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Programmable 3D silk bone marrow niche for platelet generation ex vivo and modeling of megakaryopoiesis pathologies

Christian A. Di Buduo, Lindsay S. Wray, Lorenzo Tozzi, Alessandro Malara, Ying Chen, Chiara E. Ghezzi, Daniel Smoot, Carla Sfara, Antonella Antonelli, Elise Spedden, Giovanna Bruni, Cristian Staii, Luigi De Marco, Mauro Magnani, David L. Kaplan, Alessandra Balduini

Key points

  • Natural silk protein sponge and vascular tubes reproducing human bone marrow niche environments for functional platelet generation ex vivo.

  • Programmable bioengineered model for the investigation and therapeutic targeting of altered platelet formation.

Abstract

We present a programmable bioengineered three-dimensional silk based bone marrow niche tissue system that successfully mimics the physiology of human bone marrow environment allowing us to manufacture functional human platelets ex vivo. Using stem/progenitor cells, megakaryocyte function and platelet generation were recorded in response to variations in extracellular matrix components, surface topography, stiffness, co-culture with endothelial cells and shear forces. Millions of human platelets were produced and showed to be functional based on multiple activation tests. Using adult hematopoietic progenitor cells our system demonstrated the ability to reproduce key steps of thrombopoiesis, including alterations observed in diseased states. A critical feature of the system is the use of natural silk protein biomaterial allowing us to leverage its biocompatibility, non-thrombogenic features, programmable mechanical properties, and surface binding of cytokines, extracellular matrix components and endothelial-derived proteins. This in turn offers new opportunities for the study of blood component production ex vivo and provides a superior tissue system for the study of pathologic mechanisms of human platelet production.

  • Submitted August 21, 2014.
  • Accepted January 3, 2015.