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This report examines the innovation system of cardiac tissue engineering, one of the emerging state-of-the-art biomedical technologies, by utilizing holistic approach and systems analysis to explore its advantages and disadvantages in terms of sustainability. Moreover, the relevant history, regulations and related actors in the cardiac tissue engineering innovation system as well as its obstacles in pursuing its innovation are also addressed. Finally, in order to overcome the obstacles, this report proposes a working guideline which potentially offers extensive opportunities to comprehend more deeply about cardiac tissue engineering from scientific perspective as well as social, economic, and most importantly, sustainability perspectives.
The proposed working guideline consists of 3 steps. Firstly, all of the possible scientific strategies of cardiac tissue engineering at present ought to be identified along with its advantages, disadvantages and their implications in terms of commercial development and it must be discussed from social, economic, and environmental perspectives as well as long-term perspective in order to evolve the context of sustainability within the cardiac tissue engineering innovation system. In this report, 6 main scientific strategies are identified; 1) classical strategies, 2) engineered heart tissue, 3) scaffold-less cell sheet/cell patch technology, 4) in vitro biological cell assembly, 5) in vivo biological cell assembly, and 6) decellularized heart matrix. Secondly, extensive historical analysis of the tissue engineering industry should be pursued in order to investigate more closely and precisely on the process of successful cases and failures of commercial development of tissue engineering technologies to extract successful driving and failing factors. This is because commercialization of tissue engineering technology involves a variety of challenges such as cost reduction, manufacturing challenges, clinical application and regulatory requirements, ethical issues, and recognition of appropriate business models. Finally, it is worth investigating for all the related stakeholders to comprehend the role of tissue engineering technologies at global level in order to identify how tissue engineering technology can contribute to the global sustainability.
1.1 cardiovascular diseases - the number one cause of death throughout the world
Cardiovascular diseases (CVD) such as heart failure are the number one cause of mortality around the world. Table 1.1 shows the top 20 causes of mortality throughout the world in 2004. By breaking down the ranking into the category of developed and developing countries, CVD is the highest cause of death in developed countries and second highest cause in developing countries (number one cause of death in developing countries is HIV/AIDS) . Moreover, heart failure is the second highest cause in low-income countries (2.47 million people died in 2004) and middle-income countries (3.40 million people died), and the number one cause in high-income countries (1.33 million people died in 2004) .
The fundamental cause of CVD characteristically is the fibrous tissue formation in the blood vessel within the heart and permanently impaired cardiac function due to a substantial cell loss caused by ischemia because cardiac tissue lacks natural regenerative capability . Moreover, end stage of heart failure inevitably requires heart transplantation. First-ever heart transplantation was taken place in Cape Town in South Africa in 1967 where alternative organs obtained from donor are transplanted into the patient. Since then, heart transplantation is well-known as the most promising medical treatment for such serious heart diseases. However, because of the lack of organ donors and complexities associated with treatment for immune response system after organ transplantation was taken place, engineers, scientists and surgeons are continuously seeking new alternative strategies for organ regeneration progressively .
Table 1.1: Top 20 Causes of Mortality throughout the World 
1.2. What is Tissue Engineering?
Tissue Engineering (TE), an emerging biomedical technology in the field of regenerative medicine, is defined as follows: "the application of principles and methods of engineering and life science toward fundamental understanding of structure-function relationships in normal and pathological mammalian tissue and the development of biological substitutes to restore, maintain, or improve tissue function" . TE could dramatically change our lives and help us outlive the failure of our organs as it focuses on the repair, replace or regeneration of cells, tissues or even organs in near future to restore impaired function resulting from any causes, including congenital defects, disease, trauma and ageing. TE technology targets various medical treatments for cancer, dental oral, neurology, and skin. Diagram 1.2 shows the working areas of TE technology today. Most of the working fields are still under development.
