Reading assignment 1 - Professor Kaiming Ye PDF

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Binghamton University

The Applications of Tissue Engineering An analysis of the benefits and complications associated with modern day disease treatment

Suzanna Damato B00607886 BME 201-90 Kaiming Ye 5 October 2016

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Executive Summary Within the last two decades, the rise of tissue engineering has led to numerous challenges that need to be addressed and researched so that this practice can be more widely used and fully integrated into the modern medical field. This paper primarily discusses the challenges faced in the construction of a scaffold onto which the developing tissues are to grow. The first challenge discussed is in choosing a material that is of the proper strength that will degrade at the proper rate without leaving behind any toxic waste within the body. The second challenge is in the scaffold’s architecture, as it is necessary for it to have the proper surface topography and for it to be porous. The discussion of porosity leads to the third challenge discussed, which is in vascularization. The scaffold must allow for vascularization in order to promote angiogenesis within the tissue so that cells can get the necessary amounts of oxygen and nutrition to survive. After the discussion of challenges, the applications of tissue engineering in the treatment of modern diseases are introduced. The benefits of this application are brought to light, including but not limited to the elimination of problems and complications associated with other, more traditional treatments such as donor shortage, graft failure, surgery complications, and decreased quality of life.

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Introduction Within the last 20 years, a number of medical advancements have been made in order to combat the increasing prevalence of diseases, both chronic and non-chronic, in the world. Tissue engineering, which has been a subject of much research and controversy in present years, is a multidisciplinary treatment that has had much success. Integrating fundamentals of biology, biochemistry, and engineering, tissue engineering is utilized in two major ways. The first is in an in vitro creation of tissues, generating cellular products outside of the body to be transplanted. The second way that tissue engineering is used is in the in vivo regeneration or repair of damaged tissues; that is, regeneration of tissues located within the body. Having the ability to grow and regenerate tissues within the body is revolutionary in the healthcare world. There are countless people who have died waiting for organs to become available for transplant, and with the advancements that come with tissue engineering, this problem will, in the future, be obsolete. Additionally, there are a multitude of problems that come with organ and tissue transplants. These problems can be entirely avoided by steering away from transplants, instead replacing them with engineering practices. Many individuals who receive organ transplants suffer lifelong complications, including rejection. These individuals are often forced to take immunosuppressant medications for the rest of their lives, many of which can cause other health complications later in life. If properly assimilated into the body, engineered tissues can act as a normal, healthy tissues produced by the body would, eliminating these dangerous side effects. As a whole, tissue engineering is geared towards people with tissues that have been damaged by the wear and tear of day-to-day use. The goal is to extend and improve the quality

4 of the lives of people with bone, cartilage, fat, or skin damage. These tissues are more simple to replace and more frequently in need of repair than those located in the brain or in other more complicated organs. Although many advancements have been made in tissue engineering within the last decade, there is still much to be discovered about it. As with any emerging technology, it comes with limitations and complications. This paper will largely focus on the complications associated with present day tissue engineering as well as the benefits of using tissue engineering as a supplement or even as an alternative to treating many modern day diseases that the world is faced with today.

Challenges Although tissue engineering has been used successfully in many cases, there are numerous challenges that the scientists and engineers who are involved in its research are still currently facing. Two of these significant challenges that researchers working to combat today lie in the construction of scaffolds on which to grow the tissues, and in the sourcing of cells to be used for tissue production. There are many different opinions within the tissue engineering community on how to combat these problems, some of which will be discussed and analyzed within the following section. Scaffolds are a necessary and complicated part of any tissue engineering project. The function of a scaffold mimics that of the extracellular matrix located within the body. Its key activities involve facilitation of the localization of delivery cells, provision of a temporary support onto which new tissues can grow, and finally, the scaffold guides the development of

5 new tissues, ensuring that they will carry out the desired functions within the body as they mature (Yeong, Chua, Leong, & Chandrasekaran, 2004). In providing for cell proliferation, differentiation, and biosynthesis, a scaffold must be constructed precisely, since the interaction between the new cells and the scaffold will ultimately heavily impact the functionality of the tissue, and therefore the success of the procedure being performed (Ikada, 2006). As expected, the construction of the scaffold is a heavily debated topic with many complications and challenges.

