cardiovascular tissue engineering...international symposium 6月12日（火） cardiovascular tissue...

International Symposium　6月12日（火）

Cardiovascular Tissue Engineering

Haverich AxelDivision of Thoracic and Cardiovascular Surgery, Surgical Center, Hannover Medical School

基調講演Tissue engineering concepts will enter the clinical arena in thoracic and cardiovascular surgery soon and at high speed, replacing many procedures currently in practice. Drivers for change are suboptimal implants (heart valves) and missing implants (heart muscle). Medical device industry has to include these new concepts into their future perspectives.

【略歴】1959-1963 Grammar school 1963-1972 "Gymnasium" 14.05.1972 "Abitur" baccalaureate 1972-1978 Medical study at Hannover Medical School 23.10.1978 Graduated from Hannover Medical School06.11.1979 Doctorate 1978-1985 Resident, Surgical Center, Hannover Medical School

Department of Cardiovascular Surgery, Stanford University, Stanford, California/U.S.A.01.07.1985 "Oberarzt" (senior resident), Division of Thoracic and Cardiovascular Surgery, Surgical Center, Hannover Medical

School (Director: Prof. Dr. Hans G. Borst) 24.06.1987 Assistant Professor 26.11.1992 Associate Professor 1993-1996 Head, Department of Cardiovascular Surgery at Christian Albrechts University, Kiel, Germany since 01.05.1996 Head, Department of Thoracic and Cardiovascular Surgery at Hannover Medical School, Hannover, Germany

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再生医療　日本再生医療学科雑誌　VOL.11 suppl 2012


Decellularized aortic heat valve: decellularization technology, in vivo feasibility, and in vitro assessment of blood compatibility

Kiyotaka Iwasaki1, Shigeyuki Ozaki2, Mitsuo Umezu11Center for Advanced Biomedical Sciences, Waseda University, 2Department of Cardiovascular Surgery, Toho University Ohashi Hospital

講演（1）

approaches to produce a potentially regenerative aortic heart valves. We have developed a unique technology to achieve complete decellularization of thick porcine aortic heart valves, while maintaining mechanical integrity. Aortic heart valves were decellularized by combination of pulsatile flow-and-pressure circulation of deoxycholic acid detergent with a concentration of 1wt% in parallel with irradiation of a microwave at the frequency of 24.5GHz. Animal experiments in aortic circulation demonstrated that the decellularized aortic valves functioned for one year. Scanning electron microscopic examination and eNOS staining revealed that aortic leaflets and vessel walls were repopulated with endothelial cells in six months. Moreover, calcification, which was distinctly observed in commercially available glutaraldehyde-treated bioprostheses, was inhibited in decellularized aortic valves. Currently, feasibility of aortic valve plasty using decellularized pericardium is under investigation in large animal experiments. Our in-vitro blood-compatibility tests using fresh blood of healthy volunteers demonstrated that decellularization and sterilization of bovine pericardium inhibited complement and neutrophil activation. Continuing researches are required to demonstrate effectiveness and safety of decellularized tissues in aortic circulation toward clinical settings.

【略歴】1997　早稲田大学理工学部機械工学科卒業2002　早稲田大学大学院理工学研究科機械工学専攻博士課程修了博士（工学）2001.4-04.3　早稲田大学理工学部機械工学科助手、大学院生命理工学専攻助手2003.4-04.8　芝浦工業大学工学部機械工学科非常勤講師2004.4-04.6　早稲田大学大学院理工学研究科COE 講師2004.4-　東京大学大学院医学系研究科客員研究員2004.7-　早稲田大学生命医療工学インスティテュート講師2006.4-07.2　早稲田大学生命医療工学インスティテュート助教授2004.10-07.2　米国Harvard Medical School, Brigham and Women's Hospital, Research Fellow2007.3　早稲田大学フューチャーインスティテュート（現高等研究所）客員助教授2007.4-　早稲田大学高等研究所客員准教授2007.9-　芝浦工業大学　工学部機械工学科　非常勤講師

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International Symposium6月12日（火）

Development of Cardiovascular Tissues by In Body Tissue Architecture Technology

Yasuhide NakayamaNational Cerebral and Cardiovascular Center Research Institute

講演（2）In-body tissue architecture technology, attempted as a novel and practical concept in regenerative medicine by us, can prepare completely autologous cardiovascular tissues including vascular grafts (BIOTUBEs), valved conduits with the sinus of Valsalva (BIOVALVEs), or endovascular devices (BIOVALVED STENTs for TAVI, BIOCOVERED STENTs for aneurysm embolization). They are constructed safely and economically in the recipient subcutaneous spaces using encapsulation mechanism by 1 or 2 months of embedding the preparation molds with a use of neither special clean facilities nor complicated cell procedures. Irrespective animal species, the obtained tissues had very thin wall thickness (ca. 0.1mm) but adequate mechanical property even under aortic circulation condition, and mainly consisted of autologous fibroblasts and collagen fibers with little inflammatory cells. After implantation the tissues exhibited excellent performances as cardiovascular prostheses, such as easy surgical handling, high patency for long term (over 4 years), rapid tissue regeneration (within several months). The technology will someday make it possible

autologous tissue engineering.

