Microfluidics can control how stem cells communicate

By Lily | Published: October 25, 2011
journal.pone .0022892.g001 Microfluidics can control how stem cells communicate

A-B. Microfluidic perfusion device. C. Microfluidic perfusion systems use flow to fine-tune the relative significance of convection, diffusion, and reaction.

Exciting to see the work of Dr. Katarina Blagovic from the Voldman group at MIT published in PLoS ONE last month: “Microfluidic Perfusion for Regulating Diffusible Signaling in Stem Cells.” Katarina continued and extended the work begun during my Ph.D. (I’m a co-author), and it’s wonderful to see the ideas we discussed become reality!

In diffusible signaling, cells communicate with each other by secreting signaling molecules which diffuse into the surrounding liquid before being taken up by those same cells or neighboring cells via receptors. Cell signaling is especially important for stem cells because it can determine how a stem cell specializes into various tissue types. Traditionally cells are grown in Petri dishes in standing liquid. In these conditions, the chemical makeup of the environment around the cells is constantly changing as cells secrete and take up a complex array of signaling molecules. It has been challenging for biologists to experimentally probe the details of these closed-loop interactions: what molecules are secreted when, which cells receive the signals, and what effects do the signals have on the cell?

Enter microfluidics. This paper shows how microfluidics provide a new tool for biologists to interrogate diffusible signaling loops. The idea: for cells grown under continuous, non-recirculating microfluidic perfusion, most secreted signaling molecules are swept away before binding to nearby cells. This continuous clearing enables more strict control over the cell’s environment by allowing the researcher to specify what molecules are perfused into the cell culture. In engineering terms, you have more control over the inputs (signaling molecules) to the system (the cell).

Not only did Katarina show that continuous flow can disrupt diffusible signaling, she was able to uncover a specific biological result which suggests that FGF4 is not the only cell-secreted molecule needed for differentiation of the stem cells to neuroectoderm (cells that gives rise to our nervous system during development).

On the commercial front, CellASIC, a company spun out of Luke Lee’s lab at Berkeley, has created a series of products to support microfluidic perfusion culture. And Fluidigm is developing a stem cell culture chip.

For more:

 

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NIH / DARPA solicit proposals for human-on-chip platforms to accelerate drug development

By Lily | Published: October 23, 2011

DrugChipCollage 1024x445 NIH / DARPA solicit proposals for human on chip platforms to accelerate drug development

Fantastic to hear about a new, substantial U.S. government funding effort in microfluidics research! Last month a joint effort between the NIH, DARPA, and the FDA was announced to develop human-on-chip platforms to test drug candidates more efficiently and accurately. The NIH and DARPA are soliciting proposals separately from all types of research organizations (academic, industry, government, other) and each agency plans to commit up to $70 million to the effort (up to $140 million combined).

A big problem in drug development is that current methods for testing safety and efficacy are either cheap and inaccurate (in vitro experiments, animal studies) or more accurate and very expensive (human clinical trials cost $20k – $50k per patient). Often a drug works in a mouse but doesn’t work in humans, leading to millions lost on failed clinical trials. The hope is that microphysiological environments mimicking human tissue and organ structure may enable more accurate assessment of a drug’s performance at much lower cost.  These chips wouldn’t replace clinical trials, but might allow us to hone in on effective drugs earlier in the development process, saving time and money.

DARPA has already begun soliciting proposals, and abstracts are due in just a few days (Oct 27, 2011).  Full proposals are due on Dec 12, 2011. To apply, see more information here and here.  There’s also a teaming website here to help facilitate collaboration. From the DARPA website:

DARPA is soliciting innovative research proposals to develop an in vitro platform of human tissue constructs that accurately predicts the safety, efficacy, and pharmacokinetics of drug/vaccine candidates prior to their first use in man. Alternative testing methods that rely on isolated human cells hold the promise of authentic human responses to candidate drugs, vaccines, and biologics. Recent research has shown that three-dimensional constructs of one or more cell types are able to reproduce relatively authentic human tissue and organ physiology in an in vitro environment. As a result, DARPA seeks in vitro platforms comprised of human tissue constructs that will accurately assess efficacy, toxicity, and pharmacokinetics in a way that is relevant to humans and suitable for regulatory review.

Interested vendors listed so far include InVivoSciences and Cell Therapy Group.

For more:
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Biomedspeak

By Lily | Published: October 14, 2011

In foreign language learning, there’s a concept called false friends — words that seem so familiar you’re tricked into thinking you know what they mean. But in reality they mean something different. For example, in German and Scandinavian languages the word “gift” doesn’t mean a present. It actually means poison.

