Biomaterials, Artificial Cells and Immobilization Biotechnology
ISSN: 1055-7172 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ianb18
Potential Clinical Applications of the Oxygen Carrying Solutions Naoki Minato, Tatsuya Sasaki, Ichiro Sakuma, Motomi Shiono, Setsuo Takatani & Yukihiko Nose To cite this article: Naoki Minato, Tatsuya Sasaki, Ichiro Sakuma, Motomi Shiono, Setsuo Takatani & Yukihiko Nose (1992) Potential Clinical Applications of the Oxygen Carrying Solutions, Biomaterials, Artificial Cells and Immobilization Biotechnology, 20:2-4, 221-228, DOI: 10.3109/10731199209119637 To link to this article: http://dx.doi.org/10.3109/10731199209119637
Published online: 11 Jul 2009.
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Date: 19 April 2016, At: 00:33
BIOMAT., ART. CELLS & IMMOB. BIOTECH., 20(2-4), 2 2 1 - 2 2 8 (1992)
POTENTIAL CLINICAL APPLICATIONS OF THE OXYGEN CARRYING SOLUTIONS
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Naoki Minato, M.D., Tatsuya Sasaki, M.D., Ichiro Sakuma, Ph.D., Motomi Shiono, M.D., Setsuo Takatani, Ph.D., Yukihiko Nose, M.D., Ph.D. Department of Surgery, Eiaylor College of Medicine, One Eiaylor Plaza, Houston, Texas 77030 ABSTRACT Two major areas of research of the oxygen carrying solutions are 1) utilization of hemoglobin and 2) perfluorochemicals. Even though they are not perfect red blood cell substitutes, the "oxygen carrying solutions" have many potential clinical applications because they will reach tissues more easily than normal human red cells and can deliver oxygen directly to tissues. In this paper, important examplesof such usages are suggested. Additional clinical and non-clinical applications of the oxygen carrying solutions may be added in the near future. INTRODUCTION Although blood transfusion has contributed a great deal to modem medicine, there are many problems, i.e., lack of donors, time consuming blood type analysis and cross-match tests, limitation on preservation time, immunomodulationto the recipient and viral transmission such as hepatitis and AIDS. One of the major objectives of homologous blood transfusion is to enhance oxygen delivery to tissues. It will be a great contribution in future medicine if we could get useful, effective and safe oxygen carrying solutions. To describe some important features of blood, we must mention oxygen and nutritional supply, removal of carbon dioxide and waste matters, control of osmotic pressure and metabolism and immunity. At present, some parts of blood constituent substitutes are clinically available instead of whole blood, except for red blood cells (RBC) as an oxygen carrier. Those are plasma expander (Dextran) for plasma volume, electrolytes solution for plasma electrolytes, antibiotics for white blood cells and immunoglobulin, and coagulation drugs for platelets and coagulation factors. There are no substitutes for cellular components of blood, particularly white blood cells and platelets. Thus, the term "blood substitute" is not a proper expression for the currently developing oxygen carrier. We are dealing with the oxygen carrying agent, so even an expression of "artificial red cells" is not proper. So we believe the solution containing the artificial red cells should be called "oxygen carrying solution.'' There are two major areas of research and development of "oxygen carrying solution," 1) utilization of hemoglobin, and 2) pertluorochemicals. 1) Utilization of Hemoglobin Hemoglobin is a major oxygen carrier in REX, consisting of 4 subunits (a2,82).The stroma-free hemoglobin cannot be used as an oxygen carrier immediately. Because stroma-free hemoglobin has a high oxygen affinity due to the lack of 2,3 diphosphoglycerate outside RBC, it cannot supply oxygen at all to the anoxic tissues. And it has a greatly reduced residence time
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in circulation, due to dissociation of the hemoglobin tetramer into dimer which rapidly passes through the glomeruli into the urine. Some modifications of the stroma-free hemoglobin to decrease the oxygen affinity and to increase the molecular size or weight are needed to use it as an oxygen carrier. 2) reriiuorocnemicals Perfhomchemials are solvents for all gases, i.e., oxygen, carbon dioxide, nitrogen, carbon monoxide, etc., so that perfluorochemicals are suitable for an oxygen carrier. They carry oxygen from the lungs to other tissues and transport carbon dioxide from the tissues to the lungs. As perfluomchemicals are insoluble in other materials, emulsification is needed before using it as an "oxygen carrying solution."
