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Review
. 2017 Jul;28(5):472-477.
doi: 10.1080/09537104.2016.1265922. Epub 2017 Jan 23.

Platelet Bioreactor: Accelerated Evolution of Design and Manufacture

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Free PMC article
Review

Platelet Bioreactor: Accelerated Evolution of Design and Manufacture

Jonathan N Thon et al. Platelets. .
Free PMC article

Abstract

Platelets, responsible for clot formation and blood vessel repair, are produced by megakaryocytes in the bone marrow. Platelets are critical for hemostasis and wound healing, and are often provided following surgery, chemotherapy, and major trauma. Despite their importance, platelets today are derived exclusively from human volunteer donors. They have a shelf life of just five days, making platelet shortages common during long weekends, civic holidays, bad weather, and during major emergencies when platelets are needed most. Megakaryocytes in the bone marrow generate platelets by extruding long cytoplasmic extensions called proplatelets through gaps/fenestrations in blood vessels. Proplatelets serve as assembly lines for platelet production by sequentially releasing platelets and large discoid-shaped platelet intermediates called preplatelets into the circulation. Recent advances in platelet bioreactor development have aimed to mimic the key physiological characteristics of bone marrow, including extracellular matrix composition/stiffness, blood vessel architecture comprising tissue-specific microvascular endothelium, and shear stress. Nevertheless, how complex interactions within three-dimensional (3D) microenvironments regulate thrombopoiesis remains poorly understood, and the technical challenges associated with designing and manufacturing biomimetic microfluidic devices are often under-appreciated and under-reported. We have previously reviewed the major cell culture, platelet quality assessment, and regulatory roadblocks that must be overcome to make human platelet production possible for clinical use [1]. This review builds on our previous manuscript by: (1) detailing the historical evolution of platelet bioreactor design to recapitulate native platelet production ex vivo, and (2) identifying the associated challenges that still need to be addressed to further scale and validate these devices for commercial application. While platelets are among the first cells whose ex vivo production is spearheading major engineering advancements in microfluidic design, the resulting discoveries will undoubtedly extend to the production of other human tissues. This work is critical to identify the physiological characteristics of relevant 3D tissue-specific microenvironments that drive cell differentiation and elaborate upon how these are disrupted in disease. This is a burgeoning field whose future will define not only the ex vivo production of platelets and development of targeted therapies for thrombocytopenia, but the promise of regenerative medicine for the next century.

Keywords: Biomanufacture; biomedical engineering; bioreactors; hematopoietic stem cells; megakaryocytes; platelets; pluripotent stem cells.

Conflict of interest statement

Funding Declaration of Interest Statement

J.T. is supported by NIH grants R00HL114719 and R01HL130770. J.T. is a paid consultant for, has financial interest in, and is a founder of Platelet BioGenesis, and is an inventor on their patents. B.D. is a paid consultant for Platelet BioGenesis, a company that aims to produce donor-independent human platelets from human-induced pluripotent stem cells at scale. L.B. is an employee of Platelet BioGenesis, and is partially supported by NIH SBIR grant 1R44HL131050-01. The interests of J.T. and B.D. were reviewed and are managed by the Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies.

Figures

Figure 1
Figure 1
Human platelets are produced by megakaryocytes in the bone marrow. Figure adapted from Machlus and Italiano (2013) [41] and Zhang et al (2012) [42].
Figure 2
Figure 2
Number of platelet bioreactor manuscripts published each year since 1990. Figure highlights the inception of this field.
Figure 3
Figure 3
Historical Evolution of Platelet Bioreactor Design, 2009–2016. Panel A adapted from Sullenbarger et al (2009) [17]. Panel B adapted from Dunois-Larde et al (2009) [19] and Blin et al (2016) [22]. Panel C adapted from Pallotta et al (2011) [23]. Panel D adapted from Mitchell (2011) [27] and Avanzi et al (2016) [26]. Panel E adapted from Nakagawa et al (2013) [28]. Panel F adapted from Schlinker et al (2015) [29]. Panel G adapted from Thon et al (2014) [31].

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