Microfluidics advances have hovered on the horizon as a “new way” for some time. The creation and development of new drugs can cost millions, yet many end up being recalled for toxicity, or just plain not as effective in humans as they are in lab animals.

The authors of a 2019 statistical analysis, “Impact of organ-on-a-chip technology on pharmaceutical R&D costs,” describe how high drug prices are driven by the huge expense of creating new product. They report that 60-75 percent of new drugs that succeed in non-human phases fail in later phases. “Better predictive models are needed,” they concluded, in something of an understatement.

Better predictive models include microfluidic platforms called organs-on-a-chip. These platforms are engineered to improve on the prognostic capacity of animal or in vitro models — which too often inaccurately simulate human physiology. As controlled microenvironments with vasculature perfusion that mimic the structure and function of human tissue, organ-a-chip technology has the potential to decrease the conventional roadblock of extensive development time frames, and their choking costs.

Although actual expenditures of private pharmaceutical companies are not made public, the statistical analysts estimate the potential of microfluidics to reduce R&D costs at 10-25 percent. The authors granularly analyzed some development costs by phase. They concluded that organ-on-a-chip technology could significantly reduce R&D costs by reducing the length of the early-stage research process.

The analysts note that, “Experts believed that the technology will help to make quicker and more precise decisions” during initial stages of research. One analyst said that if organ-on-chip was capable of identifying appropriate biomarkers, it would become the “Holy Grail” of biotechnology.

The authors do not pretend change arrives astride a fast horse. “The extent to which organ-on-a-chip can evolve in terms of predictability and applicability to the human biophysiology is yet to be seen,” they write. “Challenges of automation, parallelization, standardization and ease of use remain.”

Concerns driving the current conversation among experts focus on the magnitude of transformation. The tradition of utilizing in vitro and animal models is deeply ingrained and rooted, to state one obvious funding barrier. Results anticipated by innovators and early adopters can “take much longer to materialize when meeting the skepticism of the late majority and laggards.”

Not only are microfluidic devices pushing for legitimacy in the minds of some, but the very methods used to create them are often never-before-seen tools butting up against history as well. 3D bioprinting comes to mind.

There are pre-publication reports concerning vascularized micro-tissues for many major organs. For example, micro-tissued pancreatic islets have potential for insulin regulation and insulinomas. Liver buds are being researched. There has been progress in bioprinting vascularized thyroid glands.

In addition, genome engineering techniques may create genetic disease models using microfluidic platforms. Personalized medicine applications may include drug screening for patient-specific tumors.

In their study titled “Long-term Expanding Human Airway Organoids for Disease Modeling,” lung specialists wrote that “human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.”

The world certainly does have an “infectious pulmonary disease” on board.

Can regulatory shibboleths and personal proclivities accommodate the pace of innovation? Despite the complexity of research, the degree of potential is climbing. According to a recent Research and Markets report, microfluidics technology is replicating many functions of traditional healthcare, including clinical diagnostics, point-of-care diagnostics and drug delivery: “The global microfluidics market size is projected to reach USD 44.0 billion by 2025 from USD 15.7 billion in 2020.”

One research team recently described why “frontier technological tools by which infections are studied and new drugs and vaccines are tested” include “microfluidic chambers for the culture of organoids.” Given they are Milan, Italy-based, this team comprises COVID-19 experts.

The pandemic-weary world awaits “frontier tools.”

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Microfluidics and Approval Bottlenecks in a Pandemic appeared first on The MicroFluidic Circle.

All the current lung-on-a-chip devices are aiming to recapitulate the complexity of the lungs to some extent to offer an advanced cell-culture model for drug discovery purposes. They usually consist of three components: (1) an air channel where epithelial cells can be grown and transferred later to air-liquid interface, (2) a “blood” channel that serves as the vascular part of the chip, and (3) a semi-permeable membrane to separate the air and fluidic channels. Together,  all these new features can offer an in vitro model that has these advantages over more conventional in vitro models: (1)emulating the complexity of the lungs to some extent for instance by the integration of a stretchable membrane, (2)adding the respiratory breathing motions to the model either by stretching or the deflection of a thin membrane, (3) having “blood” and airflow in the apical and basal sides which can induce shear stress on cells and present a more realistic model than the other static in vitro models, and (4) the feasibility of using an extracellular matrix (ECM) based material as the membrane or added to the polymeric membrane. In some models, two sides of channels have been included to stimulate breathing by generating cyclic pneumatic pressure. This is helpful when the focus of the model is alveolar. Otherwise, a cyclic flow in the lower channel would be sufficient to mimic the physiological shear stress on cells. In addition, some biochemical factors such as proteins (collagen and fibronectin)or growth factors can be added to the chip (coated on both sides of the membrane) to recapitulate the cellular microenvironment.Polydimethylsiloxane(PDMS) is the most common material in the fabrication of these lung-on-a-chip devices since PDMS is optically transparent, biocompatible, easy to use, and flexible. Lung-on-a-chip devices aim to provide a tool for studying a drug. Besides, these devices can be used to simulate a lung disease such as inflammation, asthma, lung cancer, pulmonary fibrosis, or lung injuries and simulate the lung cells/tissue interactions at a “realistic” scale by controlling their microenvironment.

To begin with, we should mention the device designed and developed by Huh et al. in which mechanical strain was applied to stretch a porous PDMS membrane. They showed that the mechanical strain facilitated the uptake and transfer of nanoparticles by epithelial and endothelial. These results were confirmed by observing the similar effects in the whole mouse lung. The same research group later successfully modeled a human disease model-on-a-chip for pulmonary edema. This group led by DE Ingnercan be considered as one of the most dynamic teams in the field that has introduced various inventions not only to lung-on-a-chip devices but also to other organ-on-a-chip devices. In another study, they developed a small airway-on-a-chip and lined the airway with epithelial cells from patients suffering from chronic obstructive pulmonary disease. Using viral and bacterial infections, they could model the disease in their device. Moreover, they fabricated a microfluidic chip containing embedded electrodes for measuring trans-epithelial electrical resistance (TEER), which is used to monitor and quantify the integrity of cultured epithelial under statistic conditions. Later, they developed a lung alveolus-on-a-chip to model pulmonary thrombosis by co-culturing epithelium and endothelium. In another interesting work, KL Sellgren et al. designed a chip for culturing primary endothelial, epithelial, and lung fibroblasts to model the human airway. Polytetrafluoroethylene (PTFE) and polyester (PET) membranes were integrated between different layers of the chip. This work showed the feasibility of culturing primary airway epithelial cells with lung fibroblast and endothelium while providing appropriate compartmentalization in the chip. Such a triple co-culture with the capability of perfusion cannot be provided by the current commercial in vitro models. Other researchers also tried to integrate electrodes in a lung-on-a-chip device for monitoring the electrochemical and mechanical changing at the lung alveolar interface. Their device was also made of PDMS and mimicked the mechanical strain in alveolar by bulging a porous PDMS-based membrane. The advantage of this model is to create a 3D cyclic strain applied in all directions. An array of suspended gels was used instead of a porous membrane as a barrier between airway epithelial cells and airway smooth muscle cells in another work. There, the gel was a mixture of type I collagen and Matrigel which could enhance cell adhesion and growth. Xu et al.introduced an exciting approach to combine other organs in a lung-on-a-chip for studying lung cancer metastasis. This device had an upstream, lung, and three downstream organs that may be affected by lung cancer metastasis. These are only some of the works done in the field of lung-on-a-chip and more papers with details can be found in a recent review paper published in Biomicrofluics.

