Medical Coatings and Deposition

Technologies

Scrivener Publishing

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Publishers at Scrivener

Martin Scrivener (martin@scrivenerpublishing.com)

Phillip Carmical (pcarmical@scrivenerpublishing.com)

Medical Coatings and Deposition

Technologies

Edited byDavid A. Glocker and

Shrirang V. Ranade

Copyright © 2016 by Scrivener Publishing LLC. All rights reserved.

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Library of Congr ess Cataloging-in-Publication Data:

ISBN 978-1-118-03194-0

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

v

Contents

Preface xxi

Part 1 Introduction 1

1 Historical Perspectives on Biomedical Coatings in Medical Devices 3

M. Hendriks and P.T. Cahalan1.1 Introduction 41.2 Improving Physical Properties of Biomaterials:

Hydrophilic, Lubricious Coatings 51.3 Modulating Host-Biomaterial Interactions:

Biologically Active Coatings 71.3.1 Heparin Coatings 71.3.2 Antimicrobial Coatings 9

1.3.2.1 Antimicrobial-Releasing Materials 111.3.2.2 Nonadhesive Surfaces 121.3.2.3 Promoting Tissue Integration 12

1.3.3 Drug-Eluting Coatings 141.4 Bioinert Coatings Redressed? Nonfouling Coatings 151.5 Future Biomedical Coatings 16References 18

Part 2 Coating Applications 27

2 Antimicrobial Coatings and Other Surface Modifications for Infection Prevention 29

Marc W. Mittelman and Nimisha Mukherjee2.1 Introduction 292.2 Genesis of Device-Related Infections 352.3 Antimicrobial Coatings 38

2.3.1 Antibiotics 40

vi Contents

2.3.2 Non-Antibiotic Antimicrobial Compounds 412.3.2.1 Organic Compounds 412.3.2.2 Silver and Other Metals 48

2.4 Non-Eluting Antimicrobial Surfaces 492.4.1 Pendant Chemistries 49

2.4.1.1 Zwitterionic Surfaces 512.4.1.2 Topographical Modifications 52

2.5 Coating and Surface Modification Technologies 532.5.1 Passive-Release Technologies 53

2.5.1.1 Diffusion-Based Antimicrobial Coatings 532.5.1.2 Solvent Imbibing of Antimicrobials 54

2.5.2 Sputter Coating Systems 552.5.3 Covalent Surface Modification 552.5.4 Other Technologies 56

2.6 Regulatory Considerations 572.7 Future Challenges 58

2.7.1 Antimicrobial Resistance 582.7.2 Biocompatibility 61

References 61

3 Drug Delivery Coatings for Coronary Stents 75

Shrirang V. Ranade and Kishore Udipi3.1 Introduction 75

3.1.1 Coronary Artery Disease: Treatment Options and Issues 76

3.1.2 Bare-Metal Stents 793.1.3 Drug-Eluting Stents 80

3.2 Polymer Coatings for DES 813.2.1 Requirements for Coronary Stent Coatings 813.2.2 Physical and Chemical Properties 82

3.2.2.1 Stability 833.2.2.2 Sterilization 833.2.2.3 Compatibility with the

Drug and Drug Elution 833.2.3 Biological Properties 84

3.2.3.1 Biocompatibility with Vascular Tissue 843.2.4 Coating Optimization 85

3.3 Biostable (Non-Bioabsorbable) Polymers 863.3.1 Poly(Ethylene-Co-Vinyl Acetate)/

Poly(n-Butylmethacrylate)/Parylene C 87

Contents vii

3.3.2 Poly(Styrene-block-Isobutylene-block-Styrene) (SIBS) 89

3.3.3 Poly(Vinylidene Fluoride-co-Hexafluoropropylene)/Poly(n-Butyl Methacrylate) 92

3.3.4 Phosphorylcholine-Based Polymer Coating System (PC) 94

3.3.5 BIOLINX Polymer Coating 963.4 Bioabsorbable Polymers 993.5 Concluding Remarks 103References 104

4 Coatings for Radiopacity 115

Scott Schewe and David A. Glocker 4.1 Principles of Radiography 115 4.2 Use of Radiopaque Materials in Medical Devices 116 4.3 Radiopaque Fillers 117

4.3.1 Purpose of Radiopaque Fillers in Polymers 117 4.4 Types of Radiopaque Fillers 117

4.4.1 Barium Compounds 117 4.4.2 Bismuth Compounds 118 4.4.3 Metals 119 4.4.4 Material Modifications to Enhance Radiopacity 121

