Events

Implementation of the Krever Report in Quebec, Canada 

The Krever Commission was formed by the Canadian Federal Government to look into blood supply issues in Canada and to make recommendations. After extensive work, the Krever Report was tabled. Among the many recommendations to ensure safe and secure blood supplies in Canada it also recommended allocating 10% of the budget for blood supply in Canada for use in the development and research related to Hemovigillance and Transfusion Medicine. 

The Ministry of Health in Quebec has implemented this recommendation including allotting special funds for the development and research in Hemovigillance and Transfusion Medicine to be carried out by HemaQuebec and Quebec Universities. The first research group formed is on “ Blood Substitutes in Transfusion Medicine” The director of this research centre, Professor TMS Chang,OC.MD, is the principle investigator and director of this research group working with scientists and clinicians from this research centre, McGill teaching hospitals (Montreal General Hospital, Royal Victoria Hospital, Montreal Children Hospital, Montreal Jewish General Hospital) and the Laval University Teaching Hospital in Quebec City.

EDITORIAL: AN URGENT NEED TO INCLUDE BLOOD SUBSTITUTE AS A PRIORITY AREA IN ANY NATIONAL POLICIES ON BLOOD SUPPLY
T.M.S.Chang, O.C.,M.D., Editor-in-chief
(from: Artificial Cells, Blood Substitutes & Imm. Biotech. an international journal, 25:#4,i-ii,1997)

Public concerns regarding HIV in donor blood in 1986 have stimulated efforts to develop blood substitutes. Unfortunately, a product cannot be ready for clinical use without years of research and development followed by years of clinical trials. More than 10 years have passed and it will take another two years for one product and many more years for others to become available for routine use for patients

Why should this happen, when the basic ideas of encapsulated hemoglobin and cross-linked hemoglobin (Chang,TMS.Science 146:524,1964;Bunn, HF, JH Jandl. Trans Assoc Am Physicians 81:147, 1968) were already available in the 1960's? Had there been a national priority for blood substitutes in blood supply policies 30 years ago, we would have blood substitutes ready in 1986 for the HIV crisis in donor blood. As it is, since 1986, the public has continued to be exposed to the rare though a potential hazard of HIV and hepatitis in donor blood. Even in 1997, blood substitutes are still not ready for routine clinical use for another two years or more. Even when they are ready, these are only first generation blood substitutes. Much still needs to be done for the 2nd and 3rd generations of blood substitutes.

Why should we go further than the present first generation blood substitute products now in clinical trials? One only needs to imagine what would have happened in other areas if we had followed the same line of question. What would have happened if we had stopped at penicillin and did not develop further generations of antibiotics? What would have happened if we had stopped at method of detecting hepatitis B in donor blood and did not go further with hepatitis C and HIV? The first generation blood substitutes are only for short-term uses in some surgery and trauma. Their circulation half-time is only 24-30 hours, compared with the red blood cell circulation time of more than 100 days. They do not have the red blood cell enzymes needed against oxidants. These are important in reperfusion injuries and in preventing methemoglobin formation. Furthermore, little is known about the physiopathological aspects of blood substitutes.

With the present economic problems around the world, granting agencies have to divert their resources to areas of national priorities. What is left is then divided among the many other nonpriority areas, including blood substitutes. Some even suggest that the blood substitute industries can support all the research in this area. Unfortunately, most of the industries in this area are small companies that are devoting their resources to the very expensive ongoing clinical trials. We are therefore facing the same problem for research and development on blood substitutes as in the 1960's. We cannot afford to repeat the mistake. The first thing to do is urgently to establish blood substitutes as a priority in the national blood supply system. Only this way can this area receive the urgently needed priority support.

In addition, we need urgently to pool the very limited resources and to bring together the different groups. The Bayer/Canadian Red Cross Society Research and Development Fund in collaboration with the Canadian Medical Research Council is one example of joint efforts. However, we urgently need a national priority for more extensive joint efforts. This should include the national research agencies, various federal and provincial agencies, the Red Cross Societies, the blood agencies, the industries, user groups and other concerned groups. It is only by doing this with the present limited resources that we can effectively move forward and not repeat the mistake of unnecessary delays in the public use of fully developed blood substitutes.