While not as dramatic, there are false friends in biomedical lingo that you may not be aware of. The lab-on-a-chip field is especially prone to terminology-related communication barriers because it brings together a diverse crowd from all corners of the scientific, medical, engineering, business, academic, and industry worlds.  And because it’s an emerging industry, terminology is in flux.

A common principle for detecting lingo: seemingly broad terms often have narrow, specific meanings to industry insiders. In the same way that “tech industry” has come to mean software/computers/electronics (not just any type of technology), “biotech” has a specific meaning that’s more narrow than biology + technology. Here are a few examples related to the lab-on-a-chip world:

Biomedspeak: Deceptively Broad Terms

TermTo a lay person, it seems like this would mean....But the industry interpretation is actually more narrow...
Biotechnology, or biotechSeems obvious: biology + technology = any technology applied to biological or medical problems, right? Actually to an insider, "biotech" means using live micro-organisms (e.g., bacteria) to manufacture a product (typically pharmaceutical). Classic examples of biotech companies include Biogen, Genzyme, and Genentech. Medical devices are not considered biotech.
Medical devicesSeems like it would mean any device with a medical application. And many do use it this way, including the FDA. Often there's an assumption that medical devices really means therapeutic medical devices, with diagnostics considered a separate industry segment. Examples of medical device companies include Boston Scientific and Medtronic.
Molecular diagnosticsIncredibly vague term if you take it literally. Often means diagnostics based on DNA / RNA, excluding tests like immunoassays. However, some people interpret it to include tests for any protein or nucleic acid, and even include small molecules.

Bonus: An assay is just a measurement. This one is for all of you coming from non-biological backgrounds. It doesn’t fall under the common principle above, but I mention it because I’ve heard non-bio folks comment on it so often.

To make things even more confusing, a lot of these industries are beginning to collide and become interrelated. Drugs are being combined with medical devices (e.g. drug-eluting stents) and diagnostics are beginning to be linked closely with drugs to enable personalized medicine.

Do you have any examples of biomedspeak?

 

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Recent job posts — Finland and India!

By Lily | Published: October 10, 2011

Know someone looking for a job?  New job post today from BioMediTech in Finland, looking for a Post Doctoral Fellow for the development of microfluidic systems for stem cell studies.  Note the application deadline is Nov 15, 2011.  Also recently — Achira Labs in Bangalore, India is looking for a Group Lead for Assay Development.

Check them out at the job board!

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MICROmanufacturing Magazine interviews Don Ingber of the Wyss Institute

By Lily | Published: October 6, 2011

WyssMicroManufacturing MICROmanufacturing Magazine interviews Don Ingber of the Wyss Institute Just came across this MICROmanufacturing Magazine interview with Wyss Institute Founding Director, Don Ingber, about their microfluidic organ-on-a-chip work led by Ingber and Dan Dongeun Huh. Interesting to see the interview delve into a manufacturing question, highlighting the translational nature of the Wyss:

MICRO: How are these devices being manufactured?

Ingber: Manufacturing has been done by students and fellows in the lab, but we have just started to outsource that process to increase the robustness of the cell culture and quality system. Our first 50 lung-on-a-chip modules made by a commercial manufacturer should be delivered in October.

Also very exciting to hear about other creative and unexpected applications they’re exploring, such as microfluidics for window insulation:

MICRO: What do you see as the key breakthroughs in microfluidics at the Wyss Institute in coming years?

Ingber: We see more cross development of microfluidics for far-ranging applications in both medical and non-medical areas. For example, another group at Wyss is working on increasing window insulation efficiency. We noted that penguins can stay warm at the South Pole using microcapillary flow to warm their skin, so we are working with the insulation group on using microfluidic microcapillary flow inside windows to increase insulation efficiency. It’s a totally out-there concept, but because Wyss research is so broad, we constantly find synergies across platforms.

For more check out the full article here: “Last Word: The telltale heart.” Also see:

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On-Q-ity CSO Walt Carney talks about CTCs in Drug Discovery Today

By Lily | Published: October 4, 2011
Picture2 On Q ity CSO Walt Carney talks about CTCs in Drug Discovery Today

On-Q-ity CSO and Interim President, Walt Carney (right). Example of size-selective gradient chip design (left).