In the last few years, several organ-on-a-chip start-up companies have been founded, aiming to introduce a new platform for the drug discovery industry. Some of these companies offer devices at “body-on-chip” scales. Hesperos, Tissuse, CnBio, DRAPER are examples of these companies that are trying to provide a more complex model for assessing the pharmacokinetics and pharmacodynamic of new drugs on the human body than the conventional in vitro cell culture. Indeed, these models cannot completely mimic the complexity of the human body in the absorption, distributions, metabolism, and elimination of these new drugs but they are at least one step ahead of the available models. Some of the companies took another approach to construct an organ-on-a-chip that has a simulated tissue interface. Dr. Donald Ingber at Wyss Institute is one of the pioneers in this area and the founder of Emulate Inc. They offer a range of organ-on-a-chips including lung-on-a-chip or airway-on-a-chip. The strength of their technology is the ease of use for users as they developed several control modules. These modules can be used to control and monitor individual chips — another lung-on-a-chip company, Alveolix, founded by Dr. Olivier Guenatfor simulating the alveolar barrier. Not having vascular perfusion may be considered as a weakness, but it simplified the operation of the chip and would enable the users to operate multiple chips at the same time. Emulate and Alveolix are the most well-known companies in the area of lung-on-a-chip but there are more companies in the field. NORTIS, Quorum Technologies (Artery-on-a-chip Vessel), MIMETAS, SYnVIVO, 4DESIGN BIOSCIENCES, and AIM BIOTECH are good examples of these companies which have focused their efforts to bring some of the complexity of the human tissues to their in vitro models.

Regardless of all these advancements, there are still some issues that need to be addressed to introduce a more biomimetic model. For instance, the cell-to-liquid ratio should be improved to avoid the dilution of secreted proteins, metabolites, and factors. Fabricating smaller channels or growing cells in 3D may help to solve this problem. The thickness of membranes is typically around 10 µm which is much thicker than the basement membrane of blood vessels (300 – 400 nm). Molding hydrogel with integrated microchannels or 3D printing of hydrogels is a possible solution to tackle this challenge. The current models for alveolar can be improved by recapitulating the 3D shape of lungs air sacs. Instead of stretching the membrane that separates apical and basal sides, the membrane can be inflated by flowing air to the air channels.

To sum up, lung-on-a-chip and airway-on-a-chip are only one piece of the puzzle for developing a reliable platform in a drug discovery journey. As the future organs-on-a-chip or body-on-a-chip is supposed to be a comprehensive platform for testing a new drug, multiple chips should be combined to cover all aspects of human physiology. An interesting approach is to design a chip that mimics the human lungs at a smaller scale while having airways, bronchioles, and alveoli at the same time and show how various epithelial cells may interact with each other or which type is more prone to a specific disease or a drug. Realizing such a design can be very challenging based on the current technologies but 3D printing and bioprinting can bridge this gas and facilitate the progress toward a 3D lung model.

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Mohammadhossein Dabaghi

Mohammadhossein Dabaghi is currently a postdoctoral fellow at the department of medicine at McMaster University. He completed his Ph.D. at McMaster University majoring in Biomedical Engineering and worked on new microfabrication technologies to develop an Artificial Placenta device for preterm neonates with respiratory failure. He earned a master’s degree in Biomedical/Chemical Engineering (2014), and a BS in Chemical Engineering from Sharif University of Technology, Iran (2012). His research interests focus on lung-on-a-chips, biosensors for organ-on-a-chips, and bioprinting.

• https://www.researchgate.net/profile/Mohammadhossein_Dabaghi2

The post The Promise of Lung-on-a-Chip Devices appeared first on The MicroFluidic Circle.

While healthcare access has increased globally in the last three decades¹, at least half the world still lacks access to essential healthcare services². For the ones that do have access, the high costs can often push them towards extreme poverty, bankruptcies, and homelessness. While there is a direct correlation between income equality and access to healthcare, another major reason that access to healthcare remains elusive to half the world population is because of the multiple dimensions that constitute healthcare – awareness and access to information about healthcare, access to health services such as hospital, ambulance, diagnostics, medicines, trained doctors and nurses, life-saving treatments, follow-ups among several others. Covering most or all of these aspects simultaneously at a location can often be a challenging task.

Diagnostics and Microfluidics

Next to health awareness and immunizations, diagnostics are among the front liners in health services. The majority of the downstream healthcare decisions (and therefore costs) are dependent on timely and accurate diagnosis. As our understandings of human physiology and pathology have evolved, so have the diagnostic tools. Unlike lab testing which involved collecting samples from patients and transporting them to a distant laboratory and waiting to learn the results, point-of-care (POC) diagnostics have made medical testing possible at patient’s location in a much-reduced timeframe thus expediting medical decisions.

Microfluidic technologies have played a critical role in the rapid evolution of POC devices in the health industry. They offer numerous advantages: lower costs, reduced sample volumes, faster turn-around times, user-friendliness, device portability and high-throughput screening(HTS). Low costs and portability make it possible to adapt them in settings with limited or non-existent healthcare infrastructure. User-friendliness, easier result interpretations (such as through colorimetric assays) make it an attractive option in settings with limited or no access to trained health care providers.

Several companies have now successfully introduced microfluidic POC testing devices into the market. Several products have now made it to pharmacy shelves such as pregnancy tests and glucose monitoring kits. The global market for microfluidics was valued at 8.28 billion in 2017 and is expected to reach up to USD 27.91 billion by 2023³. While the majority of the market for microfluidic devices is currently in developed countries, it is the developing countries where it can serve as a major game-changer. While cancers and cardiac diseases are the top killers in developed countries such as the US, infectious diseases, such as malaria, HIV/AIDS, and tuberculosis, are the leading cause of death in several developing nations. Current diagnostic procedures for these involve benchtop tests and assays with heavy reliability on instruments and reagents and are often time-consuming. With the focus shifting towards microfluidics, there have been several recent attempts to introduce microfluidics in developing nations. Several proof-of-concept studies have indeed shown that microfluidic POC devices can be a route to provide reliable and faster diagnostic services in these areas. Chin et al used a microfluidic device to detect HIV and syphilis in the Rwandan population using blood volumes as little as 1 μl and a turn-around time of 20 minutes⁴. Hugo et al. demonstrated the potential of a centrifugal microfluidic platform for POC diagnostic applications in South Africa⁵. Taylor et al showed the potential of PCR-on-chip device for malaria diagnosis among patient samples from Uganda⁶. Diagnostics For All, a non-profit started by Dr. George Whitesides and his group at Harvard, uses paper microfluidics for development of POC diagnostics for developing countries. Field studies have been conducted in Vietnam and Kenya⁷. Commercial companies that have microfluidic POC devices for infectious diseases include Alere, Trinity Biotech, and IMMY that use lateral flow immunoassay strips for the detection of diseases such as malaria, meningitis, filariasis, HIV, flu, and Legionnaire’s Disease. Alere, a market leader in this field, partners with several non-profits for the distribution of malaria and HIV testing POC kits in developing nations⁸.

Conclusion and future perspective

While enough studies and pilot projects have demonstrated the vast potential of microfluidics in the diagnosis of infectious diseases in a developing country, the target groups are way bigger than current reach of the microfluidic research and market. This calls for an action plan involving several stakeholders, such as the World Health Organization, governments, administrators, private companies, non-profits, and locals, to work in concert and collaborations. While mass-production will undoubtedly help meet the demands and lower the cost at the manufacturer and consumer ends, affordability will always remain a huge bottleneck in the widespread use of these devices in developing countries. Current efforts and successes have only been possible due to the involvement of non-profits. This issue further calls for bridging the gap between research and policy. Governments can play major roles here by introducing schemes and subsidies to increase the reach of the products.

