1. Tissue Engineering: a new healthcare technology Asma Yahyouche Biomaterials Group Department of Materials, University of Oxford Parks Road, Oxford, OX1 3PH, UK

2. Biomaterials Biomaterials science may be the most multidisciplinary of all the sciences which encompasses aspects of medicine, biology, chemistry, engineering and materials science. Biomaterials are : “Non-viable materials used in a medical devices intended to interact with biological systems” [D.F. Williams, 1987]

3. Biomaterials: Examples Joint replacements Bone plates Bone cement Hip Joint Artificial ligaments and tendons Dental implants for tooth fixation Blood vessel prostheses Heart valves Skin repair devices Cochlear replacements Contact lenses Hip joint Heart valve Knee jointSkin

4. Biomaterials at Oxford Nano-SIMS characterization of Teeth Drug Delivery Systems Biomaterials Group Materials Dept. In vitro Testing Cell culture Tissue expander Tissue Engineering

5. Disease (e.g cancer, infection). Trauma (e.g accidental, surgery). Congenital abnormalities (e.g birth defects). Current clinical treatment based on: Human Tissue Damage Grafts and Transplants Artificial Biomaterials

6. Organ transplant High cost : $400B in USA each year US: 1July 2001- 30 June 2002 [Cooper.T (1987): Human Organ Transplantation: Societal, medical-legal, regulatory, and Reimbursement Issues ed. Cowen D.H et al, Health Administration Press Ann Arbor, MI, pp. 19-26] Organ transplant No. patients on waiting list No. patients received treatment No. Patients died waiting Cost per operation in 1987 Lung 3 7571 071463- Heart 4 0972 155589$ 110 000 Kidney 50 24014 3853 052$ 30 000 Liver 17 3795 2611 861$ 238 000 Pancreas 1 15154128$ 40 000

7. Example: Bone Fractures in UK Bone is second transplanted tissue after blood. Healthcare in the United Kingdom alone set to cost over 900£ million each year. Each year in the UK: 150,000 fractures due to osteoporosis Hip fracture is associated with high morbidity and mortality. 30-50% of these hip operations with require subsequent revision surgery.

8. 50,000 hip replacements (arthroplasties) in Britain each year. Hydroxyapatite porous coatings in orthopaedic prostheses: Bioactivity, Osteoconductivity. Problem: Infections in orthopedic surgery (10% of cases) Total Hip Joint Replacement

9. Biomaterials Prostheses have significantly improved the quality of life for many ( Joint replacement, Cartilage meniscal repair, Large diameter blood vessels, dental) However, incompatibility due to elastic mismatch leads to biomaterials failure.

10. Conclusion Tissue loss as a result of injury or disease, in an increasing ageing population, provide reduced quality of life for many at significant socioeconomic cost. Thus a shift is needed from tissue replacement to tissue regeneration by stimulation the body’s natural regenerative mechanisms.

11. National Science Foundation first defined tissue engineering in 1987 as “ 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” Tissue Engineering

12. Tissue engineering Potential advantages: –unlimited supply –no rejection issues –cost-effective

13. Bioreactor system Scaffold Biopsy mechanical stimuli electrical stimuli chemical stimuli Human Cell Suspension Nutrients, Growth Factors Implantation operation H

14. Scaffolds A 3D substrate that is key component of tissue engineering It needs to fulfil a number of requirement: - Controllably Porous structure - Interconnecting porosity - Appropriate surface chemistry - Appropriate mechanical properties - Biodegradable material - Tailorable

15. Scaffolds Materials Synthetic polymers: Aliphatic polyesters such as polyglycolic acid (PGA), polylactic acid ( PLLA), copolymers ( PLGA) and polycaprolactone ( PCL) are commonly used in tissue engineering. Natural polymers: Most popular natural polymer used in tissue engineering is collagen.

16. Synthetic polymers More controllable from a compositional and materials processing viewpoint. Scaffold architecture are widely recognized as important parameters when designing a scaffold They may not be recognized by cells due to the absence of biological signals.

17. Natural polymers Natural materials are readily recognized by cells. Interactions between cells and biological ECM are catalysts to many critical functions in tissues These materials have poor mechanical properties.

18. Cells Chen and Mooney Pharmaceutical Research, Vol. 20, No. 8, August 2003.

19. Cells

20. Growth factors [3H] thymidine uptake of chondrocytes encapsulated in collagen/chitosan/GAG scaffolds with and without TGF-β1 microspheres (S, S-TGF). Cumulative TGF-β1 release from chitosan microspheres. J.E. Lee et al. / Biomaterials 25 (2004) 4163–4173

21. Oxford Biomaterials group Collagen Rapid prototyping: 3D wax printer

22. Why collagen? It is the ideal scaffold material:  is an important ECM molecule and is the major structural component in the body.  posses ideal surface for cell attachment in the body.  biocompatible and degrades into harmless products that are metabolized or excreted.  a very poor antigen, non-toxic.

23. Collagen processing This technique allow the control over pore size and porosity. Achieved through variation of freezing temperature and collagen dispersion concentration Dry collagen scaffold

24. Indirect Solid Freeform fabrication (ISFF) Computer Aided Design

25. AutoCAD design Scaffold Jet Head Mill Elevator 2 1 Dissolve away biosupport Collagen/HA casting Negative mould Freezing at -30°C Removal of BioBuildCritical Point Drying Negative mould fabrication process Collagen scaffold fabrication

26. 3-D printing From Dr. Chaozong Liu Printing video

27. Tissue engineering scaffold: controlled architecture Featured with: Pre-defined channels; with highly porous structured matrix; With suitable chemistry for tissue growth – Collagen or HA No toxic solvent involved, it offers a strong potential to integrate cells/growth factors with the scaffold fabrication process. From Dr. Terry Socholas

28. Advantages of ISFF Control of the external structure: Technology: CT/MRI CAD

29. Heart valve tissue engineering Valve cells Collagen scaffold of heart valve Heart valve post- implantation

30. Scaffolds with microchannels Design

31. SEM images of scaffolds with channels and open porosity. Aclian Blue staining revealed that extensive chondrogenesis were produced along the channels. Sirius Red staining revealed collagens production ( osteogenesis) in the periphery. hMSCs seeded channelled collagen scaffold stained with Sirius Red and Alcian Blue

32. Take home message Biomaterials are materials interact with biological tissue It’s a multi-disciplinary subject Important application include –efficient drug delivery in the body –Development of artificial tissue replacement similar to the original for clinical use –By tracking elemental fluctuation archaeology information can be revealed