Significance and Use
4.1 Standard Structure—This standard has been organized according to a typical bioprinting operational workflow. In this way the standard has three main sections: pre-printing considerations, printing considerations, and post-printing considerations. There is also a section on bioprinting modalities and additional considerations of product release, containers, and transport. Certain processes will appear across multiple sections, for example cytocompatibility or crosslinking, as these issues have considerations that take place prior to printing, during the printing process, and following the printing process. Contents of main sections are listed below.
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| Scope | Section 1 |
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| Referenced Documents | Section 2 |
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| Terminology | Section 3 |
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| Significance and Use | Section 4 |
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| Bioprinting Modalities | Section 5 |
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| Pre-Printing Considerations | Section 6 |
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| Printing Considerations | Section 7 |
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| Post-Printing Considerations | Section 8 |
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| Additional Considerations | Section 9 |
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| Keywords | Section 10 |
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| References |
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4.1.1 Pre-Printing Considerations—Pre-printing considerations include: bioink common applications, support material, and bioink selection considerations. Bioink selection considerations include: formulation of bioinks, bioink properties, changes in properties resulting from formulations, sterility, cellular component, and fugitive element considerations. Within the bioink properties there are considerations related to the viscoelastic properties, chemical properties, structure of polymer and functional groups, purity of material, mechanism of crosslinking, and degradation considerations. Contents of the section on pre-printing considerations are listed below.
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| Bioink Common Applications | 6.2 |
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| Support Material Considerations | 6.3 |
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| Bioink Selection | 6.4 |
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| Formulation of Bioinks | 6.4.1 |
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| Concentration of Components | 6.4.1.1 |
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| Function of Each Component | 6.4.1.2 |
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| Bioink Properties | 6.4.2 |
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| Viscoelastic Properties | 6.4.2.1 |
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| Chemical Properties | 6.4.2.2 |
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| Structure of Polymer and Functional Groups | 6.4.2.3 |
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| Purity of Material | 6.4.2.4 |
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| Mechanism of Crosslinking | 6.4.2.5 |
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| Degradation of Bioink | 6.4.2.6 |
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| Changes in Properties Resulting from Formulations | 6.4.3 |
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| Formulation Modification to Influence Biological Response | 6.4.3.1 |
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| Formulation Modification to Influence Rheology | 6.4.3.2 |
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| Formulation Modification to Influence Mechanical Properties | 6.4.3.3 |
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| Sterility | 6.4.4 |
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| Sterilization Approach | 6.4.4.1 |
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| Assessments | 6.4.4.2 |
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| Cellular Component Considerations | 6.4.5 |
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| Cytocompatibility | 6.4.5.1 |
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| Cell Sedimentation | 6.4.5.2 |
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| Fugitive Element Considerations | 6.4.6 |
4.1.2 Printing Considerations—Printing considerations include: printability, specifically bioink considerations, cellular component, support material, stabilization, and aseptic printing considerations. Within the cellular component section considerations cover cell viability, temperature, cell shearing, cell distribution, sedimentation, and concentration in the bioink. Contents of the section on printing considerations are listed below.
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| Printability | 7.2 |
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| Bioink Considerations | 7.2.1 |
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| Effect of Cells on Printability | 7.2.1.1 |
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| Effect of Biomaterials on Printability | 7.2.1.2 |
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| Temperature | 7.2.2 |
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| Assessments | 7.2.3 |
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| Cellular Component Considerations | 7.3 |
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| Viability of Cells During the Printing Process | 7.3.1 |
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| Temperature | 7.3.2 |
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| Cell Shearing | 7.3.3 |
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| Cell Distribution in the Bioink | 7.3.4 |
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| Cell Sedimentation | 7.3.4.1 |
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| Cell Concentration | 7.3.5 |
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| Support Material Considerations | 7.4 |
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| Printed Support Material | 7.4.1 |
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| Support Material Used as an Embedding Medium | 7.4.2 |
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| Stabilization | 7.5 |
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| Cytocompatibility | 7.5.1 |
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| Crosslinking | 7.5.2 |
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| Temperature | 7.5.3 |
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| Aseptic Printing Considerations | 7.6 |
4.1.3 Post-Printing Considerations—Post-printing considerations include: post-print bioink, stabilization, and considerations for removal of provisional components and materials. Post-printing stabilization focuses on the modalities (such as crosslinking, temperature-induced self-assembly, and evaporation) as well as stabilization effects on the cell health, function, and modification of properties. The considerations for removal of provisional components and materials include the types of components, timing and method of removal, and the removal effects. Contents of the section on post-printing considerations are listed below.
