Efficacy of Oxidized Regenerated Cellulose/Collagen Dressing for Management of Skin Wounds: A Systematic Review and Meta-Analysis - Hindawi.com
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Hindawi
Evidence-Based Complementary and Alternative Medicine
Volume 2021, Article ID 1058671, 10 pages
https://doi.org/10.1155/2021/1058671
Research Article
Efficacy of Oxidized Regenerated Cellulose/Collagen Dressing for
Management of Skin Wounds: A Systematic
Review and Meta-Analysis
Li Zhang ,1 Simei Wang,2 Meihua Tan,2 Hongwei Zhou,2 Ying Tang,2 and Yan Zou 3
1
Department of Orthopedics and Trauma, The Affifiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China
2
Department of Wound Stoma Care, The Affifiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China
3
Department of Hand and Foot Surgery, The Affifiliated Nanhua Hospital, University of South China, Hengyang, Hunan, China
Correspondence should be addressed to Yan Zou; zy821008@sina.com
Received 13 July 2021; Accepted 22 July 2021; Published 4 August 2021
Academic Editor: Songwen Tan
Copyright © 2021 Li Zhang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. The purpose of this study was to evaluate the wound healing efficacy of oxidized regenerated cellulose (ORC)/collagen
dressing and ORC/collagen/silver-ORC dressings compared to standard of care or control in treatment of chronic skin wounds
such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), and pressure injuries sore ulcers (PISUs). Methods. An electronic
search was carried out in four popular databases PubMed, Scopus, Embase, and CENTRAL to identify thirteen included studies,
comparing the clinical efficacy of ORC/collagen dressings when compared to control in management of chronic skin wounds,
especially DFUs, VLUs, and PISUs, and skin graft donor site wounds. Results. Consolidated data from thirteen comparative
clinical studies undertaken for management of DFUs, VLUs, and PISUs showed favorable outcomes towards use of ORC/collagen
compared to other traditional and hydrocolloid foam dressings in terms of wound healing rate (P � 0.02) and percentage wound
relative reduction (P � 0.003). The time taken to achieve complete wound healing in the included studies did not show any
statistical significant difference (P � 0.24). There was no significant difference in adverse events between ORC/collagen-treated
group and comparative group (P � 0.19). Conclusion. ORC/collagen wound dressings are beneficial in terms of improved wound
healing rate and percentage wound relative reduction compared to already existing traditional standard of care with non-MMP,
inhibiting biomaterials such as moistened gauze, autologous growth factors, hydrocolloid foam dressings, or ovine
extracellular matrix.
1. Introduction faster healing and tissue regeneration [4]. The ultimate re-
quirement for complete wound healing involves proper
Wound is defined as a disruption in cutaneous structure and nursing of wound by application of wound dressings or
function, potentially involving underlying soft tissue [1]. wound care products [5]. The wound dressings used in
Various factors that can result in impaired wound healing management of chronic wounds needs to be cost-effective
include aging, malnutrition, diabetes, vascular disease, and and clinically efficient, high patient acceptance, and most
immunosuppression [2]. Chronic skin wounds occur when importantly improved patient’s quality of life [6].
normal wound healing is dysregulated, resulting in a delay or Conventional wound dressings used for wound care
arrest in one of the stages of wound healing. Prolongation of management include traditional moistened gauze or pet-
the inflammatory phase is the most common cause, usually rolatum and modern dressings including alginates, hydro-
due to wound infection or chronic irritation. Other possible fibers, hydrogels, films, and biological agents including ovine
mechanisms are tissue and wound hypoxia or failed epi- collagen [7]. However, these dressings are permeable to
thelialization [3]. Surgeons sometimes reexcise the tissue bacteria and not conducive for creating a physiological
and convert the chronic wound back into an acute one for environment. Nowadays, use of biological dressings like2 Evidence-Based Complementary and Alternative Medicine
collagen is impermeable to bacteria, thereby reducing col- (C): standard of wound care or control; outcome (O): wound
onization. The popularity of collagen dressing nowadays healing rate, wound reduction, time taken for complete
ought to its ease of application and being natural, non- healing, adverse events, etc.
immunogenic, nonpyrogenic, hypoallergenic, and pain-free
healing [7]. Autologous platelet concentrates [8, 9] also have
2.2. Search Strategy. An electronic search was carried out in
been beneficial and cost-effective in promoting wound
four popular databases PubMed, Scopus, Embase, and
healing.
