|Muhammad Hanif Nadhif||1. Department of Medical Physics, Faculty of Medicine, Universitas Indonesia, JL. Salemba Raya No.6, Jakarta 10340, Indonesia 2. Medical Technology Cluster, Indonesia Medical Education and Research I|
|Hanif Assyarify||Medical Technology Cluster, Indonesia Medical Education and Research Institute (IMERI), Faculty of Medicine, Universitas Indonesia, JL. Salemba Raya No.6, Jakarta 10340, Indonesia|
|Affan Kaysa Waafi||Department of Mechanical Engineering, Technical University of Denmark, Lyngby 2800, Denmark|
|Yudan Whulanza||1. Department of Mechanical Engineering, Faculty of Engineering, Universitas Indonesia, Kampus UI Depok, Depok 16424, Indonesia 2. Research Center for Biomedical Engineering (RCBE), Universitas Indon|
Many articles have reported a correlation between the use of mechanical stimulation and an enhancement in cultivation of various tissues engineered in bioreactors. The enhancement includes improvements in cell growth, proliferation, and functionalities. The aim of this report is to review the mechanical functionalities of tissue engineering bioreactors in terms of the forms of stimulation, types of stress, actuators, supporting modules, and, most importantly, efficacy. The Google Scholar database was searched for relevant articles. Three forms of simulation were reported: uniaxial, biaxial, and multiaxial. The types of stress exerted by bioreactors include compression, tension, shear, and dynamic stresses, which are applied solely or mutually depending on the number of axes involved. Mechanical stimulation could be actuated by stepper motors, pistons, pneumatic pumps, diaphragm pumps, piezoelectric systems, or dielectric charges. Additional modules, such as incubators, flow perfusion systems, ultrasound sensors, movement controls, and electrodes, can also support the mechanical functions of bioreactors. The efficacy of a bioreactor could be determined by investigating the biomechanical and histological properties of the engineered tissues. To facilitate the development of mechanical functionalities for tissue engineering bioreactors in the future, a seven-step framework is proposed.
Bioreactors; Mechanical functionalities; Tissue engineering
One of the bioreactors that utilized a mechanical stimulation module was first produced in the late 1990s (Vunjak-Novakovic et al., 1999). This group engineered cartilage constructs in rotating vessels, which imposed a shear stress induced by a dynamic laminar flow field. The resulting engineered cartilage constructs showed a higher fraction of collagen and glycosaminoglycans when compared to a static culture. Moreover, the artificial cartilage also showed better mechanical properties. After this finding, reports flourished regarding the use of mechanical stimulations in tissue engineering bioreactors. In most cases, mechanical stimuli were used to induce the growth and proliferation of dermato-musculoskeletal and cardiac muscle tissues, including skin (Helmedag et al., 2015), heart muscles (Mooney et al., 2012), cartilage (Vainieri et al., 2018), bones (Rauh et al., 2011), and skeletal muscles (Heher et al., 2015).
As first reported by Vunjak-Novakovic et al. (1999), the outcomes of mechanically stimulating bioreactors are often characterized by the mechanical properties of the tissues, the cell growth and proliferation, and the presence of extracellular matrix (ECM). The beating performance of the seeded cells are also considerations in engineered heart muscles (Shachar et al., 2012; Paez?Mayorga et al., 2019).
Unfortunately, reviews about the mechanical functionalities in tissue engineering bioreactors are still scattered. The existing reports mostly focus on one type of stress or one target tissue. For instance, a review by McCoy and O’Brien (2010) focused on the shear stress in bone tissue bioreactors, while a review by Anderson and Johnstone (2017) focused more on compression stress for engineered chondrocytes. A comprehensive review about various forms of mechanical stimulations for broad types of tissues is still lacking, not to mention the forms of loading and other related technical aspects.
The aim of this report was to review the mechanical functionalities for tissue engineering bioreactors in terms of the forms of stimulation, types of stress, actuators, supporting modules, and, most importantly, efficacy.
The mechanical functionalities of bioreactors can be divided into three forms of stimulation: uniaxial, biaxial, and multiaxial. The uniaxially stimulating bioreactors produce stresses that are compressive, tensile, shear, and flexural. Some articles have claimed that the uniaxial stimulation they developed could result in biaxial stress. However, that claim should be thoroughly scrutinized since the articles lacked any experimental characterizations. Most biaxial stimulations combined compression and shear, although that type of stimulation could also exist as a biaxial tension. The multiaxial system has been characterized using the bulging mechanism, actuated by a pneumatic system acting on a dielectric elastomer. To facilitate future work in developing mechanical functionalities of tissue engineering bioreactors, a seven-step framework is proposed.