Downloaded by [Laurentian University] at 00:33 19 April 2016
; The main advantage of the artificial red cell comes from its smaller size than RBC, enabling it to pass through the stenosed or occluded arteries and capillary beds to deliver oxygen to the peripheral tissues. Thus in this paper, attempt was made to classify the artificial red cells according to the size of the oxygen carrying agents as follows: 1. Microcapsules, 1-30pm in diameter, 2. Microparticles, around 0.1 pm, 3. Macromolecules, around 100 A. Microcapsules include prototype encapsulated There were not suitable for the artificial red cell because of the larger size than RBC and problems of protein deposition and aggregation. Microparticles include perfluorochemicals (around 0.1 pm)O), liposome-encapsulated hemoglobin (0.2-0.5 pm)"), liposome-embedded hemoglobin (0.04 pm)('], Macromolecules include cross-linked and conjugated hemoglobin, such as pyridoxalated hemoglobin polyoxyethlene conjugate@).The most effective candidates are supposed to be the macromolecules and not the microparticles, because of their favorable size in circulation. The ideal artificial red cells must have low oxygen affinity, long residence time in circulation, short residence time in tissues, low toxicity, non-complement activation, no infectious agents and long-term stability. There are many problems to be solved in the future; however, potential applications of the oxygen carrying solution are considered in various forms (TABLE 1). Some are experimentally proven and some are just possibilities.
CLINICAL APPLICATIONS I. Therapy 1. Blood Substitutes First for the treatment of diseases, the oxygen carrying solution can be used as the blood substitutes. Massive hemorrhage and hemorrhagic shock caused by accidents and war will be replaced by the oxygen carrying solution before getting a blood transfusiono. Secondly, the demand of blood in surgery will be decreased if the oxygen carrying solution is first infused instead of a blood transfusion. Additionally in case of anemia, artificial red cells may supply oxygen to improve the symptoms. 2. Whole Body Rinse-Out Whole body rinse-out may be indicated in the cases of acute drug-intoxication''), nuclear jaundice and acute hepatic failure. 3. Local Ischemia Ischemia is the most suitable and realistic indication for the oxygen carrying solution. Microparticles and micromolecules are able to pass the stenosed or occluded arteries and capillaries to deliver oxygen to the peripheral ischemic tissues. In the treatment of acute ischemia, anti-oxidants should be added to the oxygen carrying solution to prevent oxygen radical damage caused both by ischemia and reperhion. The critical ischemia of the cardiac muscle can be temporarily relieved in acute or evolving myocardial infarction until the adequate blood flow can be re-established by some
P O T E N T I A L OF OXYGEN C A R R Y I N G S O L U T I O N S
TABLE 1
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POTENTIAL CLINICAL APPLICATIONS OF THE OXYGEN CARRYING SOLUTIONS
CLDNICALAPPLICATIONS I.
Therapy
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1.
2.
3.
4.
Blood substitutes 1) hemorrhage (accident, war, surgery) 2) hemorrhagic shock 3) anemia Whole body rinse-out 1) acute drug-intoxication 2) nuclear jaundice 3) acute hepatic failure Local ischemia Heart 1) acute myocardial infarction 2) evolving myocardial infarction 3) unstable angina 4) ischemic cardiomyopathy any kind of cardiac failure 5) infarction Brain 1) embolism thrombosis 2) arteriosclerosis 3) dementia acute arterial thrombosis and embolism Limbs 1) 2) chronic ischemic ulcer arteriosclerosis obliterans Burger’s disease 3) sickle cell anemia Assist for endarterial maneuver 1) coronaryartery coronary angiography percutaneous transluminal coronary recanalization percutaneous transluminal coronary angiography 2) renal artery percutaneous transluminal angioplasty 3) peripheral artery percutaneous transluminal angioplasty General ischemia 1) gas embolus 2) gas intoxication (continued)
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MINATO ET A L .
TABLE 1 Continued
carbon monoxide, etc. living in hypoxic environments mountain sickness submarine sickness cyanotic heart disease Aid for organ and tissue m v e r y 1) acute renal failure acute hepatic failure, fluminant hepatitis 2) 3) acute pancreatitis peptic ulcer of the stomach and duodenum 4) prevention of granuloma formation at the anastomosis 5) Infectious disease 1) anaerobe-infectious diseases 2) anaerobe-infected cavity pyothorax pyomediastinum Adjuvant therapy tumor radiotherapy tumor chemotherapy
3)
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5.
6.
7.
II. Perfusional protection of the organs during surgery 1.
2. 3. 4.
5.
6.
Cardiopulmonary bypass Deep hypothermia Circulatory arrest Cardioplegia Spinal cord and abdominal organ protection during cross-clamp of the thoracoabdominal aorta Kidney protection during cross-clamp of the renal arteries
III. Extended preservation of the donor organs 1. Heart 2. Liver 3. Pancreas 4. Kidney 5. Musculo-cutaneousflap 6. Amputated limbs