Diagram 1.2: Tissue Engineering and Cell Therapy and applications 
1.3 The role of Cardiac Tissue Engineering
The role of cardiac tissue engineering is to create functional tissue constructs that can restore the structure and function of injured myocardium . The heart itself is a miracle of engineering by nature, and organ of extreme structural and functional complexity with crucial functions for sustaining biological human body system. The heart wall is composed of tightly packed myocytes (muscle cell) and fibroblasts (extracellular matrix and collagen) . Vunjak-Novakovic et al identified the key features of native myocardium for cardiac tissue engineering technological development are listed below ;
High density of myocytes and supporting cells
Efficient oxygen exchange between the cells and blood
Synchronous contractions orchestrated by electrical signal propagation form a set of design requirements for engineering cardiac tissue.
High density and high metabolic demand of the cell lead myocardium consume large amounts of oxygen and cannot bear hypoxia. The myocytes form a 3D syncytium that enables propagation of electrical signals across specialized intracellular junctions to produce mechanical contractions that pump blood flowing.
As mentioned above, heart failure typically results in fibrous tissue formation in the heart and permanently impaired cardiac function due to a substantial cell loss caused by ischemia as cardiac tissue lacks intrinsic regenerative capability. Heart disease and stroke (the principal components of cardiovascular disease) are the first and the third leading cause of death in the US (more than 40% of all deaths, more than all cancer combined). In Japan, malignant tumor is the 1st cause (30%) and heart disease and stroke are 2nd cause (16%). Moreover, congenital heart defects - nearly 14 of every 1000 newborn children are the most common congenital defects and the leading cause of death in the first year of life. Myocardial infarction can cause a vigorous inflammatory response to be elicited. Dead cells are removed by macrophages. Over the subsequent weeks to months, fibroblasts and endothelical cells migrate and form granulation tissue that ultimatey becomes a thick and stiff collagen scar. Scar formation reduces contractile function of the heart and leads to ventricle wall thinning and remodeling and ultimately to heart failure.
As mentioned above, Heart involves a risk of failing beyond repair, way too often, because of the intrinsic inability of the damage heart tissue to regenerate after injury. For this reason, engineered constructs can ideally serve as models reproducing the state or behavior of a real cardiovascular system and clearly are one of the crucial biomedical contributions to the studies of cardiac development and disease.
1.4 Why is tissue engineering important for sustainability?
One of the immediate sustainability issues for cardiovascular diseases is lack of organ donors available for patients. Almost every country faces the lack of organ donors which puts a significant limitation on the medical treatments for such serious disease. For example, registrations of patients who are wishing for organ transplantation are enormous and they significantly exceeds the number of people offering organ transplantations. Table 1.4 below shows the summary of registrations for each organs and comparison with the number of people who offer organ transplantation in 2010.
Table 1.4: summary of registrations for each organs and the number of people who offer organ transplantation
Because TE technology requires extensive and innovative scientific development, a lot of tissue-engineered organs are still under development. However, in near future, TE technology will possibly be able to reestablish structure and function of any injured organs so that organ donor availability issues will largely be eased. At this point of time (Feb 2011), tissue engineering technology covers only bone, cartilage, and skin available to patients.
Moreover, such state-of-the-art life science technology has a potential to contribute further to the improvement of quality of human life. For example, life expectancy has been significantly increased with time mainly by industrialization, urbanization and technological development. The world average of life expectancy is 67.2 years old whereas in early 20th century, it was around 40 years old. Table 1.3 shows world life expectancy at birth (years) as in 2008. The fact that life expectancy in the industrialized nations tends to be much higher than that in developing countries is still in question.
Table 1.3: CIA World Factbook 2008 Estimates for Life Expectancy at birth (years)
1.5 What are the disadvantages in terms of sustainability?
From resource-based point of view, one of the global sustainability issues is over population. Over population is deemed to cause various scarcity issues including food, water, employment and land use. The causes are deemed as industrial revolution, agricultural development, and urbanization. Most importantly, medical technology development is also deemed as one of the causes of over population. However, current trends such as engineering urban design and renewable energy are now moving towards sustainable development which potentially enables human development (focus on quality of human life) to move forward.
