- Email: [email protected]
Nonthrombogenic Materials and Strategies
758
SECTION II.5 Applications of Biomaterials
and rods (>450,000 per year). The economic impact is massive; in 2000 costs associated with prostheses and organ replacement therapies exceeded $300 billion US per year, and comprised >1% of the US gross domestic product (GDP) and nearly 8% of total healthcare spending worldwide (Lysaght and O’Loughlin, 2000). Thus, medical devices contribute to the expense associated with modern healthcare in the United States, which is presently in excess of 17% of GDP, continues to grow, and has become a significant public policy issue. For the widely used artificial eye lenses, at 2.5 million surgeries performed annually at a rate of about $3200 to $4500 per eye, the total expenditure is estimated at between $8 billion and $10 billion per year. The use of health technology assessment tools can assist those in leadership positions in making rational decisions as to which new technologies to adopt, based on evaluation of clinical effectiveness, cost-effectiveness, and risk to patients. Most implants serve their recipients well for extended periods by alleviating the conditions for which they were implanted. Considerable effort is expended in understanding biomaterials–tissue interactions and eliminating patient–device complications (the clinically important manifestations of biomaterials–tissue interactions). Moreover, many patients receive substantial and extended benefit, despite complications. For example, heart valve disease is a serious medical problem affecting over 30,000 people per year in the United States. Patients with aortic stenosis (the most common form of heart valve disease) have a 50% chance of dying within approximately three years without surgery. Surgical replacement of a diseased valve leads to an expected survival of 70% at 10 years, a substantial improvement over the natural course. However, of these patients whose longevity and quality of life have clearly been enhanced, approximately 60% will suffer a serious valve-related complication within 10 years after the operation. Thus, long-term failure of biomaterials leading to a clinically significant event does not preclude clinical success, for a significant duration and overall. The range of tolerable risk of adverse effects varies directly with the medical benefit obtained by the therapy. Benefit and risk go hand-in-hand, and clinical decisions are
CHAPTER II.5.2 NONTHROMBOGENIC MATERIALS AND STRATEGIES: CASE STUDY Michael V. Sefton1, Cynthia H. Gemmell1, and Maud B. Gorbet2 1Department
of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada 2Department of Systems Design Engineering, University of Waterloo, Canada
ISO Standard 10993-4, Biological Evaluation of Medical Devices Part 4: The Effects on Blood (ISO/
made to maximize the ratio of benefit to risk. The tolerable benefit–risk ratio may depend on the type of implant and the medical problem it is used to correct. Thus, more risk can be tolerated with a heart assist device (a life-sustaining implant) than with a prosthetic hip joint (an implant that relieves pain and disability and enhances function), and much more risk than with a breast implant (an implant with predominantly cosmetic benefit). As an example, total hip arthroplasties (THAs) with metal-on-metal (MoM) or more correctly cobalt alloy-on-cobalt alloy articulating surfaces, have been used clinically since the 1950s. Applications of recent generation THAs exceed hundreds of thousands. Very recently, metallic debris products in larger quantities have been associated with adverse foreign-body reactions, need for revisions, and a recall action of one design/product; for updated information on this topic, students are referred to the US Food and Drug Administration (FDA) web site (http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/default.htm), the American Academy of Orthopaedic Surgeons website (AAOS.org) and/or the American Society for Testing and Materials website (ASTM.org). An ASTM symposium Standard Technical Publication (STP) on this topic should be available in late 2012. In summary, this section explores the most widely used applications of materials in medicine, biology, and artificial organs. The progress made in many of these areas has been substantial. In most cases, the individual chapters describe a device category from the perspective of the clinical need, the armamentarium of devices available to the practitioner, the results and complications, and the challenges to the field that limit success.
BIBLIOGRAPHY US Food and Drug Administration (FDA). (2012). http://www.fda. gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/default.htm. Lysaght, M. J., & O’Loughlin, J. A. (2000). Demographic scope and economic magnitude of contemporary organ replacement therapies. ASAIO J., 46, 515–521. The Wall Street Journal. (2011). http://247wallst.com/2011/07/18/ the-eleven-most-implanted-medical-devices-in-america/. July 18.
