well as mimicking blood flow and the BBB, or neurovascular unit, will be important steps toward advancing clinically relevant brain-on-a-chip models. The next sections will describe an idealized schematic of a brain-on-a-chip concept, which details its desired physiological features. Moreover, we address novel assay development routes that exploit 3D engineered tissue architecture and provide a market outlook.

Essentially, a brain-on-a-chip is a miniaturized dish-type construct placed on a microscope slide, which hosts neuronal tissue supported by a medium replenishment unit and integrated microfluidics. To produce such a device, the appropriate cells must first be selected. This step is critical because brain tissue consists of many different neuronal subtypes Brodal, Moreover, a plethora of supporting glial cell types, including microglia, astrocytes and oligodendrocytes, are also required to design advanced brain-on-a-chip models.

To further complicate matters, cellular network bio-architecture significantly varies throughout different brain regions, forming complex structures and circuitries. Importantly, different cell types appear in precise ratios in different brain regions, where, for example, glial cells influence apoptosis and repair mechanisms and can accumulate following brain trauma Eskes et al.

Glial cells also determine the overall reaction of tissue to injury by phagocytosing dying neurons and neurite debris Hirt and Leist, Therefore, brain injury models need to reflect these altered conditions instead of only modeling healthy brain function. In addition, several metabolic pathways in the brain involve different cell types.

For example, astrocytes take up glutamate, transform it to glutamine, and provide it to neurons. Astrocytes also provide neurons with specific energy substrates or essential thiols. Therefore, co-culturing of different cells must be performed in diseased or healthy brain-on-a-chip models. For the brain model to be functional, all cell types must be present and supported by the engineered construct Figure 5.

This may be achieved by combining engineered microsystems with hiPSC technology. HiPSC-derived neuronal cell cultures are beneficial in this respect because they can contribute to a specific tissue architecture based on their level of differentiation. Differentiation can be induced within particular compartmentalized microenvironments specifically designed within the microphysiological cell culture system to fulfill the requirements of a given application.

Preliminary successes in this area have been recently demonstrated, amongst others, by Fleming and his team who utilized the Mimetas platform Moreno et al. However, in that system, the 3D space was limited to a few hundred micrometers and there was no electrical readout. Figure 5. Sambasivam and F. Muzychka, Z. Duan, and M. Muzychka, E. Walsh, P. Walsh, and V.

Tomar, G. Biswas, A. Sharma, and S. Suresh Cellular Biomicrofluidics J. Schrlau and Haim H. Nobes, Mona Abdolrazaghi, and Sushanta K. Guasto, and Kenneth S. Yap, J. Chai, T. Wong, and N. Cardoso, J. Correia, and G.

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Essentials of Micro- and Nanofluidics Essentials of Micro- and Nanofluidics
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