2. Systems Analysis
2.1 Actors relevant to the context of cardiac tissue engineering technological development
The actors relevant to the cardiac tissue engineering technological development are shown below;
Research institutions (i.e. universities) which develop scientific knowledge and its applications
Hospitals where clinical trials for the proto-type products take place
Firms (i.e. raw material manufacturers and firms which are interested in collaborating with tissue engineering research and commercialize the products)
Funding organizations (i.e. national government and venture capital)
Patients who actually receive the tissue-engineered products
Research institutions are the key player in this technological development - they procure raw materials to synthesize biomaterials for scientific research purposes and they are usually financially supported by governmental funding or investments from private financial sectors. The end goal for research institutions is to provide numerous patients with effective tissue engineered products at reasonable prices. However, commercialization of tissue engineering technology involves a variety of challenges such as cost reduction, manufacturing challenges, clinical application and regulatory requirements, ethical issues, and recognition of appropriate business models (these obstacles will be discussed in the next chapter). Therefore, tissue engineering researchers must take into account the voices of medical community and the market needs as well as the credibility of the lab-based research discoveries in the clinical trials to make sure translational research to happen. In order to make the proto-type of newly developed TE products available for clinical trials, manufacturing small- and medium-sized enterprises pre-manufacture the products from lab-scale to commercial-scale. After the proto-type is created, the products enter into the clinical trial stage where the proto-type product is tested with volunteering patients. After the clinical trial completed successfully, the product is licensed and the results will be approved by the health care governmental bodies such as Pharmaceutical and Medical Devices Agency. After licensing, the product is ready to go placed on the market. At this stage, depending on their strategies, the proto-type product can be sold to the large biomedical companies, or the original researchers or their business partners can pursue a start-up company to start selling the product.
Raw materials procurement
Required stem cells
Required stem cells for research purposes
Clinical trial participation
Products for mass production
Diagram 2.1.1: Actors relevant to tissue engineering technological development
As mentioned above, the role of cardiac tissue engineering is to create functional tissue constructs that can reestablish the structure and function of injured myocardium. Engineered constructs can serve as models reproducing the state or behavior of a real human biological system and are one of the crucial biomedical contributions to the studies of cardiac development and disease. In general, the biological potential of the cells - tissue engineer, is mobilized by providing highly controllable biomaterial-made 3D environments, so-called "scaffolds" that can mediate cell differentiation and functional assembly.
The final goal for cardiac tissue engineering innovation is to make the technology available to patients with low medical expenditures on them. As mentioned in the chapter of actors, the obstacles can be found in various stages during the innovation process including scientific challenges, clinical application and regulatory requirements, ethics, labor and manufacturing challenges and lack of appropriate business model. The following sections describe the obstacles in TE innovation one by one.
3.1 Scientific challenges
For cardiac regeneration, some of the key requirements that need to be met are; the selection of a human cell source, establishment of cardiac tissue matrix, electromechanical cell coupling, robust and stable contractile function, and functional vascularization.
The major challenges of cardiac tissue engineering are how to reestablish the unparalleled complexity of injured heart tissue. For clinical utility, engineered cardiac tissue should consist of autologous or imunetorated, phenotypically stable cardiac cell populations (myocytes, fibroblasts, vascular cells) within a native-like tissue matrix (molecular composition, structure, biomechanics). The size and thickness of an engineered graft need to be of clinically relevant size so vascularization is required. Development of an engineered graft requires almost every understanding of heart functions such as electromechanical coupling of the cells, synchronous contractile activity and generation of contractile force. Cardiac tissue engineering therapies requires a lot of requirements for reproducible manufacturing of the grafts, regulatory and public policy issues and scientific challenges to be met before available to patients.