AAMI 1995), which manufacturers of medical devices need to use as guidance to register their products, includes thrombosis and coagulation among the tests that need to be done. However, specific test methods are not detailed. With a view to clarifying this question, a series of plasma-modified tubes (along with an unmodified control and other commercially available tubing) were prepared, surface characterized, and exposed to heparinized whole blood (1 U/mL heparin) for one hour at 37°C (Sefton et al., 2001). The surface modifications included several different plasma vapors (H2O, CF4, and fluorine). The 1.5 mm
Due to an error in production the full version of this chapter is available in Appendix E.
Chapter II.5.2 Nonthrombogenic Materials and Strategies: Case Study ID (internal diameter) tubing was incubated with whole blood on a rocking platform to gently agitate the blood and keep the cells from overtly settling. This system does not probe the effect of shear on cell activation; rather the agitation and long incubation time are thought sufficient to create “well-mixed” conditions. Some of the results from this study are shown in Figure II.5.2.1 and Table II.5.2.1. One of the conclusions from this study is that the materials with the lowest levels of platelet and leukocyte activation (microparticle formation, CD11b upregulation) were the unmodified materials (polyethylene, Pellethane™, a polyurethane), and
759
that the surface modifications tested here had either no effect or only made things worse from the perspective of platelet and leukocyte activation. The scanning electron micrographs showing little cellular deposit on the polyethylene or Pellethane™ were consistent with the flow cytometry findings. Except for those materials that were worse, the other materials expressed similar levels of activation for platelets, leukocytes, and the other markers tested; i.e., the majority of the “inert” materials (in the absence of bioactive components like heparin) appear to have a similar non-specific effect on blood.
FIGURE II.5.2.1 Cell activation results after 60 min contact with whole blood (1 unit/mL heparin) at 37°C. Flow cytometry results are mean ±SD. (a) Platelet microparticle levels (percentage of platelet events); (b) Leukocyte CD11b up-regulation (expressed relative to the maximum upregulation obtained with a phorbol ester). (c) Scanning Electron Micrographs of biomaterial surfaces following exposure to blood. Scale bar is 10 µm. PE: Polyethylene; Pell: Pellethane.
760
SECTION II.5 Applications of Biomaterials
TAB L E I I . 5 . 2 . 1 Most Biomaterials are the Same Parameter Platelet count loss (%) P-selectin (% positive) Platelet–leukocyte aggregates (fluorescent intensity) CD11b upregulation (% of maximum) L-selectin shedding
EDTA* Control (or Equivalent) 0 (by definition) 6.4 46
Value for Most Materials 25–35 ~8–9 ~200–250
15
~50–60
11
~70–90
Most materials, despite very different non-specific chemical modifications, resulted in similar levels of platelet and leukocyte activation. These were higher than the corresponding negative control values. The similarity of CD11b upregulation values is seen in Figure II.5.2.1b, while the presence of exceptions that were more activating is seen in the microparticle results in Figure II.5.2.1a. *Ethylenediaminetetraacetic acid.
CHAPTER II.5.3 INTRODUCTION TO CARDIOVASCULAR MEDICAL DEVICES Frederick J. Schoen Professor of Pathology and Health Sciences and Technology (HST), Harvard Medical School, Executive Vice Chairman, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
The past several decades have witnessed a virtual explosion in the number and scope of innovative surgical and interventional diagnostic and therapeutic procedures performed on patients with cardiovascular diseases. Data from the National Center for Health Statistics and the American Heart Association indicate that approximately seven million major cardiac and vascular operations are done annually in the United States. Concurrent with and integral to the broad application of these surgical and interventional procedures is the use of various prostheses and medical devices. Data from 2006 (reported in 2009) show 641,000 percutaneous coronary interventions (almost all using endovascular bare-metal and drug-eluting stents), 253,000 coronary artery bypass graft procedures, 104,000 cardiac valve procedures (using approximately 85,000 substitute heart valves, pacemakers (418,000), implanted cardioverter-defibrillators (114,000) and their leads, and many cardiac assist devices, vascular grafts, umbrellas, patches, and others (Lloyd-Jones et al., 2009). Thus, cardiovascular prostheses and medical devices, and their constituent biomaterials, are of critical importance to interventional cardiologists, and cardiac and vascular surgeons. The number and complexity of devices permit choices among surgical or catheter-based interventional options that optimize short- and long-term patient management. The recognition and understanding of complications of these devices, many of them related to the biomaterials that comprise them, has led to iterative
The results from this study contrast sharply with other studies (many of them cited in this chapter) showing large differences in blood interactions between different biomaterials. This highlights the lack of consensus about blood–materials interactions. Reasons for this lack of consensus are discussed in Chapter II.3.5.