Researchers and developers of blood substitutes have already taken up their responsibility. They have organized an international network - the International Society for Artificial Cells, Blood Substitutes and Immobilization Biotechnology. This network has an international scientific committee on blood substitutes representing major research groups, agencies, industries and other interested groups from around the world. This international network organizes and holds the International Symposia on Blood Substitutes Series, besides the Congresses of the society. This group also publishes an international journal where a large proportion of the papers on blood substitutes are published - Artificial Cells, Blood Substitutes & Immobilization Biotechnology, an international journal. The web site for this group is: http://www.artcell.mcgill.ca It is now time for the many national committees and commissions in countries around the world to take up their responsibility. Several of them have already spent a tremendous amount of resources and time retrospectively to find and solve problems related to donor blood. It is now time to look to the future and to include blood substitutes as a priority area in national blood supply policies, on a long term basis.

EDITORIAL: IS THERE A ROLE FOR FIRST GENERATION BLOOD SUBSTITUTES IN THE RESUSCITATION OF HEMORRHAGIC SHOCK ?
also in "Artif Cells, Blood Substitutes & Immob. Biotechnology, an international journal. 26(5-6);i-iii,1998"
T.M.S.Chang,OC,MD.CM,PhD,FRCP(C), Director, Artificial Cells & Organs Research Centre, Professor of Physiology, Medicine & Biomedical Engineering, MRC Career Investigator, McGill University, Montreal, Quebec, Canada H3G 1Y6

There have been much recent discussions and controversies in the use and design of clinical trials of first generation modified hemoglobin blood substitutes for the resuscitation of severe hemorrhagic shock. There is no blood group antigen in blood substitutes and they can be stored and used at anytime. Thus it would be an ideal resuscitation fluid for use in emergency situations as in the case of severe hemorrhagic shock. However, it would be extremely important to consider the following points in the potential uses of the first generation blood substitutes for the resuscitation of severe hemorrhagic shock.

Severe hemorrhagic shock results in extensive vasoconstriction and marked decrease in blood supply to a number of important organs including the intestine, the kidney and others with resulting ischemia in these organs. When the condition persists for sufficient length of time, reperfusion of oxygen carrying fluid can result in the generation of sufficient amount of oxygen radicals to result in ischemica-reperfusion injuries. Indeed, one of the potential problems in the resuscitation of severe hemorrhagic shock is ischemia-reperfusion injuries when oxygen carrying fluid is administered, especially when hemorrhagic shock has persisted for some time before reperfusion.

The present first generation modified hemoglobin blood substitutes (1-5) are prepared from ultrapure hemoglobin with nearly all of the red blood cell enzymes removed. As a result, the red blood cell antioxidant enzymes, superoxide dismutase and catalase, are no longer present in these preparations to lessen the potential problems related to ischemia-reperfusion injuries. Furthermore, Alayash has shown that in the absence of antioxidant enzymes, hemoglobin is a very reactive molecule in ischemia-reperfusion conditions(1).

