Marfan Syndrome and Ehlers Danlos syndrome are two kinds of genetic connective tissue disorders, causing issues that affect both the organs and tissues of the body. In Marfan syndrome, the gene affected controls production of the protein fibrillin-1. Fibrillin-1 binds to other proteins and molecules to form microfibrils that provide strength and flexibility to connective tissues. In addition to providing strength and flexibility, these microfibrils also bind to growth factors, to help control the growth and repair of organs and tissues. The gene mutation of Marfan Syndrome reduces the amount of usable fibrillin-1, causing decreased microfibril formation and leaves an excess of unbound growth factor, which causes tissues to have decreased elasticity, overgrowth, and instability. In Ehlers Danlos Syndrome, the affected gene alters the production of collagen III, causing the creation of defective collagen and/or lower than normal amounts of collagen, which can have similar effects of weakened and unstable tissues.

One of the major consequence of these disorders is a weakened vascular system. Without the proteins that add flexibility and strength, vessels are weakened and prone to potentially disastrous problems, the largest of which is the possibility of aortic aneurysm or dissection. Most patients with Marfan syndrome have some kind of cardiovascular manifestations, and complications of these lead to death in 50% of patients by age 32.

The vessels of patients with Marfan Syndrome or EDS are weakened due to protein deficits, which can lead to aneurysms

While aortic dissection is often fatal, it is possible to repair via surgery. In current methods of these operations, as much of the dissected aorta as possible is removed, then blood is blocked from entering the aortic wall and the aorta is reconstructed with a synthetic vascular graft. Stents or structural scaffolds may also be placed into this graft to repair more complicated dissections.

Most existing surgeries for such patients utilize either composite grafts or autografts of vascular tissue from elsewhere in the body. However, in one study, up to 74% of these patients needed further operations within the next 20 years following their original procedure. While twenty years seems like a good lifespan for such a graft, every major surgery comes with significant risks of complications, and if at all possible should be avoided. Many of the patients in the study also had eventual recurrences of aortic dissection.

Synthetic grafts have typically utilized dacron composites, which benefit from properties of hardness, stiffness, biochemical stability and biocompatibility. Dacron gets its stability from the presence of hydrophobic aromatic groups with high crystallinity which restrict hydrolytic breakdown. However, Dacron lacks bioactive ability that could make it more dynamic in tissue engineering.

One problem with using Dacron is the possibility of modulus mismatch when compared with the rest of the remaining aorta. While it may be an appropriate substitute for a typical patient, it could produce issues when used in a patient whose vessels do not match normal expected elasticity/stiffness levels. As seen in earlier discussions of joint replacements and bone implants, this kind of mismatch could lead to further detachments or dissections near the anchor points of the new graft.

When looking at autografts, the problem of weakness and inflexibility remains. While these grafts are innately less likely to cause immunogenic responses, they are replacing weak vessels with similarly weak vessels, meaning that it is likely that future replacements will be needed as well. Additionally, supply of autografts is limited, especially in smaller persons and children, and with additional reconstructions becomes more of a concern.

One new strategy being considered is the utilization of a cryopreserved allograft that has been decellularized for to decrease immunogenicity. This approach is especially desirable for use in children, where supply of autografts is especially limited and longterm graft survival is ideal to reduce future surgeries. The decellularized tissue helps to reduce long term risk of graft infection and allows for the possibility of ingrowth. In a recent study where these grafts were utilized in infants, none of the patients studied displayed any graft stenosis or calcification in followup ultrasounds.

A shows allograft reconstruction of congenital abdominal aortic aneurysm immediately after the operation. B shows a follow up image of the reconstruction 29 months post-operation

Cryopreservervation seemed to produce allografts that were less prone to fibrosis, calcification, and degeneration, although these problems are not completely eliminated. However, traditional cryopreserved allografts still faced issues of immunogenicity. Being decellularized and antigen-reduced allows these grafts to produce significantly lower antibody responses, meaning greater compatibility and less likelihood for rejection and infection. This also signals a possibility of increased long term, possibly lifetime, durability of the grafts, as they are capable of growing along with the child and do not face modulus mismatch issues.

Sources:

https://www.sciencedirect.com/science/article/pii/S0003497501033367

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1353192/

https://www.sciencedirect.com/science/article/pii/S0022346805007876