Oxygen is an immensely important species in biological
systems. Molecular oxygen plays a crucial role in the behavior and viability of
many types of cells as well as the properties of human tissues.
Although the atmospheric oxygen level in air is 21%, the
normal level in the human alveoli is 14%.
This level decreases away from the blood vessels and forms
an oxygen gradient in many tissues, with normal levels varying from organ to
organ. Hypoxia, or inadequate oxygen levels, has a large effect on cells and
tissues, including inducing vasodilation and changing metabolic processes to
reduce oxygen consumption. Tissue hypoxia in cancerous tumors has been linked
with resistance to radiation therapy and many anticancer drugs, as well as
increased likelihood of metastasis and decreased likelihood of patient survival
and treatability. Oxygen levels in tumors are often significantly lower than
those in normal tissues, leading to the development of hypoxia-activated
anticancer drugs designed to specifically target the hypoxic tumor tissues.
Oxygen level has also been identified as an important
parameter in stem cell cultivation and differentiation. Stem cell proliferation
can be enhanced and apoptosis reduced in cultivation conditions with oxygen
levels lower than the standard 20%. Changes in stem cell cultivation
environment oxygen concentration can also be used to simulate in vitro the
effects of disease.
Stem cell differentiation patterns are also highly dependent
on oxygen levels. Embryonic development often occurs in low-oxygen
environments, and oxygen has been found to be an important signal molecule to
regulate stem cell differentiation. As such, carefully controlling the oxygen
concentrations in stem cell populations in vitro is essential for controlling
the cells’ differentiation and maintaining undifferentiated populations. In
regenerative medicine, the transplantation of new stem cells may
be used to replace cells which have been lost through
disease or injury. Understanding the dynamic oxygen conditions during normal
tissue development will be necessary to control differentiation or apoptosis of
stem cells. Oligodendrocyte progenitor cells, which may be used for the
treatment of demyelinating diseases, should be initially cultured in 5% O2 and
then differentiated in 20% O2 for increased cell production. These conditions
should be reproduced in the production of cells for replacement therapies.
Because of the profound effect oxygen has on biological
systems, controlling and monitoring oxygen concentrations is useful in many
cell culture applications. Consequently, there has been much interest in the
development of inexpensive oxygen sensors and control mechanisms that can be
easily integrated with cell culture environments. In addition to the simple
oxygen-sensing application, oxygen sensors can also be adapted for the
measurement of glucose concentrations through the addition of glucose oxidase,
which allows glucose levels to be determined from oxygen levels because an
amount of oxygen dependent on the glucose concentration is consumed in the
oxidation of glucose by glucose oxidase; this further increases the
applicability of oxygen sensors.
Much of the early work on oxygen sensors focused on
Clark-type electrode sensors, which detect a current flow caused by
reduction of oxygen. Such sensors have been miniaturized and integrated with
microfluidic devices to monitor the oxygen consumption of bacteria. The
miniaturization of such devices requires microscale electrodes, and this type
of sensor consumes oxygen (and thus requires sample stirring for accurate
measurements), is easily contaminated by sample contents, and requires
electrical connection between the sensor electrodes and the measurement
infrastructure. These factors present several significant disadvantages for
microfluidic cell culture systems.
Consequently, there has been much interest in the
integration of optical oxygen sensors with microfluidic systems. These optical
sensors present the advantages that they are easily miniaturized, are not
easily contaminated, do not require physical contact between the sensor and
optical detector, and do not consume oxygen. Most optical oxygen sensors operate
on the principle of reversible luminescence quenching of the intensity or
excited-state lifetime (as cited in) of a luminescent indicator dye or
luminophore. This process occurs when the excited state energy of a fluorescent
or phosphorescent indicator molecule is transferred to another molecule such as
oxygen rather than being emitted in the form of a luminescence photon.
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