There are innovations required on multiple fronts to tackle the issue of introducing microfluidic POC diagnostic devices to such a massive fraction of the world population. There is a need to ensure that material used for making these devices is readily available, safe, light-weight and well-suited for mass-production. The final devices also need to be handy and easy to transport. Technologies such as lab-on-a-drone⁹ need to be further advanced to ensure easy and wide distribution of these devices to remote areas. While the devices need to be user-friendly and must require minimal training, there should be provisions to store results and data for future use by integrating with everyday devices such as cell phones. Devices should also include multiple tests within the same setup to ensure high-throughput screening among populations plagued by multiple infections.

While the current issue at hand is focused on microfluidic-based affordable diagnostics for developing countries, microfluidics can play important roles even in health services downstream of diagnosis. Microfluidic organ-on-a-chip and human-on-a-chip platforms are promising technologies to advance precision medicines. Several drugs are known to have variable effects on different populations owing to genetic differences. Testing established drugs on organ-on-chip platforms based on cells from a certain sub-population can provide useful results in terms of predicting the safety of the introduction of drugs to that population. Furthermore, these platforms have also been touted as the future of novel drug development and toxicity testing.

While the field of microfluidics has now been around for 30 years, the technology still remains heavily confined to academia and basic research. Institutions and companies should now steer this field into practical real-world applications – providing healthcare access around the world being a major one due to the overwhelming size of the population that lacks basic healthcare. The low cost, low sample volumes, portability, reliability and faster turn-around times make it the most promising candidate for a tool that can bring diagnostics from bench to bedside.

References

<sup>1. https://medicalxpress.com/news/2018-05-global-healthcare-access-quality-.html

2. https://www.who.int/news-room/detail/13-12-2017-world-bank-and-who-half-the-world-lacks-access-to-essential-health-services-100-million-still-pushed-into-extreme-poverty-because-of-health-expenses

3. https://www.marketsandmarkets.com/Market-Reports/microfluidics-market-1305.html

4. Chin, C. D. et al. Microfluidics-based diagnostics of infectious diseases in the developing world. Nat. Med. 17, 1015–1019 (2011).

5. Hugo, S., Land, K., Madou, M. & Kido, H. A centrifugal microfluidic platform for point-of-care diagnostic applications. S. Afr. J. Sci. 110, (2014).

6. Taylor, B. J. et al. A lab-on-chip for malaria diagnosis and surveillance. Malar. J. 13, 179 (2014).

7. http://dfa.org/

8. https://www.alere.com/en/home/about/corporate-responsibility.html

9. Priye, A. et al. Lab-on-a-Drone: Toward Pinpoint Deployment of Smartphone-Enabled Nucleic Acid-Based Diagnostics for Mobile Health Care. Anal. Chem. 88, 4651–4660 (2016)</sup>

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Vardhman Kumar

Vardhman is a Ph.D. candidate in the Department of Biomedical Engineering at Duke University. His work in Prof. Shyni Varghese’s lab involves the development of microfluidic platforms for understanding the biophysics of development and diseases.

• https://scholars.duke.edu/person/vardhman.kumar

The post Microfluidic Diagnostics for the Developing World appeared first on The MicroFluidic Circle.

This story illustrates how I feel about much of the experimental work that I do and what I see others do in academic and clinical labs. There is an existing infrastructure sometimes far below the cutting edge of science and technology that “works” well enough to test your hypothesis and publish the paper you need for a better job where you can make others deal with the same inconvenient infrastructure. There are many logical reasons for sticking with what works, but, as in the case of the new roundabout, there is a point where superior technology becomes economical.

The tools used to develop therapies for diabetes, in all its forms, also need an upgrade. As with most biomedical research, two complementary platforms are generally used. On the one hand, cultured cells are an inexpensive resource for early-stage high-throughput studies. On the other hand, animals provide a complex, physiological environment to more accurately predict what is happening in the human body. However, the limitations of existing animal and cell culture models are not addressed by simply using both. Microfluidic platforms have natural advantages over both traditional cell culture and animal models. There are of course limitations here as well and these pain points are opportunities for commercial development. The advantages and current limitations of using microfluidic models of human tissues and organs are listed below to encourage their commercial development and adoption for diabetes research.

The Advantages We Need to Exploit

• Organ Modularity and Isolation: When experimenting on animals, it is often challenging to deduce the molecular mechanisms of disease traits due to the complexity of interactions between different organs, tissues, and cells. One can delete or overexpress a gene to demonstrate the respective necessity and sufficiency of that gene for the trait, but in which organ is the expression of that gene important? Tissue-specific genetic manipulation helps address this issue, but it remains challenging for diseases like diabetes where multiple genes operating in multiple organs contribute to pathogenesis. Moreover, many disease-associated genes and cell types are vital (i.e. lethal when deleted) necessitating alternative approaches. Engineered organ models can be connected to build systems such as the “body-on-a-chip” platforms discussed in a previous blog post¹.Microfluidics aid in the logistical difficulty of combining multiple cell types, tissues, and organs as a synthetic vasculature to promote nutrient delivery and waste removal. Relevant organ, tissue, or cellular components can be added as needed and connected in a manner that enables sampling of the inputs and outputs for each component of the system.

• Controlled Human Genetic Background: Gene networks that are most relevant to diabetes such as those involved in immunity and metabolism are also the most evolutionarily distinct between mice, the predominant animal model for diabetes², and humans³. In this regard, an experimental system with human cells is advantageous over mice. Multiple tissues derived from a single pluripotent stem cell line can be used for a completely isogenic model if desired. Alternatively, different genetic backgrounds can be combined to simulate transplantation, chimerism, or other experimental conditions. For example, combining five different organ models made from mutant and control cells from the same stem cell line is simpler than developing constructs for five separate genes each with distinct tissue-specific promoters. In addition, similar to the above point about vital genes, it is also conceivable that a tissue of interest lacks an established tissue-specific gene promoter.

• Data Quality, Automation and Cost Reduction: The temporal resolution of experimental data is often limited by the minimum sample volumes of well-based assays and the capacity of the human user. Microfluidics is naturally amenable to automated sample collection, reagent mixing, and measurement acquisition, reducing user error and manual effort. Microfluidics also have the inherent potential for cost efficiency due to the small amounts of reagents required⁴. Huge cost savings are possible if the supporting instrumentation is made to be simple and self-contained. By minimizing the time, error, effort, and expense of data collection, microfluidics simultaneously enable superior temporal resolution and data quality.

The Limitations We Need to Address

• Not quite in vivo…yet: Although genetic divergence favours a platform with a human genetic background for diabetes research, conventional cell culture falls woefully short of recapitulating important tissue-specific hallmarks of diabetes as well as the systemic nature of the disease. This is the primary criticism and limitation of cell culture and thus a major opportunity for microfluidic organ models. In my opinion, the key moving forward for diabetes research is less about making perfect and interconnected replicas of every organ in the body (which very well could take forever), and more about meeting a set of design criteria that cover the key features and phenotypes underlying specific hypotheses to be tested. The latter is achievable in our lifetime and can close the gap between patients and existing preclinical models.

• Not quite user-friendly …yet: A broadly accessible platform cannot become mainstream without industry’s help and probably its leadership, too. Academic labs simply cannot manufacture enough products with the necessary quality control for all the parties that stand to benefit by using it. Industry involvement will also be needed to achieve the right balance of standardization and flexibility. Utility for a broad range of applications will help the broad adoption of the technology. Finally, product designs need to integrate controls for tissue culture and functional readouts that allow operation without extensive training or expertise.

