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Nascent Vivo Hopes to Lure Customers for 3D Cell-Based Assays Using Human-Derived Biogel

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Having raised approximately $6 million in venture capital and federal grant money and secured an alpha-test partner with Merck, startup Vivo Biosciences now hopes to sell drug-screening services based on its human-derived biogel and accompanying imaging system for 3D cell-based assays, a company official told CBA News this week.
 
If its contract research model proves successful, Vivo may eventually sell the biogel as a drug-discovery consumable in assay-ready well plates as an alternative to 3D cell culture products sold by BD Biosciences, Invitrogen, and Chemicon. In addition, Vivo has already initiated research collaborations investigating the possible use of such consumables in a personalized medicine capacity.
 
Vivo Biosciences spun out of the University of Alabama-Birmingham in 2004 to commercialize technology developed by founder and current president and CEO Raj Singh. The technology, called HuBiogel, is the first human-derived biogel or biomatrix for 3D cell culture.
 
According to Singh, the key selling point for HuBiogel is that it provides a natural host environment for cell growth and organization that is very similar to what is found in the human body. Assays can be conducted on cells while they are still embedded in the gel in tissue-like structures, and Vivo claims that the results from such assays would provide the most relevant cell-based assay data possible short of actually testing drugs in live animals.
 
“It doesn’t replace anything that companies are doing now in their drug-discovery pipelines,” Singh told CBA News. “But they have many thousands of compounds, and then they test them in cell-based assays in 2D, often in primary screening. Then they go and sort of play a guessing game as to which compounds they should use in animal studies.
 
“But if they have 1,000 hits after primary screening, they cannot take all of them to animal testing,” Singh added. “That’s where we come in. We will take those compounds and streamline them and give [companies] better go and no-go decisions. This drug may be very toxic in 2D, but well-tolerated in 3D – or vice-versa. Animal studies are very expensive, and most of these pre-clinical drugs fail right there.”
 
Culturing cells in 3D is not a new concept. Scientists have been creating 3D cell matrices based on collagen for at least 20 years, and one of the most well-known and well-established commercial biogels is BD Biosciences’ Matrigel. Other companies selling biogels include Invitrogen, Millipore’s Chemicon division, and nascent BioStatus, which markets a thermoreversible biogel.
 
None of these biogels is human-derived, however. Matrigel, for instance, is derived from mice, and one of its common drawbacks is the presence of growth factors that adversely affect the cells being cultured in the gel.
 
HuBiogel, on the other hand, contains “all of the major proteins” found in a typical human cellular scaffold, such as collagens I, III, and IV, laminin, and fibronectin. “So basically, you have this natural medium for cells to grow and organize without changing their phenotypes,” Singh said.
 
Another limitation that has prevented 3D cell culture from being implemented in high-throughput drug discovery is the tedium of preparing samples for use with high-throughput screening tools like well plates.
 
Vivo believes it has a solution for that, as well, in the form of a rotating wall vessel bioreactor developed by NASA. Developed in the late 1990s as a model of microgravity effects on cells, the bioreactor provides an optimal environment for developing 3D cell culture scaffolds.
 
“This way, the tissue will grow uniformly, unlike in a well plate,” Singh said. “We can have 2-mm-sized tumors, fully viable, grown in these bioreactors, and we can grow up to 500 or 1,000 of them. For an assay, we would then take them out and put them in a 96-well plate.”
 
Furthermore, Vivo has developed its own imaging system to analyze its 3D cell samples. Dubbed MorphoScan, it can provide real-time images of cells in HuBiogel, as well as determine endpoints such as cell size, shape, distribution, and viability, in three dimensions. This is very similar to the types of applications enabled by commercially available high-content imaging systems, but according to Singh, none of those offers the necessary Z-dimension component.
 
“I’ve seen systems from Molecular Devices, Cellomics, and other companies,” Singh said. “None of them were able to do live-cell imaging in 3D. Generally they are for cells that are flat, and they cannot analyze in real time if the cells are going to change, like in neurogenesis or endothelial capillary formation. You cannot detect or analyze this in a quantitative manner using those devices.”
 
In addition, Singh said that the price of those systems – typically above $100,000 – does not fit with Vivo’s desire to offer a low-cost assay platform for researchers spanning pharma, biotech, and academia. He said that the MorphoScan costs between $50,000 and $70,000 and that the company can retrofit any microscope. “We use all commercially available hardware, and the software is very user-friendly – you just define what you want to see, and it automatically does it.”
 
Despite this, Vivo doesn’t plan to jump into the consumables or instrumentation market just yet. First, it hopes to use a contract research model to serve as a proving ground for its technology.
 
“At first we wanted to sell it, just like BD sells Matrigel-coated plates,” Singh said. “Also, other companies, such as Invitrogen and Chemicon, have approached us and wanted to sell HuBiogel as one of their products. But we realized the real value of this is not the plate business. The real value of it is the 3D capabilities.”
 
Singh said that the company decided to first sell HuBiogel assays as an in-house service. “Selling a new product in this market takes some time because researchers are always hesitant to try something new,” he said. “So we are providing this [for evaluation] to researchers, such as at the NIH or even academic and private companies, and we also started offering service contracts.”
 

“If they have 1,000 hits after primary screening, they cannot take all of them to animal testing. That’s where we come in. We will take those compounds and streamline them and give [companies] better go and no-go decisions.”

Vivo won its first contract in May with Merck, which is serving as an “alpha-tester” for Vivo’s assay system. Specifically, this feasibility contract is in the area of oncology. “They want us to test certain drugs that they are moving toward animal testing and even clinical testing, to see what correlations there are,” Singh said, “And it looks like we have some very exciting early results which, once finished in the next six months, we will have a better picture of.”
 
In addition, Vivo has established research partnerships with several government, non-profit, and academic institutions, including Lawrence Berkeley National Laboratory, Tufts University, the National Cancer Institute, and ADMET Technologies in areas such as tumor biomarker identification, anti-angiogenesis drug discovery, and hepatoxicity.
 
The most forward-looking of Vivo’s research collaborations is with UAB, the institution from which it was spun out. The goal of this research, Singh said, is to test the possible use of HuBiogel assays in a clinical setting in order to support personalized medicine research efforts.
 
“You can take these biopsies, and instead of freezing them and looking for a gene or some markers, we can maintain them for up to [two weeks] in HuBiogel. In MatriGel they die, but in HuBiogel they survive. That gives us a window to test the drug that the patient is being treated with, and new cocktails that may be more or equally effective.”
 
To support its efforts, Vivo has to this point raised $2 million in backing from Maryland-based venture capital firm Toucan Capital. In addition, Vivo has thus far scored some $4 million in Small Business Innovation Research grants from the National Institutes of Health and NASA, and is still in the midst of an SBIR grant that runs through 2008. This grant is for the general development and commercialization of a tumorigenesis model based on HuBiogel.
 
“If we can produce better hits, or make more substance out of that step between 2D cell-based assays and animal testing, that will save big money for a lot of these drug companies,” Singh said.

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