Synthetic blood

Synthetic blood aims to replicate the essential functions of natural blood—oxygen transport, immune response, coagulation, and metabolic support—while overcoming the limitations of donor-derived blood supplies. In whole blood, cellular components (red blood cells, white blood cells, platelets) and a plasma matrix (proteins, nutrients, hormones) work together in a finely tuned physiological system. Current efforts tend to focus on individual parts: Hemarina and KaloCyte target oxygen transport through hemoglobin-based carriers, whereas Haima Therapeutics concentrates on platelet-like particles for rapid hemostasis. Although these approaches help address specific clinical scenarios such as trauma, surgery, or emergencies where donor blood is scarce, no existing system replicates the comprehensive functionality of natural blood.

Red blood cells (RBCs) are central to oxygen delivery and carbon dioxide removal via hemoglobin. Research into RBC substitutes has produced two primary categories: hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon emulsions (PBOCs). HBOCs, including Hemarina’s HemO2, employ marine-worm-derived hemoglobin to reduce the risk of immunologic reactions, but they can still induce oxidative stress when administered in vivo. KaloCyte’s Erythromer uses a polymer-based platform to encapsulate hemoglobin, aiming to reduce oxidative stress and maintain robust oxygen (and possibly CO₂) transport. Although hemoglobin can bind CO₂ to some extent, synthetic HBOCs generally lack the enzymatic mechanisms (like carbonic anhydrase) found in natural RBCs, limiting their CO₂-handling efficiency. PBOCs, such as Fluosol-DA-20 or Perftoran, physically dissolve gases, including both O₂ and CO₂, in fluorinated molecules; while some formulations have shown promise (e.g., Perftoran is approved in Russia and Mexico), others have been discontinued over safety and cost concerns. Nevertheless, research continues on newer iterations, including albumin-derived PBOCs that may improve biocompatibility and circulation time, even if they still cannot fully replicate the CO₂ clearance strategies of intact RBCs.

White blood cells (WBCs) perform indispensable roles in immune surveillance, inflammation, and tissue repair. Although experimental nanoparticle-based approaches and engineered cell-free receptors can bind pathogens or modulate immune signaling, these methods remain far from clinical use. Another possibility—culturing natural immune cells in bioreactors—faces serious challenges in preserving full functionality at scale. Platelets, too, are vital for coagulation, adhering to damaged vessels and guiding clot formation. Lipid- or polymer-based “artificial platelets” (e.g., from Haima Therapeutics) can accelerate clotting in trauma settings but do not yet integrate with the body’s complex clotting cascade.

Beyond cellular components, plasma is a sophisticated medium that not only balances fluids and electrolytes but also carries immunoglobulins, complement proteins, and hormonal signals critical for inter-organ coordination. Volume expanders like saline or albumin solutions address fluid deficits but lack the full biochemical repertoire of natural plasma. Even specialized plasma products such as Octaplas® still require donor plasma as a base. Reproducing liver-derived proteins (e.g., clotting factors), kidney-derived hormones, and immune modulators in a fully synthetic formulation remains one of the greatest hurdles in achieving functional “blood in a bag.”

Tiered R&D Roadmap with Underlying Technologies

1. Tier 1: Core Fluid & Oxygen Delivery

   • Volume Replacement & Oncotic Pressure

     • Recombinant Albumin or Synthetic Polymers: Manufactured in mammalian (CHO) cell culture, yeast systems, or via cell-free protein expression.

     • PEGylated Colloids and Other Biopolymers: Using polymer-chemistry techniques to create stable, non-immunogenic molecules that replicate albumin’s oncotic effect.

   • Oxygen Carriers (HBOCs, PBOCs)

     • Gene-Edited Hemoglobin Production: Synthetic biology platforms that ensure minimal oxidative side effects.

     • Perfluorocarbon Engineering: Advanced emulsification technology (microfluidizers, nanoemulsions) to stabilize fluorinated molecules in aqueous environments.

   • Electrolyte & pH Control

     • Automated Formulation Systems: Inline mixing devices that monitor and adjust pH, sodium, potassium, and chloride levels in real time.

2. Tier 2: Hemostasis & Immune Support

   • Platelet-Mimicking Particles

     • Polymer Microdiscs or Lipid Vesicles: Microfabrication methods to produce particles that bind to exposed collagen or activated platelets at injury sites.

     • Surface Engineering: Functionalizing surfaces with specific ligands (e.g., von Willebrand factor–binding domains) to ensure targeted adhesion.

   • Essential Coagulation Factors

     • Recombinant Fibrinogen & Factor VIII/IX: Produced via engineered cell lines with proper glycosylation patterns. Purification involves column chromatography and advanced proteomics to verify function.

   • Passive Immune Support (Immunoglobulins)

     • Yeast or Bacterial Expression Systems: Engineered to produce polyclonal or monoclonal antibodies that match typical human IgG patterns.

     • Cell-Free Protein Synthesis: Rapid, modular assembly of immunoglobulins without relying on full-time cell cultivation.

3. Tier 3: Advanced Bioreactivity & Nutrient Delivery

   • Complement Proteins & Cytokines

     • Synthetic Biology & Glycoengineering: CHO or HEK293 cell lines (or cell-free systems) that can add the post-translational modifications necessary for functional complement complexes (e.g., C3, C5, Factor B).

     • Nanoparticle Conjugation: Protecting fragile proteins during storage and transit by encapsulating them in biodegradable carriers.

   • Nutrient Carriers & Waste Buffering

     • Enzyme-Loaded Nanoreactors: Microcapsules containing enzymes (e.g., urease, lactate oxidase) to break down metabolic byproducts, mimicking kidney or liver functions.

     • Smart Hydrogel Particles: pH-responsive materials that release glucose or other nutrients when sensors detect a drop in local blood sugar.

   • Real-Time Sensing & Feedback

     • Microelectronic Biosensors: Integrated into fluid delivery systems to measure lactate, pH, partial pressures of O₂/CO₂, and dynamically adjust composition.

4. Tier 4: Functional Cellular Components

   • Engineered Immune Cells

     • Bioreactor Cultures of WBCs (e.g., Neutrophils, Lymphocytes): Requires breakthroughs in stem cell technology and ex vivo differentiation protocols; potentially leverages 3D-printed biostructures for improved viability.

     • Cell-Free Immune Mimics: Nanoparticles with surface-bound pattern recognition receptors to neutralize pathogens—an extension of Tier 3’s advanced bioreactivity.

   • Continuous Platelet “Factories”

     • Megakaryocyte Cultures: Bioreactors that generate functional platelets in vitro, requiring microfluidic “shear” environments to induce platelet shedding.

   • Hormonal Integration

     • Recombinant Hormones (EPO, Insulin, etc.): On-demand biosynthesis tied to sensor feedback loops, ensuring hormone release mirrors physiologic needs.

This roadmap underscores the multi-layered technologies required—from synthetic biology and nanotechnology to advanced cell-free protein expression and biosensor integration—to systematically build and refine synthetic blood. While companies like Hemarina and Haima Therapeutics offer promising niche solutions, creating a universal product that unites oxygen transport, immune defense, coagulation, and metabolic homeostasis demands collaboration across bioengineering, chemistry, and systems biology.