2. Tissue Engineering Hottest job for 21 st Century Five hottest jobs for the next millennium will be bioengineering/biomedical related.

3. Bones that lose minerals after age 30 Fallible spinal disks Muscles that lose mass and tone Leg veins prone to varicosity Joints that wear Shorter limbs and stature Forward-tilting upper torso Curved neck with enlarged vertebrae Thicker disks Extra muscles and fat Leg veins with more check valves Larger hamstrings and tendons Knee able to bend backward Thicker bones Larger ears If Humans Were Built to Last Adapted from Olshansky, Carnes, Butler, Sci Am 2001 Mar Current Design Alternative Design Phil Campbell, Carnegie Mellon

4. Replacing diseased or injured tissues with tissue constructs designed and fabricated for the specific needs of each individual patient. What are Biomaterials? A material intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function in the body. What is Tissue Engineering/ Regenerative Medicine?

5. Forecasts of the American Population Aged 85 Years and Over Oxford Textbook of Geriatric Medicine 2000

6. USA $3898 United Kingdom $1317 Turkey $232 (1996 US dollars per capita) 1987-1995 Hip replacements among women rose from 143/100,000 to 1444/100,000 US Medicare expenditures for last year of life is double for aged 65 to 69 years compared to 90+ years. (excluding nursing home costs) Medical costs Oxford Textbook of Geriatric Medicine 2000

7. FDA approved products Infuse Bone Graft Bone morphogenetic protein-7, Osteogenic peptide-1 Regranex Carticel Transcyte Intergra Dermal Regeneration Template Dermagraft Apligraft Ortec

8. Apligraft

9. Adult Stem Cells Example Bone marrow-derived mesenchymal stem cells

10. Adult Stem Cells Example Bone marrow-derived mesenchymal stem cells

11.  Inadequate understanding of the basic biology of regenerative processes  Lack of adequate biomimetic materials to act as scaffolds for either induction of regeneration in vivo, or to build bioartificial tissues in vitro  Inadequate cell sources for transplantation or building bioartificial tissues  Problem of immunosuppressive regimens introduced by allogeneic and xenogeneic cells.  Bioethical issues associated with the use of fetal and embryonic stem cells as sources Tissue Engineering Roadblocks

12. Cells Principles of Tissue Engineering ECM Hormones Blood Supply DefectRegeneration Phil Campbell, Carnegie Mellon

13. -Hormonal-based tissue engineering has been around for thousands of years Castration as a means to control behavior and tissue quality in domesticated animals -Systemically targeted (purified) protein hormone therapies – mid 1900s. -Systemically targeted (recombinant) protein hormone therapies (insulin) – 1980s -Locally targeted (recombinant) protein hormone therapies (PDGF-BB, BMP-2, BMP-7) – late 1990s to present Endocrinology Applied to Tissue Engineering: A Quick History Phil Campbell, Carnegie Mellon

14. Spinal Cord Upper and Lower Jaw Upper and Lower Jaw Limb Retina and Lens An Ultimate Vision for Regenerative Medicine: Complete Tissue Regeneration Adapted from Brockes Tail Heart The Newt From Dr. Susan Bryant, Univ. of Calif., Irvine Phil Campbell, Carnegie Mellon

15. What controls biological pattern formation associated with morphogenesis- Cells to Tissues to Organism? How can patterns emerge from an initial structureless system? How do developing parts of an organism become different? How can different genetic information be activated at different spatial positions? This requires cell-to-cell communication and feedback. Cell-cell communication via secreted molecules: hormones “Morphogen” gradients provide directional cues for cell recruitment and the interaction of those gradients provide the cues for organization. Phil Campbell, Carnegie Mellon

16. 3D Inkjet Printing Tr: Thrombin Fg: Fibrinogen GF: Growth factor Co-jetting and local mixing of bio-inks Lee Weiss, Carnegie Mellon

17. Fibrin/Growth Factor Printer Lee Weiss, Carnegie Mellon

18. Example of a Biologically-Inspired, Engineered Design With Solid-Phase Spatial Patterning Why fibrin: Provisional extracellular matrix in wound healing Binds numerous growth factors of interest, i.e., the-solid-phase Supports cell attachment and migration Degrades in register with new tissue formation FDA approved (Coronal view) Fibrin scaffold Critical size defect Gradient of VEGF or FGF-2 bone brain dura Direction of cell migration (up from the dura) Calvarium Lee Weiss, Carnegie Mellon

19. In Situ Printing Lee Weiss, Carnegie Mellon

20. Conclusions Our approach is to develop toolsets to understand the biology…. control the biology…. translate that control into cost effective, clinically relevant therapies. As important as developing the bioprinter is developing the bioimaging and biological response toolsets. The most critical roadblock to overcome remains our inadequate understanding of the basic biology…what do we print? Phil Campbell, Carnegie Mellon

21. No One Discipline Can Tackle the Problem Alone Lee Weiss, Carnegie Mellon

22. Harvested tissues from cloned transgenic animals Human cloning Gene therapy Fetal stem cells Our approach is to understand how the body naturally heals itself and then provide the minimal set of cues needed to restore the body’s healing capacity. …… but all have significant technical, ethical, political, and religious issues Alternatives to Traditional Grafts/Implants Lee Weiss, Carnegie Mellon

23. Cells Growth factors Biomimetic extracellular matrix Culture Implant If needed, harvest cells from patient. Guided Tissue Repair Lee Weiss, Carnegie Mellon

24. Cells Growth factors Biomimetic extracellular matrix Culture Implant If needed, harvest cells from patient. Guided Tissue Repair Lee Weiss, Carnegie Mellon

25. Cells Growth factors Biomimetic extracellular matrix Culture Implant If needed, harvest cells from patient. Guided Tissue Repair Lee Weiss, Carnegie Mellon

26. In addition to custom geometry, key factors are: Development (adolescent, adult, geriatric) Wound site Alcohol Smoker Diabetic Libraries of surrogate models. There are no ‘one-design fits all’ silver bullets… Bone regeneration Design Parameter 11 22 Lee Weiss, Carnegie Mellon