CENTRAL to identify potential eligible studies. The key-
Chronic wounds often present with elevated levels of
words used for the search strategy include collagen, oxidized
matrix metalloproteinases (MMPs), which carryout prote-
regenerated cellulose, collagen/ORC wound dressing,
olysis and inactivate the intrinsic growth factors involved in
wound healing, chronic skin wounds, diabetic foot ulcer,
wound healing [10]. This may be the reason for which
venous leg ulcer, and pressure injuries. The keywords were
chronic skin wound takes longer time to heal [11]. The
combined in the advanced search using Boolean operators.
collagen dressings are found to inhibit the action of MMPs
Additionally, a manual search was also performed in pub-
and encourage speedy deposition and proper organization of
lished issues of Advances in Skin and Wound Care, Journal
freshly formed collagen fibrils and granulation tissue for-
of Wound Care, International Wound Journal, Wounds, and
mation, forming a bed to promote wound healing. These
International Journal of Lower Extremity Wounds. The
collagen fibrils undergo maturation and aid in epithelial
bibliography section of the potentially eligible studies and
migration from wound periphery for complete wound
previously performed systematic reviews was also inspected
closure [12].
for any relevant studies. No restriction in publication year
Oxidized regenerated cellulose (ORC)/collagen matrix is
and language was applied. The search results from different
one such MMP inhibiting biomaterial which intensifies the
electronic databases and manual search were imported to a
wound healing environment by binding and inactivating
citation manager (endnote) to remove duplicates and sub-
excess levels of proteases and gelatinases in wound exudates
sequently subjected to assessment for study selection.
[13]. Wu et al. [14] showed a statistical significant decrease in
elastase, plasmin, and gelastinase activity in patients with
venous leg ulcers (VLUs) treated with ORC/collagen matrix 2.3. Study Selection. The retrieved studies were subjected to
and also showed a significant and immediate reduction in title and abstract screening by two independent reviewers
protease activity in wound exudates from VLUs. Motzkau based on relevancy. The relevant articles were then assessed
et al. in 2011 demonstrated the effects of MMP activity in the by retrieving full text for each of the potentially eligible
exudate of chronic diabetic foot ulcers (DFUs) treated with studies. The criteria for inclusion of studies are as follows:
ORC/collagen dressing and found significantly decreased
(1) Comparative clinical studies
MMP-2 levels on day 5 of treatment [15].
Several studies have also assessed the efficacy of ORC/ (2) Application of ORC/collagen or ORC/collagen/sil-
collagen dressing and ORC/collagen/silver-ORC dressings ver-ORC dressings compared to control in man-
for wound management [16, 17]. However, to the best of our agement of chronic skin wounds (DFUs, VLUs,
knowledge, no meta-analysis has been conducted till date PIs, etc.)
proving the efficacy of ORC/collagen in different chronic (3) Studies with minimum sample size of 10 (5 per
skin wounds. Therefore, the purpose of this study was to group)
evaluate the wound healing efficacy of ORC/collagen
The case reports, case series, cohort studies, and clinical
dressing and ORC/collagen/silver-ORC dressings compared
studies assessing another MMP inhibiting dressing with
to standard of care or control in the treatment of chronic
ORC/collagen dressing were excluded. The reasons of ex-
skin wounds.
clusion of the eligible studies were also provided. Any
disagreement between the two reviewers with regard to
2. Methods study selection and exclusion was resolved by consensus
with a third reviewer.