Nearly all the published preclinical animal studies in the use of first generation modified hemoglobin blood substitutes in resuscitation are based on replacement within a very short time after severe hemorrhagic shock (1-5). Under these conditions, whole blood and modified hemoglobin appear to be superior to other fluids for improving the long term survival rates. However, we should not immediately apply these results to all cases of hemorrhagic shock. We have recently asked the following question. The intestine is one of the organs that can be severely affected by ischemia-reperfusion in severe hemorrhagic shock. What would be the effect of reperfusion of modified hemoglobin prepared from ultrapure hemoglobin on intestine with sustained ischemia? Our result shows that after 90 minutes of ischemia, reperfusion with polyhemoglobin results in a 13-fold increase in oxygen radicals in the effluence from the intestine, from the baseline level of 0.05 +/- 0.04 to a maximal level of 0.67 +/- 0.17 (nanomole/ml +/- standard deviation) (6). Oxygen radical generation is measured by the hydroxylation of 4-hydroxybenzoate to 3,4-dihydroxybenzoate (3,4 DHBA) using electrochemical detection. We carried out another study under the exact conditions but using polyhemoglobin crosslinked with superoxide dismutase and catalase (PolyHb-SOD-CAT) instead of polyhemoglobin prepared from ultrapure hemoglobin (6). Reperfusion with PolyHb-SOD-CAT results only in a minimal increase in oxygen radicals, from the baseline level of 0.05 +/- 0.04 nanomole/ml to 0.19 +/- 0.08 nanomole/ml. This shows the role of the red blood cell enzymes superoxide dismutase and catalase in lessening the generation of oxygen radicals in those conditions that can lead to ischemia-reperfusion injuries.

Thus in the use or design of clinical trial for the resuscitation of severe hemorrhagic shock it will be extremely important to take the above factors into consideration. If the resuscitation takes place almost immediately after hemorrhagic shock, then there may not be too much of a problem with ischemia-reperfusion injury. However, if the resuscitation takes place after sustained period of hemorrhagic shock, then resuscitation with the first generation blood substitutes may result in ishemic-reperfusion injuries and causing more harm than without such resuscitation. This would also apply to other ischemic conditions including reperfusion in stroke and other situations.

The first generation modified hemoglobin blood substitutes now in phase II and phase III clinical trials have important clinical potential for certain clinical conditions, especially for short-term use in surgery (1-5). However, it will be disastrous to think of the first generation modified hemoglobin blood substitutes as an universal blood substitute for use in all conditions. This further points to the need for the research and development of new generations of modified hemoglobin blood substitutes. For example, 2^nd generation system like our Poly-SOD-CAT (6) or those specially prepared from recombinant technology or Hsia’s chemical modification of hemoglobin with similar properties. There are also 3^rd generations system like encapsulated hemoglobin with hemoglobin, SOD and CAT in liposomes from the groups of Tsuchida (5) and Rudolph’s(2) or in biodegradable polymeric nanocapsules from Chang’s group of Yu & Chang(1).

References:

1. Chang, T.M.S.(ed) (1997,Vol. I) (1998,Vol. II) Blood substitutes: principles, methods, products and clinical trials. Karger, Basel, Switzerland.
2. Rudolph, AS, R. Rabinovich and GZ Geuerstein (eds) (1997) Red Blood Cell Substitutes. Marcel Dekker, Inc. N.Y.
3. Winslow, RM (1996) Blood substitutes in development. Exp. Opin. Invest 5:1443-1452.
4. Chang, T.M.S.(1998) Modified hemoglobin-based blood substitutes: crosslinked, recombinant and encapsulated hemoglobin. Vox Sanguinis 74(suppl. 2): 233-241.
5. Tsuchida E et al (eds) (in press) Red Blood Cell Substitutes.
6. D’Agnillo F and TMS Chang (1998) Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nature Biotechnology. 16: 667-671.
    

Editorial: IS THERE A NEED FOR BLOOD SUBSTITUTES IN THE NEW MILLENNIUM AND WHAT SHOULD WE EXPECT IN THE WAY OF SAFETY AND EFFICACY?
(From: Artif. Cells, Blood Sub. Immob. Biotech 28 (1), i-vii.,2000)by T.M.S.Chang,O.C.,M.D.,C.M.,Ph.D.,FRCP[C], Director, Artificial Cells & Organs Research Centre, Professor of Physiology, Medicine & Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, Canada, H3G 1Y6. 

