Original
Paper:
"New developments and future trends of artificial blood"
Original Authors:
Gopal Patidar, Arun Vazhappilly Jose, Rounak Dubey, Monique Huggins,
Behnam Rafiee, Mordechai Hershkop, Jules Zinni, Bruce Spiess, Mark T.
Friedman
Published:
Annals of Blood, March 18, 2026
DOI:
10.21037/aob-2025-1-51
1. Overview and Purpose of the Paper
This
2026 review article provides a comprehensive examination of the
current state, recent advances, and future directions of artificial
blood technologies, which are more precisely referred to as oxygen
therapeutic agents (OTAs). The paper was authored by a
multidisciplinary team of researchers and clinicians from
institutions across India, the United Kingdom, and the United States,
including the All India Institute of Medical Sciences, NYU Grossman
Long Island School of Medicine, and the University of Florida. The
review was commissioned by the editorial office of Annals of Blood as
part of a special series on artificial blood, and it underwent
external peer review prior to publication.
The
central argument of the paper is that while artificial blood products
have been under investigation for nearly a century, no single product
has yet achieved widespread clinical approval for general use.
However, the authors contend that recent technological breakthroughs
and converging innovations in nanotechnology, stem cell biology,
biomaterials engineering, and computational modeling are bringing the
field closer to realizing viable clinical applications than ever
before. The paper distinguishes itself from earlier reviews by
focusing not just on historical chronology but on translational
applicability, the reasons behind previous failures, technological
inflection points that have occurred, and how hybrid or modular
systems may overcome longstanding physiological and regulatory
barriers.
The
review also distinguishes itself from earlier publications in the
field by incorporating innovative technologies from the
nanotechnology and stem cell disciplines with a comparative analysis
of translation barriers across different platforms. Rather than
simply recounting history in a chronologically comprehensive fashion,
the current review emphasizes identifying why specific approaches
failed, where technological inflection points have occurred, and how
hybrid or modular systems may overcome longstanding physiological and
regulatory barriers. This forward-looking analytical framework is
intended to clarify the realistic clinical trajectory of artificial
blood in the coming decade and to provide actionable insights for
researchers, clinicians, regulators, and investors.
The
paper spans several major categories of artificial blood technology:
hemoglobin-based oxygen carriers (HBOCs), perfluorocarbon (PFC)
emulsions, hematopoietic stem cell (HSC)-derived red blood cells
(RBCs), platelet substitutes, and nanoscale synthetic platforms. For
each technology, the authors assess the mechanisms of action,
clinical trial outcomes, safety profiles, cost considerations,
regulatory challenges, and future directions.
2. Background and Motivation
2.1 The Persistent Need for Alternatives to Donor
Blood
The
motivation for artificial blood research stems from persistent and
well-documented challenges in traditional transfusion medicine. These
challenges include chronic blood supply shortages, the limited shelf
life of donated blood products (typically around 42 days for red
blood cells under standard refrigeration), the risk of transmitting
infectious diseases through donated blood (including viral,
bacterial, and emerging pathogens), immunological incompatibility
between donors and recipients (which can lead to transfusion
reactions), and a substantial number of adverse outcomes associated
with allogeneic blood transfusion. Taken together, these challenges
create a compelling case for developing alternatives to conventional
donor blood transfusion. The problem is not merely one of convenience
but of fundamental medical necessity: in many clinical situations,
donor blood is either unavailable, incompatible, or carries risks
that could be avoided with a suitable synthetic or manufactured
alternative. These limitations are particularly acute in emergency
and military settings, where access to properly typed and stored
blood products may be severely constrained, and where the
availability of a universal, shelf-stable blood substitute could mean
the difference between life and death for patients suffering from
hemorrhagic shock.
The
history of artificial blood research extends back to the 1930s, when
the first hemoglobin-based oxygen carrier was created using cow blood
and tested in a cat. In the 1950s, the United States Navy conducted
initial human tests using stroma-free hemoglobin solutions. The 1960s
saw the U.S. Army experimenting with diaspirin crosslinked hemoglobin
to reduce renal clearance. However, these early efforts were plagued
by significant problems, including kidney toxicity, elevated blood
pressure, and myocardial infarctions resulting from acute coronary
spasm. The fundamental issue was that free hemoglobin, when released
from the confines of a red blood cell, scavenges nitric oxide (NO), a
critical vasodilator, leading to vasoconstriction, hypertension, and
organ injury.
To
address these challenges, researchers over the decades developed
various strategies to modify hemoglobin and reduce its toxicity.
These strategies have included pyridoxilation (to modify oxygen
affinity), crosslinking (to increase molecular weight and extend
circulation time), PEGylation (attachment of polyethylene glycol
chains to reduce immunogenicity and extend half-life), and
carboxylation. Despite these modifications, the fundamental problem
of NO scavenging by cell-free hemoglobin remained a persistent
barrier to clinical success. Work continues today on new methods to
render human and animal-based hemoglobins non-toxic to endothelial
cells and renal cells while also decreasing vascular spasm.
2.2 The Emergence of Perfluorocarbon Alternatives
Parallel
to hemoglobin-based approaches, researchers explored perfluorocarbon
(PFC) emulsions as an alternative strategy. PFCs are chemically inert
synthetic compounds that dissolve oxygen physically in a linear
fashion, in contrast to the chemical binding mechanism used by
hemoglobin. This distinction is important because it means PFCs
function through a fundamentally different physiological mechanism.
The authors note that early researchers studying HBOCs mistakenly
assumed that PFCs needed high inspired oxygen concentrations to be
effective. The paper argues that this assessment was only partially
true and resulted from hemoglobin-focused thinking rather than a
genuine understanding of how PFCs function in the environment of RBCs
and tissue oxygen demand. PFCs have a unique ability to enhance
tissue oxygen delivery in situations of low flow or no flow in the
microvasculature, a capability that the authors argue has not been
sufficiently appreciated or advanced as a medical breakthrough.