Conclusion

Diabetes research presents an exciting market opportunity for the development of microfluidic organ models and systems. The powerful advantages afforded by microfluidics are much needed to complement (and perhaps eventually replace) traditional cell culture and animal testing. If designed appropriately for non-expert users and with the right biological questions in mind, these platforms will be adopted and more importantly will help pave the new and improved road to a cure.

References

<sup>1. Organ On Chips: Questions To Address Before They Can Move Into Mainstream Applications. URL: https://ufluidix.com/circle/organ-on-chips-questions-to-address-before-they-can-move-into-mainstream-applications/

2. King A. The use of animal models in diabetes research. British Journal of Pharmacology. 166(3) (2012).

3. Yue F, Cheng Y, Breschi A, et al. A comparative encyclopedia of DNA elements in the mouse genome. Nature. 515(7527) (2014).

4. https://www.fluigent.com/microfluidic-expertise/what-is-microfluidic/microfluidic-definitions-and-advantages/</sup>

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Benjamin D. Pope

Ben Pope works with a group of scientists and engineers who aim to cure diabetes. His current research leverages cellular engineering and genomics to elucidate the molecular bases of human nutrition. Originally trained in molecular biology, he identified DNA elements that define structural and functional chromosome units by both chromosome engineering in embryonic stem cells and computational analysis of genomic datasets. He has since cross-trained in bioengineering and developed a microfluidic chip for continuous sensing of insulin secreted by ex vivo human islets described in a previous blog post.

• https://scholar.harvard.edu/pope

The post Developing Diabetes Therapies with Microfluidic Organ Models appeared first on The MicroFluidic Circle.

• Seeding of organ-specific primary or induced pluripotent stem cell (iPSC) derived cells in a manner that encourages cells to assemble into physiologically relevant configurations that matches the functional units of native organ systems; this can include multiple cell types to account for the role played by different cells present in each organ as well as extra-cellular matrix.
• Perfusion with appropriate media to nourish cells, transport waste, supply/maintain oxygen levels and apply appropriate shear stress; in many systems, this includes a parenchymal compartment and a vascular compartment to mimic vascularization².
• Providing organ-specific stimuli. e.g.: electrical stimuli for heart on chips, mechanical strain for lung on chips and other organs that require contraction/expansion.

Figure 1: Examples of organ on chip systems that have been developed include (clockwise from top right) a blood-brain barrier (Wikswo lab at Vanderbilt University), cardiac muscle (Parker lab at Harvard), kidney proximal tubule (www.nortisbio.com ), female reproductive tract (DRAPER laboratories), vascularized tumor (George lab at Washington University), skin epidermis (Christiano lab at Columbia), vasculature (George lab at Washington University), liver (Taylor lab at University of Pittsburgh), and lung (www.emulatebio.com). Center image from www.ncats.nih.gov/tissuechip. Figure is taken from¹.

Various organ systems have been modelled via OOC’s using these principles (refer Figure 1) and have been covered in-depth elsewhere³. OOC platforms provide greater insight into fundamental organ biology and can model how diseases develop and progress, leading to improved therapeutics and treatment strategies¹. The potential applications of OOC’s in basic, translational, and clinical research including regenerative medicine and personalized medicine⁴ has spurred great interest from researchers and funding agencies⁵.  Meanwhile, the positioning of OOC’s as improved pre-clinical testing platforms that can augment existing animal models and eventually replace them has caught the attention of pharmaceutical companies and regulatory bodies⁶.

The current gold standard for pre-clinal testing has been animal models, for which there exists many decades worth of data to fall back on.  While no one will argue that animal models are ideal, they are still the best method currently available for pre-clinical testing, short of testing on humans.  This lack of a better model is what helped drive research into microfluidic 3D cell cultures and OOC’s forward as an alternative to animal testing.  The biggest argument for OOC’s over animal models (besides the major ethical debate over breeding animals solely for sacrificing in drug tests) is that they use human cells and model human organ function – factors that should make them a better predictive model than animals. However, since OOC’s are so new and unproven (with the kind of rigour that pharma and regulatory bodies expect), there is a fair amount of healthy skepticism that must be overcome. Some of the big questions being asked by pharmaceutical companies with regards to OOC’s are:

1. How translatable and scalable are OOC’s outside of the labs in which they are developed? Proof of concept demonstrations with low number of replicates carried out in one lab can look very promising, but how well can these be deployed in large numbers by different groups of peoples at different labs/institutes while still providing the same quality of data?
2. What are the benchmarks used to evaluate OOC’s – against each other and against animal and patient data? The lack of a standardized set of parameters by which OOC’s can be evaluated makes it difficult to compare OOC performance and identify strengths and weaknesses.
3. How valid are the predictive capabilities of these systems? How much credibility can be associated with what an OOC says about toxicity or efficacy of a new drug candidate – especially if there is conflicting data from existing preclinical models?
4. In what context can OOC models be used – can they replace animal studies or complement them? Or are they better suited for mechanistic studies? How will regulatory bodies accept data coming from OOC models?

The above questions are not trivial, and many ongoing discussions between academics, regulatory bodies, and industry are already taking place to address these issues⁶,⁷. The remainder of this article looks only at the first point raised: the transferability and scalability of OOC’s. This might at first glance appear to be a simple logistical problem; however, the complexity of OOC’s turns this into a much more complicated issue.

OOC-based experiments in academic labs are done at a low scale with most labs running 8 – 20 OOC’s in parallel at any given time. Thus, each OOC receives significant attention every step of the way from highly specialized personnel who can take preventive steps at the first sign of trouble if needed. Given the relatively small number of replicates and the proof of concept nature of the work, entire experiments can be repeated if significant issues arise. However, in highly regulated healthcare environments, for results to be accepted as valid, significant confidence must be established in the testing platform’s ability to provide repeatable, reproducible and consistent results with many replicates.  Repeating entire batches of experiments or devoting excessive resources to maintain and monitor each individual OOC does not become feasible in such situations.  For OOC’s to move into the mainstream as a standardized tool, they will have to become more “plug and play” – easy to set up in large numbers and maintain without requiring troubleshooting at every step of the way.  Bottlenecks that can get in the way of scaling up OOC platforms can arise from:

• The microfluidic device/platform:

  Most academic OOC platforms use custom microfluidic devices made in-house using soft lithography and PDMS.  While this allows complex devices to be made, batches are small and yield rates low – issues which can be tolerated in proof-of-concept platform demonstration situations where replicates are low but untenable in higher throughput rigorous screening scenarios. Translating PDMS designs to commercially viable plastic or glass devices that can be mass fabricated comes with its own set of challenges (e.g. intricate internal features that can be cast in PDMS are harder to translate to plastics/glass, PDMS is oxygen permeable, while most plastics and glass are not, organ-specific stimuli designed in PDMS might not readily translate to other materials, etc.)  Thus, developing a microfluidic device or platform that can be fabricated in large batches with high yield rates, while still enabling the OOC to be established and maintained is usually the first obstacle for scalability.  To address these needs, commercial microfluidic platforms targeted at OOC’s are being developed or already available. However, these tend to lock down a particular OOCmethod/approach/design, leaving room for multiple competing platforms to be developed if they can demonstrate competitive advantages (e.g.easier to setup/maintain, lower cost, higher throughput, or improved functionality)

• Sourcing the cells:

  Most OOC’s rely on either primary human cells or iPSC derived cell types. This represents the biggest bottleneck in scaling up OOC’s since primary human cells are scarce and variable, while current iPSC differentiation protocols can provide sufficiently mature cells for only a few organs (e.g.: brain, heart)⁸. Even with iPSC derived cells considered sufficiently mature for use in OOC’s, differentiation protocols can be lengthy with up to months at a time needed to produce adult-like cells that can still have significant batch-to-batch variability and throw off OOC performance benchmarks.  Moreover, there is the natural variation and heterogeneity between cells, organs, and individuals⁹ that adds significantly to the complexity of developing OOC’s and understanding what exactly represents normal response and what falls into aberrant behaviour.  While initial OOC’s started off by limiting themselves to one particular lot of primary cells or one particular source and protocol for iPSC cells to enable comparisons, how will measurements and performance be affected when incorporating cell types from different donors or sources? Thus, cells represent the greatest source of uncertainty when attempting to scale up OOCs¹⁰. For large scale deployment, initial solutions will most likely lie in biomanufacturing iPSC’s with well-defined differentiation protocols that have been rigorously tested and validated. Incorporating donor-specific cells for precision medicine applications though, will require further work to ensure differentiation protocols for patient-derived iPSC’s yield cells that match the patients’ own native organ cells, and ensuing OOC performance matches the patient donor organ performance before trying to develop personalized treatment strategies based off OOC predicted results.

