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Preventing hypoxia-induced cell death
Preventing hypoxia-induced cell death in beta
cells and islets via hydrolytically activated,
oxygen-generating biomaterials
Eileen Pedraza
a,b, Maria M. Coronela,b, Christopher A. Frakera,b, Camillo Ricordia,b,c,d, and Cherie L. Stablera,b,c,1
a
and
Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved February 1, 2012 (received for review August 17, 2011)
Diabetes Research Institute and Departments of cSurgery and dMedicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136;bDepartment of Biomedical Engineering, College of Engineering, University of Miami, Coral Gables, FL 33134
A major hindrance in engineering tissues containing highly
metabolically active cells is the insuf
implants, which results in dying or dysfunctional cells in portions
of the graft. The development of methods to increase oxygen
availability within tissue-engineered implants, particularly during
the early engraftment period, would serve to allay hypoxiainduced
cell death. Herein, we designed and developed a hydrolytically
activated oxygen-generating biomaterial in the form of
polydimethylsiloxane (PDMS)-encapsulated solid calcium peroxide,
PDMS-CaO
PDMS resulted in sustained oxygen generation, whereby
a single disk generated oxygen for more than 6 wk at an average
rate of 0.026 mM per day. The ability of this oxygen-generating
material to support cell survival was evaluated using a
and pancreatic rat islets. The presence of a single PDMS-CaO
eliminated hypoxia-induced cell dysfunction and death for both
cell types, resulting in metabolic function and glucose-dependent
insulin secretion comparable to that in normoxic controls. A single
PDMS-CaO
more than 3 wk under hypoxic culture conditions. Incorporation
of these materials within 3D constructs illustrated the bene
these materials to prevent the development of detrimental oxygen
gradients within large implants. Mathematical simulations
permitted accurate prediction of oxygen gradients within 3D constructs
and highlighted conditions under which supplementation
of oxygen tension would serve to bene
the generality of this platform, the translation of these materials
to other cell-based implants, as well as ischemic tissues in general,
is envisioned.
ficient oxygenation of these2. Encapsulation of solid peroxide within hydrophobicβ cell line2 disk2 disk also sustained enhanced β cell proliferation forfits offit cellular viability. Given
tissue engineering
| encapsulation | bioartificial pancreas | diabetes
T
by inadequate oxygen delivery, typically due to the
inevitable delay in angiogenesis after implantation (1
oxygen levels result in cellular necrosis and apoptosis,
as well as a shift to anaerobic metabolism and energy conservation
(3, 5
containing highly metabolically active cells, such as those comprising
pancreatic islets, is particularly challenging (8, 9). Not
only is the oxygen consumption rate for pancreatic islets elevated
compared with many other cell types, they are also susceptible to
functional impairment even at moderate oxygen tensions (9
In the initial days after device implantation, in the absence of
vascular in
the outer boundaries of the implant and progressively decreases
in square proportion to the radial distance inward. High cell
loading densities further exacerbate hypoxia, by increasing the
overall metabolic load. Thus, designing the appropriate device
dimensions and cell loadings to limit hypoxia within a transplant
is an arduous task, commonly resulting in device scales that are
impractical for clinical implantation (2, 4). Limiting or eliminating
the hypoxic period between implantation and the development
of a fully functional, intradevice, vascular network would –19). In situ oxygen–20). Although allfically calcium peroxide, which is hydrolytically1.
2CaO
2 þ 4H2O → 2CaðOHÞ
2
þ
2H2O2
→
2CaðOHÞ
2
þ
2H2O þ O2 [1]
Oxygen generation via hydration of solid peroxide, however,
is too rapid, leading to hyperoxide conditions that result in the
buildup of the reaction intermediate hydrogen peroxide and increased
susceptibility of side reactions such as hydroxyl radical
(OH
solid peroxide within a polymer could serve to temper its hydrolytic
reactivity. A solid peroxide platform using
(lactic-
oxygen-generating potential of these materials was shown
through enhanced
in a skin
however, was short lived, and the reaction kinetics were less
controlled owing to the hydrolytic degradation of the PLGA.