Sensitive screening tests for H.I.V., hepatitis viruses and other potential infective organisms have now resulted in much safer donor blood. This being the case, is there any need for blood substitutes in the new millennium? This question sounds somewhat similar to the comments made some 40 years ago regarding the first reports of "modern" approaches to blood substitutes (1-6). The result is that little or no effort was made to develop these blood substitutes. Thus, there was nothing to replace donor blood during the H.I.V. crisis in the 1980’s and patients had to take their chances until many years later when sensitive screening tests become available. This was then followed by hepatitis C etc. Many groups started to catch-up on blood substitute research and development. Unfortunately, given such a complicated product as blood substitutes, it has been more than 10 years of intensive efforts and we still have nothing ready for routine clinical use. Had serious efforts been made to develop the modern concepts of blood substitutes 40 years ago, it would be likely that blood substitutes could have been ready for the H.I.V. crisis in the 1980’s. In the new millennium is anyone willing to say that we no longer need blood substitutes and take the responsibility if something similar to H.I.V. or hepatitis C should unexpectedly come up? In addition, there is also the continuing need in emergency situations, peri-operative needs and also in less accessible regions.

Any blood substitutes must be safe and efficacious before they can be used clinically (7). However, safety and efficacy can have many interpretations. Should we demand that blood substitutes have to be equivalent to blood before they can be considered useful clinically? To answer this question, we only have to look at the most commonly used volume replacement solution in the form of Ringer-Lactate solution. It is nothing more than a solution with electrolytes and glucose in concentrations similar to that in the plasma. There is no plasma protein and no blood cell in the solution. It is not even equivalent to plasma. Yet it has been a well-established and effective solution for volume replacement in less severe blood loss and volume depletion. No one ever expects or asks for equivalency tests with blood or even with plasma. The present first generation blood substitute is nothing more than Ringer-Lactate solution with modified hemoglobin or fluorochemicals added as oxygen carrier and also for colloid osmotic pressure. They do not have clotting factors, antioxidant enzymes, white blood cells nor platelets. This being the case, can we expect this simple solution to have the same equivalency as blood or even as red blood cells? Any equivalency tests should only be done in those clinical conditions that require only volume replacement and oxygen carrier. In this regard, first generation blood substitutes like polyhemoglobin in Phase III clinical trials (8-11) and perfluorochemicals (12) are being tested in clinical trials for peri-operative surgery for hemodilution, in surgery with large volumes of blood loss and in other conditions requiring only oxygen carrier and volume replacement. In these clinical trials up to 20 to 23 units of glutaraldehyde crosslinked polyhemoglobin (8-10) have been infused (13).

What happens if one tries to test the safety and efficacy of first generation blood substitutes in conditions requiring more than volume replacement and oxygen carrier? For instance, in conditions with potentials for ischemia-reperfusion injuries including sustained ischemia in stroke, sustained severe hemorrhagic shock with intestinal ischemia, sustained cerebral ischemia and transplantation of donor organs. Unlike red blood cells, first generation blood substitutes contain no red blood cell antioxidant enzymes like catalase and superoxide dismutase. In the absence of these antioxidant enzymes, hemoglobin in the blood substitutes can break down more easily to release heme and iron in the presence of oxidants in ischemia-reperfusion and intensify injuries (14,15). In a 1998 editorial (16) I have emphasized that in these conditions, not only is first generation blood substitutes not efficacious, they are not safe to use. For these conditions, in addition to volume replacement and oxygen carrier, we need the addition of antioxidant enzymes to the blood substitutes. Thus, second generation blood substitutes that contain antioxidants as in the case of polyhemogloin-catalase-superoxide dismutase (14) are being developed.

First generation blood substitutes have a circulation half-time of only up to 24 hours and any equivalency test should only be within this time frame. Conditions requiring more than this time frame would require repeated infusion with blood substitutes or later replacement with donor blood. Studies are being actively carried out to increase the circulation time of blood substitutes. For example, lipid membrane encapsulated hemoglobin is being developed (17,18). The circulation half-time has been increased to more than 50 hours (17) and further increase are being studied. Nanotechnology and biodegradable polymer have been combined to form biodegradable hemoglobin nanocapsules and to increase their circulation time and to include multienzyme systems (19).