3. Current Available Technologies
3.1 Hemoglobin-Based Oxygen Carriers (HBOCs)
HBOCs
represent the most extensively studied and historically significant
category of artificial blood, with a research lineage extending back
to the earliest experiments in the 1930s. The most notable example is
Hemopure (HBOC-201), manufactured by HbO2 Therapeutics (Souderton,
PA, USA). Hemopure uses polymerized bovine hemoglobin and offers the
significant advantage of oxygen delivery without the need for
crossmatching, meaning it can theoretically be given to any patient
regardless of blood type. However, Hemopure and similar HBOC products
are limited by serious adverse effects, including vasoconstriction,
hypertension, and myocardial risks. These effects are primarily
attributed to nitric oxide scavenging by the cell-free hemoglobin
molecules.
The
mechanism by which HBOCs cause harm is well understood at the
molecular level. When hemoglobin molecules circulate freely outside
of red blood cells, they are small enough to penetrate the
endothelial lining of blood vessels. There, they rapidly react with
and neutralize nitric oxide, a gas that is continuously produced by
endothelial cells and serves as the body's primary vasodilator.
Without adequate nitric oxide, blood vessels constrict, blood
pressure rises, and the downstream tissues receive less blood flow.
This paradoxical outcome — where an oxygen-carrying agent actually
reduces tissue oxygenation by constricting the blood vessels that
deliver it — has been the fundamental pharmacological challenge of
the entire HBOC class. Additionally, free hemoglobin undergoes
auto-oxidation in plasma, generating reactive oxygen species that
directly damage endothelial cells through oxidative destruction,
further compounding the vascular injury.
As
a result of these safety concerns, the clinical use of HBOCs is
extremely limited. Hemopure is available for clinical use in South
Africa and Russia, and in the United States it can only be accessed
through expanded-access programs (compassionate use). Despite these
limitations, HBOCs currently hold the largest market share
(approximately 50%) in the artificial blood products market, which
was valued at $4.5 billion USD in 2024 and is expected to grow at a
compound annual growth rate of 9.8% through 2033. The shelf life of
some HBOCs is approximately 36 months, which is a considerable
advantage over donated blood, but the cost is approximately six times
higher than that of regular red blood cells, with significantly
higher side effect rates.
3.2 Perfluorocarbon (PFC) Emulsions
PFC
emulsions represent a fundamentally different approach to oxygen
transport compared to HBOCs. Rather than chemically binding oxygen as
hemoglobin does, PFCs physically dissolve oxygen in a linear fashion
proportional to the partial pressure of oxygen. The paper discusses
several PFC products currently under investigation, including
Perftoran/Perftec (Scientific-Production Company Perftoran,
Pushchino, Russia), ABL-101 (Aurum Biosciences, Glasgow, Scotland,
which is an offshoot of Oxycyte previously tested by Oxygen
Biotherapeutics), Oxygent (previously tested by Alliance
Pharmaceuticals, no longer in clinical testing but with patents and
over 100 clinical trial datasets potentially available for another
pharmaceutical company to acquire), and NuVox dodecafluoropentane
(Tucson, AZ, USA), which is currently in phase II and III human
trials for multiple indications. NuVox is described as an
ultrashort-acting PFC that dramatically enhances oxygen delivery to
tissues.
The
advantages of PFC emulsions are substantial. They are chemically
stable, have the potential for long-term storage, can be supplied in
vial or intravenous bag formats with universal applicability, and
carry no biological infectivity risk. Several companies are currently
testing PFCs as therapies for salvaging brain tissue in acute stroke
and traumatic brain injury, as well as for treating acute cardiac
arrest (which is a very low-flow situation where PFCs can excel). The
paper emphasizes that the early problems with PFC emulsions,
including transient flu-like reactions, were largely attributable to
the normal phagocytic activity of the reticuloendothelial system
(RES), which was dependent on the particle size of the emulsion.
These early reactions have been overcome and understood in
present-day PFC formulations, although the stigma from these initial
problems continues to hang over the pharmaceutical class.
A
critical point made by the authors is that the outdated view that
PFCs required 100% inspired oxygen to be effective is not true. PFCs
work effectively with normal red blood cells at only slightly higher
inspired oxygen concentrations. The paper argues that PFCs work
mostly by enhancing the diffusivity of oxygen from internal sources,
and that if one only computes oxygen delivery using the standard
hemoglobin-based oxygen content equation, they will incorrectly show
a lack of efficacy. However, when PFCs are utilized in tissues with
low plasma flow or where red blood cells are limited in perfusion due
to microcirculatory dysfunction (such as edema, arterial stenosis, or
heart and circulatory failure), they are profoundly effective. The
market for PFC emulsions is projected to grow at the fastest rate
among artificial blood products due to their high oxygen-carrying
capacity and low complication rate.
The
paper makes a particularly important scientific argument regarding
PFCs that challenges conventional thinking in the field. The standard
method for computing blood oxygen content relies on the
hemoglobin-based oxygen content equation, which calculates the total
oxygen carried by blood based primarily on hemoglobin concentration
and oxygen saturation. When PFCs are evaluated using this equation
alone, they appear to contribute very little to total oxygen content
because the amount of oxygen physically dissolved in plasma or PFC is
small compared to the amount chemically bound to hemoglobin. However,
this analysis fundamentally misrepresents how PFCs work. PFCs do not
function by dramatically increasing the total oxygen content of the
blood; rather, they enhance the diffusivity of oxygen at the tissue
level, particularly in microvascular beds where flow is restricted.
In conditions such as edema, arterial stenosis, or cardiac failure,
red blood cells may be unable to reach the tissues that need oxygen
most desperately. PFC molecules, being much smaller than red blood
cells and having excellent oxygen solubility, can penetrate into
these compromised microvascular spaces and release oxygen directly to
hypoxic tissues. This mechanism is fundamentally different from
hemoglobin-based oxygen delivery and requires a different analytical
framework to appreciate. The authors argue that the failure to
understand this distinction has been one of the primary reasons PFCs
have not received the clinical recognition they deserve.
