Platelet transfusions are used to treat deficiencies in platelet number and/or function that is seen in multiple clinical settings such as cancer and post trauma. Given changing demographics and an increasing reliance on platelet transfusion in modern medicine, its is likely that donor-derived platelets to provide this care may prove inadequate in the near future. The generation of large numbers of physiologically viable platelets in-vitro is intended to provide a new treatment option for such patients with platelet deficies. Starting with mega- karyocytes (Megs), platelet release (thrombopoiesis) is driven by shear forces typically found in the vasculatures. Previous approaches were aimed at mimicking platelet production in the bone marrow as Megs emerge from the intramedullary space into the blood stream, but new research points to significant platelet production by Megs embedded in the lung. This proposal is aimed at taking advantage of this discovery to improve both our understanding of thrombopoiesis and our ability to produce platelets in vitro focused on mimicking the particular properties of the pulmonary microvasculature. There are four aims in this application:
Aim 1 : Produce and test devices recapitulating the pulmonary vascular bed. Several different will be manufactured to entrap Megs and allow thrombopoiesis to occur.
Aim 2 : Design and test a system for platelet production under lung-mimetic mechanical strain. We will use flexible microfluidic layers will b.
Aim 3 : Design and test a system for temporal control of O2 concentration within the reactor. Switching from a low to high O2 partial will be achieved to replicated physiological changes in the lung.
Aim 4 : Optimize the combined effects of lung model parameters and test platelet functional performance. The final microfluidic devices using all of the optimal parameter determined will be tested by infusions of Megs and measurement of the efficacy to produce platelet-like particles that physically and functionally match that of freshly-drawn donor-derived platelets. Phase I research is intended to validate a consumable compatible with existing controllers that can we used widely to study platelet production lung microenvironment by controlling cappillary, shear forces, defomation of capillary bed and gas concentration. If successful, a scale-up to a clinically feasible platelet production reactor will be attepted in Phase II. This work represents a collaboration between a bioengineering company that has been supplying microfluidic research systems for the study of platelet function and a laboratory that are domain experts in the treatment of platelet disorders.
Platelet deficiency is often treated via transfusions from heathy donors, leading to challenges related to limited supply and disease transmission risks. While our ability to generate large number of platelets outside the body has seen significant developments, it is not yet efficient enough to be deployed in the clinic. If successful, this proposal will improve in-vitro platelet production systems utilizing the discovery of platelet production in the lung, and lead to improved treatment options for patients currently requiring platelet transfusions.
