There are over 200 connective tissue disorders that currently lack cures or effective treatments, many of which are seriously disabling or even fatal.
Diseases like rheumatoid arthritis, scleroderma and lupus are a just a few of a vast range of diseases that occur due to fibrosis, a term that refers to abnormalities in the connective tissues throughout the body.
Efforts to understand the pathology of fibrosis have centered on animal experiments, inserting genes to create a “transgenic model,” but these have failed to accurately mimic the human conditions.
Now, researchers from Brown University have created a 3D connective tissue model grown from human cells that replicates both the structure and mechanics of human fibrotic tissue.
A critical feature of the new model is that it doesn’t involve a plastic scaffold typically used in 3D models. This allows the cells to assemble in a more natural manner, importantly synthesizing their own extracellular matrix (ECM). The ECM was until recently thought to play only a minor part, but scientists now understand it has a key role in maintaining normal tissue function.
Using this model, the Brown researchers can apply experimental treatments to screen anti-fibrotic drugs more accurately than ever before.
The fibrosis model is one of the latest developments to come out of the Brown University Center for Alternatives to Animals in Testing. Jeffrey Morgan, PhD, a professor of medical science and engineering who directs the Center says: “Animal models are expensive, ethically contentious and not always predictive of human pathophysiology.”
Dr. Morgan is the creator of the 3D Petri Dish®, a three-dimensional cell culture mold that fabricates microtissues that mimic natural biologic properties, like the formation of capillaries and ducts.
A range of other projects without animals are in progress at the Center. Professor Agnes Kane, MD, PhD, abandoned prior work with mouse models of inhalation toxicology. She now studies the health effects of asbestos fibers and nanomaterials using human lung microtissues that mimic the myriad types of lung cells and their interactions.
Professor Kareen Coulombe, PhD, is working with other scientists at Brown using cardiac microtissues derived from human induced pluripotent stem cells. She and her team have shown that bisphenol A, found in many plastics, can cause cardiac arrhythmias by blocking vital ion channels in the heart.
She acknowledges it’s unlikely they would have found this with animal experiments. “Rodents are notoriously terrible models for predicting cardiac arrhythmias,” she says.
Dr. Morgan, who directs the Center, recognizes that despite its failures, animal testing remains the status quo.
“What we’re trying to do is change the status quo. Do better science with alternatives.” he says. “There are endless examples of animal tests failing to predict human response, from thalidomide 60 years ago to a potential Alzheimer’s treatment that was scrapped last year … They’d spent a bazillion dollars, they had a stack of data, animal data … and it still failed.”
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