It
is also worth noting that PFCs have the potential to work
synergistically with HBOCs and other technologies. Understanding how
these different platforms might complement each other in a combined
therapeutic approach is an important area for future research.
Several companies are currently testing PFC emulsions for
neurological applications, including the salvage of brain tissue in
acute stroke and traumatic brain injury, as well as therapy for acute
cardiac arrest, all of which represent very low flow situations where
PFCs are expected to be most effective.
The
first-generation PFC product, Fluosol-DA 20% (Green Cross Corp,
Osaka, Japan), was briefly approved by the FDA in 1989 for use during
certain cardiac procedures but was eventually withdrawn due to lack
of sales. A practical limitation was that Fluosol-DA was supplied
frozen and required an hour or longer of re-sonication to
reconstitute the emulsion, which limited its practical utility in
clinical settings.
3.3 Stem-Cell-Derived Red Blood Cells
Stem-cell-derived
RBCs represent a newer and biologically elegant approach to the
artificial blood problem. This technology involves the ex vivo
manufacturing of red blood cells from hematopoietic stem cells (HSCs)
or induced pluripotent stem cells (iPSCs). The concept of using iPSCs
to produce RBCs originated from an initial report in 2006, which was
followed by a proof-of-concept study in which in vitro autologous red
blood cells derived from stem cells were, for the first time,
transfused into a human subject.
A
major advantage of iPSCs over HSCs or embryonic stem cells is that
they can be produced from any cell type, both immature and mature
cells, thus avoiding the ethical concerns that arise from the use of
human embryos. In the United Kingdom, a substantial investment was
made in this technology, with a five million pound Strategic Award
granted to a consortium led by the Scottish National Blood Service
(SNBTS) with the objective of beginning the first human trials by
late 2016. However, successful RBC generation from iPSCs was limited
by high cost, low expansion rates, lack of adult hemoglobin
expression, and insufficient enucleation (meaning the cells retained
their nuclei rather than shedding them as mature red blood cells do).
The planned 2016 UK trial did not occur as scheduled due to these
limitations.
A
significant milestone was achieved by Park et al., who demonstrated
the feasibility of producing iPSC-differentiated red blood cells for
clinical transfusion in patients who had no other treatment options.
These investigators were able to successfully manufacture red blood
cells from iPSCs generated from peripheral blood mononuclear cells
from two patients with rare blood types (Jr(a-) and D-). This work
demonstrated a particularly valuable application of cultured red
blood cells: providing transfusion products for patients with
extremely rare blood phenotypes who cannot be adequately served by
the conventional donor blood supply.
The
landmark clinical milestone came with the 2022 Phase 1 Recovery and
Survival of Stem Cell Originated Red Cells (RESTORE) Trial, a
collaborative initiative by NHS Blood and Transplant, the University
of Bristol, and the National Institute for Health and Care Research
Cambridge Clinical Facility. This trial performed mini-transfusions
of laboratory-developed red blood cells to human volunteers. In 2023,
notable positive feedback was received from trial recipients,
although comprehensive results remained unpublished at the time of
this review. The RESTORE trial represented the first time that
laboratory-grown red blood cells were transfused into human
volunteers, marking a historic proof-of-concept for cultured blood.
The
significance of the RESTORE trial cannot be overstated. It
represented not merely a technical achievement in cell culture, but a
fundamental proof-of-concept that laboratory-manufactured blood cells
can survive and function in the human circulation. This demonstration
opens the door to a future in which blood products could be
manufactured on demand from renewable cell sources, potentially
eliminating the dependence on voluntary blood donation that has
characterized transfusion medicine since its inception. For patients
with extremely rare blood phenotypes, for whom finding compatible
donors can be exceedingly difficult or sometimes impossible, cultured
red blood cells derived from iPSCs that have been genetically matched
or engineered to express the appropriate blood group antigens could
represent a life-saving advance.
Despite
these achievements, stem-cell-derived RBCs face considerable
challenges. Current manufacturing processes are financially
prohibitive, costing thousands of U.S. dollars per unit. The
expansion rates remain limited, with a recent 2025 study generating
approximately 4,600 red blood cells per iPSC, which is still well
below the dose needed for full therapeutic application (approximately
10^11 to 10^12 cells per unit). Incomplete enucleation remains a
persistent technical challenge, although enucleation rates have
improved significantly. Initial methods achieved rates below 25-30%,
but a 2019 hydrochlorofluorocarbon (HCFC) method achieved up to 60%
enucleation. Research on expanding HSCs ex vivo more robustly through
better culture conditions and the use of small molecule agonists
(such as UM171) is also progressing well.
3.4 Nanoscale Synthetic RBC Analogues
A
particularly promising development described in the paper is
ErythroMer, a nanoscale, bio-synthetic artificial lipid-based
nanoparticle with proof of concept published in 2016. ErythroMer
represents a conceptually different approach from both traditional
HBOCs and cultured red blood cells. The core concept is to reduce the
toxic nature of free hemoglobin by encapsulating hemoglobin in an
artificial membrane, creating a lipid-encapsulated hemoglobin
nanoparticle.
ErythroMer
offers several practical advantages that make it particularly
appealing for emergency and military applications. It can be
lyophilized (freeze-dried) for room-temperature storage, has an
estimated one-year shelf life, and is easy to transport. With a
half-life of 18 to 20 hours, ErythroMer is positioned as a bridging
therapy rather than a complete blood replacement. Its potential
applications include treating acute bleeding, managing autoimmune
hemolytic anemia, and providing alternatives for individuals who
decline traditional transfusions due to religious beliefs (such as
Jehovah's Witnesses).