This systematic review and meta-analysis was carried out
with strict adherence to preferred reporting items for sys-
tematic review and meta-analysis (PRISMA) guidelines [18]. 2.4. Data Extraction. The data extraction from the included
A prior protocol was framed to facilitate the smooth conduct trials was carried out by two independent reviewers using an
in performing this systematic review. excel spreadsheet. The demographic data of participants
such as age, gender, type and duration of wound, and wound
area and size; interventional characteristics such as type of
2.1. Research Question. What is the wound healing efficacy wound dressing, change of dressing per week, and follow-up;
of ORC/collagen dressing and ORC/collagen/silver-ORC and outcome variables such as wound closure, percentage of
dressings compared to standard of care or control in the wound relative reduction, time taken for complete epithe-
treatment of chronic skin wounds? Patient or population lialization and granulation bed formation, and adverse
(P): participants with chronic skin wounds (DFUs, VLUs, events were recorded for each included trial. In case of any
PIs, etc.); intervention (I): wound dressing with ORC/col- missing or unclear data, the authors were contacted via
lagen or ORC/collagen/silver-ORC dressings; comparison e-mail to seek out clarifications.Evidence-Based Complementary and Alternative Medicine 3
2.5. Data Synthesis. The data extracted from the included The demographic data from all included studies is provided
trials were subjected to both qualitative and quantitative in Table 1. The interventional characteristics from all in-
analysis. The demographic data and interventional charac- cluded studies are provided in Table 2. The details of the
teristics along with certain outcomes with little similarities type, duration, area of wound, the times of dressing change
were qualitatively analyzed and tabulated for better repre- in every week, and the follow-up duration were recorded in
sentation. The qualitative analyses of the similar outcome the individual files. The follow-up duration among the in-
assessment were carried out using meta-analysis. The meta- cluded studies ranged from a minimum follow-up period of
analysis was performed by using RevMan 5.3v. The het- 5 days and maximum follow-up period of up to 16 weeks.
erogeneity among the studies was calculated using i2 sta-
tistics. A random or fixed effect model for meta-analysis was
employed based on the i2 value. i2 of less than 40% was 3.3. Meta-Analysis. The quantitative analysis for the out-
considered unimportant while that of more than 40% was comes was carried out by meta-analyzing the data only if
viewed as moderate to considerable heterogeneity. more than 2 similar studies were found to report a similar
outcome with a common unit of measurement. The meta-
2.6. Risk of Bias Assessment. The risk of bias analysis was analysis was performed for the following parameters.
carried out using Cochrane risk of bias tool [19] by two
independent reviewers. The included trials were analyzed for
bias in selection of participants by evaluating randomization 3.3.1. Wound Healing Rate. Six studies [21–23, 27, 29, 30]
process and allocation concealment methods; bias in were analyzed to compare the wound healing rate between
blinding of participants and personnel; bias in blinding of the ORC/collagen group and control group. The overall OR
outcome assessors; and bias in selective reporting of results 1.79 [1.09, 2.94] was found to be significantly favoring ORC/
and lost to follow-up. The studies were graded as low, collagen-treated group (P � 0.02). The heterogeneity among
moderate, and high risk based on adequacy of the above- the studies was found to be moderate (i2 � 57%), as shown in
mentioned domains. Figure 2.
3. Results
3.3.2. Time to Achieve Complete Wound Healing. Only three
3.1. Search Results. This systematic review assessed the data studies [27, 29, 30] were analyzed to compare the time to
from 13 included studies [13, 15, 20–30] comparing the achieve complete wound healing between the ORC/collagen
clinical efficacy of ORC/collagen dressings when compared group and control group. The overall MD −2.25 [−22.95,
to control in the management of chronic skin wounds, 18.46] between both groups was found nonsignificant
especially DFUs, VLUs, and PIs. The electronic search was (P � 0.83). The heterogeneity among the studies was also
carried out in all 4 databases and the manual search retrieved found to be high (i2 � 97%), as shown in Figure 3.
699 articles, where the total studies identified were 545 after
removal of duplicates. After careful title and abstract
screening, only eighteen studies were found potentially el- 3.3.3. Percentage Wound Relative Reduction. Only three
igible and relevant. Full text evaluations of eighteen studies studies [21, 25, 28] were analyzed to compare the percentage
were carried out to find only thirteen studies satisfying the wound relative reduction between the ORC/collagen group
inclusion criteria. The rest of the five studies were excluded and control group. The overall MD 18.15 [6.09, 30.21] was
and detailed reasons of exclusion were provided. The study found to be significantly favoring ORC/collagen-treated
selection and exclusion process is depicted in Figure 1. group (P � 0.003). The heterogeneity among the studies was
also found to be low (i2 � 29%), as shown in Figure 4.