The beginning of this new millennium will be an exciting period for blood substitutes. First generation blood substitutes suitable as oxygen carrier and volume replacement are in the final stages of clinical trials. These first generation blood substitutes would have important potentials especially for peri-operative uses as in hemodilution and in surgery with extensive blood loss. For other conditions that require more than just oxygen carrier and volume replacement, new generations of blood substitutes are being actively developed (14-22). It is hoped that we have learned from the last millennium that we cannot wait for an emergency situation before starting to do catch-up research and development on available ideas of blood substitutes (23). They need to be actively developed before it is too late. After all, no one can be sure that there will not be another crisis similar to the H.I.V. crisis of the last millennium.

1. Chang, TMS (1957). Hemoglobin corpuscles. Report of a research, McGill University, 1-25, 1957. Medical Library, McIntyre Building, McGill University,1957 (reprinted in "30th Anniversary in Artificial Red Blood Cell Research" Biomaterials, Artificial Cells and Artificiall Organs 16:1-9, 1988 ).
2. Chang, TMS(1964) Semipermeable microcapsules. Science 146(3643):524-525
3. Bunn, HF, JH Jandl (1968). The renal handling of hemoglobin. Trans Assoc Am Physicians 81:147
4. Geyer, RP, RG Monroe, and K Taylor (1968). Survival of rats totally perfused with a fluorocarbon-detergent preparation. In Organ Perfusion and Preservation (eds. JC Norman, J Folkman, WG Hardison, LE Rudolf, FJ Veith), Appleton Century Crofts, New York, pp 85-96.
5. Chang, TMS (1971). Stabilization of enzyme by microencapsulation with a concentrated protein solution or by crosslinking with glutaraldehyde. Biochem Biophys. Res Com, 44:1531-1533.
6. Chang, TMS (1972). Artificial cells. Monograph. Charles C Thomas, Springfield, IL, 1972.
7. Frantantoni, JC(1991), Points to consider in the safety evaluation of hemoglobin based oxygen carriers. Transfusion. 31:(4)369-371
8. Gould, SA, LR Sehgal, HL Sehgal, R DeWoskin, GS Moss, The clinical development of human polymerized hemoglobin, in Blood Substitutes: Principles, Methods, Products and Clinical Trials. Vol.2 (Chang, TMS, ed.) vol 2 ,pp12-28 Basel Karger1998
9. Gould, SA, F.A Moore et al. Clinical Utility of Human polymerized hemoglobin as a Blood Stubstitute after Acute Trauma and Urgent Surgery. J. Trauma: Injury, Infection and Critical Care (1997) 43: 325-332
10. Pearce, LB, MS Gawryl(1998), Overview of preclinical and clinical efficacy of Biopure’s HBOCs in Blood Substitutes: Principles, Methods, Products and Clinical Trials. (Chang, TMS, ed.) vol 2, pp82-98 Basel Karger
11. Adamson, JG & C. Moore, Hemolink TM(1998) an o-Raffinose crosslinked hemoglobin-based oxygen carrier , in Blood Substitutes: Principles, Methods, Products and Clinical Trials (Chang, TMS, ed.) vol 2, pp62-79 Basel Karger
12. Keipert, PE (1998), "Perfluorochemical emulsions: future alternatives to transfusion,development,pool"in Blood Substitutes: Principles, Methods, Products and Clinical Trials. Vol.2 (Chang, TMS, ed.) pp101-121, Basel, Karger
13. Panel on Blood Substitutes, Annual Meeting, American Society for Artificial Internal Organs, 1999.
14. D’Agnillo, F & TMS Chang (1998) Polyhemoglobin-superoxide dismutase. catalase as a blood substitute with antioxidant properties. Nature Biotechnology 16(7): 667-671
15. Alayash, AI, BA Brockner-Ryan, LL McLeod, DW Goldman & RE Cashon (1998), "Cell-free hemoglobin and tissue oxidants: probing the mechanisms of hemoglobin cytotoxicity", in Blood Substitutes: Principles, Methods, Products and Clinical Trials. Vol.2 (Chang, TMS, ed.) pp157-174, Basel Karger
16. Chang,TMS (1998). Editorial: Is there a role for first generation blood substitutes in the resuscitation of hemorrhagic shock? Artif Cells, Blood Sub Immob. Biotech, an international journal. 26(5-6);i-iii
17. Rudolph, AS, R Rabinovici and GZ Feuerstein (eds) (1997) Red Blood Cell Substitutes. Marcel Dekker, Inc., N.Y.
18. Tsuchida, E (editor) (1998). Blood Substitutes: Present and Future Perspectives. Elservier, Amsterdam.
19. Chang, TMS and WP Yu (1998) Nanoencapsulation of hemoglobin and red blood cell enzymes based on nanotechnology and biodegradable polymer. in Blood Substitutes: Principles, Methods, Products and Clinical Trials. Vol.2 (Chang, TMS, ed.) pp216-231, Basel Karger
20. Doherty, DH, MP Doyle, Curry SR, Vali RJ, TJ Fattor, JS Olson and DD Lemon (1998). Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nature Biotechnology 16: 672-676
21. Chang, TMS (1997a) Monograph on "Blood Substitutes: Principles, Methods, Products and Clinical Trials" Vol. I, Basel Karger
22. Winslow, RM, KD Vandegriff, M. Intaglietta (eds) (1997) Blood Substitutes: industrial opportunities and medical challenges, Birkhauser, Boston, 1997.
23. Chang, TMS (1997). Editorial: An Urgent need to include blood substitute as a priority area in any national policies on blood supply. Artif. Cells, Blood Sub. Immob. Biotech, an international journal 25 (4), i-ii.

