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Autologous Fibrinogen Purification and Concentration for Use in Fibrin Sealant

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Autologous Fibrinogen Purification and Concentration for Use in Fibrin Sealant Brigham Young University BYU ScholarsArchive Theses and Dissertations 2005-06-08 Autologous Fibrinogen Purification and Concentration For Use in Fibrin Sealant Steven M. Alston Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Chemical Engineering Commons BYU ScholarsArchive Citation Alston, Steven M., "Autologous Fibrinogen Purification and Concentration For Use in Fibrin Sealant" (2005). Theses and Dissertations. 443. https://scholarsarchive.byu.edu/etd/443 This Dissertation is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. AUTOLOGOUS FIBRINOGEN PURIFICATION AND CONCENTRATION FOR USE IN FIBRIN SEALANT by Steven M. Alston, Jr. A dissertation submitted to the faculty of Brigham Young University in partial fulfillment of the requirements of the degree of Doctor of Philosophy Department of Chemical Engineering Brigham Young University August 2005 BRIGHAM YOUNG UNIVERSITY GRADUATE COMMITTEE APPROVAL of a dissertation submitted by Steven M. Alston, Jr. This dissertation has been read by each member of the following graduate committee and by majority vote has been found to be satisfactory. ___________________________ _____________________________________ Date Kenneth A. Solen, Chair ___________________________ _____________________________________ Date S. Fazal Mohammad ___________________________ _____________________________________ Date William G. Pitt ___________________________ _____________________________________ Date John N. Harb ___________________________ _____________________________________ Date Larry L. Baxter BRIGHAM YOUNG UNIVERSITY As chair of the candidate’s graduate committee, I have read the dissertation of Steven M. Alston, Jr. in its final form and have found that (1) its format, citations, and bibliographical style are consistent and acceptable and fulfill the university’s requirements; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the graduate committee and is ready for submission to the university library. ___________________________ ____________________________________ Date Kenneth A. Solen Chair, Graduate Committee Accepted for the Department ____________________________________ W. Vince Wilding Department Chair Accepted for the College ____________________________________ Alan R. Parkinson Dean, Ira A. Fulton College of Engineering and Technology ABSTRACT AUTOLOGOUS FIBRINOGEN PURIFICATION AND CONCENTRATION FOR USE IN FIBRIN SEALANT Steven M. Alston, Jr. Department of Chemical Engineering Doctor of Philosophy Fibrinogen concentrates are used widely as a sealant during and after surgery to reduce blood loss. Commercially available fibrin sealants are made from pooled human blood, which carries the risk of blood-borne diseases, and are expensive. These concerns have brought to focus the need for autologous fibrinogen concentrates. This need has been addressed by utilizing a unique approach in which fibrinogen is precipitated from plasma with protamine. The physical properties of fibrin sealant prepared from fibrinogen precipitated with protamine were evaluated. The optimal precipitation conditions included a plasma protamine concentration of 10 mg/mL at room temperature. Under these conditions 96% ± 4% of the fibrinogen present in the plasma was precipitated and 98% ± 0.9% of the precipitated fibrinogen was clottable. In addition, it was shown that almost 50% of the factor XIII in the plasma was also precipitated along with the fibrinogen. The tensile and adhesion strengths and kinetics of fibrin sealant prepared from protamine-fibrinogen concentrate were evaluated. Tensile strength and adhesion strength both increased with increasing fibrinogen concentration. Addition of calcium chloride significantly increased the tensile and adhesion strengths. The addition of aprotinin and ε-aminocaproic acid (used to inhibit natural fibrinolysis) to the fibrinogen concentrate was shown to have no effect on the mechanical properties of the sealant. Kinetic experiments showed that the clotting time decreased as the thrombin and fibrinogen concentrations were increased. A rat model with controlled renal incisions was employed to evaluate the hemostatic efficacy of the fibrin sealant made from the protamine-fibrinogen concentrate. The fibrin sealant significantly reduced the blood loss and bleeding time when compared with controls (no sealant, plasma, and a commercial product). The sealant also significantly reduced blood loss and bleeding time in rats that were anticoagulated with heparin. A mathematical model based on tensile strength and adhesion strength was developed to predict the bleeding time in the animal wound. Model predictions showed that the ability of the fibrin sealant to reduce bleeding time, and therefore blood loss, was limited by the adhesion strength. ACKNOWLEDGEMENTS Completing this project would not have been possible without the help and support of many people. I would like to briefly acknowledge their contributions. Dr. Solen has been a mentor and advisor throughout this project. He has encouraged me to take ownership of the project by allowing me the freedom to make important decisions regarding the direction the project should take. I appreciate the many helpful ideas and solutions he discussed with me and then let me make the final decision. Working with Dr. Mohammad was a valuable part of my graduate education. I appreciate the many critiques of my experimental techniques and conclusions drawn from those experiments. These experiences helped to further my ability to think critically and logically. Dr. Sukavaneshvar was another important part in completing this project. I appreciate his many suggestions and critiques of my work. He helped me to realize the ultimate goal of the project. I appreciate the help given by Dr. Woolley in obtaining the required drugs for the animal experiments. The animal work would not have gone as smooth as it did were it not for his assistance. I would like to thank the many undergraduate research assistants that helped with the research. Eddie Bywater and Adam Broderick provided a lot of help with the in-vitro tests. I appreciate the time volunteered by John Ashton to help with the animal experiments. Last, but certainly not least, I wish to thank my loving wife Jackee. She has supported me every step of the way through this project. Without her love and support this project would not have been possible. TABLE OF CONTENTS LIST OF TABLES.............................................................................................................. x LIST OF FIGURES .......................................................................................................... xii CHAPTER 1: INTRODUCTION....................................................................................... 1 1.1 Reducing Blood Loss During Surgery................................................................ 1 1.2 Preparation of Fibrinogen Concentrate............................................................... 1 1.3 Goals of this Dissertation.................................................................................... 2 CHAPTER 2: BACKGROUND......................................................................................... 3 2.1 Blood and Coagulation ....................................................................................... 3 2.2 The Role of Fibrinogen....................................................................................... 4 2.3 Fibrin as a Tissue Sealant ................................................................................... 5 2.4 Composition of Fibrin Sealant............................................................................ 6 2.5 Isolation of Fibrinogen........................................................................................ 7 2.5.1 Cryoprecipitation ........................................................................................ 8 2.5.2 Ultrafiltration .............................................................................................. 8 2.5.3 Centrifugation ............................................................................................. 9 2.5.4 Chemical Precipitation................................................................................ 9 2.5.5 Chromatographic Methods........................................................................ 11 2.5.5.1 Fibrin Monomer Matrix ........................................................................ 11 2.5.5.2 Heparin Matrix...................................................................................... 12 2.5.5.3 Protamine Matrix .................................................................................. 13 2.6 Fibrin Sealant Preparations............................................................................... 13 2.6.1 Commercial Sealants ................................................................................ 13 2.6.2 Home-Made Sealants................................................................................ 15 2.6.3 Risk of Virus Transmission ...................................................................... 16 2.7 In-Vitro Evaluations.........................................................................................
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