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| Post-Print Bioink Considerations | 8.2 |
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| Structural Fidelity | 8.2.1 |
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| Viability of Cells | 8.2.2 |
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| Biomaterial Properties | 8.2.3 |
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| Cell Sedimentation | 8.2.4 |
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| Cell Morphology | 8.2.5 |
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| Stabilization Considerations | 8.3 |
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| Stabilization Modalities | 8.3.1 |
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| Crosslinking | 8.3.1.1 |
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| Temperature-Induced Self-Assembly | 8.3.1.2 |
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| Evaporation | 8.3.1.3 |
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| Stabilization Effects | 8.3.2 |
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| Cell Health and Function | 8.3.2.1 |
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| Modification of Mechanical Properties | 8.3.2.2 |
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| Considerations for Removal of Provisional Components and Materials | 8.4 |
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| Types of Components | 8.4.1 |
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| Support Components | 8.4.1.1 |
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| Bioink Elements | 8.4.1.2 |
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| Support Bath Materials | 8.4.1.3 |
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| Timing of Removal | 8.4.2 |
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| Method of Removal | 8.4.3 |
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| Chemical Removal | 8.4.3.1 |
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| Temperature-Based Removal | 8.4.3.2 |
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| Physical Removal | 8.4.3.3 |
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| Removal Effects | 8.4.4 |
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| Structural Fidelity | 8.4.4.1 |
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| Cell Health and Function | 8.4.4.2 |
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| Modification of Properties | 8.4.4.3 |
4.1.4 Additional Considerations—Additional considerations include: discussion on product release, container, and transport considerations. Container considerations focus mainly on the storage stability of bioinks, transfer of bioinks to the print cartridge, as well as container closing integrity and assessing the quality of the container. Contents of the section on additional considerations are listed below.
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| Product Release Considerations | 9.2 |
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| Bioink-Specific Release Considerations | 9.2.1 |
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| Sterility Assurance | 9.2.2 |
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| Adventitious Agent and Pyrogen Testing | 9.2.3 |
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| Functional Testing | 9.2.4 |
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| Particle Testing | 9.2.5 |
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| Container Considerations | 9.3 |
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| Storage Stability of Bioinks | 9.3.1 |
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| Transfer of Bioinks to the Print Cartridge | 9.3.2 |
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| Preparing the Working Station | 9.3.2.1 |
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| Maintenance of Sterility | 9.3.2.2 |
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| Physical Challenges | 9.3.2.3 |
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| Additional Container Considerations | 9.3.3 |
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| Container Closure Integrity | 9.3.3.1 |
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| Extractables and Leachables | 9.3.3.2 |
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| Particulates | 9.3.3.3 |
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| Container Opacity | 9.3.3.4 |
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| Transport | 9.4 |
Scope
1.1 This guide is a resource for bioprinting tissue-engineered medical products (TEMPs) with bioinks and biomaterial inks. There are existing standards that cover biomaterials and scaffolds in a more general fashion (Guide F2150, Guide F2027, ISO 10993 series). This guide focuses specifically on extrusion bioprinting utilizing bioinks and biomaterial inks with inherent or inducible fluidic properties with or without encapsulated cells used to construct TEMPs. For the remainder of this guide, both bioinks and biomaterial inks will be collectively referred to as bioinks.
1.2 For the purposes of this guide, bioprinting is defined as the three-dimensional printing of materials (bioinks) to fabricate structured constructs for use in biological or medical applications.
1.3 TEMPs may be produced by many different bioprinting modalities, including but not limited to the following: electrospinning, electrospray, extrusion-based, droplet-based, inkjet-based, and laser-assisted bioprinting. Extrusion-based bioprinting is the primary focus of this document since it is currently the most well-understood modality used to construct TEMPs, but other bioprinting modalities are also addressed.
1.4 This guide will focus on bioinks and biomaterials used as inks with inherent or inducible fluidic properties. These inks may or may not contain encapsulated cells. Chemical properties of the inks and other factors that affect printability are addressed.
1.5 Pre-printing and printing considerations are the focus of this guide, but considerations regarding post-printing product stabilization are also addressed.
1.6 This guide will address assessments regarding the sterility and cytocompatibility of bioinks, including chemical and physical benchtop tests, as well as measures of post-printing cell viability.
1.7 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.
1.8 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
