2. Outline  Discovery of blood  Important tasks of blood  Why blood substitutes?  Some current developments and products  Risks and Benefits

3. Discovery of Blood GroupsDiscovery of Blood Groups  (1868-1943 ) Karl Landsteiner  (1901) Blood of two people under contact agglutinates  Due to blood serum (blood plasma)  Identified blood groups A, B, C (later named O)  (1907) First successful blood transfusion (Reuben Ottenberg, Mount Sinai Hospital, New York) [1]

4. Principle Tasks of BloodPrinciple Tasks of Blood  Transport Oxygen throughout body  Release oxygen to tissues – pick up carbon  Hemoglobin - Oxygen-carrying protein containing erythrocytes (Red Blood Cells)  White Blood Cells  Immune Response  Platelets  Blood Clotting, wound healing

5. Reasons For Blood Substitutes  Human RBC have strict storage requirements  Designed to prolong clinical effectiveness, reduce risk bacterial infection  Blood Substitutes more amenable to sterilization  Do not require cross-matching  Donor Blood Shortages  Short-term replacement of blood during surgery

6. The Ideal Blood SubstituteThe Ideal Blood Substitute  Require no cross-matching, compatibility testing  Suitable for long-term storage (room temperature)  Survive circulation for several weeks (intravascular “dwell” time) before being cleared by kidney  Side-effect free  Free of pathogens  Effectively deliver oxygen to tissues

7. Current DevelopmentsCurrent Developments  Derived from Hemoglobin: Hemoglobin-based Oxygen Carriers (HBOCs)  Those that use perfluorocarbon emulsions

8. Hemoglobin-Based Oxygen Carriers  Cell-free solution of hemoglobin as a blood substitute  Hemoglobin maintains ability to transport oxygen outside of red blood cells  Compatibility testing not required  Can be sterilized by ultrafiltration and low heat

9. Hemoglobin ProductsHemoglobin Products  Polyheme-polymerized human hemoglobin product  Northfield Laboratories  Hemopure-polymerized hemoglobin from bovine red blood cells  Biopure/Biotech  Approved in South Africa  Phase III clinical trials in U.S.  Hemolink-partially polymerized human hemoglobin  Hemsosol  Under FDA Review

10. Polyheme  Uses expired human blood  Hemoglobin solution, no intact red blood cells  Manufacturing steps reduce risk of viral infection  Shelf life of 12 months  Can be stored at room temperature  Only provides oxygen carrying capacity  Intravascular dwell time shorter than 120 days (RBC)

11. Clinical TrialsClinical Trials  Finished Phase III trauma trial in June 2006  December 19, 2006 preliminary results released  13.2% died vs. 9.6% control group  Re-evaluation of study database-no new trials  Result: No FDA approval thus far

12. Hemopure  Developed by OPK Biotech  Based on chemically stabilized bovine (cattle) hemoglobin  Use in humans as oxygen delivering bridge when blood is not available  Stable for 36 months at room temperature  Compatible with all blood types

13. Hemopure  Carried in the plasma  Transports oxygen wherever plasma flows (partial blockages or constricted vessels)  Holds same amount of oxygen as hemoglobin  Release oxygen more readily  Introducing Hemopure into bloodstream may help RBSc offload more oxygen to tissues than would otherwise.

14. Clinical TrialsClinical Trials  Last human test (date unknown) FDA imposed ban on further clinical trials due to safety concerns  Animal testing has been ensued  Hemopure approved for human use and commercial sale in South Africa in April 2001  Result: No FDA approval thus far

15. Hemolink  Developed by Hemosol  Highly purified human hemoglobin-based oxygen carrier  Approved for clinical trials in primary cardiac bypass surgery (early 2000s)  Currently no FDA approval

16. Perfluorocarbon  Perfluorocarbons  Molecules structurally similar to hydrocarbons  Hydrogen atoms replaced with fluorine atoms  Perfluorocarbon Liquids have excellent capacity for carrying oxygen and carbon dioxide  Oxygen dissolves in chemically inert perfluorocarbon liquid  Can be easily extracted by oxygen-deprived tissue http://www.md.ucl.ac.be/virtanes/pastedoct99.html

17. Perfluorocarbon ProductsPerfluorocarbon Products  Fluosol DA  Approved by FDA as a blood substitute for heart surgery  Green Cross Corp. of Japan  (1989-1992) Used in more than 40,000 human subjects  Difficulty in storage and re-use-production ended  Oxygent  Developed by Alliance Pharmaceuticals  Stage II/III clinical trials  Study in 2008  As of February 2005, no FDA approval-safety http://www.pharmaceuti calonline.com/doc/allian ce-pharmaceutical-baxter- to-collaborate-0001

18. Risk Vs. BenefitRisk Vs. Benefit  Safety of Donor Blood Supply  Risk of transfusion-associated HIV infection as low as 1 per 185,000  Risk of transfusion-associated infection of Hepatitis C Virus (HCV) between 1 per 300,000 and 1 per 600,000- compared to 1 per 103,000 in early 1990s  New blood substitutes could potentially carry unknown risks  Intravascular dwell times need to be increased  Cost needs to be competitive  Obtaining and processing sufficient amounts must be overcome

19. Thank YouThank You