Niklason LE, Langer R. Prospects for Organ and Tissue Replacement. JAMA. 2001;285(5):573-576. doi:10.1001/jama.285.5.573
Author Affiliations: Departments of Biomedical Engineering and Anesthesia, Duke University, Durham, NC (Dr Niklason); Department of Chemical Engineering, Division of Bioengineering and Environmental Health, and the Harvard-MIT Division of Health Sciences and Technology, Cambridge, Mass (Dr Langer).
Damage or loss of a tissue or organ is common, costly, and tragic. Advances
in mechanical artificial organs and organ transplantation have improved the
treatment of organ failure, and advances in molecular immunology, tissue engineering,
and stem cell biology offer the promise of even better therapeutic modalities
for treating organ failure in the future. Enhancement of immune tolerance
of transplanted tissues, improved understanding of cellular differentiation
and tissue development, and advances in biomaterials may enable the de novo
creation of implantable tissue and organs for transplantation. Innovative
techniques for prevention and treatment of tissue loss and organ failure should
improve the quality and length of life.
A large fraction of the nation's health care costs are attributable
to tissue loss or organ failure, and approximately 8 million surgical procedures
are performed annually in the United States to treat these disorders.1 Current treatment of organ failure or tissue loss
involves transplantation or surgical reconstruction or mechanical devices
such as kidney dialyzers. These therapies have revolutionized medical practice
but have limitations. Transplantation is restricted by the donor shortage—more
than 70 000 patients are currently awaiting organ transplantation, but
fewer than 11 000 donors (cadaveric and living) are available annually.2 Donor shortages increase every year, and many patients
die while waiting for needed organs. Mechanical devices cannot perform all
of the functions of a single organ and therefore provide only temporary benefit.
With the progressive aging of the population, age-related degeneration of
organs will increase in the future. Thus, the scientific and medical communities
are working in multiple areas to develop new strategies for treatment of organ
and tissue failure.
The modern age of organ replacement began when Kolff and Berk, a physician
and an engineer, and colleagues published "The Artificial Kidney: A Dialyser
With a Great Area" in 1944.3 These investigators
reported the successful dialysis of a uremic patient for 26 days using a device
that consisted of 30 m of cellophane tubing wound around a rotating drum.
Murray and colleagues4 subsequently began the
era of solid organ transplantation by performing the first successful kidney
transplant between identical twins in 1954 and by implanting the first renal
allograft in 1959.
Heart and liver transplantation followed soon thereafter—the first
human heart transplant was reported in 1967.5
Artificial heart devices were developed in the 1970s, and the first successful
implantation in humans occurred in 1982 in a patient who survived for 112
days with an artificial heart.6 Since the 1950s,
the sophistication of life-sustaining devices has increased with the evolution
of extracorporeal membrane oxygenators,7 ventricular-assist
devices, and automatic implantable cardiac defibrillators. For organ transplantation,
organ preservation strategies (eg, University of Wisconsin and Euro-Collins
solutions) and immunosuppressive regimens (eg, cyclosporine and tacrolimus)
have enhanced graft preservation and allograft survival.
Tens of thousands of patients currently await organ transplantation,
but any significant expansion of the donor pool is unlikely. Previous efforts
to increase the number of available organs have included expansion of acceptable
donor criteria and development of living related liver and lung transplantation
procedures. However, the risks incurred by healthy donors will likely limit
living related donations to a small number of specialized situations.
Most scientific efforts in organ transplantation are now directed at
improved organ preservation during transport between donor and recipient and
at lengthening the survival of both organ and recipient following implantation.
While these efforts will not increase the organ pool per se, they should improve
transplantation outcome and thereby reduce the substantial number of recipients
who are awaiting retransplant. The use of xenograft organs that are derived
from porcine sources may increase the organ pool eventually, but substantial
scientific and immunologic hurdles currently limit their use.8,9
Development of synthetic devices to replace organ function appears to
have reached a zenith. Compact devices that serve highly specialized functions,
such as pacemakers, internal defibrillators, and insulin pumps, have excellent
long-term reliability. More complex and life-sustaining devices, such as ventricular-assist
devices,10 intra-aortic balloon pumps, and
intravenous oxygenators,11 primarily serve
bridging functions for patients awaiting definitive surgical intervention
and may never be suitable for permanent implantation.
Limitations in the cadaver organ pool and the probable finite potential
of mechanical organ replacements have spurred research into alternative strategies
to develop new organs. Advances during the last 3 decades, especially in genetic
engineering, stem cell biology, and tissue engineering should, in the long
term, increase the pool of available tissues and organs for transplantation.