• Reliable protocols for setting up and maintaining OOC’s:

  The importance of having well defined and documented protocols while setting up and establishing OOC’s cannot be overstated.  Wherever possible, processes should be quantified and/or described with technical parameters to take out any guesswork. Leaving room for interpretation by personnel while setting up OOC’s can be a recipe for disaster, since even slight ambiguities in areas such as the method of seeding cells, injecting ECM or setting up perfusion can have dramatic implications on cell distribution, viability, and function.  Protocols must also consider practical issues that may be encountered, such as how to deal with bubbles, collect efflux samples or prepare chips for imaging

• Thorough validation of the entire system:

  This is an obvious requirement since users need to have confidence in the overall test platform and the results it generates; wide variations in OOC responses from device to device or batch to batch can erode trust in the usefulness of the platform. Thus, rigorous evaluations of the entire OOC must be done to benchmark performance, establish normal baseline behaviour, and how to interpret and identify changes to lead to valid conclusions.

While the above points do not capture the entire range of issues with scaling up OOC’s, they do highlight some of the initial steps to be considered.  The field of OOC’s is one that is continuing to grow and evolve at a rapid pace.  However, it is still important to examine how end-users use and deploy OOC’s in their venues to then draw insights into remaining questions related to ease of use, practicality, and context of use.  For this to occur, OOC’s need to be scaled up and translated from academic labs to end-user settings.  Ultimately, the OOC that gets adopted might not be the one that is the most advanced, but the one that can be easily set up and replicated while still providing compelling organ-like data.

References

<sup>1. Low, L. A. & Tagle, D. A. Tissue chips – innovative tools for drug development and disease modeling. Lab Chip17, 3026–3036 (2017).

2. Osaki, T., Sivathanu, V. & Kamm, R. D. Vascularized microfluidic organ-chips for drug screening, disease models and tissue engineering. Curr. Opin. Biotechnol.52, 116–123 (2018).

3. Ronaldson-Bouchard, K. & Vunjak-Novakovic, G. Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development. Cell Stem Cell22, 310–324 (2018).

4. Low, L. A. & Tagle, D. A. ‘You-on-a-chip’ for precision medicine. Expert Rev. Precis. Med. Drug Dev.3, 137–146 (2018).

5. Zhang, B. & Radisic, M. Organ-on-a-chip devices advance to market. Lab Chip17, (2017).

6. Livingston, C. A., Fabre, K. M. & Tagle, D. A. Facilitating the commercialization and use of organ platforms generated by the microphysiological systems (Tissue Chip) program through public-private partnerships. Comput. Struct. Biotechnol. J.14, 207–210 (2016).

7. Willyard, C. Channeling chip power: Tissue chips are being put to the test by industry. Nat. Med.23, 138–140 (2017).

8. Low, L. A. & Tagle, D. A. Microphysiological Systems (Organs-on-Chips) for Drug Efficacy and Toxicity Testing. Clin. Transl. Sci.10, 237–239 (2017).

9. Mertz, D. R., Ahmed, T. & Takayama, S. Engineering cell heterogeneity into organs-on-a-chip. Lab Chip18, 2378–2395 (2018).

10. Sakolish, C. et al. Technology Transfer of the Microphysiological Systems: A Case Study of the Human Proximal Tubule Tissue Chip. Sci. Rep.8, 14882 (2018).</sup>

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Subin M. George

Subin George has a decade of biomedical research experience spanning digital microfluidics for 3D cell culture, liver microphyiological systems, and implantable sensors for non-invasive continuous monitoring of oxygen, glucose and lactate. In the process, he acquired significant inter-disciplinary experience and enjoys working with research professionals from various technical backgrounds. His current interests lie in translating biomedical research from proof of concept settings to real-world applications. Apart from research, he enjoys spending time with his wife and daughter, catching up with technology, cooking, hiking, and playing soccer. 

The post Organ on Chips: Questions to Address Before They Can Move Into Mainstream Applications appeared first on The MicroFluidic Circle.

Buzzwords aside, this microfluidic technology’s potential is very real. So real, in fact, that the United States Food & Drug Administration (FDA) launched a partnership with an organ-on-a-chip company in 2017. Understandably, increased success and commercialization makes organs-on-chips more accessible to scientists studying critical medical challenges. But it also encourages the oft-overlooked providers of elective health treatments to entice consumers with unchecked experiments and claims. This elective consumer space is less regulated and more vulnerable to abuse—especially when providers can deceive consumers with buzzwords teeming with scientific credibility. Organ-on-a-chip technology is a boon for novel experiments in labs, but only peer review and regulation can prevent its abuse by pseudoscientists.

Lessons from past malpractice

Without effective peer review, it’s easy to imagine dietary supplement manufacturers, for example, marketing the next snake oil based on staged microfluidics studies. In the United States, so long as the manufacturer does not explicitly claim its products cure disease, FDA regulation is not much of a barrier. This could practically pave the way for misleading advertisements: “Do you get TIRED at night? Our HUMAN-ON-A-CHIP studies PROVE this supplement is RIGHT FOR YOU!” The only thing protecting the consumer from deception, in this case, is peer review.

FDA White Oak Campus. Credit: Flickr

Unfortunately, deceptive marketing is not just a malevolent step-child of promising research, it is indelibly bound at the hip. Look no further than “stem cells” for proof. Stem cells can be pluripotent, meaning they can give rise to nearly any type of cell in the body. Their discovery has had a monumental impact on the future of regenerative medicine. But even before scientists devised a method to make pluripotent stem cells more ethical and accessible, this buzzword carried connotations of “miracle cells.”

Fast-forward to 2018, and the FDA has had to crack down on so-called “stem cell clinics” that endanger patients with elective stem cell injections for various ailments. Aside from being risky, these cell-therapy procedures are unproven—the cells used are often extracted from the patient’s fat and are not even pluripotent. This business model works well enough to warrant FDA involvement, but not well enough to prevent patient harm. These clinics ride the coattails of legitimate stem cell research and profit from the power of a buzzword. Unfortunately, consumer and patient exploitation are inevitably tied to commercialization, and it is fair to say that no accessible technologies—especially groundbreaking ones—are immune.

Organ-on-a-chip technology has become drastically more accessible. Two years ago, I had zero experience with microfluidic or biological research. Today, I spend the majority of my time designing organ-on-a-chip devices and experiments. The barrier for entry is low—I could plan a simple experiment and successfully grow human cells on a chip. But without the scientific expertise and integrity of the women and men around me, drawing worthwhile and reproducible conclusions that hold up against peer review would be infeasible. The danger with buzzwords is that they can only be policed by public caution and skepticism. As this technology becomes more popular, the scientific community should emphasize peer review and regulation in all of its applications.

