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Topical Oxygen inWound Care
https://t.me/medicina_free
HarikrishnaK.R.Nair
21
21.1 Introduction
Oxygen is vital for wound healing [1–3] and is
required in every phase of wound healing. An
original study by Niinikoski [4] examined murine
models, especially the scaffold formation, and
noted that the tensile strength of wounds
increased with 35–75% inhaled oxygen. In addition, oxygen is crucial in the physiology of
wound healing, especially in the production of
energy for metabolism, synthesis of the matrix,
cellular proliferation, and migration [5]. Sano
etal. [5] showed that there was thicker granulation tissue in the normoxic condition
(491.8±243.2 vs. 295.3±180.9 μm, p<0.01),
while there was increased vascular density in the
hypoxic condition (0.046 ± 0.025 vs.
0.011±0.008mm2/mm2, p<0.01) in ddY mice.
This shows that oxygen is required for granulation tissue formation in wound bed preparation,
while hypoxia helps in stimulating vasculogenesis. Incidentally, regulation of growth factor signal transduction pathways involves oxygen
interaction as a cellular signal, and this has been
recognized lately from its previous role in metabolism only [6].
However, there are some contrary ndings.
Sen and Hunt [7] discussed the fact that hypoxia
H. K. R. Nair (*)
Wound Care Unit, Department of Internal Medicine,
Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
instigates angiogenesis factors but angiogenesis,
like collagen, requires oxygen. Meanwhile, Hopf
et al. [8] studied the effect that oxygen had on
angiogenesis by exposing the mice to normoxic,
hypoxic, and various hyperoxic conditions. The
results demonstrated that oxygen is required in
angiogenesis and is proportional to partial pressure of oxygen.
Hopf and Rollins [9] discussed the instrumen-
tal role of tissue oximetry in fundamental
research, whereby wound healing requires oxygen, and it is impaired in hypoxic conditions.
Therefore, the correction of wound hypoxia
improves wound healing. Sen [10] discussed that
tissue hypoxia was caused by three factors
including peripheral vascular diseases, increased
demand for oxygen during wound healing, and
redox signalling with generation of reactive oxygen species. Allen [11] noted that increasing oxygen tension clinically will help in reducing the
infection rates as the respiratory burst is affected
primarily by oxygen tension.
However, studies with a high level of evidence
are scarce with reference to oxygen and its complex effect in the proliferative phase, especially
involving granulation and angiogenesis.
Therefore, more studies are needed to support the
usage of various modalities in nonhealing or
complex wounds [3].
Topical oxygen generated by various medical
devices as an adjunctive therapy in healing
chronic wounds is controversial as physicians are
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Maruccia et al. (eds.), Pearls and Pitfalls in Skin Ulcer Management,
https://doi.org/10.1007/978-3-031-45453-0_21
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H. K. R. Nair
biased and are not convinced that topical oxygen
therapy will be helpful in wound healing due to
lack of high levels of evidence [12], but it is
promising as there are some controlled clinical
studies which have shown good results [13].
Eisenbud [14] observed that chronic wounds
such as diabetic, venous, arterial ulcers, and pressure injuries develop or worsen due to limitation
of oxygen delivery propagated by various factors.
Therefore, managing chronic wounds such as
diabetic foot ulcers (DFUs) with topical oxygen
therapy could give better outcomes in terms of
wound healing. This assignment will discuss the
controversies surrounding topical oxygen therapy as an adjunctive therapy in the management
of diabetic foot ulcers.