Quoted from Chang (2008) Artificial Cells, Blood Substitutes & Biotechnology, an international journal, 36, 1-2
EDITORIAL: Safety of red blood cell substitutes as compared to stored donor red blood cells
Thomas Ming Swi Chang, OC, MD, CM, PhD, FRCPC, FRS(C)
Professor and Director, Artificial Cells and Organs Research Centre
Departments of Physiology, Medicine and Biomedical Engineering
Faculty of Medicine, McGill University, Montreal, QC, Canada H3G 1Y6
Artcell.med [at] mcgill.ca www.artcell.mcgill.ca

Red blood cell substitutes should be able to replace red blood cells (rbc) without causing more adverse effect than donor rbc. One of the safety concerns regarding rbc substitutes is related to vasoactivity. This problem has been greatly minimized by the removal of most of the tetrameric hemoglobin that causes vasoconstriction. Recent reviews show that liberal blood transfusions has a 20% increase in mortality and a 56% increase in ischemic events when compared to restrictive strategies (1,2). The transfusion of stored packed rbc is also associated with an increase in ischemic coronary events (1,3). However, it has been suggested that this is only if transfusions were given when the hematocrits were more than 30% (4). Stamler’s group shows that storage of donor blood for only 24 hour can lead to a marked decrease of the ability of rbc to effect hypoxic vasodilation (6). Their result suggests that storage of blood leads to rapid losses in NO bioactivity, and his is directly paralleled to decreases in the ability of rbc to effect hypoxic vasodilation. Valerie and Ragno in this issue report on how the effects of preserved red rbc can be related to the severe adverse events observed in patients infused with hemoglobin based oxygen carriers(6). It is reasonable to require that rbc substitutes should be able to replace donor rbc without causing more adverse effect than donor rbc. On the other hand, is it reasonable to require that rbc substitutes should have no side effects while standard donor rbc are associated with adverse effects including ischemic coronary events ? It also follows from the paper by Valerie and Ragno in this issue that in clinical trials that involve the use of both blood substitutes and donor blood, it will be important to differentiate between the adverse effects caused by each of these two components.
(1) Hill S, Carless P, Henry D, Carson J, Hebert P, McClell and D, Henderson K (2006) Cochrane Database Syst Rev 2:1–41.
(2) Rao S, Harrington R, Califf R, Stamler J (2005) Relationship of Blood Transfusion and Clinical Outcomes in Patients With Acute Coronary Syndromes J Am Med Assoc 293:673–674.
(3) Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, Moliterno DJ, Lindblad L, Pieper K, Topol EJ Blood Transfusion in Patients With Acute Coronary Syndrome (2004) J Am Med Assoc 292:1555–1562.
(4) Tinmouth A, Fergusson D, Yee IC, Hebert PC (2006) Clinical consequences of red cell storage in the critically ill, Transfusion 46:2014–2027.
(5) James D. Reynolds, Gregory S. Ahearn, Michael Angelo, Jian Zhang, Fred Cobb, and Jonathan S. Stamler (2007). S-nitrosohemoglobin deficiency: A mechanism for loss
of physiological activity in banked blood. Proceedings National Academy of Sciences 104: 17058–17062
(6) Robert Valeri and Gina Ragno (2008) The effects of preserved red blood cells on the severe adverse events observed in patients infused with hemoglobin based oxygen carriers. Artificial Cells, Blood Substitutes & Biotechnology 36: 3

