Twenty years of Tissue Engineering Heart Valves: More Hype than Hope - Essay Example

?20 years of Tissue Engineering as regards heart valves - More Hype than Hope? Introduction The 21st century has seen a great deal of advancement in the field of biological sciences, which has redefined progress in the arena of science and revolutionised the manner in which products are engineered, as specifically observed in cases of tissue engineering and medical implants (Vacanti and Langer, 1999). Tissue engineering, a concept that is still developing, broadly encompasses the creation of biological agents and the remodelling of specific body tissues or organs, in order to substitute, restore, regenerate or improve their functional effectiveness (Nerem and Ensley, 2004). In the last two decades from being a mere technology, tissue engineering has now evolved into a branch of regenerative biological sciences, since it currently includes regeneration and repair of body organs and tissues, along with replacement. Amongst various therapies, heart therapy has the potential to benefit significantly from advancement in tissue engineering (Lanza and Vacanti, 2007). This includes securing effective treatment for heart failure, and reversing permanent myocardial damage, where therapies using tissue-engineering promises to improve quality of life for thousands of heart patients. A study of the various scholarly contributions in the last two decades that conceptualised the multidisciplinary approach towards study of regenerative medicine (that includes tissue engineering), reveals widely varying focuses, perspectives and diagnoses that differ according to the time of the research conducted. This is natural and similar to the routes taken by various emerging subjects at different times (like biotechnology and pharmaceutical studies), where one must necessarily follow a regular pattern of practice through trial and error within methodologies and experiments. Hence, an emerging subject like tissue engineering becomes prone to constant modifications, before deriving scientifically proved hypotheses, which gives an assurance of effective practical use that would benefit medical sciences. Here the basic question that comes to the forefront is whether tissue engineering, which is still in a relatively fledgling state where the subject is still being conceptualised with more instances of failure than success, can be of ‘hope’ to millions of patients across the world (Citron and Nerem, 2004). Despite failures and critical claims of the procedure being more of ‘hype’ than actual ‘hope,’ the expected benefits (as and when they start arriving) from tissue engineering still remain high, and is seen by many clinical experts as being revolutionary in nature with positive implications for future implant patients (ibid). This paper will critically review the process of tissue engineering in relation to heart valves, and analyse the available literature to derive that after 20 years, tissue engineering, despite contentions that it is an over-hyped process, still holds out significant hope for millions of heart patients worldwide. Discussion Technique of Tissue engineering Regenerative medicine refers to a clinical process that aims at generating substitutes that make scope for remodelling of organs and/or tissues in cases of deformities (developmental or from birth, or after an injury or some disease that may have caused deformities in a patient) (Lysaght and Hazelhurst, 2004). The remodelling of the damaged tissue or organ can be affected through tissue engineering or cell therapy (using pharmaceutical mechanisms or via concurrent gene transfer, or through sole use of gene therapy) (Lysaght and Hazelhurst, 2004). A study of the processes shows that in cell therapy a group of cells is introduced into the affected parts of a patient’s body to repair, improve or replace the deformed cell population. As for example, various researchers have shown that in case of advanced Parkinson’s disease, infusion of AAV2-GAD into the patient’s subthalamic nucleus holds promise for curing the disorder a certain extent, thus proving cell therapy is advantageous while dealing with neurological disorders (LeWitt et al., 2011). Gene therapy on the other hand involves introduction of specific DNAs into host cells for rectifying gene error or for modifying specific host traits. Tissue engineering has the same objectives as gene therapy and cell therapy, even though the technique is slightly different. It can be aptly defined as ‘‘the persuasion of the body to heal itself through the delivery to the appropriate site of cells, molecules and /or supporting structures” (Willams, 1999, p. 318). The primary objective of tissue engineering is to regenerate or substitute damaged tissues and/or organ by producing functional cells, upholding the scaffolding system, promoting growth, and encoding DNA (signal) molecules to the tissues/organs in need. It combines the concepts of biology and technology (engineering), in order to comprehend the basic link that exists between the function and structure in normal and diseased tissues / organs and to create substitutes that can help in remodelling of tissues/organs for repairing, maintaining, or ameliorating the functioning of