21.2 Topical Oxygen Therapy:
Clinical Trials
Yu et al. [13] recruited 20 patients with chronic
DFUs from Grade 1a to Grade 111d according to
the University of Texas grading system which
included neuropathic and ischaemic wounds in
this prospective randomized clinical trial and
compared the topical oxygen therapy utilizing
the oxygen diffusion system (Natrox from Inotec
AMD) against a non-placebo group with standard of care which included surgical intervention, cleansing, sharp debridement, antimicrobial
dressings, and ofoading with total contact cast
or removable walker which conforms to international standards. The sample size was small with
10 patients in each arm who were randomized by
picking the ID blindly from a bag. This was a
valid and reliable process of randomization. The
ODS was placed on the surface of the wound and
closed with a secondary dressing. The ODS was
changed once a week for 8 weeks. Results
showed that 90% of patients (n=9) in the Natrox
arm healed in comparison with 30% in the other
arm. While this is clinically signicant, more
high-powered studies with a larger sample population are required to show signicant advantage
in utilizing topical oxygen as an adjunctive therapy in wound healing as the RCT is underpow-
ered and conducted in only one centre with a
small sample size.
Niederauer et al. [15] recruited 100 patients
with DFUs from 34 centres with duration of
ulcers of 30 days to 1 year. Patients received
moist wound treatment (MWT) during the run-in
period to conrm chronicity of the wounds prior
to receiving the topical oxygen therapy.
Subsequently, one arm received continuous diffusion of topical oxygen (CDO) from the TransCu
O2 system (EO2 Concepts, San Antonio, Texas),
while the other arm was treated with a sham
device which reduced the selection bias. All
patients received moist wound therapy as standard of care which was the same as Yu etal. [13].
The patients were followed up until complete
wound healing or 12 weeks unlike the study
above where the patients were followed up for
only 8weeks. Both patients and researchers were
blinded in both studies which reduce the selection and treatment bias. A larger number of ulcers
treated with continuous diffusion of oxygen
healed in comparison to the sham group (46% vs.
22%, P=0.02), and it was more pronounced in
chronic wounds (42.5% vs. 13.5%, P= 0.006).
The rate of healing was also signicantly much
faster (p < 0.001). The authors concluded that
CDO proved to be effective when added to standard of care, especially in more chronic wounds.
The trial protocol with double blinding eliminates the placebo effect, and good randomization
with standard of care per protocol was effective.
This RCT is of Level 1 evidence.
Another RCT by Lavery and Rhyan [12] with
146 patients was conducted over a 12-week
period similar to Niederauer etal. [15]. One arm
had CDO, while the other arm had placebo and
all researchers and patients were blinded. Sample
size was sufcient. There was increased wound
healing in the treatment arm (46% vs. 22%,
P = 0.02, intent to treat 31.5% vs 15.1%,
P = 0.03), and the time to healing was much
faster. However, adverse events such as these
were not reported in detail in this RCT.This is
important as CDO might help in reducing infection. Similarly, the standard of care was not
dened like in Niederauer et al. [15] such as
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debridement, dressings, and ofoading which is
important in the management of DFUs. There
was also no classication of the DFUs according
to any grading system. Yu etal. [13] utilized the
University of Texas grading system. Therefore,
we are not sure of the characteristics of the DFUs.
Infection, ischaemia, or neuropathy was not mentioned in this study. In future, more robust studies
should consider important wound healing-related
factors such as ulcer location, duration, or chronicity of the wounds, dressings, and types of
ofoading.
