Future implications of regenerative medicine on assisted reproductive technology. Regenerative medicine. History of Regenerative medicine

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1 Gyndolomiti: 2nd Congress on Gynaecology and Obstetrics February 1 6, 2015 St. Kassian / South Tyrol Regenerative medicine Future implications of regenerative medicine on assisted reproductive technology Dolomite CaMg(CO 3 ) 2 Dr. Georg A. Feichtinger University of Leeds g.feichtinger@leeds.ac.uk Regenerative medicine 'replaces or regenerates human cells, tissues, or organs to restore or establish normal function' regenerative medicine is used to refer to methods to replace or regenerate human cells, tissues or organs in order to restore or establish normal function. This includes cell therapies, tissue engineering, gene therapy and biomedical engineering techniques, as well as more traditional treatments involving pharmaceuticals, biologics and devices. Also see: Mason & Dunhill. A brief definition of regenerative medicine Regen. Med. 3(1):1-5. Major problems with organ transplantation: Donor scarcity Expense Technical difficulty Labor-intensive and complex care Paul Russel, MD (Chief of Transplantations at Massachusetts General Hospital): New approaches to organ replacement If there was an effective way to transplant only those important functional cellular elements of an organ, there would be many conceptual advantages over organ transplantation. Russell, P.S., Selective transplantation. An emerging concept. Ann Surg, (3): p John F. Burke, MD (Chief of Trauma Services at Massachusetts General Hospital): Early excision and coverage of massive burn wounds crucial. Limited donor skin supply. Creation of neodermis graft Acellular Collagen and Glycosaminoglycans. Burke, J.F., et al., Successful use of a physiologically acceptableartificial skin in the treatment of extensive burn injury. Ann Surg, (4): p J.P. Vacanti R. S. Langer Department of Surgery, Harvard Medical School Department of Chemical Engineering, Massachusetts Institute of Technology. apply these principles of cell transplantation and artificialmatrix to three-dimensional systems. appropriate biodegradable scaffold to allow cells to remain viable and permit cellular proliferation and function. concept of the engineered creation of a new organ in situ...someday will provide replacement tissue as an alternative to organ transplantation as currently practised. Adapted from: Vacanti, J.P., Beyond transplantation. Third annual Samuel Jason Mixter lecture. Arch Surg, (5): p Regenerative medicine J.P. Vacanti C. Vacanti Y. Cao Laboratory for Tissue Engineering, Department of Anaesthesia, University of Massachusetts Medical Center EARMOUSE Cao, Y., et al., Transplantation of chondrocytes utilizing a polymer-cell construct to produce tissueengineered cartilage in the shape of a human ear. Plast Reconstr Surg, (2): p ; discussion

2 Regenerative medicine Example of own work in Gene Therapy BONE INDUCTION IN VIVO Growth-factor encoding pdna Regenerative medicine Example of own work in Gene Therapy BONE INDUCTION IN VIVO DE NOVO FORMATION OF HAEMATOPOIETIC STEM CELL NICHE Ultrasound trigger Microbble contrast agent Plasmid DNA Intramuscular injection, quadriceps muscle group SONOPORATION Target cell Feichtinger et al. European Cells and Materials Feb 19;27: Feichtinger et al. Human Gene Therapy Methods Feb;25(1):57-71 Feichtinger et al. European Cells and Materials Feb 19;27: Feichtinger et al. Human Gene Therapy Methods Feb;25(1):57-71 Tissue Engineering Ideal biomaterial properties replicate biologic mechanical function of native ECM provide structural 3D support for cells to adhere and form new tissue functional modification with adhesion molecules and growth factors biomechanical tailored material properties biodegradable and bioresorbable without inducing inflammation material degradation rate not impairing support function and replacement with native tissue high porosity and ratio of surface to area volume controlled properties A. Natural Materials & Hydrogels B. Synthetic polymers & Hydrogels Gelatine Agarose Collagen Silk PGA PLA Fibrin Chitosan PLGA Alginate Calcium Phosphates e.g. Coral derived Synthetic (self-assembly) peptides 2

3 Tissue Engineering Approaches Donor tissue decellularisation & re-seeding Allogenic donor tissue decellularisation: physical chemical enzymatic Precursor cell/tissue isolation: Adult (mesenchymal) stem cells Amniotic fluid stem cells Primary cells (-> reprogramming ips) Tissue-specific precursor cells TE CONSTRUCT In vitro culture/expansion in 2D (static) Cell seeding onto scaffolds: 3D culture static Bioreactors (dynamic) Mechanical loading Fluid shear stress S. Badylak McGowan institute for regenerative medicinee Univeristy of Pittsburgh Engineered autologous organ replacement Reseeding with donor cells Non-immunogenic, acellular ECM scaffold with original tissue architecture Badylak SF, Taylor D, Uygun K. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu Rev Biomed Eng Aug 15;13: doi: /annurev-bioeng Cell sheet engineering Regenerative medicine global market sectors T. Okano Tokyos Womens Medical Universtiy Institute of Biomedical Engineering Multi-layered cell sheet construct for implantation Source: Report #S520, Tissue Engineering, Cell Therapy and Transplantation: Products, Technologies & Market Opportunities, Worldwide, Regenerative medicine and fertility treatment Urogenital Tissue Engineering Pioneering work in urogenital TE Development of hollow-organ replacement constructs: A. Atala Wake Forest Institute for Regenerative Medicine primary endothelial and smooth muscle cells expanded in vitro & seeding on to synthetic scaffolds In vivo implantation urethral, penile and vaginal TE Necessity of 2 cell populations (SMC, endothelial) for functional hollow organ regeneration without constriction in vivo. Alexandru Dan Corlan. Medline trend: automated yearly statistics of PubMed results for any query, Web resource at URL: Accessed: (Archived by WebCite at Kwon, T.G., J.J. Yoo, and A. Atala, Autologous penile corpora cavernosa replacement using tissue engineering techniques. J Urol, (4 Pt 2): p De Filippo, R.E., J.J. Yoo, and A. Atala, Engineering of vaginal tissue in vivo. Tissue Eng, (2): p Park, H.J., et al., Reconstitution of human corporal smooth muscle and endothelial cells in vivo. J Urol, (3 Pt 2): p

4 1. Vaginal Tissue Engineering 2. Penile Tissue Engineering A. Atala Wake Forest Institute for Regenerative Medicine Mayer-Rokitansky-Kuster-Hauser syndrome Vaginal Aplasia 6 publications The extraordinary procedures, carried out between 2005 and 2008, have proved a long-term, functional success with all four patients. 2. Penile Tissue Engineering 6 publications

5 5. Uterine Tissue Engineering 5. Uterine Tissue Engineering 9 publications publications Testicular Tissue Engineering 6. Testicular Tissue Engineering 5 publications publications Summary Regenerative medicine aims to restore the function of damaged organs or tissues Final goal is a true functional replacement Tissue engineering is an interdisciplinary science (biomaterial science, cell biology, molecular biology, biomechanics, chemistry ) Regenerative medicine and TE is increasingly applied for reproductive biology and represents and exciting field of new research Reproductive TE offers solutions for fertility treatments aimed at: -restoration of reproductive organ function improvement of in vitro organ culture systems for gametogenesis/preservation development of novel biological devices for HRT Future developments in complex tissue/tissue interface development, rapidprototyping and multi-cell (organ) culture will certainly lead to game-changing developments in the field of reproductive medicine and assisted reproduction if issues with precursor cell heterogeneity and complex tissue architectures can be resolved. 1 slide for TERMIS Boston 5