Professor Thomas Ming Swi Chang, OC, MD, CM, PhD, FRCPC, FRS[C]
Director, Artificial Cells and Organs Research Centre
Departments of Physiology, Medicine and Biomedical Engineering
Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Honorary President, International Society for Artificial Cells, Blood Substitutes & Biotechnology
www.artcell.mcgill.ca

The basic principles of modified hemoglobin based blood substitutes have been available since the 1960’s (Chang, 1964, Bunn & Jandl, 1968). Unfortunately there was no interest in this until HIV contaminated blood raised its ugly head in 1989. For many years, donor blood brought with it a high incidence of HIV infection. This urgent need for blood substitutes led a number of companies to carry out the impossible task of research and development in the absence of basic knowledge in this area. Granting agencies then started for a short time to support the badly needed basic research in blood substitutes. Unfortunately, this did not last long since it was thought that blood substitute was a simple product that could be easily developed by the industries themselves without the need for basic research. This resulted in much setbacks and delays in this area as developers and researchers started to realize the need for the nonexistent basic knowledge. As a result, it took 20 years to reach the present status of first generation blood substitutes that are still not approved for routine use (Alayash et al 2007, Buehler et al 2004,Chang 2007, Jahr et al 2008, Liu & Xiu, 2008, Moore et al 2009, Mozzarelli 2010, Tsuchida et al 2006, Winslow, 2006 Yu et al, 2010, and others). In any case, it was too late for the large number of patients infected with HIV contaminated blood until screening tests were implemented, as least in some countries that can afford this. This led to a false sense of security and a repeat of the earlier lack of interest in blood substitutes. The present economical crisis around the world also did not help. Again, people seem to feel that there is no need to develop blood substitutes until we need it. They seem to forget that it took more than 20 years to come to the present status of first generation blood substitutes that have not yet been approved for clinical use. It will take many more years for basic research and development to come out with a perfect blood substitute. In the meantime if another HIV-like disaster should suddenly appear, are we willing to repeat our mistake? Even at present, there are urgent needs for blood substitutes in major surgery, mass disaster, war and other situations, especially where donor blood is not readily available. Furthermore, millions of people are living in regions where there are major problems related to HIV, malaria and other contamination in donor blood. It will be important to consider both the present and the future as follows: 