IV. Hybrid artificial organs 1. 2.
Metabolic assist hepatocyte Hormonal assist islet cells of Langerhans thyroid gland cells adrenal gland cells pituitary gland cells
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TABLE 1 C o n t i n u e d
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V. Drugcarrier 1. Drug-conjugated hemoglobin 2. Drug-conjugated perfluorochemicals
VI. Contrast agent Perfluoroctylbromide as a contrast agent ultrasound computed tomography angiography magnetic resonance imaging liver and spleen imaging tumor imaging
NON-CLINICAL APPLICATIONS I. Culture medium 1. Tissue culture medium 2. Bacterial (aerobes) culture medium II. Chemical examination 1. Indicator for oxygen sensor Standard solution for oxygen calibrator 2. III. Bioreactor PARADOXICAL UTILIZATION Paradoxical utilization of high-oxygen affinity 1) oxygen absorbent oxygen pulse therapy for malignant tumors combined with radiotherapy 2) or chemotherapy
coronary intervention. An unstable angina may be converted to a stable angina if the oxygen carrying solution is given systemically. The delivered oxygen will improve the viability of the cardiac muscles in ischemic cardiomyopathy. Also in any kind of cardiac failure, the symptoms can be relieved by general oxygenation of the organs and peripheral tissues. In the event of brain infarction caused by embolism or thrombosis, the necrotic area can be reduced if the oxygen carrying solution is administered immediately. General oxygenation of the brain cells will improve the atherosclerotic brain insufficiency and vascular type dementia. In acute ischemia of the limbs caused by thrombosis or embolism, the oxygen carrying solution can prevent complete ischemia of the limbs until the blood flow is re-established surgically and hazardous complication of the myonephrotic metabolic syndrome can be prevented. The chronic ischemic ulcer caused by arteriosclerosisobliterans and Burger’s disease can be treated by systemic or selective arterial administration of the oxygen carrying solution. The potential clinical application to sickle cell anemia has been described in the aspects of improving the peripheral circulation and reversing the sickled erythrocytes@). Another application is the assist for endoarterial maneuvers of the coronary, renal and peripheral arteries. The oxygen carrying solution may include a contrast material that could be beneficial to the critically ill patients on angiography. Thrombolytic agents which contain the oxygen carrier may be safely infused into the c o r o n q artery system using percutaneous
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transluminal coronary recanalization. Selective coronary shot of the oxygen carrying solution before occluding coronary arteries will extend the ischemic-tolerance time of the heart at percutaneous transluminal coronary angioplasty. Systemic administration of the oxygen carrying solution should precede these selective uses of the solution in order to improve the oxygenation of the ischemic tissues. 4. GeneralIschemia In general ischemia, the oxygen carrying solution is effective in the treatment of gas embolism, gas intoxication, mountain sickness, submarine sickness and anoxic spell of the cyanotic heart diseases. Systemic oxygenation and improvement of the local tissue circulation will help the recovery of the impaired organs and tissues in the cases of acute renal failure"@', acute hepatic failure, fluminant hepatitis, acute pancmtitis 'I, peptic ulcer of the stomach and duodenum (mucosal ischemia is one of the causes of the ulcer formation). Granuloma formation and detachment of the surgical anastomosis (for example, trachea, bronchus) caused by local ischemia can be prevented by the improvement of the peripheral oxygenation and circulation. Anaerobe infectious disease may be more effectively treated with the aid of systemic administration of the oxygen Carrying solution. Anaerobe-infected cavity such as pyothorax and pyomediastinum can be drained and irrigated with the oxygen carrying solution together with antibiotics. Adjuvant therapy for tumor radiotherapy('" and chemotherapy (I3) has been reported.The rationale is to increase the oxygen level in the anoxic tumor, thereby increasing the efficacy of the ionizing radiation or anti-cancer drugs. II. Perfusional Protection of the Organs During Surgery This theory is based on the effect of preserving aerobic metabolism during ischemia and improving peripheral circulation by the oxygen carrying solution. Cardiopulmonary bypass is usually operated with moderate to deep hypothermia during open heart surgery, which is known as a "controlled shock state." The peripheral circulation is impaired by sludging of the RBC in the capillaries. During circulatory arrest period, anaerobic metabolism progresses. Especially, brain ischemia is a critical problem in the aortic arch surgery. All of these conditions can be improved by using the oxygen carrying solution as a perfusate during cardiopulmonary bypass to improve the peripheral circulation and oxygenation. The results of cardiac operations depend upon the protection of the heart from ischemia. Cardioplegia with oxygen carrying solution may maintain aerobic metabolism during cardiac arrest to preserve high-energy phosphates. In the operation of thoracic aneurysm and thoramabdominal aneurysm, spinal cord ischemia and abdominal organ ischemia often cause paraplegia and abdominal organ failures postoperatively, due to the ischemia of the spinal cord and the abdominal organs during aortic crossclamp. Systemic administration of the oxygen carrying solution w i l l increase the ischemic tolerance of the organs. Additionally, selective perfusion of the intercostal and lumber arteries, the celiac artery, the superior mesenteric artery and the renal arteries during aortic clamping are considered to be much more beneficial to protect the organs. LU. Extended Preservation of the Donor Organs The oxygen carrying solutions can be utilized as the preservation solution of the donor organs in transplantation. Ex vivo organs may be preserved in less-ischemic condition, and better organ function can be expected postoperatively. IV. Hybrid Artificial 0Culture of the hepatocytea and islet cells of Langerhans are more easily performed by adding the oxygen carrying solution to the culture medium. They can be used as the hybrid artificial organs in the patients with metabolic insufficiency and hormonal deficiency.