BIBLIOGRAPHY ISO/AAMI. (1995). ISO Standard 10993-4, Biological Evaluation of Medical Devices. In: AAMI Standards and Recommended Practice, pp. 45–68, Vol. 4. Washington, DC: American Association for Medical Instrumentation. Sefton, M. V., Sawyer, A., Gorbet, M., Black, J. P., Cheng, E., Gemmell, C., & Pottinger-Cooper, E. (2001). Does surface chemistry affect thrombogenicity of surface modified polymers? J. Biomed. Mater. Res., 55, 447–459.
efforts to improve their performance and safety through biomaterials and device research and development that has led to improvements which have been translated into improved patient care. The nature, frequency, and pathologic anatomy of their complications, as well as the responsible blood–tissue–biomaterials interaction mechanisms have been published for widely used devices used for many years, but are less well-appreciated for recently introduced or modified devices, and those currently in development (Schoen, 2001; Schoen and Edwards, 2001). This section, composed of 4 sub-chapters, summarizes key considerations in cardiovascular medical devices, including the underlying pathology of the conditions they are designed and used to treat, relevant biomaterials research, and the most important complications that need to be circumvented. The first chapter (II.5.3.A) summarizes cardiac valve prostheses, which have been used extensively and for approximately a half century, are clinically important; their outcomes and pathological descriptions of complications encountered with many different types of valve prostheses are well-known. The second chapter (II.5.3.B) discusses devices used for vascular repair and replacement (including vascular grafts and endovascular stents [and stent grafts]). The third chapter (II.5.3.C) discusses pacemakers and implantable cardioverter-defibrillators, cardiac assist and replacement devices and miscellaneous cardiovascular devices, including percutaneous catheter-based techniques to treat cardiovascular disease in a minimally invasive manner, such as septal defect closure devices, filters to prevent pulmonary embolism and left atrial occlusion devices, and devices to minimize the consequences of a dilated, failing heart. Finally, in the fourth chapter (II.5.3.D), specific biomaterials and engineering design issues related to implantable cardiac assist devices and artificial hearts, a complex and evolving set of technologies, are discussed.
SECTION II.5 Applications of Biomaterials
and rods (>450,000 per year). The economic impact is massive; in 2000 costs associated with prostheses and organ replacement therapies exceeded $300 billion US per year, and comprised >1% of the US gross domestic product (GDP) and nearly 8% of total healthcare spending worldwide (Lysaght and O’Loughlin, 2000). Thus, medical devices contribute to the expense associated with modern healthcare in the United States, which is presently in excess of 17% of GDP, continues to grow, and has become a significant public policy issue. For the widely used artificial eye lenses, at 2.5 million surgeries performed annually at a rate of about $3200 to $4500 per eye, the total expenditure is estimated at between $8 billion and $10 billion per year. The use of health technology assessment tools can assist those in leadership positions in making rational decisions as to which new technologies to adopt, based on evaluation of clinical effectiveness, cost-effectiveness, and risk to patients. Most implants serve their recipients well for extended periods by alleviating the conditions for which they were implanted. Considerable effort is expended in understanding biomaterials–tissue interactions and eliminating patient–device complications (the clinically important manifestations of biomaterials–tissue interactions). Moreover, many patients receive substantial and extended benefit, despite complications. For example, heart valve disease is a serious medical problem affecting over 30,000 people per year in the United States. Patients with aortic stenosis (the most common form of heart valve disease) have a 50% chance of dying within approximately three years without surgery. Surgical replacement of a diseased valve leads to an expected survival of 70% at 10 years, a substantial improvement over the natural course. However, of these patients whose longevity and quality of life have clearly been enhanced, approximately 60% will suffer a serious valve-related complication within 10 years after the operation. Thus, long-term failure of biomaterials leading to a clinically significant event does not preclude clinical success, for a significant duration and overall. The range of tolerable risk of adverse effects varies directly with the medical benefit obtained by the therapy. Benefit and risk go hand-in-hand, and clinical decisions are
CHAPTER II.5.2 NONTHROMBOGENIC MATERIALS AND STRATEGIES: CASE STUDY Michael V. Sefton1, Cynthia H. Gemmell1, and Maud B. Gorbet2 1Department