4.5 Other Radiographic Materials and Coating Systems 121 4.5.1 Metal-Loaded Polymer Suspensions 121

4.6 Radiopaque Coatings by Physical Vapor Deposition 122 4.7 Challenges in Producing Radiopaque

Coatings Using PVD 124 4.8 Gold Radiopaque Coatings 125 4.9 Tantalum Radiopaque Coatings 1264.10 Summary 129References 130

5 Biocompatibility and Medical Device Coatings 131

Joseph McGonigle, Thomas J. Webster and Garima Bhardwaj5.1 Introduction 1315.2 Challenges with Medical Devices 134

5.2.1 Toxicity 1345.2.2 Inflammation 1375.2.3 Blood Compatibility 1395.2.4 Wound Healing 1425.2.5 Encapsulation 1445.2.6 Tissue Integration 145

viii Contents

5.2.7 Vascularization 1455.2.8 Infection 146

5.3 Examples of Products Coated to Improve Biocompatibility 148 5.3.1 Stents 148 5.3.2 Surgical Mesh Materials 150 5.3.3 Orthopedic Implants 151 5.3.4 Sensors 153 5.3.5 Pacemaker Leads 154 5.3.6 Neurological Devices 154 5.3.7 Catheters/Endotracheal Tubes 156 5.3.8 Ocular 156

5.4 Types of Biocompatible Coatings 157 5.4.1 Polymers and Surface Modification 157 5.4.2 Surface Preparation and Polymer Deposition 157 5.4.3 Covalent Bonding 160 5.4.4 Biocompatible Biomaterials 161 5.4.5 Hydrophilic and Nonfouling Polymers 161 5.4.6 Small Molecule Pharmaceuticals 163 5.4.7 Extracellular Matrix Proteins and Peptides 163 5.4.8 Heparin and Polysaccharides 165 5.4.9 Antibody and Other Biomolecule Coatings 1665.4.10 Orthopedics/Calcium Phosphate/BMP 1665.4.11 Porosity 1685.4.12 Surface Roughness 169

5.5 Commercialization 170 5.5.1 Cost Challenges 170 5.5.2 Manufacturing Challenges 171 5.5.3 Animal-Derived Materials 171

5.6 Summary 172References 172

6 Tribological Coatings for Biomedical Devices 181

Peter Martin6.1 Introduction 1816.2 Hard Thin Film Coatings for Implants 187

6.2.1 Titanium- and Chromium-Based Thin Film Materials 188

6.3 Binary Carbon-Based Thin Film Materials: Diamond, Hard Carbon and Amorphous Carbon 1946.3.1 Tribological Properties 194

Contents ix

6.4 Progress of DLC, ta-C and a-C:H Films for Hip and Knee Implants 2006.4.1 Diamond-like Carbon 2006.4.2 Biocompatibility and Thrombus Formation 2056.4.3 Aluminum Oxide Thin Films 206

6.5 Wear-Resistant Coatings for Stents and Catheters 2086.6 Wear-Resistant Coatings for Angioplasty Devices 2106.7 Scalpel Blades and Surgical Instruments 2106.8 Multifunctional, Nanostructured, Nanolaminate, and

Nanocomposite Tribological Materials 210References 222

Part 3 Coating and Surface Modification Methods 233

7 Dip Coating 235

Donald M. Copenhagen7.1 Description and Basic Steps 2357.2 Equipment and Coating Application 236

7.2.1 Hand Dipping 2367.2.2 Mechanical Dipping 236

7.3 Coating Solution Containers 2377.4 Coating Parameters and Controls 2387.5 Role of Solution Viscosity 240

7.5.1 Viscosity and Withdrawal Velocity 2407.5.2 Molecular Weight of Polymers 2407.5.3 Viscosity as a Function of Solids Content 241

7.6 Coating Problems 2417.6.1 Partial Coating 2417.6.2 Vibration 2417.6.3 Humidity 2427.6.4 Run Back 2427.6.5 Orange Peel 2427.6.6 Chatter 2427.6.7 Craters 2437.6.8 Bubbles 2437.6.9 Poor Adhesion 243

7.7 Process Considerations 244

x Contents

8 Inkjet Technology and Its Application in Biomedical Coating 247

Bogdan V. Antohe, David B. Wallace and Patrick W. Cooley8.1 Introduction 2478.2 Inkjet Background 248

8.2.1 Continuous Inkjet (CIJ) 2488.2.2 Drop-on-Demand (DOD) 250

8.2.2.1 General Discussion 2508.2.2.2 Less Common Actuation Methods 2508.2.2.3 Thermal Inkjet 2528.2.2.4 Piezoelectric Inkjet 254