The
development of ErythroMer was originally funded by a $2.7 million
grant from the National Institutes of Health's National Heart, Lung,
and Blood Institute. In 2023, it received an additional $46 million
from the federal Defense Advanced Research Projects Agency (DARPA),
reflecting the significant military interest in this technology. The
encapsulation approach that ErythroMer uses creates a diffusion
barrier that retards nitric oxide scavenging, effectively addressing
the severe vasoconstriction that caused the failure of earlier
acellular HBOC products. Encapsulated carriers are also designed with
biomimetic features, such as pH-responsive oxygen affinity, to
optimize delivery to hypoxic tissues. However, the product's future
remains contingent upon successful clinical trials, and it is still
in the preclinical or early clinical development stage.
3.5 Platelet Substitutes
The
paper devotes substantial attention to platelet substitutes,
recognizing that a complete blood replacement strategy must address
hemostasis in addition to oxygen transport. Platelet substitutes aim
to provide hemostatic support without requiring donor products by
replicating key platelet functions, including adherence, activation,
aggregation, and procoagulant surface delivery. Ideal substitutes
should be safe, affordable, sterile, easy to store, and suitable for
use in both hospital environments and challenging field conditions.
Infusible
Platelet Membranes (IPMs):
The earliest platelet substitutes were infusible platelet membranes
(IPMs), which are microparticles produced from fragmented,
lyophilized outdated platelets. These products preserve key
glycoproteins like GPIb and GPIIb/IIIa, which are essential for
limited hemostatic function. Phase 1 and Phase 2 trials showed
short-lived and unpredictable safety and bleeding correction, while
alloimmunization and complement activation restricted broader use.
Despite these limitations, the studies confirmed that platelet
membrane components can promote functional clot formation if other
factors are in place, though these agents carry the risk of
uncontrolled pro-thrombotic activation.
Liposome-Based
Platelet Mimetics:
More recent advances in biomaterials have produced liposome-based
platelet mimetics. These are constructed from phospholipid bilayers
and can display adhesion peptide motifs that mimic the binding sites
found on natural platelets, including collagen-binding, von
Willebrand factor (vWF)-binding, and fibrinogen-mimetic (RGD) sites.
The most advanced version is SynthoPlate, which combines multiple
ligands to replicate the platelet plug formation process. Preclinical
studies in trauma and thrombocytopenia models have shown that
SynthoPlate shortens bleeding time and reduces blood loss without
causing thrombosis. Additionally, SynthoPlate particles can be
lyophilized for long-term storage and emergency use.
Polymeric
and Hydrogel Microparticles:
In addition to liposomal systems, researchers have developed
polymeric and hydrogel microparticles that emulate the size,
deformability, and mechanical properties of circulating platelets.
These "platelet-like particles" are primarily fabricated
from the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA)
and are conjugated with adhesion peptides to facilitate targeted
interaction with damaged vessel walls and incorporation into fibrin
networks. Due to their viscoelastic attributes, these particles
migrate toward the vessel margin under flow conditions, mirroring the
behavior of native platelets and supporting clot formation.
Preclinical studies have demonstrated that these materials reduce
hemorrhage volume and promote robust clotting, and their ability to
be stored at room temperature for extended periods enhances their
practical appeal.
Stem-Cell-Derived
Platelets:
Advances in stem cell and tissue engineering now allow the ex vivo
creation of platelet-like particles (PLPs) from megakaryocytes or
iPSCs. These anucleate particles possess major platelet receptors but
have limited hemostatic function. Early Japanese clinical trials with
iPSC-derived platelets have confirmed their safety, though they
remain few in number and minimally functional. Bioengineered hybrid
particles, formed by coating synthetic nanoparticles with cultured
cell membranes, combine biological targeting and structural
stability.
Albumin
and Fibrinogen Microparticles:
These represent another class of platelet substitutes designed to
facilitate the bridging of activated platelets. They are engineered
by depositing an albumin microsphere coating that is pre-coated with
fibrinogen or peptides containing RGD sequences. This design enables
association with activated platelet GPIIb/IIIa receptors, thereby
promoting aggregation while avoiding spontaneous activation. Initial
clinical trials have confirmed both the safety and enhanced
hemostatic efficacy of commercial products in this category,
including Thrombosphere and Synthocytes.
Freeze-Dried
Platelet Formulations:
The paper discusses Thrombosomes, a freeze-dried platelet derivative,
as another important category of platelet substitutes. Thrombosomes
aim to replicate the adhesion and aggregation functions of native
platelets and are designed for use in trauma, oncology, and
thrombocytopenia settings. The ability to freeze-dry platelet
products for long-term storage at room temperature addresses one of
the most significant logistical challenges in platelet transfusion
medicine. Natural platelet concentrates have an extremely short shelf
life of only 5 to 7 days and must be stored at room temperature with
continuous agitation, making them one of the most perishable and
expensive blood components. Freeze-dried formulations could
dramatically extend the availability of platelet support in settings
where fresh platelet products are unavailable, such as military
deployments, remote medical facilities, and disaster response
scenarios. Early clinical trials with Thrombosomes have shown
encouraging results in terms of both safety and hemostatic efficacy.
Platelet
Membrane-Coated Nanoparticles:
Platelet substitutes are now part of the broader field of
platelet-inspired nanomedicine, which recognizes the diverse roles of
platelets beyond hemostasis, including roles in immunity,
inflammation, and wound repair. Platelet membrane-coated
nanoparticles can locate vascular injuries or tumor
microenvironments, evade immune clearance, and deliver drugs such as
anti-inflammatory or chemotherapeutic agents. This development
represents a convergence of transfusion medicine, nanotechnology, and
drug delivery, and may provide applications well beyond hemostatic
replacement.
Expired
Platelet Utilization:
The paper also discusses the underutilized resource of expired
platelets for regenerative medicine and cell therapy applications.
Although platelet concentrates reach the end of their transfusion
lifespan within 5 to 7 days, they retain viable growth factors with
preserved bioactivity. Current research demonstrates their potential
in wound healing through the use of platelet gels or releasates that
promote angiogenesis and soft tissue repair. Expired platelet lysates
have been effectively employed as substitutes for fetal bovine serum
during ex vivo expansion of mesenchymal stem cells, and expired
platelets may serve as raw material for producing virally inactivated
platelet lysates, growth-factor fractions, and IPMs.