Subsequently, Niederauer et al. [16] conducted a RCT with 386 patients screened and 146
patients with DFUs recruited nally with two
arms, whereby one arm received topical continuous oxygen and the other arm received a functional sham device over a 12-week period. Both
the devices looked identical and researchers and
patients including the statisticians were blinded
in all the research centres to cut down selection
and treatment biasness. Standard of care was
maintained the same as Niederauer et al. [15]
with debridement, moist wound therapy, and
ofoading. However, the type of dressing was not
mentioned. There were more healed ulcers in the
active treatment group (32.4% versus 16.7%,
p=0.033) with shorter healing time (p=0.015)
compared to the sham arm. Overall adverse
events were documented well in both arms in this
RCT (n=11in the active arm and n=13in the
sham arm). The trial is very well-planned. It was
reported systematically in accordance with the
CONSORT guideline. Blinding was wellconcealed where Hawthorne and placebo effect
were eliminated. However, there was marked
dropout rate, especially in the placebo arm
(n=33), which might have negatively inuenced
the outcome; therefore, bias is anticipated in the
analysis of the results, and analysis was per protocol. This is due to the size of the DFUs, and
those who had high rates of closure during the
run-in period as these cases will close well with
adjunctive therapies. Interestingly, CDO worked
well in closing wounds in weight-bearing areas
(83.3%). Existing evidence suggests that age-
related impairments in would healing are of signicance [17–19]. The subjects recruited were
aged 30–90, and age-related factors should be
taken into consideration as a confounding variable where subgroup analysis could be performed
for different age categories in order to add further
information about treatment efcacy in different
age groups. Individuals with diabetes mellitus
usually have chronic DFUs and complications
such as neuropathy and peripheral vascular disease which can further affect the healing of the
wounds.
Frykberg etal. [20] undertook a randomized
controlled trial in 17 diabetic foot centres across
Europe and the United States utilizing cyclical
topical oxygen therapy in home setting with an
objective of evaluating the efcacy of topical
oxygen therapy on nonhealing DFUs as an
adjunctive therapy to standard of care in 220
patients. The University of Texas grading system
was used in this RCT [21]. Randomization was
done by a blinded statistician, and area assessment was done by a single-blinded assessor
which reduces the assessment bias. Percentage of
100% healed ulcer in both arms was analysed at
primary study end point (12 weeks). Analysis
was undertaken when 73, 146, and 220 patients
nished their active treatment to know the
unknown outcomes. Analysis was of the intention to treat group. Patients with DFUs in the
active arm had better end outcome which is the
closure rate (41.7%) in comparison to the placebo arm (13.5%). The patients also were able to
use the devices in the comfort of their homes.
Owing to the fact that the active arm was compared to the placebo-controlled arm, the treatment efcacy difference would have been
maximized where the true treatment efcacy of
cyclical topical oxygen by itself was unknown.
Standardization of dressing change and ulcer
location was not reported. However, foam dressing and hydrogel were used in all cases and
wounds underwent surgical debridement as compared to Lavery and Rhyan [12] where a type of
dressing was not stated. Standard of care has to
be documented.
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H. K. R. Nair
21.3 Topical Oxygen Therapy
andDebridement
Clinically, debridement as standard of care
should be carried out before the topical oxygen
therapy is used on DFUs as shown in the studies
above [15, 16, 20]. Lavery etal. [22] evaluated if
debridement of the 146 patients recruited
improved the clinical end point in their study.
Physicians debrided the wounds surgically. The
post hoc analysis evaluated the impact of debridement on DFU healing among patients treated
with CDO.Fundamental aspects of the debridement were taken into consideration, as in frequency of the debridement. Frequent debridement
showed better end outcome in terms of healing
and wound closure in the active arm compared to
the sham arm (51.2% vs. 21.3%, respectively;
P = 0.006). Debridement is the cornerstone of
DFU management, and therefore, it is important
to consider this in relation to any modality or
adjunctive therapy used. Debridement done by
clinicians with different expertise and training
specialty may have a variable quality of debridement, as in their types, sharp/conservative as well
as patient recovery from debridement, and the
depth of debridement. The study also involved
self-reported debridement at the most, which
could be unreliable. Hence, the result of the analysis should be interpreted with caution.