Table 3.1 below shows the nine major scientific challenges in cardiac tissue engineering.
Cells are the actual ''tissue engineers,'' we only engineer the environments that can predictably mediate their differentiation and developmental processes.
Design requirements for tissue engineering systems should be ''biomimetic,'' which is based on the information obtained from developmental and adult biology.
A range of cell types-adult, embryonic, induced and resident stem cells-is under consideration as sources of cardiac and vascular cells for heart regeneration.
Vascularization is essential for the implementation of cardiac grafts.
Functional integration between the graft and host tissues-both electromechanical and vascular-remains a major challenge.
The establishment of cardiac tissue function is most difficult to achieve and rigorously evaluate.
The question ''How much is enough?'' in terms of construct function, for implantation and in vitro studies, remains to be answered.
Advanced technologies for three-dimensional culture are critical for establishing correspondence between in vitro and in vivo studies.
Functional imaging will greatly facilitate bringing regenerative medicine to the next level of understanding.
Table 3.1: List of major scientific challenges in cardiac tissue engineering
3.2 Clinical application and regulatory requirements
One of the most important phases for such emerging biomedical technologies is the clinical application. For instance, Japanese regulatory systems and guideline for such applications are significantly slow in terms of their review, approval systems and the implementation of guidelines which are the major obstacles for the commercialization of tissue engineered products. Compared to other industrialized nations such as US and EU, the time taken for the clinical application is more than twice as long. Thus, TE technological development is heavily depended on the regulations and it is one of the main causes for Japan to slow down the TE innovation. Diagram 2.1.2 shows the procedures for product development and obtaining regulatory approval for biologics in the US and Jpan. IND represents Investigational new drug, BLA represents Biologics license application, PMDA represents Pharmaceuticals and Medical Devices Agency, MHLW represents Ministry of Health, Labour, and Welfare.
Diagram 2.1.2: procedures for product development and obtaining regulatory approval for biologics in the US and Japan
Tsubouchi et al investigated the obstacles to the clinical applications in Japan especially for tissue engineering/regenerative medicine products. Their findings include the major obstacles are the existence of two separate categories of clinical trials, the stringent review for pre-clinical assurance of quality and safety, and regulatory guidelines without practical examples showing how the pre-clinical data required for quality and safety assurance should be prepared. They suggest that simplified clinical trials such as combined pre-clinical trial and clinical trial should be required in order to speed up the clinical application in Japan.
Ethics is one of the major obstacles in TE innovation. Ethics in TE is one of the decision criteria for policy makers. For instance, in 1990, congress voted to override the moratorium on government funding of embryonic stem cell research, which was vetoed by President Bush. In 1993, President Clinton lifted the ban, but he changed his mind the following year after public outcry. And by 1995, congress banned federal funding in embryonic cell research. In 2000, President Bill Clinton allowed funding of research on cells derived from aborted human fetuses, but not from embryonic cells. On August 9, 2001, President Bush announced his decision to allow Federal funding of research only on existing human embryonic stem cell lines created prior to his announcement. His concern was to not foster the continued destruction of living human embryos. In 2009, President Barack Obama ends stem cell federal funding ban and put a positive light on the new stem cell lines. Since then, the TE technological development has been significantly active in the US.
Tissue engineering utilized the development of cellular engineering which attempts to control cell function through chemical, mechanical, electrical or genetic engineering of cells, as well as on biomaterials science. The major ethical controversial issue in tissue engineering is the use of human embryonic tissue. Genetic control of human embryo requires destroy of human embryos after harvesting the human embryonic stem cells and this concern deemed to be more visible when the large-scale cultivation of human embryos commence specially for this purpose.
Ethical issues in tissue engineering are currently addressed in the fields of bioethics, engineering ethics, and medical ethics. Tissue engineers are different from medical practitioners in that they are involved in research and development (R&D) of new technology but not engaged in the studies, diagnosis or treatment of patients. However, medical practitioners and tissue engineers have a common goal in that they aim to contribute to better patient care and healthcare.