【略歴】1986 年大阪大学工学部卒業1991年大阪大学大学院工学研究科修了国立循環器病センター研究員を経て、1997 年より独立行政法人国立循環器病研究センター研究所医工学材料研究室室長（現職）。北海道大学総合化学院客員教授、大阪大学基礎工学研究科招聘教授、関西大学理工学研究科客員教授を兼任。日本再生医療学会、日本、欧州人工臓器学会、日本バイオマテリアル学会などで多数受賞。

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Tissue engineered valve first clinical results

Thomas BreymannDirector, Division of Pediatric Cardiac Surgery, Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Germany

講演（3）

Degeneration of xenografts or homografts is a cause for reoperation in young patients after pulmonary valve replacement. We developed fresh decellulatized pulmonary homografts (DPH) and compared the early results of 38 implantation of DPH with those of bovine jugular vein (BJV: n=38) and cryopreserved homografts (CH: n=38). DPH patients revealed no increase of transvalvular gradient, cusp thickening, or aneurysmatic dilatation in contrast to BJV and CH patients. DPH valve annulus diameter converge toward normal z-values. Five-year freedom from explantation was 100% for DPH, 86% for BJV, and 88% for CH. In DPH patients, the mean transvalvular gradient was significantly lower compared with the BJV group. In contrast to conventional homografts and xenografts, decellularized fresh allograft valves showed improved freedom from explantation, provided low gradients in follow-up, and exhibited adaptive growth.

【略歴】［Current position］Director, Division of Pediatric Cardiac Surgery,Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School (2003 -)［Education］1971 Bonn University Medical School, M.D.1972 Approvation1972 Neuss Hospital, Germany (Residency of Surgery)［Positions held］1978 Assistant Professor, Department of Surgery, Bonn University Medical School1980 Assistant Professor, Department of Cardiovascular Surgery, Freiburg University Medical School1984 Chief in Pediatric Cardiac Surgery, Department of Cardiovascular Surgery, Herzzentum Bad Oeynhausen2003 Director, Division of Pediatric Cardiac Surgery, Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School

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A Prospective, Controlled, Randomized, Double-Blinded Study of Autologous Bone-Marrow Cell Transplantation During Coronary SurgeryAri HarjulaThoracic and Cardiovascular Surgery, Department of Clinical Medicine, Helsinki University, Faculty of Medicine

特別講演

Aims: Clinical studies suggest that intra-myocardial injection of bone marrow cells in conjunction with coronary artery bypass surgery improves left ventricular parameters in ischemic heart disease. However, there is a lack of properly conducted clinical trial. Methods and Results: Forty patients with coronary disease and left ventricular ejection fraction (EF) ≤45% despite maximal medical treatment were randomized in a double-blinded manner to receive either bone-marrow cells (9.1x 108±3.8x108), or plain serum during coronary revascularization operation. Cardiac magnetic resonance imaging (MRI), positron emission imaging with fludeoxyglucose (PET) and single photon emission computed tomography (SPECT) was performed preoperatively to assess nonviable scar and 12 months after the operation the examinations were repeated. There was no mortality. One year control imaging was performed in 18 patients in each group. The EF improved from 39.6±9% to 43.6±9% in the treatment group and from 37.2±9% to 42.3±8% in the control group. There was no difference between the groups. Scar area assessed by MRI T2 late enhancement was measured 21.3±5% preoperatively and 19.8±6% at one year after the operation in the treatment group and 17.8±10% and 19.3±9% in the control group, respectively (p=ns). Percentual LV wall thickening at the site of the injections in the peri-infarct area was 33.5±27% preoperatively and 41.8±38% (p=ns) in the treatment group and 33.3±25% and 46.6±29% (p=ns) in the control group, respectively. There was no difference between the groups. Conclusion: Modern heart failure medication combined with coronary bypass operation improves left ventricular function significantly. Intramyocardial injection of bone marrow cells has no measurable effects in the heart.

【略歴】［Current position］Professor of Thoracic and Cardiovascular SurgeryDepartment of Clinical Medicine, Helsinki University, Faculty of MedicineResponsible professor in training of Cardiothoracic Surgery and Common Trunk in surgical specialities, Helsinki University, Faculty of MedicineSurgeon in Chief, Department of Cardiothoracic Surgery, Helsinki University Central HospitalDirector of Education, Department of Surgery, Helsinki University Central Hospital［Education］1976 Helsinki University, Faculty of Medicine, Licenciate of Medicine 1981 Helsinki University, Faculty of Medicine, Doctor of Medical Science (Ph.D.) 1981 Helsinki University, Faculty of Medicine, Specialist in surgery (Board examination) 1984 Helsinki University, Faculty of Medicine, Specialist in Thoracic and Cardiovascular Surgery (Board examination) ［Positions held］1989-1999 Chairman, Helsinki Heart Center (Cardiology and Cardiothoracic Surgery Deaconess Hospital in Helsinki)1989- Helsinki University, Faculty of Medicine, Associate Professor in Surgery, especially in Thoracic and Cardiovascular Surgery1986-1987 Stanford University Medical Center, Department of Cardiovascular Surgery, 36th Ewarts A. Graham Memorial Travelling Fellow, American Association for Thoracic Surgery (AATS)