(1) For the present, we need to carry out careful risk/benefit analysis of available HBOC for specific conditions and specific locations in the world. This includes more narrow indications and the exclusion of patients and conditions with arteriosclerosis, diabetes and other endothelial dysfunctions especially in situations of oxidative stress. There are also potential ways to prevent adverse effects (Yu et al, 2010) including new generations of blood substitutes in development (Buehler et al 2004,Chang 2007,Tsuchida et al, 2006 and others). What is also important is that one country’s regulatory standard should not be automatically applied to all countries around the world. The risk/benefit will be different in countries with unsafe blood (HIV, malaria and other parasites, etc). The risk/benefit is also different in critical situations as in natural or man-make disasters when there is insufficient blood supply 

(2) For the future, it will be important to intensify basic research for basic information and R&D into new improved blood substitutes. Past experience shows that it is an impossible task to develop safe and effective products in the face of minimal basic knowledge in this area. The biannual series of International Symposium on Blood Substitutes (ISBS) has been organized for many years to bring together molecular biologists, biochemists, chemists, clinicians, physiologists, those in R&D and others. The most recent ones included the 2007 XI ISBS organized by Professor Liu and Professor Xiu of the Peking Union Medical College in Beijing, China. The 2009 XII ISBS was organized by Professor Mozzarelli of Parma University in Parma, Italy. Professor Zapol of MGH, Harvard Medical School will be organizing the XIII ISBS to be held at the MGH of Harvard Medical School, 27-29 July, 2011 (Please see www.artcell.mcgill.ca for a link to his URL when it is ready). We therefore have all the major researchers and developers around the world interacting closely to move this area forward. All we need now is for granting agencies around the world to give priority to support blood substitute related research in order to avoid another future major disaster like the one we had with HIV contaminated blood in 1989.

1. Chang TMS. (1964) Science 1964; 146(3643): 524
2. Bunn, H.F., and Jandl, J.H. (1968) Trans Assoc Am Phys 81:147
3. Winslow, R.M. (ed.), (2006) Blood Substitutes. Academic Press, Amsterdam.
4. E. Tsuchida, H. Sakai, H. Horinouchi, K. Kobayashi (2006). Hemoglobin-vesicles as a transfusion alternative. Artificial Cells, Blood Substitutes and Biotechnology 2006, 34 :581-588.
5. Chang TMS (2007). Monograph on “ARTIFICIAL CELLS: Biotechnology, Nanotechnology, Blood Substitutes, Regenerative Medicine, Bioencapsulation, Cell/Stem Cell Therapy” World Science Publisher/Imperial College Press, pp 1-452
6. Jahr JS, Mackenzie C, Pearce LB, Pitman A, Greenburg AG.(2008) HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopaedic surgery. J Trauma 64: 1484–97
7. Moore EE , Moore FA, Fabian TC , Bernard AC , Fulda GJ, Hoyt DB , Duane TM, Weireter Jr LJ, Gomez GA, Cipolle MD , Rodman Jr GH , Malangoni MA , Hides GA, Omert LA, Gould SA, (2009) Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial. J Am Coll Surg. 208: 1-13
8. Alayash AI, D’Agnillo F, Buehler PW (2007) First-generation blood substitutes: what have we learned? Biochemical and physiological perspectives. Expert Opin. Biol. Ther. 2007,7(5) 665- 675
9. Yu B, M Shahid, EM Egorina, MA Sovershaev, MJ Raher, C Lei, MX Wu, KD Bloch, WM Zapol (2010) Endothelial Dysfunction Enhances Vasoconstriction Due to Scavenging of Nitric Oxide by a Hemoglobin-based Oxygen Carrier, Anesthesiology 112:586 –94
10. Buehler PW, Haney CR, Gulati A, Ma L, Hsia CJ.(2004) Polynitroxyl hemoglobin: a pharmacokinetic study of covalently bound nitroxides to hemoglobin platforms Free Radical Biology & Medicine 37 (1), 124-35
11. Liu Qian, Ruijuan Xiu (2008) XI ISBS Symposium Proceeding, 3rd issue Artificial Cells, Blood Substitutes and Biotechnology,
12. A. Mozzarelli (2010) XII ISBS Symposium Proceeding, 6th issue Artificial Cells, Blood Substitutes and Biotechnology (in preparation),