Small intestinal submucosa (SIS) is a biomaterial that can induce host tissue proliferation and regeneration when it is implanted at various tissue sites. This is made possible by SIS’s response to natural, site-specific stressors present in vivo. Upon implantation of the SIS biomaterial, it is quickly remodeled to mock the site-specific structure and function. SIS biomaterial has proven to be successful in rapid capillary ingrowth without any adverse immunologic reaction and is already available on the market. Through naturally occurring properties and proper biomaterial manufacturing, SIS biomaterial is able to successfully integrate itself into the existing tissue and become “self”. SIS biomaterial can be used in the treatment of serious joint, muscle, or tendon injuries and has been proven in vivo to integrate into the host tissue and degrade quickly.

SIS biomaterial is derived from the submucosal layer of the small intestine, typically from porcine. It is made up of mostly water, is translucent, resilient, and about 0.15 to 0.25 mm thick. Its aesthetics can be viewed in figure 1 or from this previous article on SIS, as can it be seen that the biomaterial possess the ability to be stretched. SIS is a cross-linked collagen-based extracellular matrix (ECM) that has very few connective tissue cells. Researchers believe that the properties of SIS have been proven to be ideal for multiple applications such as aid in soft tissue regeneration, treatment of dermal wounds, urinary bladder repair, hernia treatment and engineered tissue scaffolds (Brown-Etris 2002).

Figure 1

SIS biomaterial promotes the regeneration of host tissue via “smart remodeling”. This is a unique property of the biomaterial to be incorporated into new tissue in a short period of time where the biomaterial is almost indistinguishable from the natural tissue because SIS proliferates and regenerates the host tissue. Through various clinical trials, it has been shown that when a single layer of SIS biomaterial is implanted into a patient, multi-layered vessels have been formed in place of the biomaterial and the layers are thicker than the SIS layer! This means that the biomaterial implant supported the development of new arterial tissue in the intimal lining of endothelial cells with a supporting outer layer of smooth muscle tissue. SIS biomaterial has successfully been shown to mock the site-specific structure and function of the host tissue (Brown-Etris 2002, Ueno 2004).

Microscopic images of SIS biomaterial upon implantation into patient are shown in figure 2. The interface between the host tissue (left) and the biomaterial (right) seems sharp, but SIS is superior in biointegration. The cross-linked collagen fibers can be viewed in figure 2A where host cells begin to integrate into the SIS biomaterial scaffold (Brown-Etris 2002).

SIS also has the potential to induce rapid capillary ingrowth, which works with “smart remodeling” (figure 2B). Angiogenesis is a vital part of tissue implantation and the SIS biomaterial scaffold has proven successful in rapid cellular infiltration and angiogenesis in numerous clinical trials. In vascular implants, SIS biomaterial successfully promotes capillary ingrowth in just four days by migrating cells into the SIS ECM. This helps the tissue to fight bacterial infection. The quick and thorough distribution of capillaries throughout the tissue allows for rapid and resilient nutrient delivery and metabolic byproduct collection to and from the injury site. This leaves little time for the tissue to be deprived of nutrients, water, oxygen, and waste removal; which helps the tissue resist bacterial infection (Brown-Etris 2002).

Figure 2

A vital property of an acellular scaffold in an engineered tissue is that it should have the ability to degrade safely and quickly. SIS biomaterial has been proven to degrade quite rapidly. More than half of the biomaterial mass is lost one month after implantation. Tests were run and animal trials were preformed to show that after three months after implantation of the SIS biomaterial, it was completely resorbed into the host tissue. By this time, the SIS biomaterial implant area looks like figure 2C and is completely covered with a dense collagenous matrix that resembles the structure and function of the host tissue. Upon complete integration of SIS biomaterial into host tissue, the wound site appears as shown in figure 2D (Gilbert 2007).

Significance
There are over ten million cases of joint, muscle, and tendon injury in North America every year. When the injury results in a complete disunion of the tissue, it needs to be treated right away because the tissue doesn’t have the ability to heal this on its own. Treatment for complete disunion involves a surgeon invasively opening up the injury site, pulling together both ends of the broken tissue, and suturing them together. Tissue engineered constructs have been studied for this treatment and they strive to be integrated into the patient’s body between the two ends of the injured tissue. The biomaterial used for this treatment is required to functionally and histologically resemble the host tissue, actively fuse together the two ends of tissue, promote vascularization throughout the injury site, and illicit minimal immune response from the host. Small Intestinal Submucosa (SIS) is a naturally derived biomaterial that has been successfully tested in vivo for the treatment of this type of injury and can induce active regeneration of the tissue (Brown-Etris 2002, MacLoed 2004).