Thanks to Bruce Booth for mentioning this article in Drug Discovery Today by Walt Carney, Chief Scientific Officer and Interim President of On-Q-ity.  We’ve covered On-Q-ity before, so it’s great to hear more of their story unfold.  My thoughts on the article:

1. Limited uptake of Veridex CellSearch due to low sensitivity could be an opportunity for later entrant microfluidic competitors: On-Q-ity is competing against a non-microfluidic product already on the market (Veridex CellSearch) in addition to emerging microfluidics-based competitors. The article explains that the CellSearch has not seen widespread uptake due to low sensitivity. High sensitivity is important to make the test meaningful in early stages of cancer where treatment has a better chance of success. Microfluidic tests have the potential for higher sensitivity, but they’ll have to prove themselves with strong data to overcome any physician skepticism associated with the CellSearch product.

2. Microfluidic design enables increased sensitivity via antibody-based capture and size selectivity: In the past couple years, On-Q-ity has demonstrated that size selectivity combined with microfluidic EpCAM capture is important for capturing a larger number of CTCs, potentially boosting the sensitivity of their test compared with Veridex.

3. Not all microfluidic designs incorporate size selectivity: However, just because a design is microfluidic, doesn’t mean it automatically incorporates size selectivity. Earlier we heard that Veridex licensed CTC-capture technology from MGH (which also licensed technology to On-Q-ity). While it’s not clear which technologies have been licensed to Veridex, MGH’s next-generation herringbone chip (for example) doesn’t appear to be size selective. According to Daniel Haber, the main advantages of the herringbone mixer design are ease of production and scale-up for manufacturing.

4. The licensing of CTC technology from MGH to two competing companies raises questions about models for academic/industry partnerships: Lately there’s been a growing trend for large biomedical corporations to purchase innovation out of academia instead of developing it from scratch in-house. For a company with limited resources (e.g., a startup), what strategy should they take when licensing a technology, especially if the academic group continues development in parallel and may license next generation technology to competitors?

For more:

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Startup spotlight: Pharyx

By Lily | Published: September 30, 2011

2011 09 29 22 10 391 Startup spotlight: Pharyx

Pharyx is a recent microbioreactor startup spun out of Rajeev Ram’s group at MIT and founded by Harry Lee and Paolo Boccazzi. They’ve been around for a few years and won a Phase I SBIR grant in 2008 ($200,000) and Phase II award in 2009 ($750,000) to develop microbioreactors for biofuels.

Bioreactors are essentially tanks for keeping micro-organisms happy while they produce a substance of value (e.g., pharmaceuticals, biofuels, fermented foods [beer!], or other industrial products). To work, bioreactors must maintain carefully controlled conditions, including temperature, flow rate, pH, oxygenation, and more. Microbioreactors are miniature, microfluidic bioreactors that may enable bioprocesses to be designed and optimized faster and at lower cost due to smaller volumes, automation, and potential for parallelization.

There isn’t much information about Pharyx; they appear to be raising funds since they participated in the Early Stage Life Sciences Conference VII in April. From their company description in the conference program:

There is a need for automated parallel bioreactor systems that can execute complex, controlled bioprocesses to reduce development costs and timelines. To meet this need, we are developing a technology platform comprising microfluidic devices that are integrated to create bioreactors, with complex fluid control capability, in a disposable plastic device the size of a deck of cards.

Parallel bioreactor systems based on this platform can be customized and scaled for different applications including bioprocess development for biopharmaceuticals, biofuels, and industrial products; and basic research such as synthetic biology, metabolic engineering, and directed evolution that employ continuous culture experiments.

While Xconomy has listed Pharyx as an energy company, their platform could be applied much more broadly. It wouldn’t be surprising if Pharyx concentrated on energy for now (currently hot with investors) as opposed to pharmaceuticals (which some VCs are shying away from), but it’ll be interesting to see which markets they eventually end up in.

For more:

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If you can make it there: Microfluidics in New York

By Lily | Published: September 29, 2011

2011 09 17 10 36 05 If you can make it there: Microfluidics in New York

Since I’m located in Boston, it’s easy to get surrounded by Massachusetts-based efforts to promote innovation. But it’s also great to see similar efforts in others locations.  For example, I ran across this 2009 report on microfluidics research in New York State published by the New York State Foundation for Science, Technology and Innovation (NYSTAR).  Like many of us, they want to support “technology development, innovation and commercialization leading to economic growth.” The report summarizes academic work in the state, with a goal of enhancing research and encouraging partnerships.