the affected tissue/organ. The field of tissue engineering has made some progress in the construction of connective tissues like bone, cartilage, bladder and skin that already have some power of regeneration (Vacanti & Langer, 1999). Here it is quite evident that the study of tissue engineering is still in its dormancy even after two decades of research work into the subject, a majority of the theories remain as mere conjectures, and the only progress made is related to tissues that already hold some degree of regenerative powers, like bone and skin. A typical tissue engineering procedure would involve removing specific cells from the body of a patient via biopsy. Once the cells are removed, they are then allowed to grow under controlled laboratory conditions (there are two approaches in the process of tissue engineering: in-vitro [in bioreactors or culture dishes] or in-vivo [in-situ production]) on 3D biomimetic scaffolding (Vacanti & Langer, 1999). These newly constructed cells are then transferred onto the desired part of the patient’s body, with further creation of new tissues within the 3D scaffolding (Vacanti & Langer, 1999). For an effective replacement or repairing of damaged tissues or organs, some of key elements that must be taken into consideration includes progenitor cells (for differentiating particular cell types), the biomaterial scaffold which supports cell differentiation, and the factors for inductive growth that control cellular movement. Here the main biological challenge faced by tissue engineering relates to treating degenerative diseases. Human bodies lack the fundamental ability to repair or regenerate damaged or destroyed body cells/tissues. While lower organisms still retain the power to regenerate, human bodies repair injured cells and tissues by generating fibrocartilagenous or fibrous scar-tissues, which are typically non-functional and non-specific in nature. Therefore, if a muscle cell is damaged, there would no new muscle cell to replace the original one; instead, the wound would simply close by the formation of fibrous scar-tissues. Often in case of damaged nerve tissues, development of scar-tissues help the wound to heal superficially, but as it lacks functional value the patient may suffer permanent damages, like paralysis or even quadriplegia. other irreversible or irreparable clinical conditions causing adverse effects on the normal daily activities of a human being include neurogenic bladder that affects the nervous system causing slow degeneration, and injury to human intervertebral discs leading to severe pain. Here, the formation of mere scar-tissues is not enough, and the wounds need replacement or regeneration of the damaged or destroyed cells/tissues/organs for normal bodily functions to resume. Therefore, the clinical importance of tissue engineering is obvious, while it also reflects the huge potential or hope (for patients with damaged organs/tissues or with degenerative medical conditions) that the field of tissue engineering offers. However, a look at the current achievements in this field show us that there are various adversities being faced while transferring this hope into commercial and medical reality, allowing some critics to label the process as more of a hype than hope. Current achievements in tissue engineering as regards heart valves in the academic arena In the last few years, there has been significant progress in clinical treatment related to cardiovascular conditions, where observations show that the process of tissue substitution, which resulted in functional replacement of damaged or destroyed tissues/organs, can save lives of many patients. Despite the large-scale heart-valve replacements through the present prosthetic therapies that take place worldwide each year, heart valve diseases still remain a significant cause for global mortality and morbidity rates, and accounts for nearly 20,000 deaths per year (Badylak, 2005). Additionally, records reveal that nearly 60% of the recipients of prosthetic valves tend to develop implant related problems that are serious in nature, within a decade of the valve replacement operation (Hammermeister et al., 2000). Being a non-living object, these implanted valves do not adjust to the surrounding physiological changes like increase or decrease in pressure. Furthermore, in cases of children who have undergone implantation, these artificial valves do not show growth along with the patient, which is considered a major medical problem. The aforementioned limitations forced medical researchers to explore other alternatives and seek new methods of valve replacement. In this context, a series of studies were undertaken to find out if the concepts of tissue engineering were viable in regenerating living valve substitutes that would possess a thrombo-resistant upper layer and a workable interstitium with abilities to remodel, regenerate and grow, unlike the prosthetic ones. Several researchers at this time demonstrated the viability of developing living cardiovascular cellular structures through the process of cell seeding on scaffolds made of xenogeneic matters, collagen and synthetic polymers (Shinoka et al., 1995; Elkins et al., 2001). Various attempts by researchers have been made to develop