Review: Heart valve tissue engineering
Hoerstrup, Simon P. and Stefan Neuenschwander. Transplant Immunology 12, 359-365 (2004).
Within the realm of cardiovascular diseases, valvular heart disease alone causes more than 20,000 annual deaths in the U.S. Current surgical techniques involving both mechanical and biological valves are not entirely efficacious due to the introduction of foreign material into the body, which could cause thromboembolic complications and the risk of infection. In addition, due to possible mechanical failure or the lack of tissue regeneration, a valve replacement is necessary within 10 to 15 years of implantation. This is a major problem with younger patients, who are susceptible to exponentially higher mortality rates as a result of repeated replacements. As such, researchers have developed various scaffolds with different types of cell seeding for resolving this very problem. The three focal issues of successful valve tissue engineering are the matrix (scaffold), the cell source from which the tissue is grown, and the in-vitro culture conditions of the construct prior to implantation.
To actually engineer autologous heart valves using synthetic scaffolds, a number of meshes are used to reconstruct valve leaflets by repeated seeding of cells. Over time, new scaffold materials and culture conditions have been tested for proper leaflet growth and long-term subsistence in an animal model. For example, the use of the thermoplastic elastomer P4HB as a coating for PGA scaffolds in combination with a biomimetic pulsatile flow conditioning for heart valve tissue engineering were completely degraded in vivo 6-8 weeks following transplantation in a juvenile sheep.
There are a number of cell sources and ways they can be cultivated. Cardiovascular derived cells are typically harvested from donor tissues, from which a further separation into endothelial and myofibroblast cell lines is done. A more comprehensive line with greater potential are bone marrow cells, as these cells are a continual source of progenitors for cells that meet the criteria for stem cells of non-hematopoetic tissue. They can be obtained from the iliac crest and maintained with standard tissue culture techniques. These mesenchymal stem cells have been show to differentiate successfully into showing a myofibroblast-like phenotype and the ability to produce a considerable amount of ECM.
While mechanical and biological heart valve prostheses have contributed to reducing the mortality and morbidity of millions of patients, there are a number of adverse side effects (lifelong anticoagulation medication for mechanical valves, and progressive dysfunctional degeneration for biological valves). The use of tissue engineering would overcome the problem of non-living replacements and the lack of regeneration and growth, two major issues with the current valve replacement techniques. With more studies and definitive results, tissue engineering techniques is promising for implants not just in valve replacement, but a number of other cardiovascular detriments as well.
4 comments:
I was wondering if the paper mentioned anything about how the tissue engineered valve would actually be transplanted into the body. Specifically focused on the transplanted cells surviving in the new environment. When the cells are growing on the different scaffolds, how are the stresses that normal heart valve tissue experiences mimicked? It seems that the stresses and pressures that heart valve tissue experiences would greatly influence exactly how it develops and maintains its functionality for prolonged periods of time.
Typically, the valve is created and cultured in-vitro. Once the cells are seeded on some type of scaffold, they are observed to make sure they are producing a fair amount of ECM (which verifies the efficacy of the scaffold). To actually engineer the leaflet itself, the scaffold is subjected to a a pulsatile flow environment, mimicking the same types of shears and stresses that a typical heart valve would experience. You are correct in saying that different stresses would be a great influence in changing the long-term functionality of the tissue. In fact, the source from which the cells are put on the scaffold has a large bearing on the extended phenotype and structural viability of the leaflet.
With regards to how the valve is actually transplanted into the body, the paper does not mention how this is specifically done. To my best knowledge, however, I believe the appropriate valve is first grown for 6-8 weeks in culture to develop a proper form. Surgery is then performed on an animal model (typically sheep). Depending on the type of scaffolding used (synthetic, biological, etc.) the graft will attach inside the heart through different mechanisms.
What inspired you to choose this article? Tissue engineering is of course a very challenging task with a plethora of considerations, most whose source is poorly understood. I have recently become an advocate of organic, genetic tissue treatment rather than tissue replacement because of its unthinkable complexity and immunogenic health risks. Unfortunately, I don't think it's an area of as much study as tissue engineering, especially with recent stem cell potential discovery. Which method do you think has greater promises?
To me, the heart has always been an area of great interest. As the central core of the body's existence, it is fairly apparant that the heart must be healthy at all times. Since cardiovascular diseases account for the most number of deaths in this country alone, novel approaches to benefit dysfunctional heart functions are always of great interest to the scientific community. As this assignment was to find a novel approach in tissue engineering, I decided to pursue cardiology as a topic. I previously did not know much about heart valves, so this review paper was enlightening in many respects.
You pose an interesting question. The immune response has always been one of the biggest issues with tissue engineering, and other approaches that could bypass this obstacle would be of great value. However, many advances in tissue engineering have begun to successfully address that problem by using biological scaffoldings and, as you mentioned, with discoveries in stem cell research. With an entirely dysfunctional heart valve, I'm not sure how gene treatments would be viable in solving the problem. One would have to precisely determine the problem with the valve - mechanical, biological, etc. - and proceed with an appropriate treatment option from there. If the problem is mostly biological, I'd imagine that gene treatments would be promising in efficacy and safety, not to mention bypassing the immune response. However, as I believe most heart valve dynfunctions stem from mechanical failures, I would imagine tissue engineering to have a greater overall promise in this field.
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