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Satellite workshop6月14日（木）

Development of Human Embryonic Stem Cell Based Therapeutics for the Treatment of Degenerative DiseasesJane S LebkowskiActing Chief Scientific Officer: Regenerative Patch Technology

SW-1

Human Embryonic Stem Cells (hESCs) can proliferate indefinitely yet, upon appropriate cues, differentiate into all

somatic cell lineages. These two properties of hESCs enable the development of hESC-derived therapeutic cell

populations which can be batch manufactured in central manufacturing facilities, cryopreserved, and distributed

islet, osteoblast, chondrocyte, and hematopoietic cell populations which are functional in either in vitro or in vivo

animal models of human disease. For example, hESCs have been differentiated into oligodendrocyte progenitors that

upon transplantation into animals with spinal cord injuries, can remyelinate denuded axons, induce axonal sprouting,

and improve locomotor activity. Extensive preclinical studies have been completed to examine the activity,

biodistribution, dosing, delivery, and potential toxicity and tumorigenicity of the oligodendrocyte progenitors. The

safety of these cells is now being tested in the clinic in subjects with complete spinal cord injuries.

【略歴】［Current Position］Acting Chief Scientific Officer: Regenerative Patch Technology

［Education］

1977: BS Biology and Chemistry, Syracuse University 1982: Ph.D. Biochemistry, Princeton University 1985: Postdoctoral Fellowship Genetics, Stanford University

［Positions Held］

1986-1995: Vice President Research and Development, Applied Immune Sciences1995-1998: Vice President Discovery Research, Rhone Poulenc Rorer (currently Sanofi)1998-2012: Chief Scientific Officer and Sr Vice President Regenerative Medicine, Geron Corporation

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SW-2

This talk will describe current FDA perspectives on scientific issues relevant to the use of cell and tissue-based

therapies, cover development of current FDA approaches to regulatory oversight in this area, and illustrate the roles

and responsibilities of the various FDA staff members in review of applications and formulation of policy.

The use of cell-based medical products promises to have a profound impact on public health. This talk will describe

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The regulatory and scientific approach used in the Office of Cellular, Tissue, and Gene Therapies and developed in

many parts of the FDA is designed to allow progress in clinical research while assuring patient safety and protection

of patient rights.


Regulatory and Scientific Considerations for Cellular and Tissue-based Therapies

Steven BauerChief, Cellular and Tissue Therapy Branch Division of Cellular and Gene Therapies Office of Cellular, Tissue and Gene Therapies, CBER / FDA

【略歴】［Current Position］Chief, Cellular and Tissue Therapies Branch, Division of Cell and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration (2005 -)

［Education］

1977 University of Maryland, College Park, BS Zoology1986 University of Maryland, College Park, PhD Biochemistry


1986 Scientific Member, Basel Institute of Immunology, Basel Switzerland1991 Senior Staff Fellow, CBER/FDA1998 Principle Investigator, Division of Cellular and Gene Therapies, CBER/FDA 2002 Chief, Laboratory of Stem Cell Biology, Division of Cellular and Gene Therapies, CBER/FDA2005 - Chief, Cellular and Tissue Therapies Branch, Division of Cell and Gene Therapies, CBER/FDA

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Quality and nonclinical aspects of Cell-based Medicinal Products - from a European regulator s perspective

Matthias RennerPaul-Ehrlich-Institut

SW-3

Rapid scientific progress in the fields of genetics, cell biology and biotechnology resulted in the development of novel

innovative cell-based therapies. In the European Union they belong to the class of Advanced Therapy Medicinal

Products (ATMPs), which are subject to a centralized authorisation procedure. A consolidated regulatory framework

for ATMPs has recently been established (Regulation 1394/2007 and Commission Directive 2009/120) and specific

Guidelines addressing scientific and technical requirements for the development of such medicinal products exist.

The European and national regulatory framework for cell-based medicinal products will be presented and specific

aspects and challenges in the quality and non-clinical development and assessment of these therapies will be

discussed.

【略歴】［Current Position］Scientific assessor and researcher, Department of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, Germany (2009)Co-Chair, CAT Gene Therapy Working Party (GTWP), European Medicines Agency (EMA) (2010)Senior lecturer, University of Veterinary Medicine, Vienna, Austria (2007)

［Education］2008 Habilitation (Virology) University of Veterinary Medicine, Vienna, Austria 1991 to 1995 Ph.D. Max-Planck-Institute of Biochemistry, Department of Virus Research, Martinsried, Germanyy


1999 to 2008 Group leader, Institute of Virology, University of Veterinary Medicine Vienna,1997 to 2001 Group leader at Bavarian Nordic A/S, Vienna, Austria1995 to 1997 PostDoc, Max-Planck-Institute of Biochemistry, Department of Virus Research, Martinsried, Germany

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cardiovascular tissue engineering...international symposium 6月12日（火） cardiovascular tissue...

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