© Springer Japan 2015
Juichi Ito (ed.)Regenerative Medicine in Otolaryngology10.1007/978-4-431-54856-0_1616. Future Prospective
(1)
Department of Otolaryngology – Head and Neck Surgery, Graduate School of Medicine, Kyoto University, 54 Kawara-chyo, Shyogoin, Sakyo-ku, Kyoto 606-8507, Japan
(2)
Department of Otolaryngology – Head and Neck Surgery, The Tazuke Kofukai Medical Research Institute, Kitaku, Osaka, Japan
Abstract
All human beings have the dream to one day completely regenerate damaged tissues and organs. The past three decades have seen the emergence and development of advanced tissue engineering and regenerative medicine and the great potential now exists to make this dream a reality. However, forecasting the future direction of tissue engineering and regenerative medicine is no simple matter. Within a span of less than 10 years, induced pluripotent stem cells (iPSCs) were established and the three-dimensional bioprinter (3D bioprinter) were developed. These innovations that seemed beyond the scope of our imagination have the potential to make remarkable progress and dramatic shifts in the medical field.
For simple tissues, such as skin and blood vessels, these innovations have achieved some marked success. However, there are major issues that limit the application of these strategies to complex tissues and organs. It is unreasonable to expect that simple implantation of organs created ex vivo into the living body will result in successful regeneration. Blood supply is an absolute requirement for engraftment into the host and innervation is also necessary for functional regeneration. The key to complete successful regeneration lies in the appropriate combination of cells, scaffolds, and regulatory factors, and critical to this is the creation of a favorable regenerative environment.
The otolaryngology, head and neck field, encompasses regions that consist of various organs and tissues that are critical for maintaining important functions such as mastication, articulation, phonation, respiration, and swallowing. These body systems also have several important neurosensory functions including hearing, balance, smell, and taste. Once these functions have deteriorated, quality of life (QOL) is greatly compromised. This field represents one of the best opportunities where tissue engineering and regenerative medicine is expected to work as an innovative strategy. However, it is important to translate successful results from the laboratory into clinical application. The development of iPSCs was one breakthrough that changed the general principle of regenerative medicine and has a great potential to advance this field. When considering the future directions, we must evaluate the current state of technology and potential trajectory in terms of clinical application and advancement of new concepts and strategies.
Keywords
RegenerationHead and neckFuture prospectiveClinical application16.1 Clinical Application
Applying tissue engineering to human subjects is no simple matter, but the translation of these technologies from laboratory achievement into innovative treatments for human patients is vitally important.
16.1.1 iPSCs
The invention of iPSCs by Yamanaka and Takahashi et al. in 2006 was a breakthrough in the area of regenerative medicine, and completely changed the notion that differentiated somatic cells cannot be reprogrammed. With this technique, new strategies for regenerative medicine have been made possible, including disease-specific modeling, drug screening, and drug development.
While a regenerative approach using iPSCs may seem most promising, serious considerations must be taken with iPSCs given their considerable potential to create tumors. However, some attempts have been made to apply iPSC technology to tissue regeneration. Takahashi et al. successfully created retinal pigment epithelial cells from autologous iPSCs [1]. This was the first attempted clinical application of iPSCs, targeting age-related macular degeneration. A phase I clinical trial is still ongoing in human patients.
In regard to the head and neck region, Imaizumi et al. [2] have conducted animal studies for regeneration of the trachea. They implanted iPSCs along with a scaffold to tracheal defects in rats and were able to confirm regeneration of the trachea in two of five rats. However, there was significant formation of teratomas observed. They also successfully induced epithelial cells of the vocal fold mucosa in vitro from iPSCs [3]. However, the potential for clinical application is still uncertain until the issue of tumorigenesis can be resolved.
A more promising usage of iPSCs could be in drug development and the use of disease-specific iPS cell lines. The use of human iPSCs allows quick, accurate, and efficient evaluation of new drugs in terms of their therapeutic effects and adverse effects. Yahata has established an Alzheimer’s disease model from iPSCs which express amyloid-beta, the causative agent of the disease, and the development of a new drug screening platform using this system is anticipated [4]. The development of disease-specific iPS cell lines is warranted for the field of otolaryngology, e.g., for the treatment of inner ear diseases and fibrotic diseases such as vocal fold sulcus, among others.
16.1.2 Autologous Stem Cells
Autologous stem cells pose no risk of immune rejection, which makes them most suitable for clinical application. Indeed, several human clinical trials have already been conducted or are currently under way using autologous stem cells. Bone marrow–derived mesenchymal stem cells (BM-MSCs) and adipose-derived mesenchymal stem cells (ASCs) have been shown the most interest because they are easy to harvest and proliferate in a culture dish. These stem cells are indeed promising, and numerous studies have been undertaken to confirm their ability to regenerate several organs. Human clinical trials using BM-MSCs have also been performed for patients with conditions such as maxillofacial defects, arthritic lesions, femoral osteonecrosis, and others. There are also many ongoing clinical trials using these stem cells.
BM-MSCs and ASCs have been used for vocal fold regeneration in animal studies and have proven useful for regenerating scarred vocal folds by local transplantation [5–9]. Both types of stem cells have similar biological activity, but some investigators prefer ASCs because they are easier to harvest and have a greater ability to secrete growth factors such as hepatocyte growth factor (HGF). ASCs can be harvested at a ratio of a single cell per 100 cells, while BM-MSCs can only be collected as a single cell per 105 cells. We have conducted a comparative study in which scarred rat vocal folds were treated with a local injection of either BM-MSCs or ASCs. The results showed similar effects on recovery of hyaluronic acid in the vocal fold lamina propria, but ASCs showed greater ability to produce hyaluronic acid synthase and HGF [10].
While the technology seems poised to use BM-MSCs or ASCs in human subjects, there are strict regulations and guidelines which govern the usage of MSCs. These GMP-compatible cells must be prepared at a certified cell processing center (CPC). In order to guarantee the high quality of cells, complete sets of cell surface markers for each cell source are needed. Additionally, full data packages must also be prepared, which certify the effects and safety aspects of the cells. Working within these restrictions, there is a human clinical trial currently being conducted at Karolinska University in Sweden focused on the head and neck region using BM-MSCs for the treatment of vocal fold scarring.
16.2 Exploratory Clinical Trials for Growth Factors
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