Range of Materials The first problem with building a successful scaffold in tissue engineering is in choosing the proper material from which to construct it. There are a number of important properties that are affected by the material chosen, so it is important that care is taken in the making of this decision. The first property affected is the degradation rate (Yeong et al., 2004). This has to do with the breakdown of the scaffold by the body. This is important because the scaffold must remain intact for long enough for the cells to anchor to it and for it to complete its job of providing support for the engineered tissue; however, problems can also occur if the scaffold remains in place for too long (Ikada, 2006). If a scaffold is not degraded quickly enough, cell regeneration can be impeded, leaving tissues incompletely formed. For this reason, it is important that a material with a correct critical rate of degradation is chosen. These critical rates are not constant for all tissues engineered and locations within the body, however, which further complicates the issue at hand (Ikada, 2006). The idea that different engineered tissues have different critical degradation rates for their scaffolds and therefore may require that

6 different materials need to be used to comprise these scaffolds shows the complex nature of the research that is being conducted in this field. The second issue having to do with the selection of material of the scaffold pertains to the degradation product. It is necessary to ensure that the products left behind when the scaffold degrades do not cause any harm to the tissue being engineered or to the body as a whole. Although most of the materials presently being used for scaffold construction are known to be largely non cytotoxic, it is still an important concept to be considered when developing and testing new materials to be used in construction (Yeong et al., 2004). Using materials that contain toxic degradation products can cause major problems within the body and render the engineered tissue useless, which is counterproductive in the long term. The final caveat in relation to material choice has to do with the strength of the material being used. Similarly to the way that scaffolds must have a critical degradation rate, there is also a critical strength that the material that the scaffold is composed of must possess. If the material is too strong, the cells cannot reorganize and attach to focal adhesion plaques (Yeong et al., 2004). This lack of adhesion leads to the inability of cells to deliver signals and execute their specifically designated functions (Yeong et al., 2006). Conversely, if the scaffold is too weak, cells are also unable to anchor to the compliant surface of the scaffold, since their developing cytoskeletons cannot gain proper traction (Yeong et al., 2004). Finding a material that has both the proper degradation rate for the tissue in question and the proper strength to promote cell adhesion proves difficult and is the cause of many of the challenges that are being faced by researchers in modern day tissue engineering.

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Scaffold Architecture The architectural design of the scaffold also greatly influences the success of tissue engineering projects. Two factors that must be considered when creating the structure of the scaffold are pore size and the topography of the scaffold surface (Yeong et al., 2004). The determination of pore size presents a significant design problem. It is known that optimal pore size differs for different type of tissues; however, there is still much to be known in regard to what these pore sizes actually are. Until more research is conducted in this area, it remains a major complication in scaffold design. The surface of the scaffold must also be carefully regulated. If it is too smooth, newly forming cells are unable to adhere, which creates difficulty in the formation of complete tissues (Yeong et al., 2004). On the contrary, if the surface is too rough, cells can be damaged, which can also lead to improperly formed tissues. In order to stimulate optimal tissue formation, the topography of the scaffold must be rough enough to encourage cell adhesion but smooth enough to not damage the cell, which further complicates the issue of scaffold design.

Vascularization If critical pore size is not achieved, the produced tissue will more than likely have major issues with vascularization. Vascularization is largely influenced by the porosity, pore size distribution, and porous network interconnectivity of the scaffold (Kumar, Mandal, Barui, Vasireddi, Gbureck, Gelinsky, & Basu, 2016). Although optimal pore size differs by type of tissue being created, a pore size of greater than 250 µm generally produces sufficiently vascular tissues (Kumar, et al., 2016). If the pores are not large enough, a necrotic core will form. A

8 necrotic core is marked by the death of cells on the inside of a tissue due to poor circulation. The cells on the outside of the tissue are able to get proper oxygen and nutrients; however, the innermost cells are cut off from these supplies, which ultimately leads to cell death. With a large enough pore size, vessels are allowed to reach into the center of the scaffold, providing all of the cells with adequate nutrients to sustain life and resulting in a healthy, well-developed tissue (Kumar et al., 2016). If the tissue is developed in vitro, angiogenesis needs to be stimulated. Traditionally, freeze casting, particle leaching, and gas foaming were all processes used to trigger this (Kumar et al., 2016). However, these practices are all flawed, often leading to random pore size distribution and poor interconnectivity (Kumar et al., 2016). The complications that these flawed practices brought about have led to the recent development of the use of growth factors to stimulate angiogenesis. The use of growth factors for this purpose in conjunction with the utilization of CAD scaffolds and 3D printing have greatly increased the precision of scaffold design.

Tissue Engineering & Disease Treatment In recent years, tissue engineering has begun to emerge as an extremely prevalent method of disease treatment. In some cases, this type of engineering has entirely replaced traditional treatment methods. In other cases, however, tissue engineering is used as a complementary solution for preexisting treatments. Either way, it is clear that tissue engineering is a discipline that will continue to advance in future years, solving problems in the healthcare world that have been prevalent for decades.