4. Comparative Clinical Outcomes and
Translational Bottlenecks
A
key contribution of this review is its systematic comparison of
translational challenges across different artificial blood platforms.
The paper identifies common translational hurdles across all
artificial blood platforms. HBOCs, despite showing some clinical
success in terms of oxygen transport, ultimately failed in broader
adoption due to systemic vasoactivity and oxidative cytotoxicity,
establishing the fundamental drawback of unencapsulated hemoglobin.
PFC blood substitutes avoided the cytotoxicity associated with
hemoglobin but were confronted by biological misinterpretation
(specifically, the incorrect assumption that they required very high
inspired oxygen levels), regulatory ambiguity, and clinical endpoints
that underestimated their microcirculatory advantages.
HSC-derived
red blood cells have excellent biological compatibility, but a number
of hurdles related to scaling up production and incomplete functional
development limit their clinical translation. Platelet substitutes
have shown promising hemostatic support but are not capable of
assuming the entire spectrum of immune and reparative functions
performed by natural platelets. Across all of these platforms, the
key bottlenecks are biocompatibility, scalability, economic
viability, and achieving acceptance by government regulatory bodies
and health officials. The authors argue that new encapsulation
technologies, hybrid technologies, and modulated whole-blood
substitutes appear to provide the most promising research direction
for overcoming these bottlenecks.
5. Safety and Efficacy Assessment
5.1 The Central Importance of Safety
Safety
remains the most critical barrier to the implementation of artificial
blood products, and this section of the paper provides the most
sobering assessment of the challenges that have historically derailed
artificial blood programs. The paper emphasizes that any artificial
blood substitute must have a known and tolerable side effect profile
that is at least as good as that of human banked blood, and that this
standard alone is not fully appreciated or embraced at this time. The
toxic adverse events associated with free hemoglobin include
oxidative stress and endothelial toxicity (hemoglobin kills
endothelial cells through oxidative destruction), nitric oxide
scavenging, and the effects of introducing foreign materials into the
body.
The
paper references a pivotal meta-analysis on hemoglobin-based blood
substitutes that covered 16 trials involving five different products
with 3,711 patients. This meta-analysis showed a significant increase
in the risk of death and myocardial infarctions in patients receiving
HBOCs, which led the FDA to suspend all trials involving HBOCs in the
United States. The free hemoglobin from HBOCs scavenges nitric oxide,
which leads to vasoconstriction and injury due to oxidative stress.
The symptoms associated with this vasoconstriction include renal
toxicity, gastrointestinal symptoms, chest pain, abdominal pain, and
coronary and cerebral vasospasm.
PEGylated
HBOCs have shown adverse events including hypertension, myocardial
infarction, high mortality, acute renal failure, and transient
ischemic attack, and their trials were stopped at Phase 3. PFC
emulsions have generally shown better tolerability. Their common
adverse events included delayed febrile reaction and flu-like
symptoms, which were attributed to the normal phagocytic activity of
the reticuloendothelial system and were dependent on the particle
size of the emulsion. Contemporary third and fourth generation PFCs
have good tolerability but are still affected by a long-standing
misunderstanding of their physiological niche. The paper reiterates
that PFCs do not need high fractional inspired oxygen (FiO2) to be
effective and work primarily by enhancing the diffusivity of oxygen
from internal sources.
5.2 Safety Profiles Across Different Platforms
HSC-cultured
red blood cells and hemoglobin vesicles (HbVs) are in clinical
testing and appear to offer acceptable safety profiles, but further
research is needed on red cell maturation and alloimmunization. The
question of alloimmunization is particularly important because
cultured red blood cells, despite being manufactured in a laboratory,
still express surface antigens that can provoke immune responses in
recipients. If cultured cells express minor blood group antigens that
differ from those of the recipient, repeated transfusions could lead
to the development of alloantibodies, complicating future transfusion
needs. This is an area that requires careful study in larger clinical
trials with longer follow-up periods.
The
paper makes an important distinction between the safety challenges
facing different platforms. For HBOCs, the primary safety concern is
the inherent toxicity of cell-free hemoglobin, which is a fundamental
molecular property that can be mitigated (through encapsulation, for
example) but not entirely eliminated. For PFCs, the safety concerns
are more manageable and primarily involve the temporary activation of
the reticuloendothelial system, which has been successfully addressed
in newer formulations. For stem-cell-derived red blood cells, the
safety profile appears to be the most favorable, as these cells are
biologically similar to native red blood cells, but concerns about
incomplete maturation, residual nucleated cells, and long-term
immunological consequences need further investigation. The authors
call for more data from larger clinical trials and the development of
improved oxygen delivery mechanisms that do not cause major
vasoconstriction events. Future work will need to include larger
randomized clinical trials with strict FDA monitoring.
6. Cost Analysis and Economic Considerations
6.1 The True Cost of Blood Transfusion
The
economic dimension of artificial blood is a significant barrier to
widespread adoption, but the paper argues that this barrier must be
understood in the context of the true total cost of conventional
blood transfusion, which is substantially higher than most people
realize. The paper provides detailed cost comparisons to
contextualize the challenge. Allogeneic blood currently costs
approximately $250 to $300 USD per unit to acquire from a blood
supplier, but the total hospital costs associated with blood
transfusion are 3.8 to 5 times higher than the acquisition cost
alone. Many reimbursement agencies do not fund blood usage in bundled
care packages such as heart surgery and orthopedics, and no hospital
is fully reimbursed for its total transfusion-related costs.
Furthermore, the adverse event costs of allogeneic blood are
substantial, largely underappreciated, and carry both human tolls and
public health costs.
Artificial
blood faces a significant cost hurdle due to high research and
development expenses and the extensive time frames required for
development. One donor unit of blood is estimated to cost around $200
to $550 USD. The cost in traditional blood processing starts even
before donation, encompassing recruitment, testing, collecting,
processing, transporting, and storing. For artificial blood, each
step of the manufacturing process, including cell culture,
purification, encapsulation, crosslinking, and emulsification in
PFCs, adds to the overall cost.