Some room for optimism

All of this is not to say that organ-on-a-chip commercialization is anything short of revolutionary and, well…good. Patients stand to benefit tremendously from new treatments and fundamental knowledge. Hesperos and Emulate, two commercial pioneers of the field have numerous collaborations in the healthcare industry. Hesperos provides a platform to accelerate drug development, and Emulate hopes to break new ground in personalized medicine with their “patient-on-a-chip” initiative. Organ-on-a-chip technology has also played a role in advancing novel treatment methods. Recently, researchers at Harvard’s Wyss Institute developed a chip that allowed accurate modeling of a portion of the human kidney using pluripotent stem cells. This work opens doors for repairing damaged kidneys—offering a legitimate stem cell therapy.

Because these are cases of medical and pharmaceutical research, peer review and regulation (in the form of double-blind studies) will have the ultimate say. The elective consumer space is more of a gray area. Fortunately, we have an opportunity to treat it with comparable scientific rigor. The FDA could one day choose to mandate using organ-on-a-chip devices for safety testing of dietary supplements. Microfluidic experiments are significantly cheaper than animal or human trials, and this may make evidenced-based policy more feasible. We could also one day request the use of organ-on-a-chip platforms to validate risky cell-therapy procedures before experimenting on live patients. If we don’t lose sight of peer review and regulation as governors of science, we can validate market claims to benefit the consumer. Reliable public scientific data, in a space where not much exists, allows us to address the credibility of lofty claims rather than to leave them unchecked.

There is an undeniable magnetism inherent to buzzwords. They attract media attention and research funding, but also opportunists, hucksters, and charlatans. To this point, we have had to take the bad with the good.  Fortunately, we can learn from ongoing malpractice and arm ourselves with the most impenetrable shield in a scientifically literate society: skepticism.

Featured image credit: NCATS

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Max Levy

Max Levy is a Ph.D. student at the University of Colorado Boulder studying chemical and biological engineering. His research focuses on the intersection of nanotechnology and drug development. He also serves as a science writer, and as a senior editor for the "Science Buffs" blog.

The post How Organ-on-a-Chip Technology Might Be Used (and Abused) in the Elective Consumer Space appeared first on The MicroFluidic Circle.

In one sense, organ on a chip devices are becoming more complex, as evidenced by the March 2018 announcement of an organ on a chip device that can model up to 10 organs and their interactions for a continuous 1 month run². In another sense, organ on a chip models are still very simplistic, as they don’t yet feature the multi-tissue structure that defines an organ. Most organ on a chip applications feature a channel or chamber in which cells are cultured, and interact with various factors, such as a liquid phase flowing adjacent to the cells, which simulates blood flow around the tissue³. However, the name “organ on a chip” paints a very different picture. A lay person who hears this term would never picture the relatively simple devices which are used today. This is where it may be worth examining organ on a chip as a PR case study for scientists.

With the increasing scientific use and commercialization of lab on a chip devices in general, it is likely that in a few years the terms “lab on a chip” and “organ on a chip” will become familiar to the general public. At that point, the name “organ on a chip” will present a problem because “organ on a chip” paints a vivid picture, but that picture is very inaccurate, and a little alarming. Many may think that these devices include full organs that are connected to some sort of chip, maybe an electronic one. Currently, the only people who have heard of this technology have read something about it. Once “organ on a chip” is a household term, it must be expected that there will be a portion of the public who have heard of the term but have no idea what it looks like, or what it does.

In that case, organ on a chip technology may face unnecessary opposition from the public, who do not want lab experiments that use human or animal organs. The myth that artificial organs are grown on chips may come about. Artificially making organs is a controversial idea that has faced ethical or religious objections, with 23% of Americans reported to oppose bioengineered organs for medical use in a 2015 report⁴. Of course, these objections have nothing to do with the actual organ on a chip technology, but it is possible that Organ on a chip researchers face them anyway from a public who is misled by the evocative name of the technology.

Cloning and stem cell technologies have faced similar problems before. Some of the objections to these technologies have come from myths about them, such as cloning technology being used to fully replicate an adult⁵. Could organ on a chip also face public opposition based on a misunderstanding of what it really is?

It is possible. First, organ on a chip would have to become a commonly recognized term. This is likely to happen as exciting breakthroughs continue to get news coverage. At that point, some people will likely associate the term with artificial organs and could oppose the idea. Whether such opposition would get any momentum may not be so much up to the scientific community. For example, if an influential TV personality started to denounce it, organ on a chip could be a hot topic. Unfortunately, some technologies are criticized or opposed based on perceived issues that are not in line with reality.

What about legislation and politics? In the US, stem cell research has been restricted or banned in many states, and federal funding for it has been restricted in the past. GMOs are heavily regulated around the world as well. However, major political resistance against organ on a chip devices are not likely, even if the public perceives the same problems with organ on a chip devices. This is because stem cell research and GMOs are very clearly defined in terms of the techniques involved. Stem cell legislation has usually defined its scope specifically based on whether embryos are involved, and how they are obtained⁶. In the case of an organ on a chip, there is not a specific technique or process step that could be targeted by legislation. It is simply a new configuration for in vitro models and microfluidic devices. This points to another reason serious opposition may never happen –would be leaders of activism against organ on a chip would first find out more about organs on a chip, and learning more about the technology could dissuade most from opposing it.

Where would this leave a potential controversy? There may or may not be a short time of 1-2 years where organs on a chip become well known, and then become a hotly debated technique. The vicissitudes of politics and media would be a big, unpredictable factor there. A lasting stigma is not likely; organs on a chip would be just another technology that some people really misunderstand. However, there is a takeaway for the scientific community. There is a lesson on managing the message and the image here, and the importance of names is obvious. By picking this very evocative, but misleading name, have we invited trouble? Will we later have to correct myths, be opposed by the public and spend our time answering nonsensical questions?

Should we have purposefully picked a different name? Should we look for an alternative now? Probably not, but it is good to think about the subject. What we should do in the future is to think from this marketing perspective every now and then, especially when coining a new term, or announcing a breakthrough. Scientists have the most control over the message when they are reporting their work – until they announce it, the world does not know about it. We should take advantage of that moment.

<sup>1. Funk, C., 2017. “Real Numbers: Mixed Messages about Public Trust in Science.” Issues in Science and Technology, 34(1), 86-88.

2. Hamzelou, J., 2018. “Miniature organs mimic human body.” New Scientist 27(3170), 1025-1031.

3. Bhatia, S. N., Ingber, D. E., 2014. “Microfluidic organs-on-chips.” Nature Biotechnology 32(8), 760-772.

4. Funk, C., Raine, L., Page, D., 2015. “Americans, politics and science issues.” Pew Research Center.

5. Miller, R. G., 2006. “Cloning: A critical analysis of myths and media.” Science Scope, 29(6), 70-74.

6. Pew Research Center, 2001. “Human Cloning: Religious Perspectives.” http://www.pewforum.org/2001/05/03/human-cloning-religious-perspectives/ (See Mr. Wasinger’s comments)</sup>

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Aytug Gencoglu

Aytug Gencoglu has a decade of microfluidics experience, primarily in academic labs. He has previously published articles on electrode deterioration, pH changes in microfluidic channels, and dielectrophoresis, and developed microfluidics components for dielectrophoretic cell characterization.

• aytuggencoglu@outlook.com

The post Scientists Should Think Like Marketers: The Organ on a Chip Case appeared first on The MicroFluidic Circle.