P O T E N T I A L OF OXYGEN C A R R Y I N G S O L U T I O N S
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V. Drugcarrier If the drug is conjugated with hemoglobin molecule or peffluorochemicals, we can use them as a drug carrier to the blocked capillary beds while increasing the drug sensitivity of the peripheral tissues by oxygenation. VI. Contrast Agent Perfluorooctylbromide can be used as a new contrast agent with oxygen carrying capability in ultrasound, computed tomography, angiography, magnetic resonance imaging, liver and spleen imaging and tumor imaging(I4). The capability will help the critically ill and other patients from having acute side effects caused by the lack of oxygen during the time of diagnosis.
NON-CLINICAL APPLICATIONS The oxygen carrying solution may be used in culture media of the tissues and bacteria (aerobes) in chemical examination such as an indicator for oxygen sensor and a standard solution for oxygen calibrator, and in some kinds of bioreactor. PARADOXICAL UTILIZATIONS If the oxygen affinity is controllable, the artificial red cells can be used as an oxygen absorbent, paradoxically. A new therapy for malignant tumors will be developed, that is, "Oxygen pulse therapy combined with radiotherapy or chemotherapy." This consists of two stages. The first stage, "low oxygen affinity solution," is used as an adjuvant therapy of radiation to deliver the oxygen to the tumors to increase radiosensitivity. The second stage, "high oxygen affinity solution," namely, oxygen absorbent, is given selectively to the feeding artery of the tumor expecting anoxic necrosis of the tumor. CONCLUSION We have many potential applications of the oxygen carrying solution; however, blood contains all the ingredients which maintain our lives normally, and there is no artificial "blood substitute" which can replace whole blood in the body. We should know that the oxygen carrying solution is a solution which contains only needed oxygen to the tissues, and that it should not be used as a "substitute" of whole blood. Even though it is not a perfect red cell substitute, this oxygen carrying solution has many additional therapeutic properties because it will reach tissues more easily than normal human red cells and deliver needed oxygen directly to tissues. In this paper, important examples of such usages are suggested. Additional clinical and non-clinical applications of the oxygen carrying solutions may be added in the near future. REFERENCES 1. Chang TMS. Semipermeable microcapsules. Science 146524, 1964. 2 Djordjevich L, Miler IF. Synthetic erythrocytes from lipid encapsulated hemoglobin. Exp Hematol 8584, 1980. 3. Geyer RP. Perfluorochemicals as oxygen transport vehicles. Biomat Artif Cells Anif Organs 16:31, 1988. 4. Farmer MC, Rudolph AS, Vandegriff KD, Hayre MD, Bayne SA, Johnson SA. Liposomeencapsulated hemoglobin: Oxygen binding properties and respiratory function. Biomat Anif Cells AnifOrgans 16:289, 1988. 5 . Tsuchida E, Nishide H, Ohno H. Liposomelheme as a totally synthetic oxygen carrier. Biomat Anif Cells Anif Organs 16:313, 1988.
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6. Malchesky PS, Takahashi T, Iwasaki K, Harasaki H, Nose’ Y. Conjugated human hemoglobin as a physiological oxygen carrier-pyridoxalated hemoglobin polyoxyethylene conjugate (PHP). Int J Anif Organs 13:442, 1990. 7. Chen HS, Yang, ZH. Perfluorowbons as blood substitute in clinical applications and in war casualties. Eiomat Anif C e h Anf Organs 16:403, 1988. 8. Agishi T, Funakoshi Y, Honda H, Yamagata K, Kobayashi M, Takahashi M. Pyridoxalated hemoglobin polyoxyethylene conjugate solution as blood substitute for normothermic whole body rinse-out. Eiomut Anif Cells Anif Organs 16:261, 1988. 9. Yabuki A, Matsushita M, Malchesky PS, Iwasaki K, Nose’ Y. In vitro evaluation of a pyridoxalated hemoglobin polyoxyethylene conjugate in reversing cell sickling. Trans Am SOCAnif Intern Organs 34:773, 1988. 10. Sonda K, Agishi T, Honda H, Funakoshi Y, Yamagata Y, Ota K. Relief of ischemic renal injury by using polyethylene glycol conjugate of pyridoxalated human hemoglobin (stabilized hemoglobin: sHb). Jpn J Anif Organs 18:361, 1989. 11. Ohyanagi H, Ohashi 0, Nakayama S, Yamamoto M, Okumura S , Saitoh Y. Experimental studies on fluosol DA administration in acute pancreatitis. Eiomat .4nif Cells Anif Organs 16585, 1988. 12. Lustig RA, Rose CM, McIntosh-LoweNL. Fluosol DA and oxygen as an adjuvant to the radiotheraputic management of advanced headlneck carcinoma. Biornar Anf Cells Anif Organs 16511, 1988. 13. Teicher BA, McIntosh-LoweNL, Rose CM. Effect of various oxygenation conditions and Fluosol-DA on cancer chemotherapeuticagents. Eiornar Arfif Cells Anif Organs 16533, 1988. 14. Long DM, Long DC, Mattrey RF,Long RA, Burgan AR, Herrick WC, Shellhamer DF.