Furthermore, catalase supplementation was required to mitigate
cytotoxicity. Thus, coculture of these materials with cells less resilient
than
stress, such as
We sought to fabricate an oxygen-generating biomaterial
through the encapsulation of solid peroxides within a highly−) generation (details in SI Text) (21). Encapsulation offilms of polyco-glycolic acid) (PLGA) has been published, whereby thefibroblast proliferation and reduced necrosisflap mouse model (16, 17). The benefit of the films,fibroblasts, particularly those sensitive to free radicalβ cells, is highly undesirable (22).
hydrophobic, biostable material, speci
(PDMS) (Fig. 1
migration through the biomaterial would result in greater temporal
modulation of oxygen generation. Furthermore, by selecting
a material with a high oxygen permeability, the diffusion of
oxygen out of the material should be ef
of controlled reactivity and clearance of end products has the
added bene
the presence of the hydrogen peroxide intermediate and the
susceptibility to generate side reactions such as hydroxyl radicals.
Herein we report the design and fabrication of PDMS-encapsulated
calcium peroxide (PDMS-CaO
we sought to evaluate (
peroxide within PDMS on long-term oxygen generation; (
ability of PDMS-CaO
death in culture; and (
to enhance cell viability within 3D tissue engineered constructs.
We also explored the correlation between oxygen availability and
fically polydimethylsiloxaneA). We hypothesized that the restriction of waterficient. The combinationfit of driving the reaction forward, thereby reducing2) disks. In this studyi) the effect of encapsulation of calciumii) the2 materials to mitigate hypoxia-induced celliii) the potential of PDMS-CaO2 materials
β
materials.
cell viability, to permit for the appropriate design of oxygengenerating
Results
Long-Term Oxygen Generation by PDMS-CaO
the effect of encapsulation of solid peroxide within a hydrophobic
material on oxygen generation, solid peroxide was encapsulated
within PDMS at 25% wt/wt (Fig. 1
potential of the system was noninvasively monitored in an incubator
using oxygen sensors. With the target oxygen tension of
the incubator set at 0.05 mM oxygen, the system represents an
open system, in which gas exchange between the solution and air
daily oxygen concentration within solutions containing
PDMS-CaO
control PDMS-only disk, the oxygen remained steady at 0.05
2 disks, as well as for control PDMS-only disk. For the±
0.0001 mM, con
of oxygen production from the PDMS-only controls. The addition
of a single PDMS-CaO
oxygen in the solution. For the
firming the stability of the incubator and the lack2 disk resulted in a significant increase infirst week, oxygen concentration
fl
oxygen levels averaged 0.12
4 wk (17
Thus, during the
that results in the shift from a hypoxic environment to that
close to optimal cell culture conditions.
uctuated, averaging 0.16 ± 0.017 mM. During the second week,± 0.003 mM, whereas for the subsequent–45 d) oxygen levels averaged 0.073 ± 0.007 mM.first 2 wk, these disks generate oxygen to a degree
Mitigation of Hypoxia-Induced
evaluate the ability of a PDMS-CaO
oxygen to minimize hypoxia-induced cell death, MIN6 cells, a
β Cell Death via PDMS-CaO2 Disk. To2 disk to generate sufficientβ
cell line, were cultured overnight under hypoxic conditions (0.01
mM) with or without a PDMS-CaO
assessed and compared with cells cultured at standard oxygen
tension (0.20 mM). As shown in Fig. 2, coculture of hypoxic
MIN6 cells with PDMS-CaO
by increased methylthiazolylphenyl-tetrazolium bromide (MTT)
levels and total protein, with concomitant decreases in lactate
dehydrogenase (LDH) release and caspase activity. Relative to
normoxic (0.20 mM) controls, MIN6 cell survival under hypoxic
conditions (0.01 mM) with the PDMS-CaO
or even enhanced, with statistically identical levels of MTT
and total protein, as well as signi
and caspase activity (
2 disk. Cell survival was2 prevented cell loss, evidenced2 disk was comparableficant decreases in LDH releaseP < 0.05). The addition of a PDMS-CaO2
disk under normoxic culture conditions resulted in a moderate
but statistically signi
in LDH release and caspase activity. These latter results indicate
a bene
under normoxic conditions.
Elevated caspase activity under hypoxia is modest compared with
LDH increases, indicating dominance of necrosis vs. apoptosis at
the time points tested. As expected, hypoxia resulted in dysfunction
in glucose-stimulated insulin secretion (Fig. 3
a drop in the stimulation index (high/low glucose) from strong
(15.30) to virtually unresponsive (1.2). Hypoxic conditions
quickly resulted in islet spheroid fragmentation and increased
cell membrane permeability, as evidenced by live/dead images
(Fig. 3
was observed with the addition of a single PDMS-CaO
with a signi
complementary decreases in LDH release and caspase activity.