• Label-free continuous monitoring of cell health inside channels
• Low volumes (picoliters) in microfluidic channels enable high sensitivity of detection
• By placing sensors close to the cells, the analyte of interest is less likely to be diluted in cell media

Truly mimicking human physiology

Living cells are sensitive even to the slightest changes in their environment and release certain molecules in response to these changes. Monitoring these molecules provides valuable information on the state of health and can predict response to drugs. For example, Zhang et al.¹ developed a multi-sensor integrated organ-on-chip platform to monitor micro-environmental parameters such as pH, oxygen, and temperature by using optical-based sensors. Additionally, the authors developed label-free electrochemical immunobiosensors for continuous monitoring of molecules secreted by tissue-engineered organs inside the microfluidic channels. This work demonstrated that organ-on-chips can integrate real-time monitoring of the biophysical and biochemical parameters in a micro-environment.

Figure 1: Schematic showing how sensors can be used to continuously monitor biochemical parameters inside a microfluidic channel.
Credit: Aditya Aryasomayajula

Figure 1 shows a schematic diagram of how feedback from the sensors integrated into a microfluidic channel can be used for regulating the microenvironment for cell culture. Sensors can continuously monitor biophysical and biochemical parameters inside a channel and directly communicate this information to a computer, which in turn adjusts the inflow of fresh cell culture media using a pump. Thismicroperfusion of the channel with cell culture media can help maintain an optimal pH, oxygen level, and temperature. This feedback can be used to improve cell viability for organ-on-chip applications and bring us a step closer to truly mimicking the human physiology.

Currently, there are developed sensors for measurement of pH², oxygen³, glucose³ and lactate⁴. Integrating any combination of these sensors into organ-on-chip devices will help define the microenvironment that may be important in drug screening applications.

Challenges integrating sensors and outlook

There are several challenges that one has to overcome in order to successfully integrate sensors into microfluidic channels. They are as follows:

a. Biofouling
One of the major challenges of using sensors for long-term monitoring is biofouling of the surface. Biofouling refers to the forming of a thin biofilm on the surface of the sensing material which results in degrading the performance of the sensors. This problem is particularly amplified when sensing in biological environments. There have been several strategies to mitigate biofouling of sensors. For example, surface modification (silanization) is a popular technique to extend the life of sensors.

b. Fabrication technologies
The conventional use of soft lithography for fabricating microfluidic devices requires modifications to integrate sensors directly into the channels. Problems, such as bonding of PDMS surface and aligning sensors inside channels, may be a challenge. New fabrication techniques like LEGO and cartridge assemblies have gained popularity for manufacturing organ-on-chip devices, as these are better suited for sensor integration.

c. Sensor sensitivity and selectivity
Sensor sensitivity refers to the detection limit of the sensors. Ultrasensitive sensors are required for sensing in low volumes (picoliters) in the mg/L or ng/L range. Recently nanomaterials like graphene⁵ and carbon nanotubes⁶ have gained popularity because of their high sensitivity to detect in low volumes. Selectivity is another major challenge for these sensors. This parameter refers to the ability of the sensors to detect only specific molecule of interest with high signal to noise ratio. The presence of various interfering species in cell culture media can be a challenge to sense specifically the molecule of interest. Aptamer-based sensors offer good selectivity with high signal to noise ratio.

In conclusion, new technology brings new demands and challenges. Organ-on-chip and tissue engineering show great promise for personalized medicine, drug development, and studying disease models with more complex physiologically relevant systems. Integrating sensors into microfluidic channels can enhance the performance of these technologies by continuous monitoring of biophysical and biochemical parameters in micro-environments.

<sup>1. Zhang, Y.S., Aleman, J., Shin, S.R., Kilic, T., Kim, D., Shaegh, S.A.M., Massa, S., Riahi, R., Chae, S., Hu, N. and Avci, H., 2017. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proceedings of the National Academy of Sciences, p.201612906.

2. Welch, D. and Christen, J.B., 2014. Real-time feedback control of pH within microfluidics using integrated sensing and actuation. Lab on a Chip, 14(6), pp.1191-1197.

3. Rodrigues, N.P., Sakai, Y. and Fujii, T., 2008. Cell-based microfluidic biochip for the electrochemical real-time monitoring of glucose and oxygen. Sensors and Actuators B: Chemical, 132(2), pp.608-613.

4. Weltin, A., Slotwinski, K., Kieninger, J., Moser, I., Jobst, G., Wego, M., Ehret, R. and Urban, G.A., 2014. Cell culture monitoring for drug screening and cancer research: a transparent, microfluidic, multi-sensor microsystem. Lab on a Chip, 14(1), pp.138-146.

5. Shao, Y., Wang, J., Wu, H., Liu, J., Aksay, I.A. and Lin, Y., 2010. Graphene based electrochemical sensors and biosensors: a review. Electroanalysis, 22(10), pp.1027-1036.

6. Jacobs, C.B., Peairs, M.J. and Venton, B.J., 2010. Carbon nanotube based electrochemical sensors for biomolecules. Analytica chimica acta, 662(2), pp.105-127.</sup>

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Aditya Aryasomayajula

Aditya currently holds a joint postdoctoral fellowship in Mechanical Engineering Department at McMaster University and Firestone Institute for Respiratory Health at St. Joseph’s Healthcare, Hamilton. He is also the project manager for the sensor division of Global Water Futures program. He has won prestigious scholarships from National Science Foundation (NSF) and Deutsche Forschungsgemeinschaft (DFG) Germany. His research interests include developing sensors for environmental monitoring and healthcare diagnostics. He is currently developing a lung-on-chip device to study disease models like asthma and drug screening for cystic fibrosis.

• aryasoma@mcmaster.ca

The post Senso-Fluidics: Continuous Monitoring Using Sensors in Microfluidics appeared first on The MicroFluidic Circle.

Imagine you get sick, you go to the doctor, who prescribes a medicine to you, most often empirically. You return to home, take the medicine, and heal. Or sometimes symptoms continue, or occasionally worsen. What do you do? You return to the doctor, complaining that the medicine does not work, and then receive another set of medicine, again very likely, by empiricism. The second medicine may heal you, or if unlucky, you may need to repeat this process for a few additional rounds prior to final recovery. Who knows. This scenario perhaps sounds familiar to most people, because it is how today’s medicine is practiced. A step forward, if the illness is much more serious than just a cold, modern technology may start to come into the play of its treatment. For example, patients with cancer typically receive molecular and genetic profiling to identify mutations, which are subsequently used to determine the class of drugs to prescribe. However, a biomarker often does not translate into a successful clinical response to the selected therapy. In a well-known case, cancer patients with wild-type KRAS protein are treated with Cetuximab, but only about 3 in 10 will ever respond to the drug, while the rest, unfortunately, instead of being cured, suffer side effects without noticeable benefits.

Organ-on-a-chip and disease-on-a-chip platforms for modeling human physiology and pathophysiology. Reprinted with permission from Elsevier. Citation: Zhang YS, Zhang Y-N, Zhang W. Cancer-on-a-Chip Systems at the Frontier of Nanomedicine. Drug Discovery Today, 2017, 22, 1392-1399.

The reality is that, even when two patients are diagnosed with the same disease, the behaviors of their respective phenotypes remain quite diversified, making each individual’s disease one of its own kind. To this end, the organ-on-a-chip technology, featuring miniaturized units of functional tissues or organs, may bring us true precision medicine, by allowing screening of drugs or drug combinations in a personalized manner before the most effective options applied to one’s own self ¹. A small-scale microfluidic chip can be designed to integrate various biomimetic cues, including those of biophysical and biochemical in nature, in addition to the tissue/organ models hosted within, which may derive from the patient’ cells – or sometimes simply a piece of patient’s explanted tissue. When multiple chips each containing a different tissue/organ model are interconnected into a compartmentalized system, the multi-tissue-drug interactions may further be picked up, to better predict how the drug is exerting effects on the patient as an organism.