ISSN: 1055-7172 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ianb18
Potential Clinical Applications of the Oxygen Carrying Solutions Naoki Minato, Tatsuya Sasaki, Ichiro Sakuma, Motomi Shiono, Setsuo Takatani & Yukihiko Nose To cite this article: Naoki Minato, Tatsuya Sasaki, Ichiro Sakuma, Motomi Shiono, Setsuo Takatani & Yukihiko Nose (1992) Potential Clinical Applications of the Oxygen Carrying Solutions, Biomaterials, Artificial Cells and Immobilization Biotechnology, 20:2-4, 221-228, DOI: 10.3109/10731199209119637 To link to this article: http://dx.doi.org/10.3109/10731199209119637
Published online: 11 Jul 2009.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ianb18 Download by: [Laurentian University]
Date: 19 April 2016, At: 00:33
BIOMAT., ART. CELLS & IMMOB. BIOTECH., 20(2-4), 2 2 1 - 2 2 8 (1992)
POTENTIAL CLINICAL APPLICATIONS OF THE OXYGEN CARRYING SOLUTIONS
Downloaded by [Laurentian University] at 00:33 19 April 2016
Naoki Minato, M.D., Tatsuya Sasaki, M.D., Ichiro Sakuma, Ph.D., Motomi Shiono, M.D., Setsuo Takatani, Ph.D., Yukihiko Nose, M.D., Ph.D. Department of Surgery, Eiaylor College of Medicine, One Eiaylor Plaza, Houston, Texas 77030 ABSTRACT Two major areas of research of the oxygen carrying solutions are 1) utilization of hemoglobin and 2) perfluorochemicals. Even though they are not perfect red blood cell substitutes, the "oxygen carrying solutions" have many potential clinical applications because they will reach tissues more easily than normal human red cells and can deliver oxygen directly to tissues. In this paper, important examplesof such usages are suggested. Additional clinical and non-clinical applications of the oxygen carrying solutions may be added in the near future. INTRODUCTION Although blood transfusion has contributed a great deal to modem medicine, there are many problems, i.e., lack of donors, time consuming blood type analysis and cross-match tests, limitation on preservation time, immunomodulationto the recipient and viral transmission such as hepatitis and AIDS. One of the major objectives of homologous blood transfusion is to enhance oxygen delivery to tissues. It will be a great contribution in future medicine if we could get useful, effective and safe oxygen carrying solutions. To describe some important features of blood, we must mention oxygen and nutritional supply, removal of carbon dioxide and waste matters, control of osmotic pressure and metabolism and immunity. At present, some parts of blood constituent substitutes are clinically available instead of whole blood, except for red blood cells (RBC) as an oxygen carrier. Those are plasma expander (Dextran) for plasma volume, electrolytes solution for plasma electrolytes, antibiotics for white blood cells and immunoglobulin, and coagulation drugs for platelets and coagulation factors. There are no substitutes for cellular components of blood, particularly white blood cells and platelets. Thus, the term "blood substitute" is not a proper expression for the currently developing oxygen carrier. We are dealing with the oxygen carrying agent, so even an expression of "artificial red cells" is not proper. So we believe the solution containing the artificial red cells should be called "oxygen carrying solution.'' There are two major areas of research and development of "oxygen carrying solution," 1) utilization of hemoglobin, and 2) pertluorochemicals. 1) Utilization of Hemoglobin Hemoglobin is a major oxygen carrier in REX, consisting of 4 subunits (a2,82).The stroma-free hemoglobin cannot be used as an oxygen carrier immediately. Because stroma-free hemoglobin has a high oxygen affinity due to the lack of 2,3 diphosphoglycerate outside RBC, it cannot supply oxygen at all to the anoxic tissues. And it has a greatly reduced residence time
221
Copyright 0 1992 by Marcel Dekker. Inc.
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MINATO ET A L .
in circulation, due to dissociation of the hemoglobin tetramer into dimer which rapidly passes through the glomeruli into the urine. Some modifications of the stroma-free hemoglobin to decrease the oxygen affinity and to increase the molecular size or weight are needed to use it as an oxygen carrier. 2) reriiuorocnemicals Perfhomchemials are solvents for all gases, i.e., oxygen, carbon dioxide, nitrogen, carbon monoxide, etc., so that perfluorochemicals are suitable for an oxygen carrier. They carry oxygen from the lungs to other tissues and transport carbon dioxide from the tissues to the lungs. As perfluomchemicals are insoluble in other materials, emulsification is needed before using it as an "oxygen carrying solution."
