Repair and regenerate

Are we one step closer to a futuristic vision where a simple injection can instantaneously repair damaged tissue or a diseased organ? That prospect is still reserved for the movie screen, but according to Karen Christman, professor of bioengineering at the University of California San Diego, we are close to having therapies that can significantly impact tissue function and improve quality of life.

Christman and her team at UC San Diego have developed a novel form of biomaterial that can be injected into the blood stream to reduce inflammation in tissues and promote cell and tissue repair. She believes it has the potential to improve the quality of life of those who have suffered heart attacks, as well as a host of other conditions, such as traumatic brain injury, pulmonary arterial hypertension and even Covid-19. The biomaterial is called “Infusible Extracellular Matrix” or iECM, and it is made from decellularised extracellular matrix. “Decellularised extracellular matrix, derived from animal or human tissue, is where you strip out the cells leaving the natural scaffolding of a tissue called the extracellular matrix,” explains Christman. “It has long been used as patches for surgical repair in patients and therapies in animal models of disease often in the form of injectable gels, but the difference with iECM is that it can be delivered through the bloodstream.”

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 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.”

In both the rat and pig MI models, the researchers observed reduced oedema in the heart, reduced inflammatory cells, improvements in survival with cardiomyocytes (the cardiac muscle cells) and increased density of blood vessels – all of which led to significant improvements in cardiac function. In the mouse model of traumatic brain injury and rat model of pulmonary arterial hypertension, the researchers saw the iECM also targeted the leaky vasculature at sites of inflammation.

“This was an exciting development,” Christman reiterates. “The ability of the iECM to target leaky vasculature in inflamed tissues and treat the microvasculature across different species and injury models suggests that it could be applied to a lot of different conditions and has led us to explore different clinical applications, such as severe Covid- 19, where there is overactive systemic inflammation and leaky vasculature. The iECM can be delivered intravenously and then it will circulate in the body and target the areas where you have inflamed vasculature,” she explains.

Clinical human trials are imminent

The first human clinical trials of iECM in MI’s are expected to be up and running within one to two years, and there are hopes that the other clinical applications will follow in the near future. Christman is confident that the research results will translate in humans: “I think we’re optimistic that this will translate well,” she says. “There’s no guarantee, of course, moving from animal to patients, but extracellular matrix is fairly conserved among species and pig is pretty close to human. So, the fact that we’ve done lots of different species in both old and young animals and are seeing very consistent results gives more robust data moving into patients.”

In regard to safety, the team conducted thorough testing on haemocompatibility due to concerns about possible clotting. In vitro, in vivo and organ pathology studies demonstrated that the material did not increase clotting or result in emboli in other areas of the body. The team plans to conduct further extensive testing as a precaution, although they do not anticipate any issues.

Furthermore, tests indicated that the material is rapidly eliminated from animal bodies through typical secretion channels, such as urine, with some minor metabolism occurring in the liver. “So far, all indications for safety are good, but we will continue to do some additional safety checks and dosage testing before clinical trials,” says Christman. “The material itself is derived from porcine material, which has a very good safety profile in patients, but you would want to avoid the very small number of patients who have a porcine allergy,” she adds.

In the case of MI, iECM would be given as a single dose delivered at the same time as other treatments, and the hope is that those suffering from a heart attack would benefit. “They’re not going to have a brand-new heart. It’s not going to be back to normal, but they’ll basically be at a better baseline with less damage and improved function, and that would equate to a better quality of life,” says Christman. “They’ll feel better. They’ll be able to do more with improved cardiac function and it will hopefully prevent heart failure from eventually occurring.”

She points out that cost is a major advantage over alternative methods. “There is a big benefit to using a biomaterial as opposed to other regenerative therapeutics, like cells or growth factors,” she explains. “Depending on the indication, we are looking at a few thousand dollars per patient, as opposed to a cell therapy which can be tens of thousands of dollars, if not $100,000.”

So, how long before we might see iECM as a routine medical treatment in heart attacks? “It would require a phase I, II and III clinical trial – so you are looking at least five to seven years to go through that full process before you would get full approval, and that would likely be the same for the other indications once they start the process,” says Christman, who is working with Ventrix Bio – the company she co-founded more than a decade ago to develop the original ECM hydrogel – to move the iECM into clinical trials.

“We think iECM is definitely a very new platform for treating damaged or inflamed tissues in a very easy, simple, minimally invasive manner,” Christman says. “It has taken over a lot of my lab and spurred a lot of new research. It is definitely one of the more exciting projects because of all the new clinical applications, and new collaborations, that this has started.”