The
cost of some HBOCs with a 36-month shelf life is approximately six
times higher than that of regular red blood cells, with significantly
higher side effects. A study in the United States showed that the
cost of recombinant hemoglobin was $11 USD per gram, but when
production and equipment costs were factored in, the cost could rise
to $200 USD per gram. When the total therapeutic dose is considered,
the cost becomes financially unviable for routine use. For artificial
blood to become mainstream and economically viable, either the
production cost must decrease substantially or the hemoglobin
efficiency must increase significantly without introducing many
adverse events.
6.2 Market Growth and Economic Projections
Despite
these cost challenges, the artificial blood products market was
valued at $4.5 billion USD in 2024 and is expected to grow at a
compound annual growth rate of 9.8% through 2033. This growth
projection reflects the significant market demand driven by blood
shortages (even in developed nations), aging populations, and
expanding healthcare infrastructure and access globally. HBOCs hold
the largest market share at approximately 50%, while PFC emulsions
are projected to grow at the fastest rate.
7. Regulatory Status and Challenges
The
regulatory landscape for artificial blood is complex, restrictive,
and in many ways has been one of the most significant obstacles to
progress in the field. The paper provides an extensive discussion of
the regulatory environment, particularly in the United States, which
has the most stringent requirements for approval of biological
products. Currently, no artificial blood substitute has received
universal approval or is commercially available for general use in
humans anywhere in the world, including the United States. While
several products, primarily HBOCs and PFCs, have been developed,
their use is extremely limited and typically restricted to specific
countries (such as South Africa and Russia), compassionate use
provisions in the United States, or veterinary medicine.
In
the United States, artificial blood products, more accurately
referred to as oxygen therapeutic agents, are strictly regulated by
the FDA as biologic drugs. These products must comply with demanding
standards under the Public Health Service Act and the Federal Food,
Drug, and Cosmetic Act. Developers face significant challenges in
ensuring safety, replicating the complex multifunctional roles of
natural blood, managing high production costs and logistical hurdles,
and navigating commercialization barriers. After decades of research,
no oxygen-carrying blood substitute has met the FDA's requirements
for general clinical use.
The
regulatory challenge is compounded by the fact that artificial blood
products are classified as biologic drugs rather than medical
devices, which subjects them to a higher standard of proof and more
extensive testing requirements. The complexity of manufacturing
processes for products like cultured red blood cells, which involve
multiple stages of cell expansion, differentiation, and purification,
creates additional regulatory challenges related to consistency,
quality control, and batch-to-batch variability. Each step in the
manufacturing process must be validated and documented to Good
Manufacturing Practice (GMP) standards, which adds considerable time
and expense to the development process.
Some
investigational products have achieved "Orphan Drug" status
from the FDA, which is intended to facilitate the development of
treatments for rare conditions. For patients with severe,
life-threatening anemia without other treatment options, the FDA may
grant expanded access for the experimental use of unapproved blood
substitutes. Despite these regulatory pathways, the main challenge
remains definitively proving both safety and efficacy in rigorous
clinical trials.
8. Ethical, Social, and Professional
Considerations
8.1 Patient Acceptance and Trust
The
paper addresses several ethical and social dimensions of artificial
blood that will shape its adoption, and this discussion adds an
important human dimension to what is otherwise a highly technical
review. Patient acceptance is identified as one of the primary
challenges. Acceptance is particularly significant in relation to
trust, safety, and religious issues surrounding synthetic or
genetically engineered tissue, including stem cell-based blood. While
some patients may view artificial blood as a welcome means of
avoiding donor blood transfusion (with its associated risks), others
may display reluctance toward gene-engineered or laboratory-created
components.
From
a clinical perspective, the adoption of artificial blood would depend
on proven safety, reliable efficacy, and well-defined clinical
indications. Clinicians are likely to support artificial blood
initially in high-risk or resource-limited settings where
conventional transfusion is unavailable or contraindicated, such as
battlefield medicine, remote trauma situations, or for patients with
extremely rare blood types.
8.2 Equity, Access, and Stem Cell Ethics
Equity
is another important ethical consideration. The high production costs
associated with bioprocessing could create disparities in access,
potentially limiting the availability of artificial blood to wealthy
nations or well-resourced healthcare systems. Other ethical issues
that are expected to arise relate to the sourcing of stem cells and
ensuring that the procurement process is not exploitative in any way.
These considerations underscore the importance of transparency and
ethical governance as the field advances toward clinical
applications. The paper also implicitly raises the question of
informed consent in clinical trials for artificial blood products.
Given the novel and experimental nature of these technologies,
ensuring that trial participants fully understand the risks and
potential benefits is essential. The history of the field, which
includes instances where safety concerns were not adequately
communicated or were downplayed, makes robust informed consent
processes even more important for maintaining public trust and
ethical integrity.
The
religious dimension of artificial blood is also noteworthy. Certain
religious communities, most notably Jehovah's Witnesses, refuse
allogeneic blood transfusion on religious grounds. For these
patients, artificial blood products that do not contain human donor
blood components could be medically life-saving, providing a
treatment option where none currently exists. This creates an
interesting ethical dynamic where the development of artificial blood
serves not only a medical need but also a moral and religious one,
potentially expanding the autonomy of patients who would otherwise
face limited treatment options.
The
paper also touches on the broader societal implications of a world in
which blood products can be manufactured rather than donated. The
current voluntary blood donation system relies on altruism and
community engagement, and the widespread availability of manufactured
blood could potentially undermine the culture of blood donation.
Conversely, manufactured blood could also relieve the constant
pressure on blood banks and reduce the emotional burden on patients
and families who depend on the availability of compatible donor
blood.
9. Future Trends and Directions
The
paper identifies two major strategic shifts that will define the
future of artificial blood development: the move toward comprehensive
modular replacements for whole blood, and the industrial scaling of
cell-based therapies.