Background
SIS was accidentally discovered in 1987 at Purdue University when Dr. Stephen Badylak and his team were searching for a naturally derived vascular graft. Their goal was to discover a natural substitute to replace synthetic polymeric vascular grafts due to their 50% failure rate at five years in smaller blood vessels. Due to the small intestine’s tubular configuration, abundance in the body, and strength, the team searched to use small intestinal tissue as a vascular graft. Initially, every layer of the small intestine was used to conduct tests, however the enzymatic activity of this multi-layered material was too high. Therefore, researchers began pealing off various layers from the small intestine (see figure 1) and testing them individually. When the submucosal layer passed several clinical studies, it was named SIS, small intestinal submucosa, and utilized in further research (Badylak 2004).

Figure 1

When SIS treatments were proven successful in clinical trials on animals by Dr. Badylak and his team, they found that the extracellular matrix (ECM) was key in tissue healing. This lead the curious team into using SIS biomaterial for wound healing in patients. The team also discovered that this biomaterial could be converted into sheets, gels, powders, and/or multilaminates to be of use in numerous applications. A sample of the appearance of SIS sheet can be seen in figure 2. By 1994, Dr. Badylak and his team worked in conjunction with the Methodist Hospital in Indianapolis to receive four patents to use SIS biomaterial in humans. Human trials for numerous applications began in 1995. Not too long after, DePuy, Inc. aided the Badylak group in manufacturing SIS ligaments for human trails. Models like these SIS ligaments are now being used to treat joint, muscle, and tendon disunions (Badylak 2004). A start-up company called Cook Biotech, Inc. began near Purdue University to further research and commercial use of SIS biomaterial. The company is still rather successful and has many other products on the market now (www.cookbiotech.com).

Figure 2

Why SIS?
What sets SIS apart from other biomaterials is that it is completely naturally derived and it is capable of interacting with host cells to send and receive messages and signals of tissue growth and maintenance. SIS biomaterial provides a natural, cross-linked ECM with a three-dimensional structure that acts as a scaffold for host tissue remodeling (see figure 3). After SIS is implanted into the patient, tissues adjacent to it immediately begin to deliver cells and nutrients into its acellular construct. The cells rapidly invade the SIS material and capillary growth follows to allow nutrients to enter the SIS matrix. SIS is extremely strong at the time of implant and is gradually resorbed while the host tissue reinforces and remodels the damaged site with new cells. The integrity of the tissue is maintained and the new tissue quickly becomes completely “self” by integrating itself into the host tissue.

There are many applications for SIS, such as management of gastrochisis, coating stents, replacing dermal layers, repairing abdominal walls, and repairing bladder walls. SIS is used in tissue disunion to induce cell migration into the ECM, actively vascularize the ECM, and activate tissue regeneration into the ECM. This can successfully heal the injury or close the disunion in the tissue as the SIS biomaterial resorbs/degrades into the host tissue to become “self”. When disunion occurs in a tissue, it must be treated in order to restore functionality of the body part. The only way to do this is to “reattach” or regrow the two ends of tissue and immobilize the area to allow repair (Gilbert 2007). Tissue disunion is very painful and can cause great damage to a patient’s lifestyle, depending on where the injury occurs. Tendon disunion often occurs in the patellar area of a patient; without proper treatment, these patients would never be able to walk again (Kroeger 1999).

Disadvantages
Due to the fact that there is no “perfect” replacement material for natural body tissue, disadvantages of SIS biomaterial also need to be taken into consideration. Some of the disadvantages include the fact that although SIS biomaterial doesn’t demonstrate any adverse immunologic response in most trials, there is still possibility of rejection due to differences in individual immune systems. The “golden standard” will always be an autologous model, and SIS biomaterial is xenogeneic. Autologous samples are taken from another part of the patient’s body. These samples do not cause any averse immune response since they are from self. Xenogeneic is a tissue from a different species than the patient, as is SIS biomaterial. The complete degradation kinematics and communication between SIS and host tissue are not yet completely understood, therefore ongoing research is being conducted to fully understand the capacity of this multi-faceted biological system. Since SIS is a naturally derived material, batch-to-batch variations exist in every sample. When compared to synthetic biomaterials, natural materials are generally more difficult to process on a large scale. There is also no degradation control of SIS biomaterial, as may exist in certain synthetic materials. If a certain type of injury requires a slower degradation rate to heal, this is not adjustable when using SIS because the degradation rate is constant. Despite the shortcomings of SIS biomaterial, it is still an ideal choice for the treatment of many joint, muscle, and tendon injuries.