Efforts to prevent ischemia-reperfusion injury in donor organs range
from antibody-mediated blockade of neutrophil adhesion to donor cell surfaces
to gene transfection of the organ during preservation and transport.12 Transfection strategies involve the use of genes
such as superoxide dismutase and bcl-2 to decrease
cellular injury in allograft tissues. Immunotherapy for transplant recipients
may be improved by induction of costimulatory blockade, in which recipient
T cells are rendered dormant and unable to mount an immune response to donor
Engineering of replacement tissues from autologous cells cultured on
biocompatible synthetic or natural substrates is now
(Figure 1).15 Engineered tissues such
as blood vessels and bladder are functional in preclinical studies.16,17 Engineered skin and cartilage are
currently in clinical use,1 urologic tissue
is being tested in advanced clinical trials, and an engineered liver is being
studied as a "bridge to transplant."18 Autologous
corneas engineered from limbal epithelial cells are being evaluated in patients
with corneal opacification or scarring.19
The potential of tissue engineering using undifferentiated stem cells
to replace organ function is even more profound. For example, it may be feasible
to use pancreatic stem cells to replace islet function in vivo.20
Neural stem cells from adult animals have been stimulated to form tissues
from all 3 germ layers when cultured with collections of embryonic stem cells.21 Thus, pluripotent stem cells may one day provide
a means of culturing many required tissues for a given individual.
Techniques for promoting immune tolerance of solid organ allografts
have markedly advanced in the last 25 years but remain an important area for
research.22 Selective suppression of immunity
to alloantigens, with retention of normal immune function against infectious
pathogens, is the ultimate goal of transplantation immunology. Improved understanding
of the specific processes that mediate allograft immune tolerance, perhaps
combined with clonal T-cell deletion or costimulatory blockade, should increase
graft survival and decrease patient morbidity.23
Further advances in the engineering of tissue replacements from autologous
cells are necessary before widespread applicability to multiple organ systems
can become a reality. In vitro culture systems for tissue growth are at best
crude approximations of the complex biochemical and physical environments
that are experienced by cells during organ development and repair in vivo.17 Likewise, the synthetic substrates that serve as
scaffolds for cell growth are imperfect approximations of extracellular matrices.
Development of synthetic or natural "templates" for cell culture that mimic
the architecture and surface biochemistry of the target tissue (eg, collagen
and fibronectin) will enhance development of functional replacement organs.24 In addition, techniques that promote complex tissue
microarchitectures such as capillary networks will be critical for growth
of solid organs having adequate mass transfer characteristics.
Stem cell biology holds enormous potential for artificial organ development
and transplantation. However, current techniques to isolate multipotent and
pluripotent stem cells from adult tissues are complex and can result in mixed
populations of cells.25,26 Factors
that determine the lineage commitment of stem cells in vitro are only beginning
to be understood.27,28 Advances
in the understanding of stem cell isolation, culture, and lineage commitment
will enhance the clinical applications of these cells for use in organ replacement.
Selective immune tolerance of alloantigens and transplanted tissues
will improve significantly in the future. Possible strategies to induce tolerance
to foreign tissues may include clonal T-cell deletion, induction of bone marrow
chimerism, manipulation of regulatory cytokines, and blockade of CD28- or
CD40-mediated costimulation.23 Induction of
selective immune tolerance could make it possible to minimize, or dispense
with, immunosuppressive regimens that now cause end-organ toxicity, life-threatening
infection, and neoplasm development.
Multiple issues must first be resolved before xenogeneic sources of
transplantable organs become a reality. For example, endogenous retroviruses
that are incorporated into the animal (eg, porcine) genome and that could
be transmitted to immunosuppressed human recipients must be excluded. Hyperacute
rejection, which occurs when porcine solid organs are transplanted into humans
and primates, can be mitigated by the development of transgenic pigs that
express human regulators of complement activation. Scientific efforts will
continue to identify ways to prevent delayed xenograft rejection and thrombosis.9
Investigation and characterization of embryonic and adult pluripotent
stem cells will continue to gain momentum. Elucidation of specific morphologic
and surface markers will enable isolation of pluripotent cells with greater
efficiency. Intracellular signaling pathways, transcription factors, and sequences
of gene activation that control the differentiation and lineage commitment
of pluripotent and totipotent stem cells will be defined and characterized.
Cloning technologies that produce totipotent cells from somatic nuclei that
are transferred into enucleated oocytes29,30
may produce cellular clones that enable the growth of new tissues both in
vitro and in vivo.
Elucidation of the control mechanisms that determine stem cell differentiation,
in parallel with the development of tissue engineering strategies to culture
ever more complex organs such as the kidney,31
may lead to the creation of autologous "spare parts" that can be transplanted
into patients. There has been much progress since 1944 when Kolff and Berk
described their "dialyser with a great area"3;
the future should prove to be even more revolutionary.