of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada 2Department of Systems Design Engineering, University of Waterloo, Canada
ISO Standard 10993-4, Biological Evaluation of Medical Devices Part 4: The Effects on Blood (ISO/
made to maximize the ratio of benefit to risk. The tolerable benefit–risk ratio may depend on the type of implant and the medical problem it is used to correct. Thus, more risk can be tolerated with a heart assist device (a life-sustaining implant) than with a prosthetic hip joint (an implant that relieves pain and disability and enhances function), and much more risk than with a breast implant (an implant with predominantly cosmetic benefit). As an example, total hip arthroplasties (THAs) with metal-on-metal (MoM) or more correctly cobalt alloy-on-cobalt alloy articulating surfaces, have been used clinically since the 1950s. Applications of recent generation THAs exceed hundreds of thousands. Very recently, metallic debris products in larger quantities have been associated with adverse foreign-body reactions, need for revisions, and a recall action of one design/product; for updated information on this topic, students are referred to the US Food and Drug Administration (FDA) web site (http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/default.htm), the American Academy of Orthopaedic Surgeons website (AAOS.org) and/or the American Society for Testing and Materials website (ASTM.org). An ASTM symposium Standard Technical Publication (STP) on this topic should be available in late 2012. In summary, this section explores the most widely used applications of materials in medicine, biology, and artificial organs. The progress made in many of these areas has been substantial. In most cases, the individual chapters describe a device category from the perspective of the clinical need, the armamentarium of devices available to the practitioner, the results and complications, and the challenges to the field that limit success.
BIBLIOGRAPHY US Food and Drug Administration (FDA). (2012). http://www.fda. gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/default.htm. Lysaght, M. J., & O’Loughlin, J. A. (2000). Demographic scope and economic magnitude of contemporary organ replacement therapies. ASAIO J., 46, 515–521. The Wall Street Journal. (2011). http://247wallst.com/2011/07/18/ the-eleven-most-implanted-medical-devices-in-america/. July 18.
AAMI 1995), which manufacturers of medical devices need to use as guidance to register their products, includes thrombosis and coagulation among the tests that need to be done. However, specific test methods are not detailed. With a view to clarifying this question, a series of plasma-modified tubes (along with an unmodified control and other commercially available tubing) were prepared, surface characterized, and exposed to heparinized whole blood (1 U/mL heparin) for one hour at 37°C (Sefton et al., 2001). The surface modifications included several different plasma vapors (H2O, CF4, and fluorine). The 1.5 mm
Due to an error in production the full version of this chapter is available in Appendix E.
Chapter II.5.2 Nonthrombogenic Materials and Strategies: Case Study ID (internal diameter) tubing was incubated with whole blood on a rocking platform to gently agitate the blood and keep the cells from overtly settling. This system does not probe the effect of shear on cell activation; rather the agitation and long incubation time are thought sufficient to create “well-mixed” conditions. Some of the results from this study are shown in Figure II.5.2.1 and Table II.5.2.1. One of the conclusions from this study is that the materials with the lowest levels of platelet and leukocyte activation (microparticle formation, CD11b upregulation) were the unmodified materials (polyethylene, Pellethane™, a polyurethane), and
759
that the surface modifications tested here had either no effect or only made things worse from the perspective of platelet and leukocyte activation. The scanning electron micrographs showing little cellular deposit on the polyethylene or Pellethane™ were consistent with the flow cytometry findings. Except for those materials that were worse, the other materials expressed similar levels of activation for platelets, leukocytes, and the other markers tested; i.e., the majority of the “inert” materials (in the absence of bioactive components like heparin) appear to have a similar non-specific effect on blood.
FIGURE II.5.2.1 Cell activation results after 60 min contact with whole blood (1 unit/mL heparin) at 37°C. Flow cytometry results are mean ±SD. (a) Platelet microparticle levels (percentage of platelet events); (b) Leukocyte CD11b up-regulation (expressed relative to the maximum upregulation obtained with a phorbol ester). (c) Scanning Electron Micrographs of biomaterial surfaces following exposure to blood. Scale bar is 10 µm. PE: Polyethylene; Pell: Pellethane.