9.1 Hybrid Whole Blood Surrogates
Perhaps
the most conceptually significant shift described in the paper is the
recognition that the traditional approach of developing a single
molecule or cell type to replace blood has been fundamentally
misguided. Blood is not simply an oxygen carrier; it is a complex
living tissue that simultaneously performs oxygen delivery, carbon
dioxide removal, hemostasis (clot formation to stop bleeding), immune
defense, nutrient transport, waste removal, pH buffering, temperature
regulation, and hormonal signaling. No single artificial product can
replicate all of these functions, and attempting to do so with a
single molecule has led to decades of frustration and failure. A key
insight is that no single agent can replicate the full functionality
of native blood, which performs oxygenation, hemostasis, hemodynamic
support, immune defense, and nutrient transport simultaneously.
Research is therefore heavily invested in developing hybrid,
multicomponent systems that combine multiple technologies into a
single product. These "whole blood surrogates" aim to
provide the three core functions of blood (oxygenation, hemostasis,
and hemodynamics) in a single, stable, and universal product.
A
prime example is the collaboration integrating ErythroMer (a
lyophilized nanoscale oxygen carrier) with SynthoPlate (a synthetic
hemostatic agent) along with freeze-dried plasma components. The
resulting products are stable at room temperature for an estimated
shelf life of at least a year, positioning them as essential bridging
therapies for acute trauma and battlefield scenarios. This modular
approach allows each component to be optimized independently and then
combined for comprehensive functionality.
9.2 Industrial Scale-Up of Cultured RBCs
The
transition from laboratory-scale to industrial-scale production
represents one of the most formidable engineering challenges in the
field of artificial blood. For cultured HSC red blood cells derived
from iPSCs, the critical challenge is transitioning from biological
proof-of-concept to industrial scale-up. The gap between what can be
achieved in a research laboratory and what is required for
clinical-scale production is enormous. A single unit of transfusable
red blood cells contains approximately two trillion cells, and
producing this quantity consistently, reliably, and at an acceptable
cost requires entirely different engineering approaches from those
used in academic research settings. While the feasibility of human
transfusion has been demonstrated, current manufacturing processes
are financially prohibitive. The path to commercial viability is
focused on breakthroughs in bioprocess engineering. Key future
developments include developing modified iPSC lines, such as Kitjak2
cells, that can continually self-renew and proliferate for up to 70
cell-doubling cycles in cost-effective, cytokine-free media. This
approach could greatly reduce the high input cost barriers of
traditional culture protocols. Additionally, focus remains on
improving enucleation efficiency to ensure quality and long-term in
vivo survival of cultured red blood cells.
9.3 Nanotechnology and Encapsulation
Advances
in HBOCs now prioritize nanotechnology for safety improvement.
Encapsulated HBOCs, such as hemoglobin vesicles (HbVs), physically
shield the hemoglobin inside a lipid shell, creating a diffusion
barrier that retards nitric oxide scavenging and effectively
eliminating the severe vasoconstriction that caused the failure of
earlier acellular products. Encapsulated carriers are also designed
with biomimetic features, such as pH-responsive oxygen affinity, to
optimize delivery to hypoxic tissues where oxygen is most needed.
9.4 Artificial Intelligence and Computational
Design
The
application of artificial intelligence to artificial blood
development represents one of the most exciting recent developments
in the field. Computational modeling and artificial intelligence (AI)
are being leveraged to accelerate the design of complex artificial
blood molecules. Traditional approaches to optimizing hemoglobin
modifications, encapsulation formulations, and PFC emulsions have
relied heavily on trial-and-error experimental methods, which are
time-consuming and expensive. The introduction of AI-driven
approaches enables researchers to computationally screen thousands of
potential molecular designs, predict their behavior in biological
systems, and identify the most promising candidates before any
laboratory work begins. AI is used to predict and optimize the
stability, half-life, and oxygen affinity of HBOCs, allowing
fine-tuning to minimize risks like oxidative degradation and NO
scavenging before costly and time-consuming preclinical trials are
conducted. This multidisciplinary integration of AI with biological
and chemical engineering is expected to accelerate the translation of
specialized artificial blood components into clinical reality.
9.5 Key Priority Areas
The
paper identifies six key priority areas for future progress:
First,
scaling manufacturing to achieve cost-effective, large-scale
production of HSC-cultured red blood cells and synthetic oxygen
carriers through optimized bioreactors and continuous culture
systems. Second, enhancing biocompatibility by reducing vasoactivity
and oxidative stress through encapsulation, antioxidant coatings, and
hemoglobin engineering. Third, regulatory harmonization to establish
unified global standards for Good Manufacturing Practice (GMP) and
long-term safety evaluation, with particular focus on renal and
cardiovascular outcomes. Fourth, the development of hybrid and
modular systems that explore carriers combining biological and
synthetic mechanisms, such as hemoglobin vesicles within PFC
nano-emulsions. Fifth, AI-driven design employing artificial
intelligence to predict structure-function relationships and optimize
oxygen affinity, stability, and in vivo kinetics. Sixth, ethical and
economic considerations ensuring equitable access and transparency in
stem cell sourcing, gene editing, and cost allocation.
9.6 Timeline and Clinical Milestones
The
paper includes a helpful visual timeline (Figure 1 in the original)
that traces the major clinical and technological milestones in
artificial blood development from the 1930s to the present. Key
milestones include the first stroma-free hemoglobin experiments in
the 1930s through 1950s, animal models demonstrating oxygen transport
in the 1960s through 1980s, crosslinked and modified hemoglobin
formulations and the introduction of early perfluorocarbon emulsions
in 1989, the FDA approval of Fluosol-DA for cardiac procedures in
1989 (with subsequent withdrawal), large-scale HBOC clinical trials
in the 1990s through early 2000s that ultimately identified the
nitric oxide scavenging and vasoconstriction problems, the 2008
meta-analysis reporting increased myocardial infarction and mortality
with HBOCs, encapsulation strategies development in the 2010 to 2015
period, the proof of concept for ErythroMer nanoscale synthetic red
blood cells published in 2016, the landmark RESTORE trial performing
the first human mini-transfusion of cultured red blood cells in 2022
to 2023, and the emergence of hybrid whole blood surrogates and
AI-assisted molecular design from 2023 onward. This timeline
illustrates both the long history of the field and the accelerating
pace of innovation in recent years.