Downloaded by [Laurentian University] at 00:33 19 April 2016
; The main advantage of the artificial red cell comes from its smaller size than RBC, enabling it to pass through the stenosed or occluded arteries and capillary beds to deliver oxygen to the peripheral tissues. Thus in this paper, attempt was made to classify the artificial red cells according to the size of the oxygen carrying agents as follows: 1. Microcapsules, 1-30pm in diameter, 2. Microparticles, around 0.1 pm, 3. Macromolecules, around 100 A. Microcapsules include prototype encapsulated There were not suitable for the artificial red cell because of the larger size than RBC and problems of protein deposition and aggregation. Microparticles include perfluorochemicals (around 0.1 pm)O), liposome-encapsulated hemoglobin (0.2-0.5 pm)"), liposome-embedded hemoglobin (0.04 pm)('], Macromolecules include cross-linked and conjugated hemoglobin, such as pyridoxalated hemoglobin polyoxyethlene conjugate@).The most effective candidates are supposed to be the macromolecules and not the microparticles, because of their favorable size in circulation. The ideal artificial red cells must have low oxygen affinity, long residence time in circulation, short residence time in tissues, low toxicity, non-complement activation, no infectious agents and long-term stability. There are many problems to be solved in the future; however, potential applications of the oxygen carrying solution are considered in various forms (TABLE 1). Some are experimentally proven and some are just possibilities.
CLINICAL APPLICATIONS I. Therapy 1. Blood Substitutes First for the treatment of diseases, the oxygen carrying solution can be used as the blood substitutes. Massive hemorrhage and hemorrhagic shock caused by accidents and war will be replaced by the oxygen carrying solution before getting a blood transfusiono. Secondly, the demand of blood in surgery will be decreased if the oxygen carrying solution is first infused instead of a blood transfusion. Additionally in case of anemia, artificial red cells may supply oxygen to improve the symptoms. 2. Whole Body Rinse-Out Whole body rinse-out may be indicated in the cases of acute drug-intoxication''), nuclear jaundice and acute hepatic failure. 3. Local Ischemia Ischemia is the most suitable and realistic indication for the oxygen carrying solution. Microparticles and micromolecules are able to pass the stenosed or occluded arteries and capillaries to deliver oxygen to the peripheral ischemic tissues. In the treatment of acute ischemia, anti-oxidants should be added to the oxygen carrying solution to prevent oxygen radical damage caused both by ischemia and reperhion. The critical ischemia of the cardiac muscle can be temporarily relieved in acute or evolving myocardial infarction until the adequate blood flow can be re-established by some
P O T E N T I A L OF OXYGEN C A R R Y I N G S O L U T I O N S
TABLE 1
223
POTENTIAL CLINICAL APPLICATIONS OF THE OXYGEN CARRYING SOLUTIONS
CLDNICALAPPLICATIONS I.
Therapy
Downloaded by [Laurentian University] at 00:33 19 April 2016
1.
2.
3.
4.
Blood substitutes 1) hemorrhage (accident, war, surgery) 2) hemorrhagic shock 3) anemia Whole body rinse-out 1) acute drug-intoxication 2) nuclear jaundice 3) acute hepatic failure Local ischemia Heart 1) acute myocardial infarction 2) evolving myocardial infarction 3) unstable angina 4) ischemic cardiomyopathy any kind of cardiac failure 5) infarction Brain 1) embolism thrombosis 2) arteriosclerosis 3) dementia acute arterial thrombosis and embolism Limbs 1) 2) chronic ischemic ulcer arteriosclerosis obliterans Burger’s disease 3) sickle cell anemia Assist for endarterial maneuver 1) coronaryartery coronary angiography percutaneous transluminal coronary recanalization percutaneous transluminal coronary angiography 2) renal artery percutaneous transluminal angioplasty 3) peripheral artery percutaneous transluminal angioplasty General ischemia 1) gas embolus 2) gas intoxication (continued)
2 24
MINATO ET A L .
TABLE 1 Continued
carbon monoxide, etc. living in hypoxic environments mountain sickness submarine sickness cyanotic heart disease Aid for organ and tissue m v e r y 1) acute renal failure acute hepatic failure, fluminant hepatitis 2) 3) acute pancreatitis peptic ulcer of the stomach and duodenum 4) prevention of granuloma formation at the anastomosis 5) Infectious disease 1) anaerobe-infectious diseases 2) anaerobe-infected cavity pyothorax pyomediastinum Adjuvant therapy tumor radiotherapy tumor chemotherapy
3)
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5.
6.
7.
II. Perfusional protection of the organs during surgery 1.
2. 3. 4.
5.
6.
Cardiopulmonary bypass Deep hypothermia Circulatory arrest Cardioplegia Spinal cord and abdominal organ protection during cross-clamp of the thoracoabdominal aorta Kidney protection during cross-clamp of the renal arteries
III. Extended preservation of the donor organs 1. Heart 2. Liver 3. Pancreas 4. Kidney 5. Musculo-cutaneousflap 6. Amputated limbs
