Tissue Engineering

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     1  Tissue Engineering Goal and history Natural examples of tissue engineering Examples of tissue engineering Survey of applications Case study of small-diameter vascular grafts
     2  Some Goals of Tissue Engineering Langer and J. Vacanti “Tissue Engineering”. Science 260: 920-6, 1993. donors << potential recipients
     3  A Definition Tissue engineering is an interdisciplinary field that applies the principles of engineering and the life sciences towards the development of biological substitutes that restore, maintain, or improve tissue function. Langer and J. Vacanti “Tissue Engineering”. Science 260: 920-6, 1993. But…
     4  My definition Making or modifying a tissue for some useful purpose. But…
     5  How to make or modify tissues In vitro tissue engineering In vivo tissue engineering Bone defects Ex vivo tissue engineering Extracorporeal liver support Langer and J. Vacanti “Tissue Engineering”. Science 260: 920-6, 1993.
     6  History of tissue engineering For modern history (~1985-2003) NSF report: The Emergence of Tissue Engineering as a Research Field. http://www.nsf.gov/pubs/2004/nsf0450/start.htm My summary of the recent history of TE… 1980 1990 2000 2010
     7  Early tissue engineering
     8  Replicating Complex Biological Environments Cell culture Tissue culture Organ culture Organism culture Ecosystem culture
     9  Organ Culture: A Sister of Tissue Engineering In practice - shared techniques. From a historic perspective - shared goals.
     10  Alexis Carrel Pioneering work on cell culture 1912 Nobel Prize for Medicine Technique for vascular anastomosis Enabled vascular grafting and organ transplantation Early work on organ storage (e.g., cold storage) Organ culture
     11  Carrel’s Goals for Organ Culture A tool for scientific inquiry- “phenomenon of regeneration, growth, nutrition, and internal secretions could be rendered more comprehensible by studies with prolonged organ perfusion.” Autografts for clinical use – “if it were possible to culture whole organs, a diseased organ or part thereof could be removed, treated outside the body, and grafted back into the patient.” Malinin TI and Lindergh CA “Organ culture and perfusion by the Carrel method.” In Alexis Carrel: Papers of the Centennial Conference at Georgetown University.
     12  Carrel’s Goals for Organ Cultureare also the goals of TE A tool for scientific inquiry- “phenomenon of regeneration, growth, nutrition, and internal secretions could be rendered more comprehensible by studies with prolonged organ perfusion.” Auto- or allografts for clinical use – “if it were possible to culture whole organs, a diseased organ or part thereof could be removed, treated outside the body, and grafted back into the patient.” Malinin TI and Lindergh CA “Organ culture and perfusion by the Carrel method.” In Alexis Carrel: Papers of the Centennial Conference at Georgetown University.
     13  Carrel noted that “the culture of organs is, from a technical point of view, very difficult” Contamination
     14  Carrel noted that “the culture of organs is, from a technical point of view, very difficult” Contamination! But why?
     15  Carrel noted that “the culture of organs is, from a technical point of view, very difficult” Contamination! But why? Cell culture – small distances – diffusion OK Organ culture – large distances – diffusion inadequate Need a sterile perfusion system.
     16  Interdisciplinary BE Research Charles Lindbergh Engineer 1927 1930 1935
     17  Lindbergh Apparatus All glass Semi-closed system Pulsatile flow of liquid is generated by cyclic changes in gas pressures in several chambers.
     18  Carrel-Lindbergh Organ Culture 1935-9 used to conduct 898 organ perfusion Thyroid 3 Weeks Maintained normal histology Secreted hormone
     19  Carrel-Lindbergh Organ Culture Heart Heart removed from refrigerated primate carcasses ~90% cadaver hearts responded to perfusion by contractions ~ 1hr culture – strong A/V contractions > 1hr frequency and amplitude of contractions decreased Perfusion at decreased T ? longer survival ex vivo. 37C ? ~1 day 22C ? ~2 day 12C ? 10 days!
     20  Past as Prologue Prediction: Organ culture and tissue engineering will remain entwined.
     21  Organ Culture ?Tissue Eng. Positive control Source of info – technical and scientific Alternative route
     22  Organ Culture ?Tissue Eng. Organ culture – a positive control for in vitro TE conditions. Time Quality Native tissue ?
     23  Organ Culture ?Tissue Eng. Organ culture – a positive control for in vitro TE conditions. Time Quality Native tissue ?
     24  Organ Culture ?Tissue Eng. Organ culture – a positive control for in vitro TE conditions. Time Quality Native tissue ?
