Table of Contents Author Guidelines Submit a Manuscript
Stem Cells International
Volume 2019, Article ID 4685137, 3 pages

Engineering Cell Systems

1iBB-Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
2The Discoveries Centre for Regenerative and Precision Medicine (Lisbon Campus), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
3Cell and Gene Therapy Catapult, 12th floor Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
4The New York Stem Cell Foundation, New York, USA

Correspondence should be addressed to Tiago G. Fernandes; tp.aobsilu.ocincet@sednanreft

Received 20 March 2019; Accepted 20 March 2019; Published 2 June 2019

Copyright © 2019 Tiago G. Fernandes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The term “engineering cell systems” can be used to describe the application of engineering principles to the understanding of biological systems, solve biological problems, and ultimately contribute to the translation of new therapeutic approaches into clinical practice [1, 2]. Eventually, for the widespread use of stem cells in biomedical applications, it will be essential to recognize the complexity and the dynamics of stem cell systems, and therefore, the application of engineering principles will become crucial to the understanding of important biological questions, ranging from the cell level to the whole organism [3, 4]. This interesting concept is based on truly interdisciplinary methodologies and integrates contributions from multiple scientific and technological fields.

Currently, one can easily identify several key technologies that are gaining substantial attention in this area. Among these, we can find novel bioprocesses for the maintenance and expansion of human stem cells, as well as their differentiated progeny [57], and micro-/nanofabrication to produce tissue-like substitutes [8]. Moreover, these technologies should be developed with the objective of being implemented under Good Manufacturing Practice (GMP) conditions, in order to facilitate their translation to the clinic [9]. Several contributions featured in this special issue focus their attentions on these topics. Particularly, S. Dakhore et al. review current strategies for human pluripotent stem cell (hPSC) culture and discuss the challenges associated with the development of appropriate conditions to promote large-scale, quality-controlled expansion of hPSCs. On the same note, F. C. Paccola Mesquita et al. present an interesting study on the use of a closed hollow-fiber system that provides the necessary environment to scale up production of hPSCs while maintaining their stemness. They also demonstrate that laminin 521 can be used to promote the attachment of cells in the hollow-fiber reactor, resulting in a greater yield of viable hPSCs when compared with vitronectin. These results highlight the potential of such culture systems to yield high cell numbers in controlled environments, particularly when the scarcity of the initial cell population is an issue. Both contributions of A. T. Serra et al. and K. Chen et al. also tackle such questions by using microcarriers and spontaneously formed spheroids to expand cancer stem cells and compact bone-derived cells, respectively.

Another important objective of the field is the elucidation of the mechanisms that will allow the generation of functional human tissue-like substitutes [3, 6, 10]. To this end, mechanotransduction is of paramount importance, since this process may strongly influence cell fate and, thus, augment the precision of the differentiation of hPSCs into specific cell types, like cardiomyocytes. In this special issue, R. Santoro et al. review the main integrin-dependent mechanisms and signaling pathways involved in mechanotransduction, with particular emphasis in the cardiovascular field, focusing on biomaterial-based in vitro models of hPSC differentiation into cardiomyocytes. Generically, human morphogenesis is a complex process involving distinct microenvironmental and physical signals that are manipulated in space and time to give rise to complex tissues and organs. The development of organoids from hPSCs represents one reliable system to modeling such events, and T. P. Silva et al. review the main bioengineering methods used to promote the self-organization of stem cells, including assembly, patterning, and morphogenesis in vitro, contributing to tissue-like structure formation.

Other emerging topics of this area include the development of cellular products based on innovative scaffolds for the cultivation of stem/progenitor cells [11, 12] and controlled-release particles to program the differentiation of stem cells [13, 14]. In this special issue, M. Haagdorens et al. describe a collagen-like peptide biomaterial for tissue engineering of the cornea, while W. Qin et al. present a drug delivery system, consisting of calcium phosphate cement-containing chitosan with controlled release of metformin, to promote cell viability and odontogenic differentiation of human dental pulp cells, favoring dentin regeneration. In fact, stimuli-responsive materials, also known as smart materials, can change their structure and, consequently, original behavior in response to external or internal stimuli. D. K. Patel et al. also address this topic and review the physiochemical properties of graphene and graphene-based hybrid materials for stimuli-responsive drug delivery, tissue engineering, and antimicrobial applications. Additionally, taking advantage of the strong tropism that stem cells exhibit towards tumors, different researchers have proposed them as attractive candidates for targeted drug delivery in cancer treatment with minimal side effects. In this special issue, P. Wang and A. Aguirre describe the latest stem cell-based approaches for the treatment of cancer and also summarize the emerging imaging techniques being applied for monitoring anticancer stem cell therapy. This known tropism of certain stem cell populations to chronic tissue damage is typically complemented by regulatory effects on the immune microenvironment. Certain cells can regulate the immune microenvironment during tissue repair and provide a good “soil” for tissue regeneration. H. Li et al. discuss the regulation of immune cells by mesenchymal stem cells in the local tissue microenvironment and the subsequent tissue damage repair mechanisms.