IV. Hybrid artificial organs 1. 2.
Metabolic assist hepatocyte Hormonal assist islet cells of Langerhans thyroid gland cells adrenal gland cells pituitary gland cells
POTENTIAL OF OXYGEN C A R R Y I N G SOLUTIONS
225
TABLE 1 C o n t i n u e d
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V. Drugcarrier 1. Drug-conjugated hemoglobin 2. Drug-conjugated perfluorochemicals
VI. Contrast agent Perfluoroctylbromide as a contrast agent ultrasound computed tomography angiography magnetic resonance imaging liver and spleen imaging tumor imaging
NON-CLINICAL APPLICATIONS I. Culture medium 1. Tissue culture medium 2. Bacterial (aerobes) culture medium II. Chemical examination 1. Indicator for oxygen sensor Standard solution for oxygen calibrator 2. III. Bioreactor PARADOXICAL UTILIZATION Paradoxical utilization of high-oxygen affinity 1) oxygen absorbent oxygen pulse therapy for malignant tumors combined with radiotherapy 2) or chemotherapy
coronary intervention. An unstable angina may be converted to a stable angina if the oxygen carrying solution is given systemically. The delivered oxygen will improve the viability of the cardiac muscles in ischemic cardiomyopathy. Also in any kind of cardiac failure, the symptoms can be relieved by general oxygenation of the organs and peripheral tissues. In the event of brain infarction caused by embolism or thrombosis, the necrotic area can be reduced if the oxygen carrying solution is administered immediately. General oxygenation of the brain cells will improve the atherosclerotic brain insufficiency and vascular type dementia. In acute ischemia of the limbs caused by thrombosis or embolism, the oxygen carrying solution can prevent complete ischemia of the limbs until the blood flow is re-established surgically and hazardous complication of the myonephrotic metabolic syndrome can be prevented. The chronic ischemic ulcer caused by arteriosclerosisobliterans and Burger’s disease can be treated by systemic or selective arterial administration of the oxygen carrying solution. The potential clinical application to sickle cell anemia has been described in the aspects of improving the peripheral circulation and reversing the sickled erythrocytes@). Another application is the assist for endoarterial maneuvers of the coronary, renal and peripheral arteries. The oxygen carrying solution may include a contrast material that could be beneficial to the critically ill patients on angiography. Thrombolytic agents which contain the oxygen carrier may be safely infused into the c o r o n q artery system using percutaneous
Downloaded by [Laurentian University] at 00:33 19 April 2016
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transluminal coronary recanalization. Selective coronary shot of the oxygen carrying solution before occluding coronary arteries will extend the ischemic-tolerance time of the heart at percutaneous transluminal coronary angioplasty. Systemic administration of the oxygen carrying solution should precede these selective uses of the solution in order to improve the oxygenation of the ischemic tissues. 4. GeneralIschemia In general ischemia, the oxygen carrying solution is effective in the treatment of gas embolism, gas intoxication, mountain sickness, submarine sickness and anoxic spell of the cyanotic heart diseases. Systemic oxygenation and improvement of the local tissue circulation will help the recovery of the impaired organs and tissues in the cases of acute renal failure"@', acute hepatic failure, fluminant hepatitis, acute pancmtitis 'I, peptic ulcer of the stomach and duodenum (mucosal ischemia is one of the causes of the ulcer formation). Granuloma formation and detachment of the surgical anastomosis (for example, trachea, bronchus) caused by local ischemia can be prevented by the improvement of the peripheral oxygenation and circulation. Anaerobe infectious disease may be more effectively treated with the aid of systemic administration of the oxygen Carrying solution. Anaerobe-infected cavity such as pyothorax and pyomediastinum can be drained and irrigated with the oxygen carrying solution together with antibiotics. Adjuvant therapy for tumor radiotherapy('" and chemotherapy (I3) has been reported.The rationale is to increase the oxygen level in the anoxic tumor, thereby increasing the efficacy of the ionizing radiation or anti-cancer drugs. II. Perfusional Protection of the Organs During Surgery This theory is based on the effect of preserving aerobic metabolism during ischemia and improving peripheral circulation by the oxygen carrying solution. Cardiopulmonary bypass is usually operated with moderate to deep hypothermia during open heart surgery, which is known as a "controlled shock state." The peripheral circulation is impaired by sludging of the RBC in the capillaries. During circulatory arrest period, anaerobic metabolism progresses. Especially, brain ischemia is a critical problem in the aortic arch surgery. All of these conditions can be improved by using the oxygen carrying solution as a perfusate during cardiopulmonary bypass to improve the peripheral circulation and oxygenation. The results of cardiac operations depend upon the protection of the heart from ischemia. Cardioplegia with oxygen carrying solution may maintain aerobic metabolism during cardiac arrest to preserve high-energy phosphates. In the operation of thoracic aneurysm and thoramabdominal aneurysm, spinal cord ischemia and abdominal organ ischemia often cause paraplegia and abdominal organ failures postoperatively, due to the ischemia of the spinal cord and the abdominal organs during aortic crossclamp. Systemic administration of the oxygen carrying solution w i l l increase the ischemic tolerance of the organs. Additionally, selective perfusion of the intercostal and lumber arteries, the celiac artery, the superior mesenteric artery and the renal arteries during aortic clamping are considered to be much more beneficial to protect the organs. LU. Extended Preservation of the Donor Organs The oxygen carrying solutions can be utilized as the preservation solution of the donor organs in transplantation. Ex vivo organs may be preserved in less-ischemic condition, and better organ function can be expected postoperatively. IV. Hybrid Artificial 0Culture of the hepatocytea and islet cells of Langerhans are more easily performed by adding the oxygen carrying solution to the culture medium. They can be used as the hybrid artificial organs in the patients with metabolic insufficiency and hormonal deficiency.