760
SECTION II.5 Applications of Biomaterials
TAB L E I I . 5 . 2 . 1 Most Biomaterials are the Same Parameter Platelet count loss (%) P-selectin (% positive) Platelet–leukocyte aggregates (fluorescent intensity) CD11b upregulation (% of maximum) L-selectin shedding
EDTA* Control (or Equivalent) 0 (by definition) 6.4 46
Value for Most Materials 25–35 ~8–9 ~200–250
15
~50–60
11
~70–90
Most materials, despite very different non-specific chemical modifications, resulted in similar levels of platelet and leukocyte activation. These were higher than the corresponding negative control values. The similarity of CD11b upregulation values is seen in Figure II.5.2.1b, while the presence of exceptions that were more activating is seen in the microparticle results in Figure II.5.2.1a. *Ethylenediaminetetraacetic acid.
CHAPTER II.5.3 INTRODUCTION TO CARDIOVASCULAR MEDICAL DEVICES Frederick J. Schoen Professor of Pathology and Health Sciences and Technology (HST), Harvard Medical School, Executive Vice Chairman, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
The past several decades have witnessed a virtual explosion in the number and scope of innovative surgical and interventional diagnostic and therapeutic procedures performed on patients with cardiovascular diseases. Data from the National Center for Health Statistics and the American Heart Association indicate that approximately seven million major cardiac and vascular operations are done annually in the United States. Concurrent with and integral to the broad application of these surgical and interventional procedures is the use of various prostheses and medical devices. Data from 2006 (reported in 2009) show 641,000 percutaneous coronary interventions (almost all using endovascular bare-metal and drug-eluting stents), 253,000 coronary artery bypass graft procedures, 104,000 cardiac valve procedures (using approximately 85,000 substitute heart valves, pacemakers (418,000), implanted cardioverter-defibrillators (114,000) and their leads, and many cardiac assist devices, vascular grafts, umbrellas, patches, and others (Lloyd-Jones et al., 2009). Thus, cardiovascular prostheses and medical devices, and their constituent biomaterials, are of critical importance to interventional cardiologists, and cardiac and vascular surgeons. The number and complexity of devices permit choices among surgical or catheter-based interventional options that optimize short- and long-term patient management. The recognition and understanding of complications of these devices, many of them related to the biomaterials that comprise them, has led to iterative
The results from this study contrast sharply with other studies (many of them cited in this chapter) showing large differences in blood interactions between different biomaterials. This highlights the lack of consensus about blood–materials interactions. Reasons for this lack of consensus are discussed in Chapter II.3.5.
BIBLIOGRAPHY ISO/AAMI. (1995). ISO Standard 10993-4, Biological Evaluation of Medical Devices. In: AAMI Standards and Recommended Practice, pp. 45–68, Vol. 4. Washington, DC: American Association for Medical Instrumentation. Sefton, M. V., Sawyer, A., Gorbet, M., Black, J. P., Cheng, E., Gemmell, C., & Pottinger-Cooper, E. (2001). Does surface chemistry affect thrombogenicity of surface modified polymers? J. Biomed. Mater. Res., 55, 447–459.
efforts to improve their performance and safety through biomaterials and device research and development that has led to improvements which have been translated into improved patient care. The nature, frequency, and pathologic anatomy of their complications, as well as the responsible blood–tissue–biomaterials interaction mechanisms have been published for widely used devices used for many years, but are less well-appreciated for recently introduced or modified devices, and those currently in development (Schoen, 2001; Schoen and Edwards, 2001). This section, composed of 4 sub-chapters, summarizes key considerations in cardiovascular medical devices, including the underlying pathology of the conditions they are designed and used to treat, relevant biomaterials research, and the most important complications that need to be circumvented. The first chapter (II.5.3.A) summarizes cardiac valve prostheses, which have been used extensively and for approximately a half century, are clinically important; their outcomes and pathological descriptions of complications encountered with many different types of valve prostheses are well-known. The second chapter (II.5.3.B) discusses devices used for vascular repair and replacement (including vascular grafts and endovascular stents [and stent grafts]). The third chapter (II.5.3.C) discusses pacemakers and implantable cardioverter-defibrillators, cardiac assist and replacement devices and miscellaneous cardiovascular devices, including percutaneous catheter-based techniques to treat cardiovascular disease in a minimally invasive manner, such as septal defect closure devices, filters to prevent pulmonary embolism and left atrial occlusion devices, and devices to minimize the consequences of a dilated, failing heart. Finally, in the fourth chapter (II.5.3.D), specific biomaterials and engineering design issues related to implantable cardiac assist devices and artificial hearts, a complex and evolving set of technologies, are discussed.