 -Amy Shah

Recently written articles on www.AmyShah.com, like The Basics of Stem Cells and some Weekly Updates, helped inform readers of the difficulties researchers have experienced when trying to experiment with stem cells. The morality of using embryonic stem cells is constantly challenged and the current presidential office opposes any further embryonic stem cell lines to be obtained.

So what’s going on with embryonic stem cells right now? Despite the moral challenges, high costs, difficulty of obtaining approval for research, and poor quality of several existing stem cell lines, over 500 companies (with collaborators) are currently conducting embryonic stem cell research. Experts from Nature say that these “hard cells” bring about an entirely new type of bioengineering that will reign over this field for decades to come.

Stem cells have had a larger impact on society than most scientific discoveries. It’s up to us to decide whether to speed up this research by supporting it, or slow down the healing process for millions of dying people.

Coronary Artery Disease and Coronary Bypass Grafting

Coronary artery disease (CAD) is the leading cause of death for both men and women in the United States. The process of atherosclerosis is the hardening of an artery due to a lipid build up, resulting in functional loss. Fatty deposits, or plaques, may accumulate inside the arterial wall and cause stenosis, or an abnormal narrowing the artery wall. This causes the flow of blood to be reduced or completely stop and the vessel wall to lose its flexibility and ability to handle pulsatile flow. There are several forms of treatment available for CAD depending on the severity of the disease, including lifestyle changes, medicines, angioplasty, and coronary artery bypass grafting (CABG).

CABG is the preferred treatment for patients with multiple areas of coronary artery narrowing or blockage and also for patients with higher percentages of stenosis, this relation can be seen in figure 1 above. Patients typically have 1 to 5 bypasses within one surgical procedure. This form of treatment is the most common type of surgery in the United States, with about 500,000 surgeries per year. Typically, the patient’s saphenous vein from the leg, internal mammary artery (IMA), or the radial artery from the arm is used. Figure 2 shows the location of the saphenous vein and IMA. These vessels are removed and grafted onto the hardened artery to revascularize the affected area.

Figure 2

Advantages and Disadvantages of the Current Gold Standard

The current gold standard for the CABG procedure is the use of autologous (from self) saphenous vein and IMA because of their resemblance to the native coronary artery and their relatively high patency rates. It was not until recently that the radial artery has been widely studied as another source for this procedure. The five and ten year artery patency rates for these have all shown to be greater than 70% and 50%, respectively. These rates vary depending on the blood vessel used for the procedure.

Even with the success this procedure has had, there are several disadvantages that may lead to complications. Removing an autologous vein for the procedure may cause donor site morbidity, which can lead to problems such as groin infection near the site of the saphenous vein removal. In addition, there is only a limited supply of donor vessels for this procedure. Up to 30% of patients undergoing lower limb bypass do not have a suitable vein. This can be problematic for patients who need multiple CABGs or have had previous procedures. There is also a greater risk with the use of multiple vessels. For example, there are more incidents of deep sternal wound infection when both IMAs are used for this procedure, especially for patients with obesity and diabetes.

Existing Vascular Grafts and Improvements

Although living autologous vessels seem to be the ideal conduits for CABG, there are several factors, as discussed above, which have prompted efforts to develop a more suitable donor vessel. The ideal blood vessel substitute should mimic the characteristics of a native blood vessel, including its composition, structure, function, and mechanical properties. It should be durable enough to endure the mechanical stresses, as well as the threat of biodegradation and infection within the body after implantation. The vessel should be made up of materials that promote cell-specific interactions and needs to be able to have similar viscoelastic properties as a normal artery to avoid a compliance mismatch. It should be flexible in order to maintain its contour, yet rigid enough to prevent kinking. The materials used, especially on its luminal surface, must be nonthrombogenic to prevent blood clotting in the vascular graft. It is favorable that the vessel is easily and quickly manufactured, and should be readily available in multiple lengths and sizes.

However, no existing conduit possesses all the properties and qualities of the ideal arterial vascular graft listed above. Current alternatives to autologous vascular grafts are prosthetic conduits based on expanded polytetrafluoroethylene (ePTFE) and polyethylene terephthalate (Dacron ®). Their patency at 5 years is 40% to 50%, which is acceptable but relatively low. Tissue engineering has proven to be successful in wound management, burns, and cartilage repair; therefore their has been a growing interest in designing biological blood vessels as an alternative to autologous vascular grafts and current prosthetic conduits. However, previously proposed and designed tissue engineered vascular grafts were not durable, were prone to early thrombosis, and had poor patency rates. This means that a new vascular graft with all the above mentioned qualities is yet to be manufactured, but is a hopeful potential cure for the future.