8.2.3 Comparison of CIJ and DOD 2588.2.4 Drop Formation 260

8.3 Equipment Used 2608.3.1 Dispenser/Printhead 2618.3.2 Motion 2638.3.3 Auxiliary Equipment 264

8.3.3.1 Drive Electronics 2648.3.3.2 Pressure Control 2648.3.3.3 Temperature Control 2658.3.3.4 Environmental Control 2658.3.3.5 Optics 2668.3.3.6 Maintenance 2668.3.3.7 Other Auxiliary Components 267

8.3.4 Software 2678.3.5 Printing Platform Manufacturers 268

8.4 Capabilities 2688.4.1 Surface Activation and Passivation 268

8.4.1.1 Microarrays 2688.4.1.2 Tissue MALDI – Application of Matrix

Solutions 2688.4.1.3 Nerve Conduits – Fabrication and

Coating to Create a Nerve Growth Factor (NGF) Gradient 270

8.4.1.4 Coating for Activation 2718.4.2 Drug Release/Delivery 276

8.5 Limitations and Ways around Them 2808.5.1 Requirements of Dispensed Materials 280

8.5.1.1 Viscosity 2808.5.1.2 Surface Tension 2818.5.1.3 Volatility/Boiling Point 281

Contents xi

8.5.2 Operational Limitations 2818.5.3 Liquid – Substrate Interaction 282

8.5.3.1 Single or Multiple Drops Placed at one Location 282

8.5.3.2 Feature Generation (Lines or Area Coverage) by Drop Distribution 284

8.5.4 Failure Modes 2878.5.4.1 Clogging 2888.5.4.2 Drop Placement Errors 288

8.5.5 Minimizing Operational Limits and Failure 2908.5.5.1 Printhead 2908.5.5.2 Solution Formulation 2908.5.5.3 Substrate Treatment and Containment

Features 2928.5.5.4 Maintenance 2928.5.5.5 Other Elements of the Printing Process 293

8.6 Manufacturing Advantages and Future Directions 2938.6.1 Advantages 2938.6.2 Potential Applications 294

8.6.2.1 Tissue Engineering 2958.6.2.2 Scaffolds 2958.6.2.3 Skin Regeneration 2958.6.2.4 Transdermal Drug Delivery 2978.6.2.5 Visual Prosthesis 2988.6.2.6 Packaging – Adhesives 298

8.7 Conclusions 299References 300

9 Direct Capillary Printing in Medical Device Manufacture 309

William J. Grande9.1 Introduction 309

9.1.1 Origins and Brief History 3109.1.2 Competitive Technologies 312

9.1.2.1 Direct Writing 3129.1.2.2 Competitors Outside of Direct Writing 3139.1.2.3 Example of the Evolution of

Manufacturing Techniques over Time 3149.1.3 Strategic Considerations for Medical Device

Manufacture 3169.1.4 Summary 319

xii Contents

9.2 Fundamental Elements of Direct Capillary Printing 3209.2.1 Ink Systems 321

9.2.1.1 Single-Phase Inks 3229.2.1.2 Multi-Phase Inks 3239.2.1.3 Curing Temperature 323

9.2.2 Applying Force to the Ink 3279.2.3 The Fluidic Channel 3289.2.4 The Pen Tip 3289.2.5 The Motion Control System 3319.2.6 The Ink-Substrate-Printhead System 3319.2.7 Special Considerations for Medical Devices 333

9.2.7.1 Adhesion and Cohesion Testing 3339.2.7.2 Biocompatibility 3339.2.7.3 Electrochemical Stability 3359.2.7.4 Conflict Minerals 335

9.3 Practical Operational Considerations 3379.3.1 Starting, Stopping, and Idling 3379.3.2 Substrate Effects 3389.3.3 Ink Effects 3419.3.4 Motion Effects 3429.3.5 Lateral Misalignment, Eccentricity, and

Substrate Shape Errors 3439.3.6 Pattern and Tool Path Effects 3459.3.7 Multi-Level Pattern Effects 3489.3.8 Process Integration 348

9.4 Manufacturing Considerations 3499.4.1 Low Volume Manufacturing 3509.4.2 High Volume Manufacturing 351

9.5 Medical Device Examples 3529.5.1 Tube and Catheter Devices 352

9.5.1.1 Instrumented Endotracheal Tube for Cardiac Output Monitoring 352

9.5.1.2 LED-Instrumented Medical Devices for Photodynamic Therapy 355

9.5.2 Balloon-Based Devices 3579.5.2.1 Improved Radiopaque Markings for a

Bone Fracture Repair Catheter 3579.5.2.2 Ablation Electrodes for Denervation 361

9.5.3 Ceramic- and Metal-Based Devices 3639.5.3.1 Bipolar Hemostasis Ablation Probe 3649.5.3.2 Immersion Heater for Ablative Therapies 365