21.4 Topical Oxygen Therapy
andCost-Eectiveness
It is important to consider the health economics
when utilizing topical oxygen therapy in DFU
management, especially during this period of
time, as cost is an issue and cost-effectiveness
needs to be supported by evidence. Chan and
Campbell [23] were the rst to compare treatment costs in 10,000 individuals with chronic
DFUs between topical oxygen therapy and negative pressure wound therapy (NPWT) which is
utilized more extensively. Incidentally, the two
devices are used for different indications and one
supplies oxygen, while the other device removes
the air to form a vacuum. The modes of action too
are different as well as the underlying physiological effects. Both modalities are portable and can
be used in the home setting. The comparison of
the 5-year costs and quality-adjusted life years
was done which revealed that the expenditure
was much lower with better clinical outcomes
with the utilization of topical oxygen therapy in
DFUs in the rst year and up to 10years. There
were disparities between the studies being compared [16, 24] which would have negatively
biased the outcome, for example, study follow-up
period and healing rate of the wound. There was
a relative paucity of long-term clinical evidence
of diabetic foot ulcer treatments in the literature,
hence limiting the cost analysis of the time frame
covered.
21.5 Retrospective Study
There are a lot of case series and observational
studies with a low level of evidence in wound
healing, especially with the utilization of topical
oxygen therapy in DFUs. These constitute realworld evidence as mentioned by Wang etal. [25]
as it is not easy to develop high-level welldesigned randomized controlled trials with double blinding and the costs are quite phenomenal.
This restricts a large number of clinicians from
conducting major trials and most of them resort
to clinical observational studies or case series.
Clinical outcomes are observed, and the treatment modalities are utilized without signicant
ndings statistically.
While RCTs are considered a high level of
evidence, observational studies can also provide
clinical evidence in practice. Copeland and
Purvis [26] examined 9.5years of retrospective
data on the utilization of topical oxygen for a
minimum of 2 weeks on 4127 chronic wounds
(34.2% had Diabetes). The aim of the study was
to look at factors affecting healing and amputation in these patients. Topical oxygen therapy in
this study was administered by the patient or the
caregiver in the home setting. The results showed
59.4% area reduction, while there was no healing
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199
in the rest of the cases. 2.4% underwent amputation during the treatment (n = 97) (3.2% had
diabetes). The location of the wound was documented in this study compared to the previous
RCTs, and 46% of the wounds were on the foot.
This retrospective study extracted electronic data
from a database. The data analysis focus was on
descriptive statistics. Data quality issues may
give rise to information bias in this study.
Simultaneously, retrospective data might not
have documentation of all parameters or variables that have to be collected in this type of
study. Therefore, the parameters in the design
have to be scrutinized carefully.
21.6 Cases (Courtesy
oftheWound Care Unit,
Kuala Lumpur Hospital)
All patients gave written consent to be included
in this case series. The topical oxygen device was
used. Two diabetic foot ulcers and one venous
ulcer case are shown here. Standard of care was
maintained, whereby an semi-occlusive dressing,
e.g., foam, was used as a secondary dressing on
top of the oxygen diffusing system and the foot
was ofoaded in the diabetic foot cases, while the
patient with the venous ulcer had compression
bandage over the leg.
Case 1. 45-Year-Old Gentleman with Diabetic
Foot Ulcer
Day 1 Day 31
Case 2. 58-Year-Old Gentleman with Diabetic
Foot Ulcer
Day 1 Day 34 Day 41
Case 3. 48-Year-Old Gentleman with Venous
Leg Ulcer
Day 1 Day 12 Day 80 Day 94
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H. K. R. Nair
21.7 Conclusion
The studies support the utilization of topical oxygen therapy with standard of care in wound healing and closure [12, 13, 15, 16, 20] In addition,
Castilla etal. [2] discussed topical oxygen therapy as an effective adjunctive therapy in the management of chronic wounds, especially diabetic
foot ulcers. Similarly, [27] recommended the
adjunctive administration of topical oxygen therapies in clinical practice and the Grade system
was used in this joint document.
Niederauer etal. [15] found that topical oxygen therapy was more effective in wounds that
were more chronic. It is an inexpensive modality,
and the application is easy as it can be used in the
home care setting which increases its usage and
appeals to the clinician and the patient [20, 26].
