What would you do with a biocompatible substance that is a liquid at 4° Celsius and a solid gel at 37° Celsius?
That's the question tiny UK-based reagent maker BioStatus is asking its current customers and beta-testers about CyGel, the thermoreversible hydrogel it developed and is now attempting to sell to a variety of biomedical markets to identify "killer applications."
One area in particular in which BioStatus thinks CyGel can make an impact is high-content image-based cellular analysis. To that end, the company has been engaged "in conversation with a number of well-plate manufacturers" about developing ready-to-use microwell plates to sell directly to the HCS market, BioStatus CEO Stefan Ogrodzinski told CBA News in an interview at the Society for Biomolecular Screening conference held in Geneva, Switzerland, earlier this month.
Ogrodzinski added that BioStatus was "close" to coming to an agreement with a plate manufacturer, though he declined to provide any further details due to confidentiality reasons, instead only hinting that potential candidates may have been represented at the SBS conference.
The most obvious candidates from that relatively narrow list are Corning, Nunc, and Matrical. Corning declined comment regarding its knowledge or interest in CyGel; a drug-discovery product representative from Nunc's US headquarters was unfamiliar with the technology; and CBA News was unable to contact a Matrical spokesperson before press time.
"The end user would get to see suspension cells in a high-throughput context; the assay manufacturers expand the market for the assay; and the well-plate manufacturers have another plate to sell."
The biggest selling point for CyGel as an HCS reagent is that it may allow suspension cells to be used in image-based screening, something that has for the most part eluded assay developers, said Wales University College of Medicine professor Paul Smith, a co-founder of BioStatus who also sits on the company's board of directors and acts as a scientific advisor.
"You can put suspension cells into image-based screens," Smith said. "The problems are two-fold: First you have a spherical cell, which acts as a lens, and secondly, you have cells that move around and you get relatively poor-quality images. Also, you have the inability to return to a known position on a plate for a second form of analysis.
"The gel solves those two issues, in that a spherical cell trapped will not be moving around, and therefore its lensing effect can actually be used to your advantage by, for example, highlighting a fluorescence signal within the cell," Smith added. "Also, it's an overlayering medium, so you have these cells that are trapped like a sandwich, and you can deliver reagents from the gel itself to attached cells. Here we see real inroads into conventional assays for reagent delivery."
Drug developers want to be able to conduct image-based screens on suspension cells primarily to study cancers of the blood, such as leukemia and lymphoma, as well as "to trap cells in transitional states, for instance, if you're doing metastasis research, where you're looking for targets for molecules that change the ability of a cell to detach from a surface, and go into a blood vessel," Smith said.
Ogrodzinski also told CBA News that BioStatus has talked with "a number" of HCS vendors who would potentially be interested in participating in any collaboration, if one were reached, that BioStatus might strike with a plate manufacturer.
"It would be a win-win-win all the way around," Ogrodzinski said. "The end user would get to see suspension cells in a high-throughput context; the assay manufacturers expand the market for the assay; and the well-plate manufacturers have another plate to sell.
"We cannot manufacture well plates, so we're going to sub-contract manufacture that," he added. "The well-plate manufacturer would license from us, and I think that if we've done our job correctly on the patent side of things, then potentially a well-plate manufacturer or even an assay developer or owner could hold exclusive rights to a suspension cell assay protocol. I think that would be very attractive to the well-plate manufacturer, the assay developer, and us, as well."
Much of this, however, may only be wishful thinking at this point for BioStatus, which claims that it has seen revenues from CyGel, but declined to identify any customers or beta-testers due to confidentiality reasons. The bulk of the firm's revenues are derived from its flagship product, the nuclear counterstain reagent DRAQ-5 (see related story, this issue).
"We've sent out a lot of samples, and a lot of people have bought CyGel and continue to," Ogrodzinski said. "Something like this suddenly opens up a window of opportunity to things that weren't possible before."
Ogrodzinski acknowledged, however, that the versatility of the technology also presents some risk for the small firm. "Because there are so many things you can do with CyGel, it would be very easy for us to diversify into dead-end arenas," he said.
"We want to find the killer applications CyGel will have," he added. "We're a small company, and we need to focus on those applications that will be prosperous for us and our customers. So at the moment we are talking with our customers closely, and we can formulate the gel very differently. At some point we'll sort of stop all of this and produce the products that we know the market will need."
"Because there are so many things you can do with CyGel, it would be very easy for us to diversify into dead-end arenas."
Joe Zock, senior customer support scientist and manager of HCS user services at HCS vendor Cellomics, told CBA News that although Cellomics has not yet had the chance to evaluate CyGel, he immediately sees some of the benefits it could bring to HCS.
"I think there is an enormous groundswell in high-content screening to move beyond simply cells in the bottom of a dish, and more towards 'How can you create a microenvironment that better stimulates disease states?'" Zock said.
"This may allow you to potentially immobilize cells — for instance, suspension cells, or larger structures, like neurospheres… and more complex cellular structures," Zock added. "If they're immobilized, then it's much easier to go and snap a picture of them."
The most popular method of trapping cells currently for image-based screens is Becton Dickinson's MatriGel, which Cellomics uses in its recently released bioapplication for angiogenesis tube formation.
However, a common problem that researchers encounter with MatriGel, according to Zock, is unwanted stimulation of cells. MatriGel "is filled with stuff that stimulates cells, because it's derived from some kind of extracellular matrix of tumors," he said. CyGel might not have such problems, he noted, because it is a synthetic material.
"If it pans out that this is a viable way to do various kinds of assays, partnering with a plate manufacturer to produce valid plates would take one step away from the researcher, who would have to do it him or herself," Zock said.
Besides saving time for researchers, ready-to-use CyGel microplates may also save researchers some discomfort, since current protocol necessitates that they prepare their cellular assays with CyGel in a cold room to keep it from solidifying too soon.
"In fact, we've even said to customers that if they purchase enough CyGel, we'll throw in a free jacket," Ogrodzinski joked.
— Ben Butkus ([email protected])