Biomanufacturing aims to manufacture products with biological functions through bioprinting or bioassembly methods. In biofabrication processes, automated and computer-controlled techniques are used to position cells at defined locations in three-dimensional space. Materials suitable for biomanufacturing are often called bioinks and have become an important research direction in this field.
The Origin of Bioink
The bioink was first used in an article on organ printing in 2003, where it was introduced together with the term biopaper. The original concept refers to living cells or tissue balls that can be used as bioink by bioprinting on a kind of biopaper (hydrogel). Thus, the term bioink originally referred to cellular components positioned within 3D cultures or hydrogels. Cells and cell aggregates are used as bioinks in many advanced studies in this field. During this period, some researchers argued that actual bioink formulations should be structurally and functionally more complex. At the same time, the number of manufacturing technologies available for bioprinting continues to increase over time, including microextrusion printing, droplet jetting technology (inkjet and microvalve technology), laser direct writing technology and stereolithography technology, each of these technologies has different physical and rheological requirements for suitable bioinks.
The Diversity of Bioinks
With the further development of the field of bioprinting, the original single and unified concept of bioink is no longer maintained. The definition of bioink is extended to the direction of additive manufacturing materials. For example, the term fugitive bioink has been used for sacrificial materials. Sacrificial materials can be processed by an additive manufacturing technology to make a leaching, washing remove or dissolve biocompatible structures that form pores. Recently, the bioink terminology has been proposed to be split into four subcategories: supportive bioinks, fugitive bioinks, structural bioinks, and functional bioinks. Supportive bioinks are designed to support cell populations during implantation and act as an extracellular matrix during cell proliferation. Fugitive bioinks are sacrificial or temporary materials that can be removed quickly to form internal voids or channels in the printed mechanism. Structure bioinks are used to provide mechanical integrity to printed structures, which may disappear, but after a relatively long period of time (such as thermoplastic materials such as polycaprolactone). Functional bioinks can provide biochemical, mechanical, or electrochemical signals influence cellular behavior. This four-category classification of bioinks is driven by the final function of the constituent materials in the printed structure, rather than by the manufacturing process itself.
Bioinks and Biomaterial Inks
The definition of biomaterials has long been an important discussion and is still being discussed. This is due to the strong diversity of a wide range of biomaterials (including metals, ceramics, polymers, and semiconductors, as the most important examples) and the corresponding wide range of applications. This has resulted in application- and purpose-driven definitions of biomaterial terms rather than definitions based on the biomaterials themselves. From the perspective of ultimate purpose and application, biomaterials comprise a variety of materials and are suitable for a wide range of manufacturing and processing technologies, including spinning, knitting, extrusion, machining, cutting and additive manufacturing. Biofabrication, however, is more focused on research and is characterized using automated procedures to directly create a 3D arrangement containing cells, often with the help of biological materials.
Fig.1 The difference between bioink and biomaterial ink (Groll J., et al. 2018).
To further classify and distinguish bioinks, biomaterials that can be printed and directly inoculated with cells after printing, but are not formulated directly with cells, are not qualified to be called bioinks. We propose that this material be called biomaterial ink. These biomaterial inks can be used to produce scaffolds for cell seeding, bioreactors, implant scaffolds, and can also be used in parallel for bioink manufacturing or built-in mechanical support within the scaffold. According to this, sacrificial materials that can be printed or dissolved in a way that does not affect or cells are not bioinks, but biomaterial inks. Biomaterial ink materials include biodegradable polycaprolactone, nondegradable polypropylene, nondegradable but temperature-sensitive polyoxazoline, biopolymers (such as gelatin), inorganic materials, etc. These materials typically come in powder form and the high-resolution properties of these materials enable scaffold material fabrication, cell seeding, or microfluidic device fabrication, but do not contain cells, making them separate from bioresins.
In summary, compared to biomaterials, bioinks should be defined from a process and technology perspective. Bioink is defined as a cellular formulation that may contain bioactive ingredients or biomaterials suitable for manufacturing through automated biofabrication techniques. Bioinks may contain cells in different environments and forms, such as: single cells, cells aggregated into spheroids, rod-shaped cells, cells organized in tissues or organoids, cells coated with a very thin layer of material, seeded in cells on microcarriers, cells encapsulated in custom colloidal microenvironments. In addition, bioinks may contain bioactive molecules, such as growth factors, DNA, miRNA, cytokines, exosomes, or biomaterials.
References
- Groll J.; et al. A definition of bioinks and their distinction from biomaterial inks. Biofabrication. 2018, 11(1): 013001.
- Mironov V. Printing technology to produce living tissue. Expert Opinion on Biological Therapy. 2003, 3(5): 701-704.
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