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Bioengineering approaches to blood cell production
Conclusions
Replicating erythrocyte and platelet production ex vivo is particularly challenging in the light of the unique architec- ture and composition of the native bone marrow microen- vironment whose biochemical and mechanical signals influence progenitor cell differentiation and function.12 Like building a house brick-by-brick, tissue-engineering approaches have combined all the knowledge collected over years of in vivo and in vitro research on hematopoiesis to develop bone marrow mimics with different levels of complexity (Figure 4). Nevertheless, there are aspects that still need to be addressed in order to increase the yield of cells produced and thereby enable clinical advances. Bone marrow mimics will need to be scaled-up several orders of magnitude to produce 3x1011 platelets,107 the equivalent of one apheresis platelet unit, or 2x1012 erythrocytes, the number normally contained in one unit of blood. To achieve this, the whole process has to become more cost- efficient to match the current prices of high-quality blood products.108 According to a current estimate, producing a number of erythrocytes in the desired range would cost thousands of dollars per unit just in consumables, without considering the investment in facilities, while the hospital costs for donated samples are in the order of magnitude of hundreds of dollars.109, 110 Producing blood on a commercial scale will require substantial investment, and it will be challenging to maintain momentum in the direction of research and development of increasingly more efficient bone marrow models. Future advancement in this field will require scalable biomaterials and cell manufacturing tech- niques to produce blood cost-effectively in clinical-grade conditions. Costs could be reduced if specific culture com- ponents were to be produced in a bulk. The field is moving towards the discovery of novel agents, cytokines and/or chemically defined media that could be competitively priced compared to current reagents.74,111,112 However, it is clear that optimization as well as research into safety and stability are needed before clinical application. Other approaches include genetic manipulation of human
pluripotent stem cells to allow enhanced cell expansion but preserved differentiation, the decrease of device manufac- turing costs, the reduction of total operating volume and cytokines, and optimization of methods for recovery and concentration of the final products.113-115 However, in the short term the goal of this research is not to compete with the costs of blood donations. The most likely initial appli- cations would be for the treatment of allo‐immunized patients and those with rare blood groups. Indeed, gene therapies, with their potential to cure several benign and malignant hematologic diseases and develop cultured products to improve transfusion support for individuals with rare blood types, are currently in the therapeutic spot- light.116 Optimized 3D culture systems could provide invaluable insight for studying disease mechanisms, sup- porting cell growth prior to gene manipulation and testing the safety of gene-edited blood products or new pharma- cological treatments on patient-derived samples before in vivo use. This is a complex and multidisciplinary task that is focused on synergistic interactions between engineering, medicine and key biological processes. Bioengineering the complex structural and dynamic microenvironment of the bone marrow is on the verge of changing the landscape of healthcare in a revolution that is only just starting.
Disclosures
No conflicts of interest to disclose.
Contributions
AA, PMS, ABo, CPM and GM wrote the manuscript. CADB and ABa conceived the review, wrote the manuscript and gave overall direction.
Funding
This paper was supported by Cariplo Foundation (Grant 2017-0920) and by the European Commission (H2020- FETOPEN-1-2016-2017-SilkFusion, Grant Agreement 767309). The funders had no role in the design of the review, decision to publish it, or preparation of the manuscript.
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