10. Strengths and Limitations of the Review
The
authors acknowledge several strengths and limitations of their
review. Among its strengths, the review integrates clinical trial
data, translation studies, and emerging technology across various
artificial blood modalities to provide a comprehensive and
forward-looking perspective. It offers a unique analytical framework
that focuses on why specific approaches failed, where technological
inflection points have occurred, and how hybrid or modular systems
may overcome longstanding barriers.
The
review also provides a valuable service by integrating information
about economic considerations, regulatory landscapes, and ethical
dimensions alongside the scientific and clinical data. This
multidimensional approach reflects the reality that the path to
clinical adoption of artificial blood depends not only on scientific
breakthroughs but also on navigating complex economic, regulatory,
and social landscapes. Too often, reviews of biomedical technologies
focus exclusively on the science without adequately addressing these
equally important translational dimensions.
However,
the review faces challenges due to its reliance on early clinical
trial data for various technologies and the rapidly progressing
nature of the field, which means some conclusions may be
time-specific. While the comparison highlights key roadblocks,
definitive clinical success for any of the methods discussed remains
unattained. The paper also acknowledges that the field is moving
rapidly enough that some of the assessments made may become outdated
relatively quickly as new trial results and technological
developments emerge.
11. Conclusions
The
paper concludes that artificial blood research has made notable
progress over the past decade, advancing across all major technology
platforms: HBOCs, PFC emulsions, stem-cell-derived RBCs, platelet
substitutes, and nanoscale analogues. Each of these technologies aims
to address the well-known limitations of donor blood, including
supply shortages, short shelf life, and infectious risks. However,
each platform also faces unique challenges in terms of safety,
scalability, and cost.
Despite
improvements such as reduced toxicity in newer formulations and
longer shelf life, widespread clinical use remains limited by
regulatory, economic, and manufacturing barriers. Current efforts are
focused on scaling up lab-grown red blood cell production, improving
biocompatibility across all platforms, and leveraging innovations in
nanotechnology and artificial intelligence to optimize product design
and performance.
The
overarching message of the paper is cautiously optimistic: while
artificial blood cannot yet replace donor transfusions for routine
clinical care, promising clinical trials and niche regulatory
approvals suggest that specialized applications are likely in the
near future. These applications are most probable in military
medicine, emergency and trauma settings, and for patients with rare
blood disorders or those who refuse transfusion for religious
reasons. Continued interdisciplinary collaboration among stem cell
biologists, materials engineers, computational scientists,
clinicians, and regulatory authorities, along with careful attention
to ethical and economic considerations, will be essential to
achieving the long-sought goal of transfusion-independent oxygen
therapeutics.
11.1 The Convergence Opportunity
The
convergence of multiple technological advances, including
nanotechnology, stem cell biology, biomaterials engineering,
computational modeling, and artificial intelligence, creates an
unprecedented opportunity to finally overcome the barriers that have
stymied artificial blood development for nearly a century. The
modular approach, combining optimized components for oxygen delivery,
hemostasis, and hemodynamic support into a single stable product,
represents perhaps the most promising path forward. If current trends
continue and the remaining scientific, manufacturing, and regulatory
challenges can be addressed, the coming decade may finally see the
realization of clinically viable artificial blood products for
targeted applications, marking a transformative advance in
transfusion medicine and emergency care.
11.2 Most Promising Near-Term Applications
Based
on the evidence presented throughout the paper, the most promising
near-term applications for artificial blood technologies appear to be
in several specific clinical niches. Military and battlefield
medicine represents perhaps the most compelling use case, where the
logistical challenges of maintaining a cold chain for donated blood
products are extreme, and where the availability of a
room-temperature-stable, universal oxygen carrier could save lives
that are currently lost due to hemorrhagic shock before evacuation to
definitive care. Emergency trauma medicine in civilian settings
presents a similar opportunity, particularly in rural or remote areas
where blood bank access is limited. Patients with rare blood
phenotypes, for whom finding compatible donor blood is extremely
difficult, represent another high-value clinical niche. And patients
who refuse conventional blood transfusion for religious or personal
reasons constitute a population with an acute unmet medical need that
artificial blood could address.
The
paper also suggests that PFC emulsions may have significant near-term
potential in neurological applications, including acute stroke,
traumatic brain injury, and cardiac arrest, where the ability to
enhance oxygen diffusion in low-flow microvascular beds could provide
meaningful clinical benefits. These applications leverage the unique
physiological mechanism of PFCs rather than attempting to make them
compete directly with hemoglobin-based oxygen delivery, which has
been the source of much of the misunderstanding and undervaluation of
PFC technology.
11.3 Final Assessment
Ultimately,
this review provides a balanced and well-informed assessment of a
field that has been characterized by both remarkable scientific
ambition and repeated clinical disappointments. The authors neither
overstate the readiness of current technologies for widespread
clinical use nor understate the genuine progress that has been made.
By focusing on the reasons for past failures and identifying specific
technological inflection points, the paper provides a roadmap for how
the field might finally achieve the breakthroughs that have eluded it
for nearly a century. The integration of nanotechnology, stem cell
biology, materials science, computational modeling, and artificial
intelligence into a unified research framework represents a paradigm
shift that may finally overcome the barriers that have kept
artificial blood in the realm of the investigational for so long.
Whether this potential will be realized will depend on sustained
financial investment from both public and private sources, thoughtful
and adaptive regulatory engagement that balances patient safety with
the urgent medical need for these products, and continued scientific
creativity and interdisciplinary collaboration in the coming decade.
Summary
written from: Patidar G, Jose AV, Dubey R, et al. New developments
and future trends of artificial blood. Ann Blood 2026;11:1.