Glucose responsiveness of the islets was maintained, with stimulated
insulin secretion comparable to that in controls, but at
a reduced overall stimulation index (6.94) due to increased basal
insulin secretion. This was further supported by live/dead imaging,
which exhibited intact, highly viable islet spheroids.
B), withE). Alternatively, substantial enhancement in islet survival2 disk,ficant increase in overall cell metabolic activity and
Enhanced Long-Term Proliferation of Cells Cocultured with PDMSCaO
2
Disks.
proliferation and viability of cells under low (0.05 mM) oxygen
tensions was investigated by incubating MIN6 cells (3
per well) with a single PDMS-CaO
cell loading and oxygen tension, our multiphysic models predicted
maintenance of overall cell number for controls, whereas
cells supplemented with a PDMS-CaO
owing to the increased oxygen availability. As expected, overall
cell viability for controls remained steady during the course of
the experiment, with no change in MTT metabolic activity (
0.101). Conversely, MIN6 cells cultured under low oxygen with
a PDMS-CaO
the
twofold higher than controls (average 2.32
23 d,
between days 7 and 23 for this group (
P =2 disk quickly increased in metabolic activity withinfirst 3 d and plateaued at a level equivalent to more than± 0.31-fold from 3 toP < 0.001). No significant change in viability was observedP = 0.141). If the PDMSCaO2
disk was removed, MTT measurements made 3 d later
were statistically equivalent to those in low oxygen controls (Fig.
4
days 3, 7, and 17). Overall,
with the PDMS-CaO
cells cultured at standard oxygen tension (0.20 mM) (
A; dashed lines track readings before and after disk removal onβ cells cultured at 0.05 mM oxygen2 disk were statistically equivalent to controlFig. S1;
P
0.2 mM oxygen level, however, did not substantially affect overall
cellular metabolic activity per MTT absorbance (
lack of bene
limiting factor for MIN6 proliferation; rather other factors, such
as glucose availability or contact inhibition, are preventing further
increases in overall cell proliferation. Controls of PDMSonly
disk (no CaO
controls (
PDMS has no effect on cell survival.
DNA content of the cells within these experimental groups
followed similar trends as the MTT results: the total DNA for
wells cultured with the PDMS-CaO
higher than in controls under identical low oxygen conditions
from day 7 to 24 (Fig. 4
sustained increase in overall cell number during the course of the
experiment. Live/dead time course confocal images of MIN6
cells cultured under low oxygen tension (0.05 mM) revealed
enhanced viability and proliferation of cells when a PDMS-CaO
disk was present. In addition, cells incubated with PDMS-CaO
2
disks tended to form larger cellular spheroids, because of either
growth of the cells into clusters or aggregation.
Enhanced
β Cell Viability for 3D Agarose Constructs Containing PDMSCaO2
Disks.
materials within a 3D tissue-engineered implant, MIN6 cells
(25
3 d under hypoxic (0.05 mM) or normoxic (0.20 mM) conditions
with a centrally placed PDMS-only (control) or PDMS-CaO
To evaluate the potential of our oxygen-generating× 105 total cells) were cultured within agarose constructs for2
disk (Fig. 5
metabolic activity of each group, compared with day 0 controls.
At 0.20 mM oxygen, no enhancement in cell viability was observed
for either group after the 3 d culture. For control constructs
cultured at 0.05 mM oxygen, however, the viability of the
cells was substantially reduced (53%). The viability of the cells at
0.05 mM oxygen was signi
A). Fig. 5B summarizes the fold change in MTTficantly improved when a PDMS-CaO2
disk was present (93%), proving to be statistically identical to the
0.20 mM oxygen group (
sections of the constructs exhibited varying cell viability
patterns after 3 d in culture (Fig. 5
a rim of live cells can be discerned on the outer edge of the
construct, surrounding a central core of dead cells. As expected,
the thickness of the viable core is slightly larger for the higher
oxygen culture condition. This pattern is typical for implants,
whereby the highest oxygen tension is at the periphery of the
implant. On the contrary, this viable demarcation is absent when
the PDMS-CaO
number of viable cells may be observed at normoxic conditions,
live and dead cells are intermingled within the slice, and no
spatial preference is visible. These results indicate that the oxygen
gradient that typically leads to inner pockets of dying or
dysfunctional cells is absent when a PDMS-CaO
placed within the construct.
