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The Work of a Bloodsmith: Progress in the Quest for Complete Blood Substitutes

By August 7, 2018No Comments

The Canadian Blood Services estimates 100,000 new donors are needed each year to meet the clinical demand for blood transfusions. As blood transfusions are one of the most common lifesaving procedures, there is an increasing global effort to reduce the demand for blood donations through the development of blood substitutes. Blood substitutes are synthetically derived molecules and materials which can recapitulate the functional role of blood. Some advances have been made through chemical approaches such as perfluorocarbons and hemoglobin-based products, which mimic the oxygen carrying capacity of blood. These substitutes, however, cannot recapitulate the full array of physiologic functions carried out by components of whole blood, such as white blood cells for combating infection and platelets for carrying out clotting processes. While chemical blood substitutes offer a niche application in emergency and mass casualty situations, a more complete therapeutic is needed to fill the gap in clinical settings.

A promising avenue currently being investigated is the derivation of various blood cells from patient-derived pluripotent stem cells. By inducing stem cell differentiation into the various types of blood cells, this avenue can be used to carry out the full spectrum of functions of whole blood. Additionally, stem cells can be procured autologously. These donations come from the patients themselves, which reduces the need for laborious type-matching. Early studies have demonstrated the feasibility of this approach toward generating blood cells by isolating stem cells from cord blood and inducing their differentiation in vitro through an array of reprogramming growth factors.As advances in cellular manufacturing continue to progress, the potential to scale up from small petri dishes to large bioreactors of cells becomes an increasingly feasible future.

Stem cell-derived platelets may be especially useful in resolving a tremendous unmet clinical need, as donated platelets have a shelf life of only 5 – 7 days. This limitation often forces blood banks to discard donated platelets if not used within this time frame. While a number of investigators have been able to induce the production of platelets from stem cells, none have been able to produce them in quantities that match physiological platelet production. Dr. Jonathan Thon, CEO/CSO of Platelet Biogenesis, is taking a new approach to platelet generation by focusing on the environment of platelet production. Currently, Platelet Biogenesis is working towards mimicking the physiological conditions by developing a microfluidic platform for culturing platelets that is able to reflect the vascular flow, composition, and microenvironment of the bone marrow.2

Recently, Cornell University Investigator Dr. Shahin Rafi published a study that demonstrated a method for the conversion of blood vessel cells from the lung of an adult mouse into stem cells.3 The converted stem cells demonstrated the capacity for self-renewal and successfully differentiated into the various functional types of blood cells. While further studies are needed to assess the long-term stability of these cells, advances in stem-cell derived blood products could not only be a solution to many hematologic disorders, but could also potentially serve patients whose stem cells have limited self-renewal capacities, such as elderly individuals and those undergoing cancer treatments.

CBR investigators are taking another approach to reduce the demands on blood donations. Rather than re-building blood synthetically or deriving components from progenitor stem cells, researchers are reimagining how banks could repurpose red blood cells (RBC’s) that are already at their disposal. The four main blood groups: A, B, AB, and O remain the largest of the limiting factors of blood donations due to incompatibility between donor-recipient types. Blood type-specific carbohydrate groups on the surface of the A, B, and AB cells can elicit an immune response from the recipient if not matched with the correct type. The powerful immune response ultimately leads to the destruction of the transfused red blood cells. As a result, O-negative type blood – comprising ~ 8% of the population – is left as the only “safe” blood group for transfusion, as it lacks these reactive groups that give rise to incompatibility reactions. In collaboration with Dr. Stephen Withers, researchers in the laboratory of Dr. Jayachandran Kizhakkedathu are working towards developing a method to enzymatically convert A, B, and AB blood types to the universal donor O-type blood. Paired with work done by Dr. Mark Scott and collaborators who use polymer technology to ‘camouflage’ minor red cell antigens from the immune system, 3 these modified cells could allow clinicians to broaden the compatibility of their donation stores and reduce the waste of precious RBC donations.

These complete blood substitutes paint a new picture of blood donation, where typing instruments may eventually be replaced with bioreactors and freezers, previously reserved for post-donation ice cream, but instead, lined with vials of patient-specific cells. The scale-up and delivery of these products still needs to be optimized before this “picture” can truly come into focus for the general population. However, it is the efforts of these pioneering “bloodsmiths” that provoke an optimistic outlook for a complete blood substitute. In the interim, blood donations remain an irreplaceable gift of life for those in need.