
Another Perspective on 4D Bioprinting
Introduction
3D bioprinting has been promoted and even implemented to varying degrees for more than a decade [1]. Proposed applications abound, although for some their component technologies remain to be completely established [2]. The recent invention of 4D printing naturally points to the general concept of 4D bioprinting. However, the principles and terms inherent to the concept of 4D bioprinting are still in early development. Here an outline of the proposed implementations of 4D bioprinting is reviewed and a comprehensive definition introduced.3D Printing
3D printing refers to various processes used to synthesize a three-dimensional object [3]. It is also known as additive manufacturing (AM). A key concept here is that layers of material are sequentially deposited under computer control to create a solid object. [4] The technology is already successful with many applications in full operation and employing many diverse materials.4D Printing
4D printing is a new process for printing of “smart” products. These are printed objects that, for example, respond to environmental conditions by such conformational changes as deforming, oscillating, shrinking, twisting or growing. The environmental variations initiating these changes include temperature, moisture, electrical pulse, light (or other direct energy input), air pressure/shear/turbulence, stress, etc. When a 4D printed drain cover is exposed to water, for example, it could warp and open-up or un-seal the drain. Here the bilayer printed material drain cover is flat when dry, but when it becomes wet warps or curves, generating a poor seal around the drain that allows water to flow out and escape. For the most part, reversibility and cyclability of the activity is understood. However, one can clearly envision a 4D printed object that is specifically engineered to deform to a particular shape through a defined environmental stimulus only once. Or one that is engineered with a capability to cycle multiple times, but with that capability intended to be employed only once. This adaptability and dynamic response can be very simple, such as in the drain example, or much more complex, such as in complex adaptive products like responsive garments or even material-integral robotic-like behavior. But definitions can be tricky. For example, there are many other smart objects that respond by design to environmental input, such as photochromic eyeglass lenses. But, these are not printed. 3D printed thermoplastic objects may bend or deform under pressure or heat, but this is not a designed or functional change. Hence, a more specific definition of these particular smart objects might be “single multi-material printed objects that demonstrate engineered actuation, sensing or material logic resulting in its physical transformation in response to designed user-demands or changing environment”. The actual 4D printing process begins with the 3D printing of an object composed of multiple, “responsive” materials. These materials can be composed of almost anything─ for example, metals, plastics or glasses that determine the shape transformation, by material state-change, that the printed object will make. This builds “solid-state” functionality and change mechanisms directly into the printed objects.4D Bioprinting
4D bioprinting is analogous to 4D printing in that it is the printing of smart, environmentally responsive biological structures, tissues and organs. 4D bioprinting begins with the printing of multiple cells or biological matrices resulting in structures that
- immunological signals and input
- adjacent cell or basement membranes
- juxtacrines / paracrines / endocrines, etc.
- physicochemical “stress” or response inducers
- differentiation signals and epigenetic modulators
- nutritional / factor components and their gradients
- cellular “CD” development and display
- cell receptor characteristic development
- cellular type differentiation / adaptation
- functionality development in organoid culture
- cellular polarization influencing self-organization
- dynamic, pluri-consequential or reversible responses
- mutations and chromosome silencing in transplantation chimera
- multipotent in situ cell differentiation
- restricted chimerism with human naïve iPSCs
- in situ tissue vascularization or organ development
- admixtures determining the potency of cells in organ development
4D Bioprinting Definition
Considering all of the above, we propose the following definition for 4D bioprinting:The construction of individual multi-material printed objects from either living or preliminary substrates for medical or biotechnological applications when they are specifically engineered to respond in anticipated ways to user-demands or a changing environment by self-actuated morphogenesis, cellular differentiation, tissue patterning, defined biological characteristic alteration or functionality development.
Conclusion
4D bioprinting is analogous to 4D printing in that it is the printing of “smart” biological structures. It begins with the printing of cells or matrices that result in structures that undergo designed and self-actuated biological responses. By any definition, some examples of such a technology have already been accomplished. These examples range from current therapeutic and diagnostic tissues to experimental vascularized or chimeric constructs. However, as the practice of even 3D bioprinting is still in its infancy, the composition and functional boundaries of true 4D bioprinting remains understandably in debate. References- Sargent B, 3D Printing and 3D Bioprinting – Changing the Healthcare Landscape, July 2, 2015
- Golson K, 3D Bioprinting – Research Successes, Challenges, and Future Possibilities, The Cell Culture Dish, July 9, 2015.
- Excell J. “The rise of additive manufacturing”. The Engineer. Retrieved 2013-10-30.
- Jump up “3D Printer Technology – Animation of layering”. Create It Real. Retrieved 2012-01-31.
- An J, Chua K and Mironov V, 2016, A Perspective on 4D Bioprinting. International Journal of Bioprinting, vol.2(1): x–x. http://dx.doi.org/10.18063/IJB.2016.01.003.
- Whitford W, Development Strategies for Bioprinting Media and Buffers, International Bioprinting Congress, 9-10 July 2015, Singapore.
- Regalado A, Human-Animal Chimeras Are Gestating on U.S. Research Farms, Biomedical News, MIT Technology Review, January 6, 2016.
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