Contents xiii

9.5.4 3D Printing 3669.5.4.1 Flat Flexible Electrode Array 3669.5.4.2 Stents 367

9.6 Conclusions 367Acknowledgments 369References 369

10 Sol-Gel Coating Methods in Biomedical Systems 373

Bakul C. Dave10.1 Introduction 37410.2 Overview of Sol-Gel Coatings in Biomedical Systems 377

10.2.1 Tailored Surfaces 379 10.2.2 Surface Passivation 379 10.2.3 Biocompatibility 380 10.2.4 Release and Growth Media 381

10.3 The Sol-Gel Process 381 10.3.1 Chemistry and Processing 382

10.4 Coating Methods and Processes 385 10.4.1 Dip Coating 386 10.4.2 Spin Coating 387 10.4.3 Spray Coating 388 10.4.4 Self-Assembly 388 10.4.5 Other Methods 389

10.5 Factors Influencing Coatings Characteristics/ Performance 390

10.5.1 Processing Conditions 391 10.5.2 Native Composition/Excipients 392 10.5.3 Porosity 393 10.5.4 Deposition Method 393 10.5.5 Uniformity and Homogeneity 394

10.6 Summary and Concluding Remarks 394References 397

11 Chemical Vapor Deposition 403

Kenneth K. S. Lau11.1 Introduction 40311.2 Process Description 405

11.2.1 Precursor Selection 406 11.2.2 Vapor Delivery 407 11.2.3 Reactor Configuration 407 11.2.4 Precursor Activation 408

xiv Contents

11.2.5 Pressure Management 409 11.2.6 Exhaust Handling 410 11.2.7 Other Peripherals 410

11.3 Process Mechanism 410 11.3.1 Mass Transport 411 11.3.2 Reaction Kinetics 412 11.3.3 Thermodynamics 412 11.3.4 Rate-Limiting Behavior 413

11.4 Technology Advances 414 11.4.1 Thermal CVD of Graphene 414 11.4.2 HWCVD of Nanodiamond 421 11.4.3 ALD of Oxides and Nitrides 426 11.4.4 iCVD of Polymers 433

11.5 Future Outlook 442References 443

12 Introduction to Plasmas Used for Coating Processes 457

David A. Glocker 12.1 Introduction 457 12.2 DC Glow Discharges 459 12.3 RF Glow Discharges 463 12.4 RF Diode Glow Discharges 464 12.5 Ionization in RF Diode Glow Discharges 466 12.6 Inductively Coupled RF Discharges 466 12.7 Mid-Frequency AC Discharges 468 12.8 Pulsed DC Discharges 469 12.9 Comparison of Plasma Properties 47012.10 Plasma Species 47012.11 Summary 471References 472

13 Ion Implantation: Tribological Applications 473

Peter Martin13.1 Introduction 47313.2 Applications 474

13.2.1 Nitrogen Ion Implantation 474 13.2.2 Implantation of C+ Ions 476 13.2.3 Titanium Alloys 479 13.2.4 Tribological Testing 479

13.3 Nanocrystalline Diamond 487 13.3.1 Ti Ion Implanting into DLC 491

Reference 492

Contents xv

14 Plasma-Enhanced Chemical Vapor Deposition 495

Kenneth K. S. Lau14.1 Introduction 49514.2 Process Description 497

14.2.1 Plasma Configuration 498 14.2.2 Plasma Chemistry 499 14.2.3 Plasma Field 500 14.2.4 Plasma Diagnostics 501

14.3 Plasma Effects on Materials Deposition 501 14.3.1 Plasma Configuration: Titanium Dioxide 502 14.3.2 Plasma Chemistry: Ultrananocrystalline

Diamond 507 14.3.3 Plasma Electric Field: Carbon Nanofibers 513

14.4 Future Outlook 520References 521

15 Sputter Deposition and Sputtered Coatings for Biomedical Applications 531

David A. Glocker 15.1 Introduction 531 15.2 Overview of Sputter Coating 533 15.3 Characteristics of Sputtered Atoms 536 15.4 Sputtering Cathodes 539 15.5 Relationship between Process Parameters and

Coating Properties 541 15.6 Biased Sputtering 544 15.7 Adhesion and Stress in Sputtered Coatings 545 15.8 Sputtering Electrically Insulating Materials 546 15.9 Recent Developments 54915.10 Summary and Conclusions 549References 550

