Manufacturing of Functional Tissues In Vitro Using Bioprinting and Bioreactors

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The lack of tissue regeneration in human beings, the deficiency of allogeneic transplants, and longer average life expectancy make the creation of functional tissues in the laboratory one of the most important problems of humanity right now. However, the results obtained are still less than desired since the tissue construct obtained must be functional for specific applications in regenerative medicine and advanced therapies. 

Many new bioprinting groups have been created around the world in the past few years, and a variety of commercial systems are now available to the researchers. More and more publications on the matter are coming up. The results obtained are still far from true clinical application. For example, the organogenesis efforts well covered by the media, including the regeneration of the skin, cornea, or the heart are still too far away from human testing. In addition, a common misconception by the industry is that we directly create functional tissue to be used directly in clinical application; but in reality, we are bioprinting a scaffold loaded with cells. The key is to make these cells to behave as they do in ‘’in vivo conditions’’ and to promote the creation of functional tissues. This requires defining the right biofabrication strategy, but also the right maturation strategy.

For the creation of living tissue, both the bioprinting process and the maturation of the construct are crucial.

 Thanks to the effort of tissue engineering technology and recreating in vivo conditions in the lab we can get results that open us the to the clinical application. 

We try to keep it simple. In our research, we follow a 2-step approach to create functional tissues: 1) Bioprinted constructs (or scaffold) and under the right biofabrication strategy with the proper mechanical conditions. 2)  In order to translate this matrix into functional tissue, it is necessary to use the method of accelerated maturation with the right stimuli (mechanical stress) in a special device. 

We think that the best stress distribution is the key to success, and other approaches failed as they do not closely mimic the true physiologic conditions happening in nature. 

To create specific functional living tissue, it is crucial that the bioprinting process and the ingredients selected such as the scaffold, the cells, and the bio inks (first step of the image) will promote the formation of the right tissue. What is equally important is the maturation procedure applied to the 3D cell-laden constructs (second block of the image). If we only think about bioprinting as a technology to recreate all the structure in the same form as shown in living tissue, we are going to fail. We must think of bioprinting as a way of creating cell-laden 3D constructs as a precursor of (but not final) functional tissue. The maturation and tissue formation process needs as much attention if not more than the bioprinting step. Focusing on the strategies related to both blocks in the diagram will be important to obtain the desired functional knee cartilage tissue, for example. 

Literature search and real-life experience tell us that mechanical stress distribution is crucial as stimuli to create the right tissue. Unloaded muscle is absorbed, the unloaded bone loses its matrix.  Also, the scaffold architecture will affect the stress distribution and other important parameters as the biodegradation occurs. This approach will open a wide research area for tissue engineers to develop protocols with different mechanical stress to create functional tissues, either using direct or indirect bioprinting methods. For example, using molds as temporal containers, a fiber structure holding loads and a cell-friendly matrix or scaffold, even adipose tissue containing blood vessels) 

I predict that even more research and publication will happen in the coming years, making the generation of functional, vascularized, ready to be used tissues and organs a soon possibility.

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(bioprinted scaffold seeded with human cells)


References:

1 Tissue Engineering and 3D Printing Platform (PITI3D), IDIPAZ, Hospital Universitario de La Paz, Madrid, Spain.

2 Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain.

3 REGEMAT 3D S.L., Avenida de la innovación 1, 18100, Armilla, Granada, Spain.

Author’s Biography 

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José Manuel Baena is Ph.D. in Biomedicine from the University of Granada, Spain, MSc Engineering from Polytechnic University of Valencia, Spain and TU Braunschweig, Germany, and MSc from Oxford Brookes University, UK. He serves as scientific coordinator of the Tissue Engineering and 3D Printing Platform (PITI3D), IDIPAZ, Hospital Universitario de La Paz, Madrid, Spain and he is research associate in the group “Advanced therapies: differentiation, regeneration and cancer” IBIMER, CIBM, University of Granada, Spain. He has published several research papers and 1 book. He has presented his work in dozens of congresses around the globe. As a biotech entrepreneur, Baena founded BRECA Health Care, a pioneer in 3D printed custom made implants for orthopedic surgery, and REGEMAT 3D, a leader in the bioprinting industry. Expert in innovation, business development, and internationalization, lecturer in some business schools, he is passionate about biomedicine and technology. 

  

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