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  • Review Article
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Bioreactors for engineering patient-specific tissue grafts

Nature Reviews Bioengineering volume 1, pages 361–377 (2023)Cite this article

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Abstract

Bioreactors have the potential to advance the clinical application of cell-based therapies. Cell expansion bioreactors have been used commercially for therapeutic applications; however, bioreactor-based engineering of 3D tissue grafts remains challenging owing to the complexity of tissue architectures, cellular heterogeneity and the lack of non-invasive, tissue-specific biomarkers with which to assess graft viability and maturation. Consequently, only a few bioreactor-based start-up companies that engineer patient-specific tissue grafts have emerged. In this Review, we discuss patient-specific bioreactors that can be used to engineer skin, small-diameter arteries and musculoskeletal tissues. We evaluate the impact of precision manufacturing, including 3D bioprinting, automation and non-invasive sensing, on optimizing the biological, chemical and physical parameters of the bioreactors that are required for specific tissue regeneration. We discuss the commercially available tissue-engineering bioreactors and the potential of digital twins and automation, and we outline the scientific and regulatory pathways that must be followed to enable the translation of tissue-specificbioreactors to the clinic.

Key points

  • Tissue-engineering bioreactors have driven major technological innovations in commercialized cell expansion; however, the clinical translation of bioreactor-based cell-based tissue-engineered constructs remains limited.

  • Bioreactors can be designed to engineer autologous cell-based, patient-specific and tissue-specific grafts, including cartilage, tendons, ligament, bone, skin and small-diameter vascular grafts.

  • Several tissue-engineering bioreactors have been commercialized that enable the engineering of large-scale, economically viable and clinically accessible tissues.

  • The biological, chemical and physical parameters of bioreactors need to be optimized to allow automation, non-invasive sensing, 3D bioprinting and computational modelling for patient-specific tissue regeneration.

  • Distinct clinical, biological and regulatory pathways must be followed to allow the clinical translation of bioreactor-based tissue engineering.

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Fig. 1: Bioreactors for patient-specific tissue engineered grafts.
Fig. 2: Patient-specific 3D tissue grafts grown in bioreactor systems.
Fig. 3: Computational prediction of tissue growth inside an additively manufactured titanium scaffold cultured in a perfusion bioreactor.

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Acknowledgements

The authors would like to acknowledge support from the NIH National Institute for Dental and Craniofacial Research (grant number 5 R01 DE027957 to W.L.G.).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Naboneeta Sarkar & Warren L. Grayson

  2. Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Naboneeta Sarkar & Warren L. Grayson

  3. EpiBone Inc, Brooklyn, NY, USA

    Sarindr Bhumiratana

  4. Prometheus Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium

    Liesbet Geris & Ioannis Papantoniou

  5. Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    Ioannis Papantoniou

  6. Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA

    Warren L. Grayson

  7. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA

    Warren L. Grayson

  8. Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA

    Warren L. Grayson

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  1. Naboneeta Sarkar
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All authors contributed equally to the preparation and writing of this article.

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Correspondence to Warren L. Grayson.

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S.B. is the co-founder and Chief Scientific Officer of EpiBone. W.L.G. is a shareholder of EpiBone. The other authors declare no competing interests.

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Cardiovascular disease caused by coronary artery occlusion: https://www.cdc.gov/heartdisease/facts.htm

Transplant waiting lists: https://www.organdonor.gov/learn/organ-donation-statistics

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Sarkar, N., Bhumiratana, S., Geris, L. et al. Bioreactors for engineering patient-specific tissue grafts. Nat Rev Bioeng 1, 361–377 (2023). https://doi.org/10.1038/s44222-023-00036-6

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