Biosynthetic blood surrogates: Current status and future opportunities

Abstract

Blood is a liquid connective tissue containing cellular and non-cellular components. Blood circulation is vital to life since it transports gases and nutrients, maintains immune surveillance, promotes necessary clotting to prevent hemorrhage, and maintains oncotic pressure and body temperature. Blood transfusion is a life-saving procedure where donor-derived blood is administered into a patient when the patient's own blood is diseased or depleted. However, blood transfusion faces tremendous challenges due to donor shortage, limited shelf life, transfusion-associated infection risks, and complex logistics of blood banking and transport. A robust volume of research is currently focused on resolving these issues, including pathogen reduction technologies, temperature-reduced storage, and bioreactor-based production of blood cells from stem cells in vitro. In parallel, significant interest has developed toward biomaterials-based engineering of synthetic blood surrogates that can provide critical functions of blood components while circumventing the limitations of donor-derived blood products. Here, the major efforts have focused on the design of RBC surrogates for oxygen transport and platelet surrogates for hemostatic functions, and only limited efforts have focused on WBC mimicry. Processes have also been developed to isolate plasma or coagulation factors to treat specific bleeding risks, as well as freeze-dry or spray-dry plasma for long-term storage and on-demand use. The current article will provide a comprehensive review of various blood surrogate approaches highlighting biomaterials design and applications, important challenges, and future opportunities.

Keywords: Global Health; biomaterials; biosynthetic blood surrogate; blood transfusion; nanoparticles.

FIGURE 1

Schematic of cellular and molecular composition of blood along with normal cell counts and size ranges for the various blood cells.

FIGURE 2

(a) Multiscale schematic of RBC and encapsulated hemoglobin within the RBC (Hb); (b) Schematic showing conformational changes in Hb regulated by 2,3‐DPG associated with binding and release of oxygen (O₂); (c) Representative O₂‐binding curves for Hb in its natural form (in RBC) versus for Hb incorporated in various “RBC surrogate” oxygen carrier technologies showing the sigmoid nature of the oxygen binding kinetics of Hb (adapted from Reference [97]).

FIGURE 3

Hemoglobin (Hb) based oxygen carrier technologies utilizing cell‐free hemoglobin that is chemically modified via various biomaterials and bioconjugation approaches to improve stability, function, and in vivo safety.

FIGURE 4

Hemoglobin (Hb) based oxygen carrier technologies utilizing encapsulated hemoglobin where various biomaterials‐based carrier platforms are loaded with hemoglobin and other regulatory molecules to improve hemoglobin stability, function, and in vivo safety.

FIGURE 5

(a) Representative chemical structures of perfluorocarbon (PFC) molecules with oxygen‐binding capability, which can form microemulsion or nanoemulsion droplets stabilized by lipidic surfactants; (b) Characteristic oxygen binding profile of hemoglobin (sigmoid) compared to that of PFC (linear) indicating that compared to oxygen partial pressure (pO₂) required to saturate hemoglobin, a much higher pO₂ is required to saturate PFCs.

FIGURE 6

Various biomaterials‐based designs incorporating iron porphyrin systems for oxygen carrying applications.

FIGURE 7

Schematic of hemostasis mechanisms involving platelet adhesion and aggregation, platelet‐mediated coagulation amplification for thrombin production and fibrin generation, and platelet granule secretion for augmenting coagulation outcomes and fibrin stability; representative scanning electron microscopy (SEM) images of activated platelets, fibrin, and final hemostatic clot are shown.

FIGURE 8

Representative designs of biomaterials‐based intravenous hemostatic technologies that mimic adhesive, aggregatory, procoagulant, or secretory properties of platelets.

FIGURE 9

Schematic representation of leukocyte interactions with endothelium (e.g., via selectins, integrins, and other cell adhesion molecules) and design of “leukocyte surrogate” constructs that mimic such interactions via ligand decoration or membrane biointerfacing.

FIGURE 10

Disparity in blood donation at a global scale across high‐income, middle‐income, and low‐income regions (adapted from Global status report on blood safety and availability 2016. Geneva: World Health Organization; 2017. License: CC BY‐NC‐SA 3.0 IGO.)