In R&D, ethical issues involve human and animal experimentation and the use of biomaterials as well as conflicts of interests. Biomedical engineers are required to design for medical practices in the way that technology and techniques are designed in a manner consistent with and supportive of ethical principles. Such principles are listed below;
Benegicence - benefit to patients
Nonmaleficence - doing not harm
Patient autonomy - the right to choose or refuse treatment
Justice - equitable allocation of scare health resources
Dignity - dignified treatment of patients
Confidentiality of medical information
Informed consent - consent to treatment based on ap roper understanding of the facts
Other ethical issues include whether human donors of cells should be able profit from the use and whether to have a right to informed consent to very use of their cells (i.e. patent of tissues). Privacy of protected cells is also another ethical issues where donor storage so-called biobanks store biospecimens used for clinical and/or research purposes. The issue is whether private or public organization should store those biospecimens to protect their privacy and confidentiality.
Finally, there is a growing concern in how to balance the prolonging of life with the quality of life in tissue engineering - to what extent lengthening the life span of humans is a goal of tissue engineering and how such a goal should be balanced against the goal of improving the quality of life.
3.4 Labor and manufacturing challenges and lack of appropriate business model
After developing any of tissue engineering technologies, its goal must be linked to commercialization which finally reaches patient care and healthcare. However, there is much to do before successfully commercializing tissue engineered products, such as cost reduction to produce, maintain and transport the products. Commercialization of tissue engineering technologies can be categorized into 3 generation industry - 1st generation industry which is characterized by its demonstrated clinical applications and products in the market place, 2nd generation industry which involves emerging clinical applications, and 3rd generation industry which involves apparitional clinical applications. Diagram 3.4 shows a road map of three generation industries and key engineering and business challenges.
Diagram 3.4: Road map of three generation industries and key engineering and business challenges
All of the generation industries face business challenges such as achieving from breakeven to profit to realize market opportunity. In 2005, allogeneic therapies and wound dressing are emerged and major challenges there were manufacturing system analysis and redesign, process improvement and optimization techniques, increasing the application of allergenic approaches and most importantly, technology diffusion. This phase is deemed as 2nd generation industry. Skin, cartilage, bone, and bone marrow emerged in clinical applications in 2008 where the cost reduction of tissue engineered product was the major challenge. In other words, determination of business and manufacturing models through automation and scalable process technology were the key challenge for the production strategies. Finally, key challenges of 3rd generation industry involve underlying scientific data to inspire the tissue engineering industry. This phase heavily depends on scientific development of tissue engineering technology.
Throughout generation industry periods, appropriate business model is crucial to sustain their economic activities. For example, Organogenesis (Canton, MA) and Advanced Tissue siences (ATS; La Jolla, CA) went bankrupt in 25 Sept and 10 Oct in 2002 respectively. The common causes were the significant decrease in sales and the increase in their operating costs. The main reason for this was unstable business model which did not fcus on the importance of communication with targeted community. This technology push approach without listening to the needs of medical community caused unbalanced supply and demand.
4. Possible solutions and innovation process simulation
4.1 Strategies in cardiac tissue engineering
Tissue engineering innovation faces a variety of obstacles as discussed above. In order to overcome those obstacles, just solving one particular issue might ease the situation but would not solve the essence of the issues. In this case, holistic strategic approach to problem-solving is required.
First, scientific strategies of cardiac tissue engineering must be identified along with advantages and disadvantages in long-term perspective and must be discussed from social, economic, and environmental perspectives in order to consider sustainability. For instance, Tee et al summarized some of the scientific cardiac strategies in order to compare the pros and cons of each strategy. Table 4.1 shows the list of cardiac tissue engineering strategy in terms of cells, scaffold and transplantation strategy.
