Biomaterials
Professor Christman holding a vial of iECM in her lab at UC San Diego.
Enter the matrix Christman’s laboratory has had a long-standing focus on developing biomaterials for treating Myocardial Infarction (MI) – more commonly known as a heart attack. The creation of the innovative iECM evolved out of their efforts to develop a hydrogel specifically to treat the disease. The hydrogel is made from a liquid form of decellularised extracellular matrix and it is injected directly into the heart muscle. Results from a phase I clinical trial involving patients showed good safety and preliminary efficacy. The hydrogel helped to repair the heart tissue by targeting inflammation, preventing some continual cardiac muscle cell death, reducing fibrosis and increasing the growth of blood vessels that lead to improvements in cardiac function following MI. Despite these impressive results, there were also some downsides. “Delivery of the hydrogel requires needle-based injections directly into the heart tissue, which cannot be performed immediately after MI, owing to the risk of arrhythmias and rupture,” says Christman. “You can’t inject the material immediately after someone is having a heart attack. You have to wait, and during that time the heart can have increasing damage. Also, the injections are delivered using a catheter which although is minimally invasive, it is not a routine medical procedure and therefore requires specialised training.”
So, the team set out to create a new form of the material that could be promptly administered through the blood stream in a less invasive manner following a heart attack. Specifically, they wanted to incorporate it into the routine procedures of an interventional cardiologist, such as angioplasty or
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stent placement, by infusing it directly into a blood vessel leading into the heart.
The team worked to the hypothesis that because the blood vessels in the region of the heart attack become leaky (gaps and separations appear in the normally tightly packed endothelial cells that line blood vessels), any material being infused would pass through the gaps between the endothelial cells and enter the damaged heart tissue. They reformulated the liquid form of the original ECM hydrogel, to an appropriate size, which involved fractionating and filtering, to create a version that was either soluble, or had particles smaller than 200nm in diameter. This way it could easily pass through the gaps of the leaky vasculature. They tested the efficacy and safety of their new formulation in rat and pig MI models; they also assessed its ability to target areas of inflammation in a mouse model of traumatic brain injury and a rat model of pulmonary arterial hypertension when the iECM was delivered intravenously.
Plugging the gaps
The results surprised them; instead of passing through the gaps and separations in the endothelial cells at the site of ischaemia and inflammation, the team found that the iECM plugged the gaps with beneficial effects. “We found that the iECM actually did not go through the gaps in the leaky vasculature, like we intended, but it actually bound inside of those gaps, which ended up being a more exciting result because it essentially was treating the damaged blood vessels,” says Christman. “This helped to immediately reduce that leakiness and help the vasculature heal itself quicker.”
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David Baillot/University of California San Diego
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