P = 0.52). Live/dead images of transversalC). For control constructs,2 disk is present. Although a slightly higher2 disk is centrally
Effect of Oxygen Availability on
the relationship between
the oxygen availability within agarose constructs was varied via
(
presence or absence of the oxygen-generating material. Simulation
modeling via COMSOL multiphysics modeling was used to
assist in predicting the oxygen gradients within 3D agarose
constructs. Modeling results not only provide a spatial distribution
of oxygen throughout the construct but can also be used to
quantitatively predict the percentage volume of the construct
exposed to severe hypoxia, which may then be used to predict
and/or characterize experimental results.
COMSOL models of constructs were run with a variation in
MIN6 cell loading density from 5 to 25
an external oxygen tension of low (0.05 mM) or standard (0.20
mM) oxygen levels, and with a PDMS-only or a 25% wt/wt
PDMS-CaO
expected, oxygen gradients become more pronounced as the
external oxygen tension is decreased and as the cell loading is
increased, thereby reducing overall oxygen availability. For
control constructs, because oxygen migration is dependent upon
diffusion and consumption by the cells, a precipitous decrease in
oxygen tension within this construct is predicted. This decrease
in oxygen toward the center of the construct is mitigated, if not
eliminated, with the introduction of the PDMS-CaO
these gradients shift to high oxygen tensions both externally
and centrally.
In examining the individual cell loading models, the effects of
these oxygen gradients on cell viability may be predicted. For
25
(61% vol at 0 mM oxygen), with minimum effects under standard
oxygen (5% vol at 0 mM oxygen). The models predict that the
introduction of an oxygen-generating disk signi
areas of hypoxia under low oxygen tension (11% vol at 0 mM
oxygen) and eliminates hypoxia for constructs under standard
oxygen tension. As the cell loading is decreased to 15
oxygen gradients within the constructs become less pronounced.
Under a low external oxygen condition (0.05 mM), a smaller
portion of the construct is severely hypoxic (12% vol at 0 mM
oxygen), indicating that the lower cell loading serves to increase
overall oxygen availability. Simulations predict that the addition
of the PDMS-CaO
0.2 mM external oxygen, severely hypoxic regions are minimal
for this cell loading (
PDMS-CaO
and the oxygen tension within the control constructs is
maintained well above zero oxygen at both low and standard
surrounding oxygen tensions. The addition of the PDMS-CaO
β Cell Viability. To fully characterizeβ cell viability and oxygen availability,i) total cell loading, (ii) external oxygen tension, and (iii) the× 105 cells per construct,2 disk at the center (Fig. 6A and Fig. S3). As2 disk, where× 105 cells, a substantial hypoxic core is formed at low oxygenficantly reduces× 105 cells,2 disk eliminates these hypoxic regions. At<0.5%), thereby limiting the benefit of the2 disk. For 5 × 105 cells, oxygen gradients are minimal,2
disk only further increases oxygen levels. Overall, these models
predict a moderate to substantial enhancement in cell viability
for cell loadings from 15
a low oxygen environment (0.05 mM). Of note, simulation
models do not account for cellular proliferation and remodeling,
thereby restricting their accuracy to initial stage cultures.
To correlate model predictions of oxygen availability to experimental
results, MIN6 cells were loaded within agarose constructs
and incubated at both low (0.05 mM) and standard (0.20
mM) oxygen conditions at the three cell densities tested: 5
15
Results are expressed as the fold increase of each PDMS-CaO
× 105 to 25 × 105 cells, when cultured in× 105,× 105, and 25 × 105 MIN6 cells per construct (Fig. 6B).2
group over its corresponding PDMS-only control, whereby fold
values greater than 1.0 indicate that the PDMS-CaO
a positive effect on cell viability, and values less than 1.0 indicate2
groups over controls is higher for the lower oxygen culture
condition. For relatively low cell loading densities (5
the treated groups have lower viability compared with controls
(
a decrease in cell viability when the PDMS-CaO
present. For 15
at 0.20 mM oxygen but has a neutral effect at 0.05 mM oxygen.
At the highest cell loading tested, 25
treated groups is greater than that of controls, at both oxygen
tensions. Overall, a general trend of enhanced bene
of PDMS-CaO
both low and standard oxygen culture conditions. These results
correlate strongly with multiphysics modeling predictions.