Table 4.1: Cardiac tissue engineering strategies
Tee et al identified 6 main strategies used in cardiac tissue engineering which are; 1) classical strategies where desired cells are seeded into a biomaterial-made scaffold in vitro with/without manipulation and then implanted in vivo, 2) engineered heart tissue which is the most creative and promising approach to cardiac tissue engineering by utilizing neonatal rat cardiomyocytes, collagen type I from rat tails and MartgelTM and a mechanical stretching device, 3) Scaffold-less cell sheet/cell patch technology which employs a thermo-sensitive cell culture surface, 4) biological cell assembly where cells are seeded into hydrogel-based scaffolds which provide an environment for the cells to migrate and assemble into contractile tissues and it can be done either in vitro by using gravity-enforced techniques to form spheroid-like microtissues or 5) in vivo biological cell assembly by using an arteriovenous loop embedded chamber to vascularize the assembled cardiomyocytes, 6) decellularized heart matrix where donor hearts are decellularized to obtain a whole heart extracellular matrix scaffold and then cardiomyocytes and endothelial cells are seeded to recellularize the whole heart. Table 4.2 illustrates the main strategies used in cardiac tissue engineering.
Table 4.2: Main strategies used in cardiac tissue engineering
4.2 Critical review of tissue engineering industry - lessons learnt from the history
As discussed in the section of obstacles above, commercialization of tissue engineering technology involves a variety of challenges such as cost reduction, manufacturing challenges, clinical application and regulatory requirements, ethical issues, and appropriate business model. In order to investigate more closely and precisely on the process of successful cases and failures, extensive analysis of the industry is required today. The analysis should be pursued by utilizing several social science techniques such as bibliometrics to track the trends of research publication to investigate the network and relationships between related stakeholders, patent analysis and systems analysis to utilize holistic approach to investigate how various stakeholders and behaviors influence one another. By finding the essence of the causes of successes and failures, proposals and/or new strategies are expected to be applied to the case of commercialization of cardiac tissue engineering technology.
4.3 Tissue engineering/life science and sustainability
The goal of the development of life science technology including tissue engineering is to help patient live longer and contribute to the improvement of quality of their lives. Recently, concerns towards sustainability have been rapidly increasing as the poverty issue and global warming are becoming visible in public more and more. In today's environment, clarification of the role of each developmental technology, especially for life science technologies are required at global level. Therefore, by implementing the proposals mentioned above, how tissue engineering technology can contribute to the global sustainability is also a crucial point to be addressed.
This report explored cardiac tissue engineering, one of the emerging biomedical technologies, by utilizing holistic approach and systems analysis to discuss its advantages and disadvantages in terms of sustainability. Moreover, the relevant history, regulations and related actors in the cardiac tissue engineering innovation as well as obstacles in pursuing its innovation are also addressed. Finally, this report proposed several working guidelines which potentially offer extensive opportunities to comprehend more deeply about cardiac tissue engineering from scientific perspective as well as social, economic, and most importantly, sustainability perspectives.
With the proposals, 3 steps are suggested. Firstly, all of the possible scientific strategies of cardiac tissue engineering must be identified along with its advantages, disadvantages and implications in terms of commercial development and it must be discussed from social, economic, and environmental perspectives in order to evolve the context of sustainability. In this report, 6 main scientific strategies are identified - 1) classical strategies, 2) engineered heart tissue, 3) scaffold-less cell sheet/cell patch technology, 4) in vitro biological cell assembly, 5) in vivo biological cell assembly, and 6) decellularized heart matrix. Secondly, in order to investigate more closely and precisely on the process of successful cases and failures of commercial development in tissue engineering technologies, extensive historical analysis of the tissue engineering industry should be pursued. This is because commercialization of tissue engineering technology involves a variety of challenges such as cost reduction, manufacturing challenges, clinical application and regulatory requirements, ethical issues, and recognition of appropriate business models. Finally, it is worth investigating the role of tissue engineering technologies at global level in order to identify with how tissue engineering technology can contribute to the global sustainability.