9 One important application of tissue engineering is in kidney disease. Kidney failure is a result of many prevalent, modern-day diseases, chronic and non-chronic. Because of this, there is an extremely high volume of individuals who would and do benefit from engineering of kidney tissue. This section will explore the benefits of using engineering as opposed to traditional methods to treat kidney disease in patients with renal failure. Many patients are currently reaping the benefits of kidney tissue engineering. Prior to its development, the only available treatments for renal failure were dialysis and kidney transplantation. Although these methods are often successful, they also often come with a number of complications. For example, transplant patients often suffer from graft failure, surgery complications, and organ rejection. There is also an extreme shortage of donors, both living and deceased. Many patients die on organ transplant waiting lists without ever receiving the transplant that they desperately need. Dialysis is also an imperfect treatment for treating renal failure. Dialysis machines function by filtering toxins from the blood, but are ultimately unable to produce hormones such as erythropoietin or activate vitamin D, which are necessary for bodily processes (Moon, Ko, Yoo, & Atala., 2016). In this way, dialysis serves simply as an aid for failing kidneys, rather than as a replacement. This can lead to a decreased quality of life and ultimately to decreased survival rates within patients. The utilization of tissue engineering to treat patients with kidney failure and disease serves as a prime example for the way that tissue engineering can be used to treat a multitude of different diseases in a more efficient and effective way. In many cases, tissue engineering replaces the need for organ transplants, which are intrinsically risky and often unavailable. Eliminating them where possible reduces the risk of antibody rejection, surgery complications,

10 and other issues that are associated with transplants of any type. Additionally, there are times when disease leads to the destruction of an entire organ or tissue that is not easily replaced, such as skin or cartilage (Williams, 2004). In this case, it is easier to engineer the tissue than to acquire a donor. Because of this reduction of risk, elimination of the need for organ and tissue donors, and increase in quality of life, tissue engineering is becoming an increasingly prevalent treatment for diseases that doctors have been struggling to cure for years.

Conclusion As tissue engineering emerges as a viable solution to treat diseases and replace tissues damaged by everyday life, it is important to analyze the challenges that the field is facing and needs to combat. Once more research is performed on the scaffolds necessary for success in the practice, the possibilities for tissue engineering in the future are virtually limitless. In upcoming years, it may be possible to apply the principles of tissue engineering to treat a great number of diseases and maladies.

11 Works Cited

Amini, A.R., Laurencin, C.T., & Nukavarapu, S.P. (2012). Bone tissue engineering: recent advances and challenges. Critical Reviews in Biomedical Engineering, 40(5), 363-408. doi: http://dx.doi.org.proxy.binghamton.edu/10.1615/CritRevBiomedEng.v40.i5.10

Ikada, Y. (2006). Challenges in tissue engineering. Journal of The Royal Society Interface, 3(10), 589-601. doi: 10.1098/rsif.2006.0124

Kumar, A., Mandal, S., Barui, S., Vasireddi, R., Gbureck, U., Gelinsky, M., & Basu, B. (2016). Low temperature additive manufacturing of three dimensional scaffolds for bone tissue engineering applications: Processing related challenges and property assessment. Materials Science and Engineering: Reports, 103, 1-39. doi: http://dx.doi.org.proxy.binghamton.edu/10.1016/j.mser.2016.01.001

Moon, K.H., Ko, I.K., Yoo, J.J., & Atala, A. (2016). Kidney disease and tissue engineering. Methods, 99, 112-119. doi: http://dx.doi.org.proxy.binghamton.edu/10.1016/j.ymeth.2015.06.020

12 Pahnke, A., Conant, G., Huyer, L.D., Zhao, Y., Feric, N., & Radisic, M. (2016). The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective. Biochemical and Biophysical Research Communications, 473(3), 698- 703. doi: http://dx.doi.org.proxy.binghamton.edu/10.1016/j.bbrc.2015.11.060

Rezvani, Z., Venugopal, J.R., Urbanska, A.M., Mills, D.K., Ramakrishna, S., & Mozafari, M. (2016). A bird’s eye view on the use of electrospun nanofibrous scaffolds for bone tissue engineering: Current state-of-the-art, emerging directions and future trends. Nanomedicine: Nanotechnology, Biology, and Medicine, 12(7), 2181-2200. doi: http://dx.doi.org.proxy.binghamton.edu/10.1016/j.nano.2016.05.014

Williams, D. (2004). Benefits and risk in tissue engineering. Materialstoday, 7(5), 24-29. doi: http://dx.doi.org/10.1016/S1369-7021(04)00232-9

Yeong, W., Chua, C., Leong, K., & Chandrasekaran, M. (2004). Rapid prototyping in tissue engineering: challenges and potential. Trends in Biotechnology, 22(12), 643-652. doi: http://dx.doi.org.proxy.binghamton.edu/0.1016/j.tibtech.2004.10.004...