× 105 cells),<1.0) at both low and standard oxygen tensions, exhibiting2 disks are× 105 cells, the PDMS-CaO2 disk is detrimental× 105 cells, the viability offit of the addition2 disk as cell loading increases is observed at
Discussion
In this study, we sought to encapsulate calcium peroxide within
PDMS disks for use as an oxygen-generating biomaterial suitable
for sustaining cell viability and function within hypoxic conditions.
Without encapsulation, peroxide-based compounds quickly
release oxygen upon contact with water, resulting in bursts of oxygen
that are too severe and transient for use (21). By encapsulating
solid peroxide within a highly hydrophobic biomaterial, we
have introduced a diffusional barrier that substantially reduces its
reactivity, consequently modulating the release of oxygen for more
than 40 d. The reactivity of the encapsulated peroxide is heavily
dictated by the rate of water diffusion into the PDMS, because
water permeability in PDMS is very low, although it is likely increased
by the incorporation of solid peroxide particulates (23).
Furthermore, oxygen diffusion and permeability in PDMS is particularly
high (24), thereby ensuring the ef
out of the material and into the surrounding milieu. With this
degree of control, the geometry and dimensions of the disk, as well
as the calcium peroxide loading, can be manipulated to achieve the
desired release kinetics of oxygen. Given that the reactivity of the
peroxide is reversible, in situ oxygen generation is also dependent
upon the surrounding oxygen conditions, thereby permitting further
modulation of the kinetics. Future studies are focused on fully
characterizing the effects of each of these parameters on oxygen
generation within this material platform.
We were particularly interested in evaluating the capacity of
this material to preserve cell viability and function under hypoxic
conditions for
with MIN6
PDMS-CaO
death and dysfunction, limiting activation of cell stress pathways
and the shift to anaerobic metabolism. Furthermore, this effect
can be observed long term, as evidenced by the sustained enhanced
survival of cells over 3 wk in culture. Removal of PDMSCaO
ficient diffusion of oxygenβ cells. Coculture of oxygen-generating materialsβ cells and pancreatic rat islets demonstrated that2 disks dramatically mitigated hypoxia-induced cells2
disks from treated groups reinforces the theory that the
observed enhancements are due solely to oxygen release and not
due to an artifact or initial shielding from hypoxia. It should also
be noted that no free radical or peroxide scavenging materials
were used in this study, in contrast to other published reports
using solid peroxides in which catalase was used for all experimental
studies (17).
Evaluation of PDMS-CaO
also illustrated the bene
materials when cells are exposed to hypoxic conditions. Placement
of the oxygen-generating disks at the center of the construct
resulted in the greatest bene
gradients. This is veri
correlated strongly with experimental results whereby cellular
metabolic activity was comparable to constructs cultured at oxygen
pressures fourfold higher. Imaging of viable
within agarose constructs permitted evaluation of cellular proliferation
and remodeling in response to oxygen availability.
Control constructs exhibited viability patterns typical of limited
oxygen availability, with live cells relegated to a thin rim on the
outer edge of the construct and a core of predominantly dead cells
(25). Constructs containing PDMS-CaO
a uniform distribution of predominantly live cells, indicating
a divergent pattern in cellular remodeling. This further
establishes that the PDMS-CaO
providing an additional source of oxygen originating in the center
of the construct, where it is most needed.
Studies seeking to evaluate the correlation between oxygen
availability and
oxygen-generating materials within 3D constructs when oxygen is
limited. Decreases in cell loading decreased the positive effect of
PDMS-CaO
oxygen consumption, which, when coupled with oxygen release
from the PDMS-CaO
Hyperoxia conditions can be as detrimental to cells as hypoxia,
particularly for cells that are more sensitive to free radical stress,
such as
con
detrimental oxygen gradients are likely to develop. As illustrated
in this study, mathematical modeling can be used to predict what
cell loadings and implant geometries will lead to oxygen limitations.
Hence, the dosing of the oxygen-generating material, per
peroxide loading, geometry, and surface/volume ratio, can be
subsequently tailored.
