Decellularized Tissue and Marfan Syndrome

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

 

BMGs: The Next Big Thing in Dental Care?

While diabetes, lupus, and other immune disorders have many known symptoms, like fatigue and headaches, other symptoms of autoimmune disorders are often less visible or well-known to those unaffected by the condition. It’s easy to understand that an autoimmune disease causes a person’s immune system to attack their own body, but there is often an underlying assumption that the target of this attack is a major organ, like the liver, or the thyroid, which can cause visible, full body symptoms if malfunctioning. However, even smaller and seemingly less important areas of the body can fall victim to a misdirected immune system.

In this post, I’ll be focusing on the salivary glands—as it turns out, many autoimmune conditions have the potential to target them, from diabetes to arthritis to Sjogren’s syndrome. This may sound more like an annoyance than a life altering issue, but you’d be surprised: if salivary glands are under-functioning, you can experience difficulty speaking and swallowing and even a changed sense of taste. What’s more, prolonged dry mouth can lead to sores, infections, and tooth decay, as saliva is helps to protect your teeth from bacteria. If untreated, these symptoms can contribute to nutrition problems due to difficulty eating.

Visible effects of dry mouth

Existing treatments for cavities and tooth decay often involve fillings and implants made up of resins, porcelain, or metals (amalgam), which carry their own advantages and disadvantages.

A visual depiction of different materials used as fillings for damaged teeth.

Ceramics, or porcelains, are generally the most natural looking implant choice and is quite durable and strong, but have some detriments due to the way they are placed. These implants must be cemented into the defect of the tooth, and thus are not usable for less-accessible cavities near the gumline or sides of the teeth, and can sometimes require a portion of healthy tooth be removed to place the implant. These implants can still experience chipping and breakage as well, though this is not common. These are generally the most similar to the natural mechanical properties of teeth.

Resins for example have a benefit of being able to closely match appearance of the teeth, and to spare the remaining dental structures as they can be directly bonded onto the tooth. They are also versatile, as they can be used for chips and wear in addition to cavities, and come with less risk of corrosion. However, resins are more prone to shrinkage, which can then lead to additional secondary cavities as debris and bacteria are trapped under and around the ill-fitting filling. Resins are also less durable, and can be broken or worn out, requiring restorations or replacement.

Metals are highly durable, tolerant of moisture during placement, and are better at avoiding problems with ill-fitting seals.  These are one of the best options when considering long term strength and durability, but aesthetically are the worst option, as they cannot be readily blended in with surrounding teeth and often darken over time. In spite of their great functional properties many countries’ dental associations have supported scaling down their usage of metal implants because they often contain mercury, and while the exposure levels very low, there is still a risk of toxicity. Additionally, there is some concern for long-term success of these implants because of the difference in their mechanical properties when compared to the surrounding natural tooth, which can cause stress shielding and fatigue failures.

While BMGs don’t provide much improvement in the aesthetic side of implants, they have great promise for providing a strong, durable, non-corrosive implant suitable for the often-harsh and wear-inducing environment of the mouth. BMGs, lacking long-range order, have high yield strength, low Young’s modulus, high resistance to corrosion and fatigue, and good formability. In short, with the exception of appearance, they are able to combine all of the benefits of existing dental implant materials with none of the disadvantages.

BMGs have a lower young’s modulus than pure metallic implants, but retain great compressive strength, as shown by these images of BMG surfaces after application of a compressive load.

Another benefit of BMGs for use in dental implants is their ability to osseointegrate into the surrounding material, which can provide support to the surrounding tooth without creating the same stress-shielding problems present in metal implants. BMG alloys can also be made with no or very low presence of toxic materials, giving them an edge over metal implants that frequently make use of mercury. Another benefit:  extremely minimal corrosion rate and lack of change in the surface morphology of samples when they were immersed in a PBS mixture meant to simulate a body environment. This means that there is unlikely to be leaching of metal ions into the surrounding tissue and solution, and lower incidence of particle disease that is found in other replacements.  

Corrosion resistance doesn’t just help to avoid toxicity problems, but also mechanical issues. In metals, it can lead to integrity failure, which can lead to additional surgeries or procedures to fix or replace the implant. This comes at added financial cost but also potentially at the cost of existing tooth; metal implants are more likely to require drilling out when they are removed, which significantly affects the surrounding tissue.

An added bonus of BMGs: antimicrobial performance. Because of the silver-containing composition and the corrosion-resistance of BMGs, the material helps to ward off bacteria and fungi, which were mentioned above as main concerns for dry mouth patients. The alloy is capable of inhibiting plaque accumulation, which is of great importance when saliva is not present to aid in this process.

Jaws may not have had the prettiest smile, but look at functionality!

sources:

https://www.sciencedirect.com/science/article/pii/S0925838814016004

https://onlinelibrary.wiley.com/doi/full/10.1002/adma.201505347

Ceramics as New Treatments for Orthopedic Degeneration

A number of chronic diseases are associated with cartilage or bone degradation: Arthritis is caused by the wearing away of cartilage from either overuse injuries or immune attacks on the joints, leaving the bones to rub against one another and cause pain and stiffness while other conditions, like Marfan syndrome, are associated with lower bone density, which can make skeletal injuries more likely to occur. With this degradation there is often increased daily pain and decreased mobility, which can serve to make other symptoms worse by discouraging exercise or affecting sleep.

Degenerative diseases can cause the breakdown of skeletal tissue, decreasing mobility and causing pain

While older implants and replacements have generally used metals for their great strength and durability, these carry unique risks like toxicity due to corrosion of the implant releasing debris into the bloodstream. Local adverse reactions are not uncommon, and some people are even allergic to metals, although this is very rare. With these issues, and a desire to prevent degradation of surrounding bone that is associated with high molecular weight plastic alternatives, new implants are increasingly based in ceramics.

While old ceramics implants faced significant failure rates due to design issues, new ceramics have shown great promise and wide applications. Ceramics are currently readily used for joint replacements because of their great durability, which is ideal for allowing patients to return to activity and for long-lasting solutions for younger patients, as for those suffering from chronic conditions, rather than elderly populations dealing with age-related bone and cartilage degradation. With ceramic-on-ceramic hip replacements, nearly all patients in one study reported being able to participate in daily physical activities, and every patient in the study demonstrated osseointegration with no complications like implant loosening or implant-related bone loss in follow-up appointments. Perhaps surprisingly, ceramic-on-ceramic joint replacements were shown to have significantly lower wear rates than metal-on-plastic or metal-on-metal replacements, showing that durability is no issue for these new implants either.

Ceramics have miniscule levels of surface erosion and debris release

One major issue with ceramics for joint replacements, however, is squeaking of the joint, which can make patients uncomfortable and in some cases lead them to get additional surgeries to correct the problem. This happens when edge-loading causes increased friction and wear, leading the implant to lose its seal on the corresponding socket. In some cases, the ceramic liner itself fractures, causing both squeaking and sharp pain for patients. Revision surgery is much more complicated and likely to lead to complications, so it should be avoided if at all possible to preserve mobility and prevent ongoing pain issues. To solve this, some researchers have suggested making this socket liner thicker to prevent seal loss or in some causes, altering the material or shape of the implant to reduce the resonance of the sound coming from the joint.

Various causes of joint replacement squeaking

While the material itself is ideal, with little degradation and great biocompatibility and integration, the design behind ceramic-on-ceramic implants needs ongoing development to maintain its integrity to provide an increasingly successful long-term implant for younger and more active patients.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247519/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976577/

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