If you’re at an academic lab or company in New York State, you should also be aware that NYSTAR runs a number of funding initiatives, including research grants and technology transfer incentives.  For example, in 2005 the Sachs Lab was awarded $750,000 in a partnership with Reichert to develop and commercialize a microfluidic cell volume measurement device. In the excerpt below from the 2009 report, we see that this partnership grant eventually led to a successful licensing deal with Reichert (links added):

University at Buffalo has three technology disclosures involving microfluidics that were combined into a single patent application:

  • #5850 Microfabricated device for monitoring cell volume
  • #5912 High Throughput Bacterial Screening Device: Microfluidics Biosensor
  • #5913 High Throughput Screening Device for Crystallography

This intellectual property is licensed to Reichert, Inc., a Buffalo‐based company. This microfluidics technology is directed to measuring cell volume changes, initially for use as a research tool. It may also be used for studying drug activity since many drug reactions have an immediate impact on cell volume. The primary inventor was Dr. Fred Sachs, SUNY Distinguished Professor of Physiology and Biophysics, 716‐829‐3289 x105 or sachs@buffalo.edu.

Are there similar programs where you are?

Check out the full report here: Inventory of Research Expertise in Microfluidics at New York’s Universities and Labs

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Diagnostics For All featured in the New York Times

By Lily | Published: September 27, 2011
DFAchip2 Diagnostics For All featured in the New York Times

Diagnostics For All liver test chip. (Image credit: New York Times)

Diagnostics For All and their paper microfluidic liver tests were featured yesterday in the New York Times as part of its “Small Fixes” series. The series focuses on low-cost innovations for the developing world.  A few themes:

  • Evolution from academic to commercial design: “Originally, Dr. Whitesides used a plastic that hardened in ultraviolet light, but wax is cheaper and faster.”  This is a theme we’ve heard from other startups — the team must successfully adapt the initial proof-of-concept design to make it more manufacturable.
  • Unmet need for lower-cost lab instrumentation: “Reagents are spotted on by hand with a pipette — a tedious job, but the $100,000 machine that can automate it is not in the budget…” Is it possible to create lower-cost spotting machines akin to desktop inkjet printers?  If so, is there enough of a market for them?
  • How low can we go?:  How low do costs have to be for developing countries? While paper may be the cheapest substrate, what about the cost of reagents? (the article says one of the next steps is to move into immunoassay-based tests that would use [presumably expensive] antibodies)  Also, in this article they put down plastics as being too expensive for developing countries. But what about the many companies making plastic chips for global health? How does cost-per-chip depend on the particular country or disease indication/use?
  • Additional markets in the G7: Dr. Ryan mentions potential additional markets in the G7 (marathon runners testing electrolyte balance, or patients on statins testing for liver damage).  This is another theme we’ve heard from global health startups — many of these innovations have potential value in lucrative G7 markets that could help offset the challenges of cost-constrained markets in the developing world.
  • Room for more innovation: According to George Whitesides, “…we’re still a long way from getting to the end of what’s inventable.”  Looking forward to new inventions in this area and their potential impact on world health!

Check out the full article here (and make sure to see the short video which shows the test in action, from fingerprick to color spot on the chip): Far From Any Lab, Paper Bits Find Illness

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Microfluidics: a stealth technology?

By Lily | Published: September 22, 2011

Recently I’ve been wondering if microfluidics is a “stealth” technology that will be adopted quietly, with most people never realizing that a device they use has a microfluidic component, and without recognizing terms like “microfluidic,” “lab on a chip,” or “bioMEMS.” By comparison, some other technologies have been talked about more:

Picture1 Microfluidics: a stealth technology? I threw in cloud computing just for comparison (it’s definitely a different animal — software, fast adoption, unregulated industry, different markets). But why are there so many more Google hits on “nanotechnology,” and does it matter?  I ran a similar search a couple years ago, and the number of hits for “microfluidic” has more than doubled since then (seems like a good sign!), although microfluidics is still mostly unknown outside of the field.

One argument that microfluidics will stay under the radar is that people care about how technology changes lives, not about the technology itself. People talk about miniaturized, point-of-care diagnostics, but not about the microfluidic aspect. In many devices, microfluidics is an enabling technology, but akin to something like interconnect on a computer chip. Users don’t talk about the microprocessor, let alone the interconnect. So as microfluidic devices enter the market, they’ll be tucked into discussions on lab automation, point-of-care diagnostics and other fields, often without being acknowledged as microfluidic.

This isn’t especially surprising. In practical terms, does external awareness and perception of the term “microfluidic” matter?  Maybe not, although more exposure would probably be a good thing.  One area I wonder about is fundraising for startups. Because of the initial hype (and subsequent disappointment) around early commercialization efforts, are investors turned off by the mention of microfluidics?  There are plenty of new microfluidics-based startups around, and we’ve learned a lot over the past decade that should help increase the chance of success. And diagnostics startups have picked up steam recently. But I wonder if/how the pitches are different now than they were ten years ago?

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