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V. Drugcarrier If the drug is conjugated with hemoglobin molecule or peffluorochemicals, we can use them as a drug carrier to the blocked capillary beds while increasing the drug sensitivity of the peripheral tissues by oxygenation. VI. Contrast Agent Perfluorooctylbromide can be used as a new contrast agent with oxygen carrying capability in ultrasound, computed tomography, angiography, magnetic resonance imaging, liver and spleen imaging and tumor imaging(I4). The capability will help the critically ill and other patients from having acute side effects caused by the lack of oxygen during the time of diagnosis.
NON-CLINICAL APPLICATIONS The oxygen carrying solution may be used in culture media of the tissues and bacteria (aerobes) in chemical examination such as an indicator for oxygen sensor and a standard solution for oxygen calibrator, and in some kinds of bioreactor. PARADOXICAL UTILIZATIONS If the oxygen affinity is controllable, the artificial red cells can be used as an oxygen absorbent, paradoxically. A new therapy for malignant tumors will be developed, that is, "Oxygen pulse therapy combined with radiotherapy or chemotherapy." This consists of two stages. The first stage, "low oxygen affinity solution," is used as an adjuvant therapy of radiation to deliver the oxygen to the tumors to increase radiosensitivity. The second stage, "high oxygen affinity solution," namely, oxygen absorbent, is given selectively to the feeding artery of the tumor expecting anoxic necrosis of the tumor. CONCLUSION We have many potential applications of the oxygen carrying solution; however, blood contains all the ingredients which maintain our lives normally, and there is no artificial "blood substitute" which can replace whole blood in the body. We should know that the oxygen carrying solution is a solution which contains only needed oxygen to the tissues, and that it should not be used as a "substitute" of whole blood. Even though it is not a perfect red cell substitute, this oxygen carrying solution has many additional therapeutic properties because it will reach tissues more easily than normal human red cells and deliver needed oxygen directly to tissues. In this paper, important examples of such usages are suggested. Additional clinical and non-clinical applications of the oxygen carrying solutions may be added in the near future. REFERENCES 1. Chang TMS. Semipermeable microcapsules. Science 146524, 1964. 2 Djordjevich L, Miler IF. Synthetic erythrocytes from lipid encapsulated hemoglobin. Exp Hematol 8584, 1980. 3. Geyer RP. Perfluorochemicals as oxygen transport vehicles. Biomat Artif Cells Anif Organs 16:31, 1988. 4. Farmer MC, Rudolph AS, Vandegriff KD, Hayre MD, Bayne SA, Johnson SA. Liposomeencapsulated hemoglobin: Oxygen binding properties and respiratory function. Biomat Anif Cells AnifOrgans 16:289, 1988. 5 . Tsuchida E, Nishide H, Ohno H. Liposomelheme as a totally synthetic oxygen carrier. Biomat Anif Cells Anif Organs 16:313, 1988.
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6. Malchesky PS, Takahashi T, Iwasaki K, Harasaki H, Nose’ Y. Conjugated human hemoglobin as a physiological oxygen carrier-pyridoxalated hemoglobin polyoxyethylene conjugate (PHP). Int J Anif Organs 13:442, 1990. 7. Chen HS, Yang, ZH. Perfluorowbons as blood substitute in clinical applications and in war casualties. Eiomat Anif C e h Anf Organs 16:403, 1988. 8. Agishi T, Funakoshi Y, Honda H, Yamagata K, Kobayashi M, Takahashi M. Pyridoxalated hemoglobin polyoxyethylene conjugate solution as blood substitute for normothermic whole body rinse-out. Eiomut Anif Cells Anif Organs 16:261, 1988. 9. Yabuki A, Matsushita M, Malchesky PS, Iwasaki K, Nose’ Y. In vitro evaluation of a pyridoxalated hemoglobin polyoxyethylene conjugate in reversing cell sickling. Trans Am SOCAnif Intern Organs 34:773, 1988. 10. Sonda K, Agishi T, Honda H, Funakoshi Y, Yamagata Y, Ota K. Relief of ischemic renal injury by using polyethylene glycol conjugate of pyridoxalated human hemoglobin (stabilized hemoglobin: sHb). Jpn J Anif Organs 18:361, 1989. 11. Ohyanagi H, Ohashi 0, Nakayama S, Yamamoto M, Okumura S , Saitoh Y. Experimental studies on fluosol DA administration in acute pancreatitis. Eiomat .4nif Cells Anif Organs 16585, 1988. 12. Lustig RA, Rose CM, McIntosh-LoweNL. Fluosol DA and oxygen as an adjuvant to the radiotheraputic management of advanced headlneck carcinoma. Biornar Anf Cells Anif Organs 16511, 1988. 13. Teicher BA, McIntosh-LoweNL, Rose CM. Effect of various oxygenation conditions and Fluosol-DA on cancer chemotherapeuticagents. Eiornar Arfif Cells Anif Organs 16533, 1988. 14. Long DM, Long DC, Mattrey RF,Long RA, Burgan AR, Herrick WC, Shellhamer DF.