This research was supported by the Universitas Indonesia Grant PIT9 in 2019 with Contract Number: NKB-0084/UN2.R3.1/HKP.05.00/2019.
Anderson, D.E., Johnstone, B., 2017. Dynamic Mechanical Compression of Chondrocytes for Tissue Engineering: A Critical Review. Frontiers in Bioengineering and Biotechnology, Volume 5, pp. 1–20
Bai, Y., Lee, P.-F., Humphrey, J.D., Yeh, A.T., 2014. Sequential Multimodal Microscopic Imaging and Biaxial Mechanical Testing of Living Multicomponent Tissue Constructs. Annals of Biomedical Engineering, Volume 42(9), pp. 1791–1805
Bilgen, B., Chu, D., Stefani, R., Aaron, R.K., 2013. Design of a Biaxial Mechanical Loading Bioreactor for Tissue Engineering. Journal of Visualized Experiments, Volume 74, pp. 1–10
Birla, R., 2014. Introduction to Tissue Engineering: Applications and Challenges. New York: Wiley-IEEE Press, pp. 1–327
Costa, J., Ghilardi, M., Mamone, V., Ferrari, V., Busfield, J.J.C., Ahluwalia, A., Carpi, F., 2020. Bioreactor with Electrically Deformable Curved Membranes for Mechanical Stimulation of Cell Cultures. Frontiers in Bioengineering and Biotechnology, Volume 8, pp. 1–9
Engelmayr, G.C., Hildebrand, D.K., Sutherland, F.W.H., Mayer, J.E., Sacks, M.S., 2003. A Novel Bioreactor for the Dynamic Flexural Stimulation of Tissue Engineered Heart Valve Biomaterials. Biomaterials, Volume 24(14), pp. 2523–2532
Heher, P., Maleiner, B., Prüller, J., Teuschl, A. H., Kollmitzer, J., Monforte, X., Wolbank, S., Redl, H., Rünzler, D., Fuchs, C., 2015. A Novel Bioreactor for the Generation of Highly Aligned 3D Skeletal Muscle-like Constructs through Orientation of Fibrin via Application of Static Strain. Acta Biomaterialia, Volume 24, pp. 251–265
Helmedag, M.J., Weinandy, S., Marquardt, Y., Baron, J.M., Pallua, N., Suschek, C.V., Jockenhoevel, S., 2015. The Effects of Constant Flow Bioreactor Cultivation and Keratinocyte Seeding Densities on Prevascularized Organotypic Skin Grafts based on a Fibrin Scaffold. Tissue Engineering Part A, Volume 21(1–2), pp. 343–352
Huang, A.H., Lee, Y.-U., Calle, E.A., Boyle, M., Starcher, B.C., Humphrey, J.D., Niklason, L.E., 2015. Design and Use of a Novel Bioreactor for Regeneration of Biaxially Stretched Tissue-Engineered Vessels. Tissue Engineering Part C: Methods, Volume 21(8), pp. 841–851
van Kelle, M.A.J., Oomen, P.J.A., Bulsink, J.A., Janssen-van den Broek, M.W.J.T., Lopata, R.G.P., Rutten, M.C.M., Loerakker, S., Bouten, C.V.C., 2017. A Bioreactor to Identify the Driving Mechanical Stimuli of Tissue Growth and Remodeling. Tissue Engineering Part C: Methods, Volume 23(6), pp. 377–387
Ladd, M.R., Lee, S.J., Atala, A., Yoo, J.J., 2009. Bioreactor Maintained Living Skin Matrix. Tissue Engineering Part A, Volume 15(4), pp. 861–868
Liu, H., MacQueen, L.A., Usprech, J.F., Maleki, H., Sider, K.L., Doyle, M.G., Sun, Y., Simmons, C.A., 2018. Microdevice Arrays with Strain Sensors for 3D Mechanical Stimulation and Monitoring of Engineered Tissues. Biomaterials, Volume 172, pp. 30–40
McCoy, R.J., O’Brien, F.J., 2010. Influence of Shear Stress in Perfusion Bioreactor Cultures for the Development of Three-Dimensional Bone Tissue Constructs: A Review. Tissue Engineering Part B: Reviews, Volume 16(6), pp. 587–601