16 Cathodic Arc Vapor Deposition 553

Gary Vergason16.1 Introduction 55316.2 Medical Uses of Cathodic Arc Titanium

Nitride Coatings 55616.3 Brief History and Commercial Advancement of

Cathodic Arcs 55716.4 Review of Arc Devices 559

xvi Contents

16.5 Description of PVD Coating Manufacturing 561 16.5.1 Order Entry 562 16.5.2 Cleaning 563 16.5.3 Coating Fixturing and Masking 563 16.5.4 PVD Coating 563

16.5.4.1 Substrate Loading 564 16.5.4.2 Pump Down 565 16.5.4.3 Substrate Heating and Cleaning 565 16.5.4.4 Coating 565 16.5.4.5 Cooldown 566 16.5.4.6 Unloading 566

16.6 Macroparticle Generation and Mitigation 56716.7 Considerations for Coating Success 568

16.7.1 Surface Finish and Contaminants 569 16.7.1.1 Heat Treating 570 16.7.1.2 Abrasive and Chemical Cleaning 570 16.7.1.3 Unbalanced Final Grinding 570 16.7.1.4 Low Temperature Materials 571 16.7.1.5 Press Fit Components 571 16.7.1.6 Polishing Carriers 571

16.7.2 Cleaning for PVD 572 16.7.2.1 Ultrasonic Cleaning 572 16.7.2.2 Plasma Cleaning 572

16.7.3 PVD Masking and Fixturing 573 16.7.4 Inspection and Certification 573

16.7.4.1 Coating Thickness 574 16.7.4.2 Coating Adhesion 575 16.7.4.3 Post Cleaning and Shipping 576

16.8 Materials Used in Biomedical PVD Coatings 576References 576

Part 4 Functional Tests 581

17 Antimicrobial Coatings Efficacy Evaluation 583

Nimisha Mukherjee and Marc W. Mittelman17.1 Introduction 58317.2 In-Vitro Methods 584

17.2.1 Biofilm Development 584 17.2.2 Quantitative Recovery of Cells from Surfaces 586 17.2.3 Zone-of-Inhibition (ZOI) Assays 587

Contents xvii

17.2.4 Antimicrobial Surface Activity (Agar Overlay Technique) 587

17.2.5 Direct Observation 588 17.2.5.1 Epifluorescence Microscopy 588 17.2.5.2 Scanning and Transmission Electron

Microscopy 588 17.2.5.3 Atomic Force Microscopy 589

17.2.6 Characterization of Bacterial and Fungal Cells 590

17.3 In-Vivo (Animal) Methods 59017.4 Equipment and Laboratory Resources 59017.5 Human Clinical Trial Considerations 59017.6 Regulatory Considerations 590

17.6.1 U.S. FDA 590 17.6.2 EU 595 17.6.3 Japan, Australia 595

References 596

18 Mechanical Characterization of Biomaterials: Functional Tests for Hardness 605

Vincent Jardret 18.1 Introduction 60518.2 Basic Principles of Hardness and

Indentation Testing 607 18.2.1 Classic Hardness Scales 607

18.2.1.1 Brinell Hardness Number 607 18.2.1.2 Meyer Hardness 610 18.2.1.3 Vickers Hardness 610 18.2.1.4 Knoop Hardness 610 18.2.1.5 Rockwell Hardness Scale 611

18.3 Depth-Sensing Indentation Testing 611 18.3.1 Determination of the Contact Depth 612 18.3.2 Determination of the Contact Area 615 18.3.3 Determination of the Nanoindentation

Hardness 616 18.3.4 Determination of the Reduced and Young’s

Elastic Modulus 61718.4 Dynamic Indentation Testing: A More Advanced

Hardness Measurement Technique for More Complex Material Behavior 617

18.4.1 Continuous Stiffness Measurement Technique 618

xviii Contents

18.4.2 Constant Strain Rate Experiments 619 18.4.3 Viscoelastic Measurements 623 18.4.4 Case of Strain-Dependent Behavior 623 18.4.5 Case of Very Soft Materials and Influence of

Adhesion 62518.5 Special Case of Coatings Configuration Under

Indentation Testing 62618.6 Conclusions 628References 629

19 Adhesion Measurement of Thin Films and Coatings: Relevance to Biomedical Applications 631

Wei-Sheng Lei, Kash Mittal and Ajay Kumar19.1 Introduction 63119.2 Mechanical Test Methods of Adhesion Measurement 634

19.2.1 Peel Test 634 19.2.2 Scribe (Scratch) Test 635 19.2.3 Pull-Off Test 640 19.2.4 Blister Test 643 19.2.5 Microindentation Test 644 19.2.6 Small Punch Test 648 19.2.7 Edge Delamination Test 649 19.2.8 Four-Point Bending Test 652