living heart valve substitutes using tissue-engineering techniques that are functionally viable with the ability to regenerate, grow and remodel (as represented in Fig. 1). In tissue engineering, cells from the patient are isolated, and allowed to grow via the normal cell culture processes, after which they are planted onto the scaffold prepared in a shape similar to that of a heart valve (Mol, 2005). Further stimulation takes place through the culture medium, which is known as biological stimuli; or through tissue ‘conditioning’ within bioreactors, and the stimulations help in the development of tissues, which leads to implantation of a living, functional, and autologous heart valve (Mol, 2005). In the context of tissue engineered heart valves, the first successful substitution was observed in case of a valve (pulmonary) leaflet, which was replaced by an autologous valve leaflet, created through tissue engineering (Shinoka et al., 1995). Thus, here we find that even though progress has been slow in the last two decades, there have been some achievements in the field of tissue engineering (heart valves), which holds out hope for the patients and the medical field. Fig 1: “Tissue engineering of heart valves. 1) Isolation of cells from a blood vessel of the patient and separation of myo?broblasts and endothelial cells. 2) Seeding of myo?broblasts onto a scaffold material in the shape of a trilea?et heart valve and subsequent seeding of endothelial cells onto the surfaces. 3) The cell/scaffold construct is placed into a bioreactor to stimulate tissue development” (Mol, 2005, p. 10). A review of the various researches conducted in the arena of the tissue engineering related to heart valves in the past two decades, show promising results. Here there are various approaches regarding the use of cell sources or matrix materials for developing heart valves, which came into existence right after the first scientific article on tissue engineered heart valves was published by Shinoka et al., in 1995. In the most popular approach, researchers preferred using biodegradable sources for developing heart valves (Shinoka et al., 1995; Hoerstrup et al., 1998).  Here the focus was on planting in scaffolds that were made of synthetic biodegradable matter like, polyhydroxyalkanoate or polyglycolic acid webs. Scaffolds that were composed of polyglycolic acid webs were extremely porous and too rigid to develop a completely functional heart valve (Shinoka et al., 1995) with a potential for being immunogenic. The scaffolds that comprised of polyhydroxyalkanoate were less rigid, but they required special preparations to conduct salt leaching, in order to produce the correct cell porosity. Other approaches used are gel based fibrin (from human cells) scaffolding (Ye et al., 2000a) while some experiments have used no scaffolding at all (Ye et al., 2000b), in order to attempt and solve problems associated with synthetic scaffoldings. Other group of researchers have used acellularised matrix matter (Dohmen et al., 2002) while others have used aortic root as cell sources (matric material) for developing heart valves (Bader et al., 1998). After conducting extensive researches on the viability of using human cells for developing heart valves it can be been derived that human cells that hold out maximum hope are derivatives from bone marrow (Hoerstrup et al., 2002), umbilical cord (Sarugaser et al, 2005), vascular cells (Schnell et al., 2001), chorionic villi (Schmidt, 2006) and blood cells (Schmidt et al., 2004). Despite the extensive researches that attempt at locating appropriate cellular matrices for growing living and functional heart valves in order to provide a better alternative than the current prosthetic ones in use, there are major disadvantages reported within the research results. Scientists theorise that if one takes into consideration the synthetic scaffolds that show fast hydrolysation effects, there are chances that the entire process may result in breaking down of the constructs developed (Cebotari et al., 2002). In cases of substitution of the acellular aorta (xenogeneic matrix) tested on rats, there have been failures, in the form of ‘aneurysmal dilatation’ (Allaire et al., 1994). Researches using substitutes of acellularised and non-seeded porcine valves have led to devastating results, where matrices degenerated at a very early stage (Simon et al., 2003). From the above study, it is clear that despite many pilot studies focusing on generating living and functional heart valves though tissue engineering, under present circumstances it cannot be scientifically derived that concepts of tissue engineering is most suitable for clinical purposes in developing heart valves, as majority of the researches have resulted in failures (Simon et al., 2003). Besides failing to develop the appropriate cellular sources or matric materials for heart valve regeneration, there are chances that use of immature cells like the progenitors could cause tumours from unregulated cellular differentiation through genetic modifications, an aspect that future researchers must necessarily keep in mind. Even though the present rate of success in recreating heart valves through tissue engineering is minimal with greater number of failures than