Meinert, C., Schrobback, K., Hutmacher, D.W., Klein, T.J., 2017. A Novel Bioreactor System for Biaxial Mechanical Loading Enhances the Properties of Tissue-Engineered Human Cartilage. Scientific Reports, Volume 7, pp. 1–14
Meyer, U., Büchter, A., Nazer, N., Wiesmann, H.P., 2006. Design and Performance of a Bioreactor System for Mechanically Promoted Three-Dimensional Tissue Engineering. British Journal of Oral and Maxillofacial Surgery, Volume 44(2), pp. 134–140
Mooney, E., Mackle, J.N., Blond, D.J.P., O’Cearbhaill, E., Shaw, G., Blau, W.J., Barry, F.P., Barron, V., Murphy, J.M., 2012. The Electrical Stimulation of Carbon Nanotubes to Provide a Cardiomimetic Cue to MSCs. Biomaterials, Volume 33(26), pp. 6132–6139
Nadhif, M.H., Whulanza, Y., Istiyanto, J., Bachtiar, B.M., 2017. Delivery of Amphotericin B to Candida Albicans by using Biomachined Lab-on-a-Chip. Journal of Biomimetics, Biomaterials and Biomedical Engineering, Volume 30, pp. 24–30
Oomen, P.J.A., van Kelle, M.A. J., Oomens, C.W.J., Bouten, C.V.C., Loerakker, S., 2017. Nondestructive Mechanical Characterization of Developing Biological Tissues using Inflation Testing. Journal of the Mechanical Behavior of Biomedical Materials, Volume 74, pp. 438–447
Paez?Mayorga, J., Hernández?Vargas, G., Ruiz?Esparza, G.U., Iqbal, H.M.N., Wang, X., Zhang, Y.S., Parra-Saldivar, R., Khademhosseini, A., 2019. Bioreactors for Cardiac Tissue Engineering. Advanced Healthcare Materials, Volume 8, https://doi.org/10.1002/adhm.201701504
Pakazad, S.K., Savov, A., van de Stolpe, A., Dekker, R., 2014. A Novel Stretchable Micro-Electrode Array (SMEA) Design for Directional Stretching of Cells. Journal of Micromechanics and Microengineering, Volume 24(3), p. 034003
Rauh, J., Milan, F., Günther, K.-P., Stiehler, M., 2011. Bioreactor Systems for Bone Tissue Engineering. Tissue Engineering Part B: Reviews, Volume 17(4), pp. 263–280
Shachar, M., Benishti, N., Cohen, S., 2012. Effects of Mechanical Stimulation Induced by Compression and Medium Perfusion on Cardiac Tissue Engineering. Biotechnology Progress, Volume 28(6), pp. 1551–1559
Shen, N., Knopf, A., Westendorf, C., Kraushaar, U., Riedl, J., Bauer, H., Pöschel, S., Layland, S. L., Holeiter, M., Knolle, S., Brauchle, E., Nsair, A., Hinderer, S., Schenke-Layland, K., 2017. Steps toward Maturation of Embryonic Stem Cell-Derived Cardiomyocytes by Defined Physical Signals. Stem Cell Reports, Volume 9(1), pp. 122–135
Vainieri, M.L., Wahl, D., Alini, M., van Osch, G.J.V.M., Grad, S., 2018. Mechanically Stimulated Osteochondral Organ Culture for Evaluation of Biomaterials in Cartilage Repair Studies. Acta Biomaterialia, Volume 81, pp. 256–266
Vunjak-Novakovic, G., Martin, I., Obradovic, B., Treppo, S., Grodzinsky, A.J., Langer, R., Freed, L.E., 1999. Bioreactor Cultivation Conditions Modulate the Composition and Mechanical Properties of Tissue-Engineered Cartilage. Journal of Orthopaedic Research, Volume 17(1), pp. 130–138
Yusoff, N., Abu Osman, N.A., Pingguan-Murphy, B., 2011. Design and Validation of a Bi-Axial Loading Bioreactor for Mechanical Stimulation of Engineered Cartilage. Medical Engineering & Physics, Volume 33(6), pp. 782–788