It is recommended to debride DFUs frequently
when utilizing topical oxygen therapy as there is
better clinical outcome [22] and debridement has
been included in the standard of care of many
RCTs [15, 16, 20]. In addition, the cost of managing DFUs is lower with topical oxygen therapy
[23]. More robust high-level studies with proper
randomization and large sample size from multicentres with double blinding are required to
increase the level of evidence for topical oxygen
therapy.
References
1. Bishop A.Role of oxygen in wound healing. J Wound
Care. 2008;17(9):399–402.
2. Castilla DM, Liu ZJ, Velazquez OC. Oxygen:
implications for wound healing. Adv Wound Care.
2011;1(6):225–30.
3. Yip WL.Inuence of oxygen on wound healing. Int
Wound J. 2015;12(6):620–4.
4. Niinikoski J.Effect of oxygen supply on wound healing and formation of experimental granulation tissue.
Acta Physiol Scand Suppl. 1969;334:1–72.
5. Sano H, etal. Inuence of oxygen on wound healing
dynamics: assessment in a novel wound mouse model
under a variable oxygen environment. PLoS One.
2012;7(11):1–7.
6. Tandara AA, Mustoe TA. Oxygen in wound
healing--more than a nutrient. World J Surg.
2004;28(3):294–300.
7. Sen CK, Hunt TK. Oxygen: at the Foundation
of wound healing—introduction. World J Surg.
2004;28(3):291–3.
8. Hopf HW, etal. Hyperoxia and angiogenesis. Wound
Repair Regen. 2005;13(6):558–64.
9. Hopf HW, Rollins MD. Wounds: an overview
of the role of oxygen. Antioxid Redox Signal.
2007;9(8):1183–92.
10. Sen CK.Wound healing essentials: let there be oxygen. Wound Repair Regen. 2009;17:1–18.
11. Allen DB, et al. Wound hypoxia and acidosis limit
neutrophil bacterial killing mechanisms. Arch Surg.
1997;132:991–6.
12. Lavery LA, Ryan EC. Does continuous diffusion
of oxygen improve diabetic foot ulcer healing? J
Diabetes Sci Technol. 2017;11(5):892–3.
13. Yu J, etal. Topical oxygen therapy results in complete
wound healing in diabetic foot ulcers. Wound Rep
Reg. 2016;24(6):1066–72.
14. Eisenbud DE. Oxygen in wound healing nutrient,
antibiotic, signaling molecule, and therapeutic agent.
Clin Plastic Surg. 2012;39:293–310.
15. Niederauer MQ, et al. A prospective, randomized,
double-blind multicenter study comparing continuous diffusion of oxygen therapy to sham therapy in
the treatment of diabetic foot ulcers. J Diabet Scie
Technol. 2017;11(5):883–91.
16. Niederauer MQ, etal. Continuous diffusion of oxygen
improves diabetic foot ulcer healing when compared
with a placebo control: a randomised, double-blind,
multicentre study. J Wound Care. 2018;27(9):S30–45.
17. Blair MJ, et al. Skin structure-function relationships
and the wound healing response to intrinsic aging.
Adv Wound Care. 2020;9(3):127–43.
18. Gould L, etal. Chronic wound repair and healing in
older adults: current status and future research. J Am
Geriatr Soc. 2015;63(3):427–38.
19. Sgonc R, Gruber J. Age-related aspects of cutaneous wound healing: a mini-review. Gerontology.
2013;59(2):159–64.
20. Frykberg RG, et al. A multinational, multicentre,
randomized, double-blinded, placebo-controlled trial
to evaluate the efcacy of cyclical topical wound
oxygen therapy (TWO2) in the treatment of chronic
diabetic foot ulcers: the TWO2 study. Diabetes Care.
2019;42:1–9.
21. Armstrong, etal. Treatment-based classication system for assessment and care of diabetic feet. J Am
Podiatr Med Assoc. 1996;86:311.
22. Lavery LA, etal. Does debridement improve clinical
outcomes in people with diabetic foot ulcers treated
with continuous diffusion of oxygen? Wounds.