     25  Organ Culture ?Tissue Eng. Organ culture – a source of ideas Time Quality Native tissue ?
     26  Organ Culture ?Tissue Eng. Organ culture – a source of ideas Time Quality Native tissue ?
     27  IGF in TE cartilage
     28  Tissue Engineering Goal: Tissue replacement/repair & Science Approaches (in vitro, in vivo, and ex vivo) History Next… Natural examples of tissue engineering
     29  Natural examples of TE
     30  Normal development
     31  Alternative development Transgenic animals gene
     32  Alternative development Cloning Tells about the potential of DNA
     33  Alternative development Tells about the potential of early embryo cells
     34  Embryonic stem cells are totipotent Have potential to differentiate to any cell type Great proliferation potential Can develop teratomas when implanted in vivo
     35  Later in development, most/all cells loose this potential Cell culture Cell transplant studies Implications for tissue engineering Origin of cells Precursor / stem cells Simple division Permanent cells
     36  Differentiation and determination Differentiation –when a cells expresses outward markers of a given cell type. (e.g., mature beta cell – insulin) Determination - when a cell has committed to a particular differentiation fate.
     37  Test for determination Figure 21-7. The standard test for cell determination. MBC
     38  Determination and positional value http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/mboc4/ch21f8.gif
     39  Normal development Increase in organism size
     40  The four essential processes by which a multicellular organism is made: http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/mboc4/ch21f1.gif
     41  The four essential processes by which a multicellular organism is made: http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/mboc4/ch21f1.gif
     42  Specialization http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/mboc4/ch21f1.gif http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/mboc4/ch7f72.jpg Environment “Genetic”
     43  Cell interaction Induction - when one cell/tissue alters the developmental fate of an adjacent cell or tissue
     44  Cell interactions
     45  Natural examples of TE
     46  Regeneration: Liver as a model
     47  Homeostasis: Regulates blood sugar, lipids and cholesterol, amino acids. Detoxify: remove hormones, hemaglobin, and toxins from the blood. Forms of red blood cells in the young embryo. Makes plasma proteins including albumin and clotting factors. Stores and makes vitamins
     48  Structure of liver Homeostasis: Regulates blood sugar, lipids and cholesterol, amino acids. Detoxify: remove hormones, hemaglobin, and toxins from the blood. Forms of red blood cells in the young embryo. 9. Making heparin: this is a substance that prevents the blood from clotting as it travels through the blood system. Makes plasma proteins including albumin and clotting factors. Stores and makes
     49  The livers regeneration potential Resection studies Transplant studies Dogs Humans Gene defect and rescue studies Mechanism – local factor or systemic factor?
     50  Symbiotic circulation
     51  Hepatocyte growth factor Stimulates hepatocyte proliferation in culture Increased following partial resection of liver A simplified conceptual model Body tissue makes HGF and delivers to circulation Liver tissue removes HGF from circulation Liver grows if [HGF] > some value Simple test of conceptual model?
     52  Does HGF stimulate liver growth in vivo? HGF ? HGF + Collagenase ?
     53  Implications of liver regeneration for Tissue engineering Why even need TE? Massive acute problems Chronic insults
     54  Implications of liver regeneration for Tissue engineering Type of system needed? Massive acute problems Chronic insults
     55  Extracorporeal device  Algenix Inc.'s LIVERX2000 System http://biomed.brown.edu/Courses/BI108/BI108_2002_Groups/liver/webpage/liverxpg.htm
     56  Natural examples of TE Soluble factor (HGF) ECM Negative factors for regen Potential of DNA Differentiation and determination / Plasticity of cells. Role of TF (myoD) Role of cell shape Role of cell-cell interactions
     57  Wound healing: skin as a model system For a good review of this topics, see Wound Healing--Aiming for Perfect Skin Regeneration by Paul Martin http://www.sciencemag.org/cgi/content/full/276/5309/75 Scar Not healing
     58  Structure of skin
     59  Stages of wound healing Fibrin Clot Recruitment of Inflammatory cells Reepithelialization
     60  Fibrin Clot Stops bleeding Formation of provisional matrix Source of mitogens and chemotaxic factors PDGF
     61  Recruitment of Inflammatory cells Recruited by factors derived from clot and infections. Recruitment mediated by endothelial cells. Neutrophils Monocytes Secrete factors that stimulate next step.
     62  Reepithelialization Epithelial cells migrate (crawl) into wound Alter integrin expression Secrete proteases t-PA MMPs As horizontal surface area covered, a striated epithelium is formed.
     63  Better healing Embryonic wounds heal without scar. Why? (environment, tissue, ?) Different mechanism?
     64  Embryonic vs. Adult Different mechanism?
     65  Molecular mediators of wound healing Transforming growth factor beta Stimulates fibroblasts in the wound to become myofibroblasts.
     66  Examples of TE skin (science)
     67  Tissue engineered skin (clinic)
     68  Tissue-engineered skin (clinic)
     69  Blood vessel