19.3 Summary and Remarks 654Appendix 656References 665

20 Functional Tests for Biocompatibility 671

Joseph McConigle and Thomas J. Webster20.1 Introduction 67120.2 Inflammation 672

20.2.1 Macrophage Activation 673 20.2.2 Cytokines 673 20.2.3 Histology 674

20.3 Blood Compatibility 675 20.3.1 Protein and Fibrinogen Adsorption 676 20.3.2 Platelet Adhesion and Activation 680 20.3.3 Hemolysis 681 20.3.4 Complement Activation 681 20.3.5 Clotting and Thrombin Activity Testing 682

Contents xix

20.3.6 Blood Loop Assays 682 20.3.7 In Vivo Thrombosis Assays 683

20.4 Wound Healing 685 20.4.1 Cell Growth 685 20.4.2 Skin Wound Healing Models 687

20.5 Encapsulation 688 20.5.1 Drug Transport 689 20.5.2 Histology (Foreign Body Response) 690

20.6 Tissue Integration 691 20.6.1 Cell Attachment 691 20.6.2 Orthopedics/Mineralization/Osteoblast/

Osteoclast Activation 692 20.7 Vascularization 692

20.7.1 Endothelial In Vitro Cell Assays 693 20.7.2 Angiogenesis In Vitro Assays 694 20.7.3 Endothelialization 695 20.7.4 Vascular Staining and Imaging 697 20.7.5 Functional Blood Flow Measurements 698

20.8 Toxicity 699 20.8.1 In Vitro Tests 699 20.8.2 In Vivo Tests 699

20.9 Infection 700 20.9.1 In Vitro Tests 700 20.9.2 In Vivo Tests 701

20.10 When to Move In Vivo? 701References 702

21 Analytical Requirements for Drug Eluting Stents 707

Lori Alquier and Shrirang V. Ranade21.1 Introduction 70721.2 Instrumentation 70821.3 API and Excipient Characterization 70921.4 Analytical Methods 712

21.4.1 Appearance 712 21.4.2 Identification 713 21.4.3 Drug Assay and Related Impurities/

Degradation Products 713 21.4.4 Residual Solvents (Organic Volatile Impurities) 714 21.4.5 Uniformity of Dosage Units

(Content Uniformity) 714 21.4.6 Polymer Molecular Weight and Content 715

xx Contents

21.4.7 Drug Elution 716 21.4.8 Leachables and Extractables 718 21.4.9 Specifications 719

21.5 Conclusion 719References 719

Part 5 Regulatory Overview 723

22 Regulations for Medical Devices and Coatings 725

Robert J. Klepinski22.1 Introduction 72522.2 Types of Regulated Products 726

22.2.1 Devices 726 22.2.2 Drugs 728 22.2.3 Biologics 729 22.2.4 Combination Products 729 22.2.5 Human Tissue 731

22.3 Scope of Regulation 73222.4 Marketing Clearance of Medical Devices 733

22.4.1 PMA 734 22.4.2 Premarket Notification (PMN or 510(k)) 734 22.4.3 Marketing Clearance of Combination Products 736

22.5 Comparison to EU Regulation 73722.6 Good Manufacturing Practices 739

22.6.1 Device GMPs 739 22.6.2 Drug GMPs 740 22.6.3 Combination Products 741

Part 6 Future of Coating Technologies 743

23 The Future of Biomedical Coatings Technologies 745

Shrirang V. Ranade and David A. Glocker23.1 Introduction 74523.2 The Continuing Evolution of Biomaterials 74923.3 Tissue Engineering and Regenerative Medicine 74923.4 Coating Process Development 750References 751

Index 753

xxi

Preface

Medical devices sit at the crossroads of diverse disciplines such as chemistry, materials science, mechanical and biomedical engineering not to mention biology and medicine. Coatings technology evolved via empir-ical trial and error, but the past few decades have shown a vast increase in the understanding of the applicable principles and elucidation of the underlying science and engineering. The successful development of a coated medical device involves a coordinated effort amongst practitioners in these fields and usually is undertaken to address an unmet clinical need. A coating is provided on a device to either enhance surface properties or impart functionality to better serve the rationale for the design of the device. The point of this book is to showcase examples of how coatings are employed in the enhancement and functioning of medical devices and also survey the manufacturing techniques deployed to produce them. Each chapter focuses on an example of how coatings impart critical func-tionality to the device or espouses upon the technology that makes them possible. The various coating methods are also covered in detail so that a reader with an interest in design of medical devices may learn the options available to provide a coating and gain understanding from the commer-cialized examples detailed within the text.