success, this procedure still carries great hope (from whatever little success has been achieved) for the clinical world. This is primarily owing to the fact that the present medical alternatives used for heart valve replacements through synthetic prosthetics are inadequate and fraught with risks and various disadvantages. Current achievements in tissue engineering as regards heart valves in the commercial arena In the 1990s, commercial activities along with academic activities showed a marked rise in arena of tissue engineering. This created a great deal of hype within the mass media, which is evident when we find a well-known business journal Barron’s in its article “Spare Body Parts” referring to the bright future of tissue engineering, and projecting it as a promising $100 billion industry of the future (Palmer, 2000). Besides the print media, the television also added to the hype, where researches on genetics and tissue engineering were given a great deal of prominence, over space researches and computer related innovations. The pioneering firms that were taking part in various researches associated with tissue engineering, were thus caught in a loop, where they had a great deal of funds owing to the hype created by mass media, but along with it they were also faced with high expectations from public and investors, again due to media hype. However, the industrial or the commercial sector, despite being under great pressure, did manage to introduce some products into the market even during the initial years, which were mostly skin replacement agents. The various skin substitutes introduced into the market included Dermagraft, Appligraf and TransCyte, which were created by Advanced Tissue Sciences and Organogenesis (Naughton, 1999). Another product introduced during the 1990s was the Carticel, which involved autologous cell process for cartilage damage therapy. These companies, being pioneers in this line, faced various issues that ranged from inadequate scientific knowledge base, to underestimating problems of the new technology, to overestimating market requirement (Lysaght, Deweerd and Jaklenec, 2007, pp. 1265-1270). Other issues caused further delay in the product launch, were due to pending approval of rightful remuneration, and other ethical and regulatory barriers. Besides these, various management decisions taken by these firms at that time were not appropriate, and finally several of the companies started facing financial crunch, which continued into the 2000s. In the magazine Barron’s, which had projected a $100 billion future industry, in 2006 it was found that at an average count, total sales in tissue engineering market were around US$240 million (Lysaght, Deweerd and Jaklenec, 2007, pp. 1265-1270). From an overview, Lysaght, Deweerd and Jaklenec, presented an estimate, which encompassed stem cell therapies, tissue engineering, and regenerative medicine. The authors claimed that at an average count, yearly sales were at $1.5 billion in 2007 and another $860 million in the pipeline (for development stage pay out) (ibid). Currently, it is estimated that there are around 170 companies in the line of tissue engineering that have more than 6000 workers (Lysaght, Jaklenec, and Deweerd, 2008). Thus, we find that despite facing initial setbacks the commercial sector related to tissue engineering presently is showing a good deal of hope and promise, and if new researches prove to be successful in creating heart valves, it would be advantageous for the clinical world. During the 1990s, US firms dominated the tissue engineering market; however, new players are now emerging from all over the world, making the industry a global phenomenon (Mason, 2007). Therefore, we find that despite setbacks and problems, there are positive signs within the commercial aspect of tissue engineering that are now being perceived. Organogenesis, which launched their skin substitute Apligraf, has already started acquiring profit; and Smith & Nephew, which bought the bankrupt firm Advanced Tissue Sciences, has launched new skin substitute products (ibid). However, market products related to regeneration of heart valves or even other parts of the heart, yet remain undelivered. However, with proper researches there is a distinct possibility of such products being available in the future market. Therefore, to describe the commercial venture of tissue engineering as more of hype and a failure would be wrong, and looking at the products already available one can presume that in future there is hope for the heart patients. Conclusion Despite various setbacks and other associated problematic issues, it is evident that tissue engineering related to regeneration of heart valves holds a great deal of hope for creating a functional, autologous and a living, heart valve substitute. This would be especially advantageous for the children that require valve replacement, and they will significantly benefit from developing substitute materials for treating congenital heart problems. Nevertheless, prior to clinical application of regenerated heart valves created through use of tissue engineering concepts, the problematic issues as currently being faced by the researchers (discussed in the paper), must first be resolved. References