With all the best hopes, this may still sound too futuristic to be true. Indeed, many challenges remain before an organ-on-a-chip system generated according to a patient’s own traits can be treated as an equivalent of that patient, which he/she can rely all decision of drug selection on. Currently, the field is lacking validations of these platforms – a few studies have shown a preliminary correlation of drug results from chips with those observed in human patients ^{2 3}. Nevertheless, there are way more chip designs reported in the literature that have never been shown for their predictive power. Most probable failure could well lie in the inaccurate scaling of the organoids with their human counterparts, leading to biased pharmacokinetics and pharmacodynamics during screening ⁴. Besides, ergonomics can be the key to the translation of the organ-on-a-chip platforms to the clinics – they have to be sufficiently sophisticated to model tissue/organ functions while operationally simple enough for them to be adopted by non-expert end-users, such as clinicians. Eventually, it is standardization of these platforms that will facilitate their widespread applications at the bedside, through large-scale industrial production. To this end, the Tissue Chip Testing Centers recently instated by the United States National Institutes of Health ⁵ certainly represent a fair start towards the goals of both chip validation and standardization. There is perhaps no doubt that the organ-on-a-chip technology will land successfully in materializing personalized medicine, just how long this “journey to the west” takes.

<sup>1. Bhatia, S.N. and D.E. Ingber, Microfluidic organs-on-chips. Nat Biotech, 2014. 32(8): p. 760-772.

2. Wang, G., et al., Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nature medicine, 2014. 20(6): p. 616-623.

3. Majumder, B., et al., Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. Nat Commun, 2015. 6: p. 6169.

4. Wikswo, J.P., et al., Scaling and systems biology for integrating multiple organs-on-a-chip. Lab on a chip, 2013. 13(18): p. 3496-3511.

5. Tissue Chip Testing Centers. 2016 [2017/11/20]; Available from: https://ncats.nih.gov/tissuechip/projects/centers.</sup>

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Yu Shrike Zhang

Shrike Zhang currently holds a faculty position in the Division of Engineering in Medicine at Brigham and Women's Hospital, Harvard Medical School. His research is focused on innovating medical engineering technologies to recreate functional biomimetic tissues and their models, spanning from organ-on-a-chip, 3D bioprinting, and bioanalysis to regenerative engineering and nanomedicine. In collaboration with a multidisciplinary team, his laboratory seeks to ultimately translate these cutting-edge technologies into the clinics. Dr. Zhang is the author of more than 110 peer-reviewed publications. His scientific contributions have been recognized by >30 international, national, and regional awards. He is serving as Editor-in-Chief for Microphysiological Systems, and is also on Editorial Board of Bioprinting.

• yszhang@research.bwh.harvard.edu
• https://www.shrikezhang.com/

The post Personalizing Medicine with the Organ-on-a-Chip Technology: Where Do We Stand? appeared first on The MicroFluidic Circle.

Muscle disease is one example. One of the NCATS awards is for “Systemic Inflammation in Microphysiological Models of Muscle and Vascular Disease.” This Duke University project focuses on skeletal muscle and blood vessels. The models will replicate inflammation, in order to assess variation in responses to drugs. A similar award went to Cedars-Sinai Medical Center for “Development of a Microphysiological Organ-on-Chip System to Model Amyotrophic Lateral Sclerosis and Parkinson’s Disease,” to highlight novel biomarkers. There is no cure for ALS, a neurological condition that stops voluntary muscle movements including chewing, walking, talking and ultimately, breathing. Animal rights proponents welcome these endeavors because they have been vexed for years by the use of dogs for research that leaves them crippled with muscular dystrophy and unable to walk, swallow, or breathe.

“For decades, generations of dogs have suffered and died in gruesome experiments that haven’t led to a cure for muscular dystrophy in humans,” proponents claim. They have also campaigned against the use of birds in related neurotransmitter research, as being “cruel and pointless” while not yielding usable information.

Harvard University researchers received another of the NCATS awards, to develop “Lung-on-a-Chip Disease Models for Efficacy Testing.” Microfluidic organ-on-chip devices replicating influenza virus infection will be used to define new antivirals. This influenza disease model will be linked to human liver chips, to conduct pre-clinical safety testing of existing antiviral drugs, and to identify new therapeutics that target the host response to infection, rather than the virus itself. This too is a welcome mission for animal rights workers, because lung organoids help “scientists get a much better idea of how human lungs respond to airborne substances than they can by forcing animals to inhale chemicals and then trying to apply the results to a completely different species.” Moreover, it could mean an end to animals“ being forced to inhale toxic chemicals for hours at a time before being killed.”

Source: pixabay.com

University of Washington teams received an award to investigate “A Microphysiological System for Kidney Disease Modeling and Drug Efficacy Testing.” Chronic kidney disease affects more than 20 million U.S. adults and is the ninth leading cause of death in the U.S. UW scientists will create in vitro models that mimic critical aspects of kidney function, response to injury, and repair. They will architect “virtual clinical trials” for candidate drugs.

A related project award is “Kidney Microphysiological Analysis Platforms to Optimize Function and Model Disease” at Brigham and Women’s Hospital. Microfluidics, stem cell biology, microfabrication and bioprinting will be used to model kidney diseases, and to screen for kidney toxicity. Kidney disease research historically relies upon multiple types of animal studies.

Two of the NCATS awards target heart functions. They include “A 3-DIn Vitro Disease Model of Atrial Conduction,” a University of California Davis project utilizing patient-derived induced pluripotent stem cells. “Drug Development for Tuberous Sclerosis Complex and Other Pediatric Epileptogenic Diseases Using Neurovascular and Cardiac Microphysiological Models” at Vanderbilt University will formulate neural and cardiac tissue-chip models that replicate drug response more reliably than those currently in use. In a 2017whistleblower case, a Veterans Affairs employee reported mistreatment of dogs being used for cardiac research.

The experiments he alleged included induced heart attacks. Many of the dogs died at project conclusion, and sometimes their hearts were harvested for further research.

The actions of the whistleblower, himself an Iraq veteran, drew several responses from the VA, some of which read in part: “At VA, we have a duty to do everything in our power to develop new treatments to help restore some of what veterans have lost on the battlefield. One of the most effective ways for VA to discover new treatments for diseases that affect veterans and non-Veterans alike is the continuation of responsible animal research . . . While there are ethical concerns associated with conducting animal research, they are far outweighed by ethical concerns associated with not doing animal research. The broad consensus of medical and scientific experts in the United States and around the world is that animal research is necessary. That’s why VA will continue conducting animal research like someone’s life depends on it — because it does.”

There’s no debating that most life-saving medical treatments were developed around animal research, including insulin, liver transplants, numerous cancer drugs, nicotine patches and pacemakers. Can scientists shift away from the baked-in pull of history? Animal activists have been buoyed by celebrity support, including comedienne Lily Tomlin’s efforts to defang their image as humorless fringe players.

Will organs-on-chips stop animal testing of drugs? Perhaps some of it, but not all. “It’s an illusion to think they can be used to completely replace animal research,” biologist Jurgen Knoblich told The Scientist in 2016.

Alternatively, “The key to staying hopeful is to operate on an assumption of success rather than failure,” Friends of Animals President Priscila Feral writes, summing up the perspective of many other activists.

While the pace of advance accelerates, it’s unknown which of these two predictions will prove realistic. But one thing is certain: NCATS’support for organs-on-chips energizes animal lovers’ central hope — that this horse is out of the barn.

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

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