Because the PDMS-CaO
loading densities, they represent an ideal tool for enhancing
2 disks embedded within 3D hydrogelsfits of these oxygen-generatingfit by decreasing internal oxygenfied via predictive modeling results, whichβ cell distribution2 disks, however, illustrated2 disk alleviates central hypoxia byβ cell viability illustrate the benefits of these2 materials, likely owing to the lower total rate of2 disks, results in a local surplus of oxygen.β cells (22). Therefore, use of these materials withinfined constructs has to be relegated to scenarios whereby2 disks are most beneficial at high cell
Fig. 6.
simulation models of oxygen gradients within 3D agarose constructs containing
either PDMS-only or PDMS-CaO
outlined in Fig. 5
(0.2 mM in
range (0.05 to 0 mM) is shown on far right. Black, 0 mM oxygen tension. (
Experimental outcomes of oxygen availability on MTT metabolic activity.
Oxygen availability varied via total MIN6
cells), external oxygen tension (0.2 mM or 0.05 mM), and the presence of
a PDMS-CaO
expressed as fold increase over control at identical cell loading density and
oxygen concentration (fold = treated group with PDMS-CaO
group without the PDMS-CaO
indicate a positive effect of the PDMS-CaO
values
Effect of oxygen availability on MIN6 β cell viability. (A) Multiphysics2 disk. (Dimensions identical to thoseA). Models run with 0.05 mM external oxygen are shownFig. S3) at the total MIN6 cell loadings indicated Predicted oxygenB)β cell loading (5–25 × 105 total2 disk. Measurements were collected after 3 d culture and2 disk/control2 disk). Fold increase values greater than 1.02 disk on cell viability, whereas<1 indicate a detrimental effect. Error = SD; n = 3.
Pedraza et al. PNAS
| March 13, 2012 | vol. 109 | no. 11 | 4249
ENGINEERING MEDICAL SCIENCES
oxygenation of cell-based engineered tissues, particularly during
the initial engraftment period. By supplementing oxygen during
the precarious vascularization period, hypoxia-induced cell loss
could be reduced. It is envisioned that PDMS-based implants
would be highly desirable to transplant applications, given its
proven clinical safety pro
of agents (26). With low adhesion properties, the PDMS insert can
be easily removed once the embedded solid peroxide is expired or
the local supplementation of oxygen is no longer desired. Although
one potential drawback of this approach is that hypoxia
inducible factor pathways that stimulate release of angiogenic
growth factors would be suppressed and potentially delay implant
vascularization, we anticipate that this effect could be mitigated
through the codelivery of proangiogenic factors (13, 14). Overall,
we have demonstrated the usefulness of our materials to mitigate
hypoxia-induced cell death, which would be highly desirable for
preserving the viability of the transplanted cells after transplant,
particularly for implants for which cell dosage is critical for ef
such as in the transplantation of file and prolific use in the local deliveryficacy,β cells for type 1 diabetes.
a detrimental effect. One trend that can be readily observed is
that for all cell loading densities, the fold increase of PDMSCaO
2 disk has= 0.65). Introduction of the PDMS-CaO2 disk to cells at theFig. S1). Thisfit at normoxia indicates that oxygen is no longer the2) were statistically identical to material-freeFigs. S1 and S2), verifying that the presence of the2 disks was 2.51 ± 0.36-foldB; P < 0.001), indicating a substantial and2The long-term effects of PDMS-CaO2 material on the× 105 cells2 disk for 3 wk (Fig. 4). At this2 disk would proliferateficant increase in total protein and decreasefit of the presence of the oxygen-generating material even2 Materials. To evaluateB), and the oxygen-generating
dramatically reduce hypoxia-induced cell death and permit for
more clinically translatable devices. Such methods include prevascularization
of the transplant site (12), hastening vascularization
through the delivery of growth factors (13, 14), incorporation
of oxygen carriers within biomaterials (15), or the in
situ generation of supplemental oxygen (16
generation is a highly desirable approach, in that it does not
require multiple surgeries and provides supplemental oxygen
immediately upon implantation. Various agents have been investigated
for their oxygen-generating potential, from the electrochemical
decomposition of water to the photosynthesis of
microalgae to the use of oxygen chambers (18
these agents highlight the potential of in situ oxygen generation
to enhance cell viability, most of these complicate the transplant
site by increasing the size of the implantable device and/or possibly
introducing toxic by-products.
One potent source of oxygen generation is the decomposition
of solid peroxides, speci
activated to generate oxygen via the reaction shown
in Eq.
he implantation of cellular-based devices is commonly hampered–4). Insufficient–7). Providing sufficient oxygen delivery for implants–11).filtration, the maximal oxygen concentration occurs at
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