2019;2019:1–6.
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23. Chan BC-F, Campbell KE.An economic evaluation
examining the cost-effectiveness of continuous diffusion of oxygen therapy for individuals with diabetic
foot ulcers. Int Wound J. 2020;17(6):1791–808.
24. Blume PA, et al. Comparison of negative pressure wound therapy using vacuum-assisted closure
with advanced moist wound therapy in the treatment of diabetic foot ulcers. Diabetes Care. 31.
2008;31:631.
25. Wang SV, etal. STaRT-RWE: structured template for
planning and reporting on the implementation of real
world evidence studies. BMJ. 2021;2021:372.
26. Copeland K, Purvis AR.A retrospective chart review
of chronic wound patients treated with topical oxygen
therapy. Adv Wound Care. 2017;6(5):143–52.
27. Gottrup F, etal. Use of oxygen therapies in wound
healing, with special focus on topical and hyperbaric
oxygen treatment. J Wound Care. 2017;26(5):S1–S42.
Part IV
https://t.me/medicina_free
Regenerative Medicine and Tissue
Bioingeneering
Evidence-Based andClinical
https://t.me/medicina_free
Experimentation onCell Therapy
AndreaFerrari, ChiaraStocco, RobertaBulla,
SerenaZacchigna, andGiovanniPapa
22
22.1 Background
Wound healing is a dynamic process that involves
various cell types, including inammatory cells,
broblasts, keratinocytes, and endothelial cells.
These cells function by releasing a variety of
growth factors that control cellular activation and
proliferation, remodeling of extracellular matrix,
collagen deposition, and neoangiogenesis in the
wound bed.
In physiological conditions, the reparative
process is the result of a balanced interaction
between activating and inhibiting growth factors,
resulting in controlled inammation.
This process can be compromised by several
conditions, including malnutrition, immunosup-
A. Ferrari · C. Stocco
Plastic Surgery Unit, University of Trieste,
Trieste, Italy
R. Bulla
Department of Life Sciences, University of Trieste,
Trieste, Italy
e-mail: rbulla@units.it
S. Zacchigna
ICGEB– International Center for Genetic
Engineering and Biotechnology, Trieste, Italy
e-mail: serena.zacchigna@icgeb.org
G. Papa (*)
Plastic Surgery Unit, University of Trieste,
Trieste, Italy
Plastic Surgery Clinic, Cattinara University Hospital,
Trieste, Italy
e-mail: giovanni.papa@asugi.sanita.fvg.it
pressive statuses, pregnancy, medications, hematologic disorders, and metabolic diseases [1–3].
For instance, metabolic disorders such as diabetes are associated with impaired healing, due to
both macrovascular and microvascular decits,
thus increasing infection rates [4, 5]; in addition,
diabetic patients often present additional conditions that further compromise healing, such as
altered nociception in response to pressure and
shear-related damage, autonomic impairment,
dry skin, and endothelial dysfunction [6].
Parallel with the progressive aging of our society and associated chronic diseases, the incidence
of ulcers is steadily increasing, signicantly
impacting on both patient quality of life and
healthcare systems [7, 8].
Wound dressing technologies have been
remarkably improved over the past decades. The
most important approaches in ulcer treatment
currently entail advanced occlusive dressings to
maintain a moist environment and negative pressure wound therapy (NPWT). However, some
chronic wounds, especially in subjects with poor
healing capacity, cannot be treated properly with
the sole use of dressings. Non-healing ulcers still
represent a major clinical burden, with a prevalence of 2–5% and high social impact and healthcare costs.
As summarized above, several clinical conditions could lead to the healing impairment of
ulcers. Although pathophysiological alterations could differ among the various etiologies,
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Maruccia et al. (eds.), Pearls and Pitfalls in Skin Ulcer Management,
https://doi.org/10.1007/978-3-031-45453-0_22
205
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A. Ferrari et al.
non- healing ulcers usually share a chronic
inammation state, driven by impaired modulation of enzyme activity, matrix metalloproteases (MMPs), reactive oxygen species (ROS),
and excessive levels of pro-inammatory
cytokines.