The scope of medical coatings is so great that one of the most significant challenges we faced was deciding what to include and what to leave out. Our goal was to give the reader enough background in the most widely used types of coatings, coating processes and test methods to provide an understanding of the fundamentals and enough references to guide further reading. We also wanted to include some of the context within which medical devices are produced and have done so in the chapters on historical perspectives and regulatory issues. Finally, we included a perspective on the future of coatings technologies as applied to medical devices in particular. We hope this book is of interest to scientists and engineers in the medical device arena as well as students of biomedical engineering and science who would like to learn more about industrial applications of their art.

xxii Preface

A work like this, of course, is a product of the contributors. We would like to thank the many experts in their fields who devoted their time and energy to creating this book. We are grateful to Martin Scrivener (our long suffering publisher) for his patience and steady encouragement that made this project possible – we largely underestimated the time commit-ment needed to herd authors, juggle careers and of course families over the course of several months. We would also like to acknowledge and thank Aparna Bhave for her early work on the project especially in its infancy.

Shrirang V. Ranade & David A. GlockerApril 10th, 2016.

Part 1

INTRODUCTION

3

David A. Glocker and Shrirang V. Ranade (eds.) Medical Coatings and Deposition Technologies,

(3–26) © 2016 Scrivener Publishing LLC

1

Historical Perspectives on Biomedical Coatings in Medical Devices

M. Hendriks1* and P.T. Cahalan2

1DSM Biomedical Inc., Berkeley, CA, USA 2Ension Inc., Pittsburgh, Pennsylvania, USA

AbstractIn this chapter we will discuss the evolution of biomedical coatings from the

perspective of three generations of biomaterials: From the initial emphasis on “do

no harm” bioinert coatings to second and third generation biomedical coatings

having increasingly more activity and the ability to obtain a beneficial response

through interaction with the biological environment.

After a half century of effort, the arc of progress in biomedical coatings

in medical devices bends towards positive clinical outcomes. Indisputable

demonstration that better management of the material’s biointerface yields

positive impact on clinical outcome remains the most challenging goal and need

for the future.

We conclude that for biomedical coatings to truly deliver such evidence of

clinical outcome improvement it is of quintessential importance to step away from

the tendency to focus on individual aspects and rather focus on the total picture of

the clinical problem. In other words, to bring together a multifactorial approach

to surface science and the cellular and molecular pathophysiology of implanted

devices, so as to optimally calibrate the clinical impact that surface modification

of medical devices will have.

Keywords: Medical coatings, surface modification, biocompatibility, blood

compatibility, biomaterials, medical devices, heparin, antimicrobial

*Corresponding author: marc.hendriks@dsm.com

4 Medical Coatings and Deposition Technologies

1.1 Introduction

The use of biomedical materials has a long and fascinating legacy charac-terized by creativity, innovation and positive medical outcomes. Since the dawn of civilization mankind has been exploring ways in which natural materials might replace or enhance the natural functions of the human body. Archaeological evidence suggests, for example, that the ancient Egyptians used seashells to replace missing teeth and linen to close wounds, creating what may have been the first dental implants and sutures. Natural materials have been the key source of biomedical materials throughout much of the history of their use, from coconut shells used to close holes in skulls to elephant ivory that was used to create the first recorded hip implant in 1891.

The real revolution in biomedical materials began in the 20th century, with the introduction of synthetic materials that enabled medical device makers to break free from many of the limitations and risks associated with relying solely on natural materials. For example [1], polymethyl-methacrylate (PMMA) was used in dentistry in the 1930s and cellulose acetate was used in dialysis tubing in the 1940s. Dacron was used to make vascular grafts; polyetherurethanes were used in artificial hearts; and PMMA and stainless steel were used in total hip replacements. Characteristically, these materials were brought in from other areas of science and technology without substantial redesign for their clinical use purpose. Their choice was based on achieving a suitable combina-tion of physical properties to match those of the replaced tissue with a “biopassive,” minimal toxic response in the host. However, while these materials did enable the development of new medical treatments, critical problems including biocompatibility, thrombogenicity, fibrous encapsula-tion, infectious complications and biostability—oxidative and hydrolytic degradation—remained. A quest for the perfectly inert material, harmless to the host tissue environment ensued. This “do no harm” paradigm is best illustrated by the way professor David Williams defined biocompat-ibility [2]: “The ability of a material to perform with an appropriate host response in a specific application.”

Scientific efforts started to be focused on engineering the materials’ surfaces, both involving physical and chemical methods. Baier disclosed a number of surface property concepts that were hypothesized to be beneficial [3]. The majority of surfaces he listed are in essence attempts to create surfaces with minimal effect, termed either low protein or platelet adhesion. Despite a tremendous amount of scientific and technological effort, the quest for the holy grail of inert materials turned out to be “20 years of frustration” [4].