Finally, the development of in vitro tests for toxicity, cell differentiation, genomic stability of expanded cells, and biocompatibility can profit from these scientific and technological advancements [4, 9, 15], and several contributions to this special issue focus on discussing these issues and the implications of these novel technologies for cell therapies, regeneration, and precision medicine.

Conflicts of Interest

The editors declare no conflicts of interest regarding the publication of the special issue.


The guest editorial team would like to express gratitude to all the authors for their interest in selecting this special issue as a venue for disseminating their scholarly work. The editors also wish to thank the anonymous reviewers for their careful reading of the manuscripts submitted to this special issue collection and their many insightful comments and suggestions.

Tiago G. Fernandes
Ricardo P. Baptista
Howard Kim


  1. C. M. Madl, S. C. Heilshorn, and H. M. Blau, “Bioengineering strategies to accelerate stem cell therapeutics,” Nature, vol. 557, no. 7705, pp. 335–342, 2018. View at Publisher · View at Google Scholar
  2. M. Tewary, N. Shakiba, and P. W. Zandstra, “Stem cell bioengineering: building from stem cell biology,” Nature Reviews Genetics, vol. 19, no. 10, pp. 595–614, 2018. View at Publisher · View at Google Scholar
  3. E. Lau, D. T. Paik, and J. C. Wu, “Systems-wide approaches in induced pluripotent stem cell models,” Annual Review of Pathology: Mechanisms of Disease, vol. 14, no. 1, pp. 395–419, 2019. View at Publisher · View at Google Scholar
  4. Y. Y. Lipsitz, P. Bedford, A. H. Davies, N. E. Timmins, and P. W. Zandstra, “Achieving efficient manufacturing and quality assurance through synthetic cell therapy design,” Cell Stem Cell, vol. 20, no. 1, pp. 13–17, 2017. View at Publisher · View at Google Scholar
  5. S. M. Badenes, T. G. Fernandes, C. A. V. Rodrigues, M. M. Diogo, and J. M. S. Cabral, “Microcarrier-based platforms for in vitro expansion and differentiation of human pluripotent stem cells in bioreactor culture systems,” Journal of Biotechnology, vol. 234, pp. 71–82, 2016. View at Publisher · View at Google Scholar
  6. M. H. Kim and M. Kino-Oka, “Bioprocessing strategies for pluripotent stem cells based on Waddington's epigenetic landscape,” Trends in Biotechnology, vol. 36, no. 1, pp. 89–104, 2018. View at Publisher · View at Google Scholar
  7. G. M. C. Rodrigues, C. A. V. Rodrigues, T. G. Fernandes, M. M. Diogo, and J. M. S. Cabral, “Clinical-scale purification of pluripotent stem cell derivatives for cell-based therapies,” Biotechnology Journal, vol. 10, no. 8, pp. 1103–1114, 2015. View at Publisher · View at Google Scholar
  8. C. C. Miranda, T. G. Fernandes, M. M. Diogo, and J. M. S. Cabral, “Towards multi-organoid systems for drug screening applications,” Bioengineering, vol. 5, no. 3, p. 49, 2018. View at Publisher · View at Google Scholar
  9. Y. Y. Lipsitz, N. E. Timmins, and P. W. Zandstra, “Quality cell therapy manufacturing by design,” Nature Biotechnology, vol. 34, no. 4, pp. 393–400, 2016. View at Publisher · View at Google Scholar
  10. I. Heemskerk, K. Burt, M. Miller et al., “Rapid changes in morphogen concentration control self-organized patterning in human embryonic stem cells,” Elife, vol. 8, 2019. View at Publisher · View at Google Scholar
  11. T. B. Bertucci and G. Dai, “Biomaterial engineering for controlling pluripotent stem cell fate,” Stem Cells International, vol. 2018, Article ID 9068203, 12 pages, 2018. View at Publisher · View at Google Scholar
  12. Y. Ma, M. Lin, G. Huang et al., “3D spatiotemporal mechanical microenvironment: a hydrogel-based platform for guiding stem cell fate,” Advanced Materials, vol. 30, no. 49, article 1705911, 2018. View at Publisher · View at Google Scholar
  13. P. Jayaraman, C. Gandhimathi, J. R. Venugopal, D. L. Becker, S. Ramakrishna, and D. K. Srinivasan, “Controlled release of drugs in electrosprayed nanoparticles for bone tissue engineering,” Advanced Drug Delivery Reviews, vol. 94, pp. 77–95, 2015. View at Publisher · View at Google Scholar
  14. J. L. Madrigal, R. Stilhano, and E. A. Silva, “Biomaterial-guided gene delivery for musculoskeletal tissue repair,” Tissue Engineering Part B: Reviews, vol. 23, no. 4, pp. 347–361, 2017. View at Publisher · View at Google Scholar
  15. C. C. Miranda, T. G. Fernandes, S. N. Pinto, M. Prieto, M. M. Diogo, and J. M. S. Cabral, “A scale out approach towards neural induction of human induced pluripotent stem cells for neurodevelopmental toxicity studies,” Toxicology Letters, vol. 294, pp. 51–60, 2018. View at Publisher · View at Google Scholar