In chronic wounds, effectively, the downregulation of balancing agents like tissue inhibitor of
metalloproteinase-1 (TIMP-1) and TIMP-3 leads
to overexpression of several proteases such as
elastase, plasminogen activator (PA), MMP-1,
MMP-2, MMP-8, MMP-9, and MMP-13; this
results in higher proteolytic degradation of extracellular matrix (ECM) and slowing down the
healing process but also amplifying the inammation. In fact, ECM fragments stimulate the
release of pro-inammatory cytokines and the
production of ROS by leukocytes, thus increasing
inammation and ECM damage in a vicious circle [9, 10].
Another fundamental mechanism lacking in
non-healing ulcers is neoangiogenesis. In a physiological setting, after tissue damage, endothelial
cells (ECs) rapidly proliferate, migrate, and organize themselves into tubular structures. This process is mainly mediated by vascular endothelial
growth factor-A (VEGF-A) and the interaction
with its specic receptor VEGFR-2, also known
as Flk-1 or KDR. Other molecules take part in
this mechanism, including angiopoietin-1
(ANGPT-1), integrins, and several chemokines.
In particular, the ANGPT-1-Tie (TEK) pathway
has been shown to be involved in balancing
angiogenic stimulation and vessel maturation,
intervening in the later steps of the signaling cascade to promote 3D capillary organization, proliferation, and migration. At the same time, the
TEK pathway is thought to inhibit EC permeability and enhance an anti-inammatory phenotype
under certain conditions [11].
Because of changes in the expression levels of
pro- and anti-angiogenesis proteins due to underlying diseases—for instance in diabetic
patients—this dynamic regulation of angiogenesis may change, worsening the local environment
and lowering the healing potential of the wound.
In addition, insufcient vascularization is also a
risk factor for poor take of skin grafts and dermal
substitutes, which is a major limitation in the
treatment of chronic wounds [11].
Current literature shows no signicant correlation between pro- and anti-angiogenetic molecules and clinical evidence of neovascularization
capacity of chronic ulcers [12].
This is due to other mechanisms implied in the
homeostasis of the wound. In fact, another pathophysiological nding in non-healing wounds is
cell senescence. The cell cycle is affected by several external events depending on the etiology;
for instance, diabetes can lead to DNA damage
due to persistent oxidative stress, ensuing defective biochemical pathways of broblasts such as
the GSK-3β/Fyn/Nrf2 pathway. As a result, in
chronic ulcers various cell types including broblasts but also endothelial cells, macrophages,
and keratinocytes are less responsive to molecular signaling, and therefore, their proliferative
capacity is diminished. Moreover, during inammation, endothelial cells trigger leukocyte adhesion to the blood vessel walls, extravasation, and
accumulation of macrophages and neutrophils,
contributing to chronic inammatory state and
fueling the vicious cycle described above [10].
For this reason, it is now understood that it is
not sufcient to introduce growth factors for the
treatment of chronic non-healing ulcers, as they
need active and healthy cells capable of providing a favorable environment by secreting and
regulating growth factors, chemokines, and cytokines in a balanced manner thanks to their paracrine effect [13].
Current treatment healing treatment consists
of surgical debridement and tissue coverage
when possible. Other treatments involve the local
application of anti-inammatory and anti-oxidant
agents, or also the use of growth factors and
matrix metalloproteinase inhibitors.
Innovative approaches to difcult healing
wound include the use of cultured adult multipotent cell suspension [14].
Numerous studies have shown a promising
and potential role of cell therapy in regenerating
damaged tissues [15], although this relatively
new eld brings numerous limitations concerning costs and technologies for stem cell isolation,
purication, culture, harvesting, and transfer
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