Historical Perspectives on Biomedical Coatings 5

The mid-70s’ emergence of molecular biology analytical tools, like RIA and ELISA, opened up the possibilities of looking at the molecular and cellular aspects involved at the surface. With the consequent increasing understanding of the pathophysiology of host-material interactions at the cell and molecular level, the field of biomaterials moved toward emphasis on improved management of the material’s biointerface. Rather than trying to exclusively achieve the bioinert response, it instead moved to pursuit of strategies aimed at optimizing the biological interactions with the syn-thetic material. An example is the incorporation of bioactive components that could elicit a controlled action and reaction in the physiological envi-ronment. Very prominent examples of these second-generation “bioactive” biomaterials are heparin coatings for improved blood compatibility, and drug-eluting stent coatings for prevention of vascular restenosis.

Now third-generation biomaterials are being designed to stimulate specific cellular responses at the molecular level. Taking contemporary understanding of molecular and cell biology further, biology is incorpo-rated into materials design: molecular modifications of polymer systems elicit specific interactions with cell surface integrins and thereby direct cell proliferation, differentiation, and extracellular matrix production and organization. These third-generation “bio-interactive” biomaterials stimu-late regeneration of living tissues.

Circling back to the definition of biocompatibility, some 20 years after his original definition, the same professor, David Williams, revised the original definition of biocompatibility [5] to now read: “The ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appro-priate beneficial cellular or tissue response in that specific situation, and optimizing the clinically relevant performance of that therapy.” Clearly this reflects the evolution of biomaterials into second and third generations; those materials having increasingly more activity and interaction with the biological environment. With regard to biocompatibility, next generations of biomaterials not only focus on “do no harm,” but actually have the ability to obtain a beneficial response.

1.2 Improving Physical Properties of Biomaterials: Hydrophilic, Lubricious Coatings

The use of hydrophilic coatings on medical devices has probably the long-est clinical use history. More recently their increasing use appears to go

6 Medical Coatings and Deposition Technologies

hand in hand with medical devices getting smaller and smaller. Various clinical fields increasingly turn to percutaneous therapies or minimally invasive procedures. The reasons are obvious: Smaller devices help to reduce trauma, speed recovery time, and shorten hospital stays, all con-tributing to reducing the burden on our healthcare systems, thus at the end of the day reducing costs.

The majority of substrates found in medical devices are hydrophobic with surface energies generally spanning the range between 42 and 20 mN/m [6]. For a surface to wet perfectly and thus assist lubrication, its surface energy should be above that of the wetting fluid. Knowing that the surface tension of water at room temperature is around 72 mN/m and that of blood at body temperature around 52 mN/m [7], most medical materials are thus poorly suited to many medical applications in the absence of suitable sur-face modification [8]. With poor wetting and self-lubrication, an invasive device can compromise the host’s health due to tissue trauma and sub-sequent infection. Self-lubrication of medical devices, such as catheters and guidewires, can be imparted by applying a hydrophilic coating. Hydrophilic coatings are beneficial in reducing trauma damage. The coating’s increased surface energy facilitates wetting and provides the ability to tune lubricity (reduce coefficient of friction) in an aqueous environment. These features can be leveraged to improve the usability or performance of a device.

Polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP), along with various PEG derivatives and PVP copolymers, are the most common poly-mers used in hydrophilic lubricious coatings. Further, derivatives of phos-phoryl choline, such as 2-methacryloyloxyethylphosphorylcholine (MPC) in acrylic copolymers and water-soluble polyvinylethers, are used, as well as the natural polymer hyaluronic acid [6].

Having been extensively tested and used as a plasma substitute, PVP has an extensive safety record [9]. It has demonstrated to be well suited for short-term device applications and is the key ingredient in market- leading hydrophilic lubricious coatings of Surmodics (Harmony advanced lubricity coatings) and DSM (ComfortCoat hydrophilic coating). Both use photo-initiated crosslinking, grafting and entanglement as the method of producing their PVP-based coatings, taking advantage of the proton abstraction capability of type II photoinitiators and in particular the labile alpha-hydrogen found on the backbone of PVP. While the techno-logical approach differs, both aim to immobilize a film of a hydrophilic polymer on a substrate, whereby the resulting coating swells in water to fulfill its function as a hydrogel, yet remains sufficiently well bound to the substrate for the application in question. The latter is an important aspect. Good adhesion of the hydrophilic coating is essential. Vascular devices, for