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Scaffold-free versus scaffold-based bioprinting

3D bioprinting is an emerging technique that revolutionizes tissue engineering, drug discovery, and regenerative medicine. It is an extension of traditional 3D printing, but unlike 3D printing, it prints biomaterials and cells in a 3D manner. Scaffold-based and scaffold-free bioprinting are two approaches used in 3D bioprinting to create tissue constructs.

Scaffolds are structures of artificial or natural materials on which new tissue can be grown to replace damaged tissue. They can be made of ceramic, synthetic polymer, or natural material.

The primary purpose of scaffolds is to provide a porous architecture, support for cells growth and differentiation, bioactivity, and mechanical properties (2)

There are two main ways of using the scaffold. In the traditional one, 3D cell culture is done by seeding the cells on a prepared scaffold (a porous matrix) and then implant into a patient body, where the cells continue to proliferate and differentiate, leading to tissue or organ repair.

In a second manner, the cells can also be embedded with growth factors and hydrogel (natural or synthetic) and printed in a computer-assisted manner in a 3D structure. (1) The hydrogel has an ECM-like behavior, allowing cells to grow and possess a degree of flexibility similar to the natural one.

Scaffold-based approaches have been used in clinical settings to restore several types of damaged tissue, such as bone, cartilage, ligaments, skin, and skeletal muscle defects [2], but also for drug delivery (3). Scaffold systems present many advantages compared to other vehicles because of their high porosity and surface area, excellent biocompatibility, controllable degradation, effective integration with the host tissue, and the ability for local and targeted delivery of therapeutics.

Scaffold-free bioprinting is a different approach that does not rely on a scaffold to support the cells. Instead uses a single-cell suspension, spheroid cell aggregates, tissue strands, or cell sheets as building blocks. It can be characterized by the self-organization of cells without external forces and self-assembly depending on natural features without external forces. It can start with more cells than scaffold-based bioprinting, so it doesn’t need to wait for the cells to proliferate. Then, it can recapitulate the native tissues in a shorter period of time, making it a promissory technique. This approach has been used to create complex tissues with a high degree of architectural control, such as blood vessels and cardiac tissue.

Both scaffold-based and scaffold-free bioprinting have their advantages and disadvantages. Scaffold-based bioprinting provides a more defined and controlled environment for the cells to grow and differentiate. Still, scaffold-free bioprinting provides better control over the architecture of the tissue construct, as the cells themselves form the structure. But, as it requires many cells, it can be more expensive. Then, the choice between the two approaches will often depend on the specific application and the desired outcomes.

On top of that, scaffold-based and Scaffold-free bioprinting might have an interesting future being used together (4). In a paper, Ibrahim T. Ozbolat described a hybrid model where a vascular network could be printed using scaffold-based bioprinting and the parenchymal tissue using scaffold-free bioprinting. Upon printing, scaffold-free parenchymal tissue can fuse, maturate, and self-assemble around the vasculature.(fig1)

Figure1: Hybrid bioprinting of scaffold-based vascular constructs in tandem with scaffold-free parenchyma tissue, where fusion, tissue remodeling, and self-assembly of tissue strands take place and sprouting can take place between the macrovascular network and capillaries in tissue strands. This concept generalizes the tissue used; however, for different tissue types, modifications on the system would be essential.

Do you want to create scaffold-based or scaffold-free models for your research? We are here to help you! Contact our support team by accessing our website, and start bioprinting today!


1 Alghuwainem A, Alshareeda AT, Alsowayan B. Scaffold-Free 3-D Cell Sheet Technique Bridges the Gap between 2-D Cell Culture and Animal Models. Int J Mol Sci. 2019 Oct 4;20(19):4926. doi: 10.3390/ijms20194926. PMID: 31590325; PMCID: PMC6801996.

2 Chan BP, Leong KW. Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur Spine J. 2008 Dec;17 Suppl 4(Suppl 4):467-79. doi: 10.1007/s00586-008-0745-3. Epub 2008 Nov 13. PMID: 19005702; PMCID: PMC2587658.

3 Gil CJ, Li L, Hwang B, Cadena M, Theus AS, Finamore TA, Bauser-Heaton H, Mahmoudi M, Roeder RK, Serpooshan V. Tissue engineered drug delivery vehicles: Methods to monitor and regulate the release behavior. J Control Release. 2022 Sep;349:143-155. doi: 10.1016/j.jconrel.2022.04.044. Epub 2022 Jul 6. PMID: 35508223.

4 Ozbolat, Ibrahim T.. “Scaffold-Based or Scaffold-Free Bioprinting: Competing or Complementing Approaches?” Journal of Nanotechnology in Engineering and Medicine 6 (2015): 024701.

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