Allaire, E., Guettier, C., Bruneval, P., Plissonnier, D., and Michel, J., 1994. Cell-free arterial grafts: morphologic characteristics of aortic isografts, allografts, and xenografts in rats. J Vasc Surg 19, 446-456. Bader, A., Schilling, T., Teebken, O., Brandes, G., Herden, T., Steinhoff, G., and Haverich, A., 1998. Tissue engineering of heart valves--human endothelial cell seeding of detergent acellularized porcine valves. Eur J Cardiothorac Surg 14, 279-284. Badylak, S., 2005. Regenerative medicine approach to heart valve replacement. Circulation 111, 2715–2716. Palmer, J., May 15, 2000. Spare body parts. Barron's,  Citron, P., and Nerem, R., 2004. Bioengineering: 25 years of progress –– but still only a beginning. Technol. Soc. 26, 415–431. Cebotari, S., Mertsching, H., Kallenbach, K., Kostin, S., Repin, O., Batrinac, , A., Kleczka, C., Ciubotaru, A., and Haverich, A., 2002. Construction of autologous human heart valves based on an acellular allograft matrix. Circulation 106, I63-I68. Dohmen, P., Lembcke, A., Hotz, H., Kivelitz, D., Konertz, W., 2002. Ross operation with a tissue-engineered heart valve. Ann Thorac Surg 74, 1438- 1442. Elkins, R., Goldstein, S., Hewitt, C., Walsh, S., Dawson. P., Ollerenshaw, J., et al., 2001. Recellularization of heart valve grafts by a process of adaptive remodeling. Semin Thorac Cardiovasc Surg 13, 87–92. Hammermeister, K., Sethi, G., Huderson, W., Grover, F., Oprian, C., Rahimtoola, S., et al., 2000. Outcomes 15 years after valve replacement with a mechanical versus bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol 36, 1152–8. Hoerstrup, S., Kadner, A., Melnitchouk, S., Trojan, A., Eid, K., Tracy, J., et al., 2002. Tissue engineering of functional trileaflet heart valves from human marrow stromal cells. Circulation 10, I 143–50. Hoerstrup, S., Zund, G., Schoeberlein, A., Ye, Q., Vogt, P., Turina, M., 1998. Fluorescence activated cell sorting: a reliable method in tissue engineering of a bioprosthetic heart valve. Ann Thorac Surg 66, 1653- 1657. Lanza R., and   Vacanti, J., 2007. Principles of Tissue Engineering. Academic Press, California. LeWitt, P. et al., 2011. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10(4), 309-19. Lysaght, M., Deweerd, E., and Jaklenec, A., 2007. “The tissue engineering industry.” In, Lanza, R., Langer, R. and Vacanti, J. (eds.), Principles of Tissue Engineering (3rd Ed), pp. 1265-1270. Elsevier Academic Press, NY. Lysaght, M., Jaklenec, A., and Deweerd, E., 2008. Great expectations: private sector activity in tissue engineering, regenerative medicine, and stem cell therapeutics. Tissue Eng. Part A 14(2), 305–315. Lysaght, M., and Hazelhurst, A., 2004. Tissue engineering; the end of the beginning. Tissue. Eng. 10, 309–320. Mason, C., 2007. Regenerative medicine: the industry comes of age. Med. Dev.Technol. 18(2), 25–28. Mol, A., 2005. Functional tissue engineering of human heart valve lea?ets. Universiteitsdrukkerij TU Eindhoven, Eindhoven, The Netherlands. Naughton, G., 1999. Skin: the first tissue-engineered products –– the advanced tissue sciences story. Sci. Am. 280(4), 84–85. Nerem, R., and Ensley, A., 2004. The tissue engineering of blood vessels and the heart. Am J Transplant 4, 36–42. Sarugaser, R., Lickorish, D., Baksh, D., Hosseini, M., Davies, J., 2005. Human umbilical cord perivascular (HUCPV) cells: A source of mesenchymal progenitor cells. Stem Cells 23, 220–9. Schmidt, D., Mol, A., Breymann, C., Achermann, J., Odermatt, B., Gossi, M., et al., 2006. Living autologous heart valves engineered from prenatally harvested progenitors. Circulation 114: I125–31. Schmidt, D., Breymann, C., Weber, A., Guenter, C., Neuenschwander, S., Zund, G., et al, 2004. Umbilical cord blood derived endothelial progenitor cells for tissue engineering of Vascular Grafts. Ann Thorac Surg 78, 2094–8. Schnell, A., Hoerstrup, S., Zund, G., Kolb, S., Sodian, R., Visjager, J., et al., 2001. Optimal cell source for cardiovascular tissue engineering: venous vs. aortic human myofibroblasts. Thorac Cardiovasc Surg 49, 221–5. Shinoka, T., Breuer, C., Tanel. R., Zund. G., Miura. T., Ma, P., et al., 1995. Tissue engineering heart valves: valve leaflet replacement study in a lamb model. Ann Thorac Surg 60, 513–6. Simon, P., Kasimir, M., Seebacher, G., Weigel, G., Ullrich, R., Salzer- Muhar, U., Rieder, E., and Wolner, E., 2003. Early failure of the tissue engineering porcine heart valve synergraft in pediatric patients. Eur J Cardiothorac Surg 23(6), 1002-1006. Vacanti, J., and Langer, R., 1999. Tissue engineering: The design and fabrication of living replacement devices for surgical reconstruction and transplantation. Lancet 354 (Suppl. 1), SI 32 – S34 Williams, D., 1999. The Williams Dictionary of Biomaterials. Liverpool University Press, Liverpool. Ye, Q., Zund, G., Benedikt, P., Jockenhoevel, S., Hoerstrup, S., Sakyama, S., Hubbell, J., and Turina, M., 2000 a. Fibrin gel as a three dimensional matrix in cardiovascular tissue engineering. Eur J Cardiothorac Surg 17, 587-591. Ye, Q., Zund, G., Jockenhoevel, S., Hoerstrup, S., Schoeberlein, A., Grunenfelder, J., and Turina, M., 2000 b. Tissue engineering in cardiovascular surgery: new approach to develop completely human autologous tissue. Eur J Cardiothorac Surg 17, 449-454. Read More