3.2. Demographic and Interventional Characteristics.
There were 10 randomized clinical trials [13, 15, 21,
22, 24–27, 29, 30], 2 comparative clinical trials [23, 28], and 1 3.3.4. Adverse Events in Wound Healing. Four studies
comparative retrospective study [20], comparing the use of [21, 22, 29, 30] were analyzed to compare the adverse events
ORC/collagen dressings and other wound dressings as in wound healing between the ORC/collagen group and
control. 8 included studies [15, 22–24, 26–29] assessed the control group. The overall RD −0.08 [−0.21, 0.04] between
effect of ORC/collagen on healing of DFUs, 2 studies [13, 21] both groups was found nonsignificant (P � 0.19). The
evaluated healing of VLUs, 1 study [25] evaluated healing of heterogeneity among the studies was also found to be
PIs, and another study assessed healing of skin graft donor moderate (i2 � 54%), as shown in Figure 5.
site wounds. A consolidated total of 1538 wounds were
evaluated in 13 included studies [13, 15, 20–30]. Out of
which, 782 wounds were treated with ORC/collagen dressing 3.4. Risk of Bias Assessment. The included studies were
and rest of 736 wounds were treated either with standard assessed to have low to moderate risk of bias, except 2 studies
wound care, moistened gauze, hydrocolloid foam, or ovine- [15, 23], which were assessed as high risk due to lack in
based extracellular matrix. The age range of the patients randomization and blinding of outcome assessor, respec-
presented with chronic skin wounds is from 18 to 88 years. tively, as shown in Figure 6.4 Evidence-Based Complementary and Alternative Medicine
Records identified through Additional records identified
database searching through other sources
Identification
(n = 697) (n = 2)
Records after duplicates removed
(n = 545)
Screening
Records screened Records excluded
(n = 545) (n = 527)
Full-text articles assessed Full-text articles excluded
for eligibility with reasons
(n = 18)
Eligibility
(n = 5)
Cohort studies = 3
Case series = 2
Studies included in
qualitative synthesis
(n = 13)
Included
Studies included in
quantitative synthesis
(meta-analysis)
(n = 8)
Figure 1: PRISMA flow chart showing study selection process.
Table 1: Demographic data of all included studies.
No.
Authors Study design Centres Age Gender (M/F) Test dressing Control dressing Type of wound
of patients
58.3 ORC/collagen
Veves et al., 2002 [29] RCT 11 276 203/73 Gauze DFUs
(23–85) matrix
ORC/collagen Nonadherent
Vin et al., 2002 [30] RCT 14 73 33–88 26/47 VLUs
matrix dressing (Adaptic)
Lobmann et al., ORC/collagen Good standard
RCT 1 33 64 ± 11 NR DFUs
2006 [26] matrix wound care
Luis Lazaro-Martinez ORC/collagen
RCT 1 40 NR NR Hydroactive dressing DFUs
et al., 2007 [27] matrix
Kakagia et al., ORC/collagen Autologous growth
RCT 1 54 NR 22/29 DFUs
2007 [24] matrix factors
Smeets et al., ORC/collagen Hydro-colloid
RCT NR 27 63 ± 8 NR VLUs
2008 [13] matrix dressing
Motzkau et al., ORC/collagen Good standard
RCT 1 19 NR NR DFUs
2010 [15] matrix wound care
ORC/collagen Hydro-colloid
Ulrich et al., 2011 [28] CCT 1 32 >18 22/10 DFUs
matrix dressing
Gottrup et al., ORC/collagen/
RCT 2 39 NR 35/4 Open wound healing DFUs
2013 [22] silver-ORC
ORC/collagen
Kloeters et al., Foam hydropolymer
RCT 1 33 >18 NR with foam PIs
2015 [25] dressing
dressing
ORC/collagen/
Cullen et al., 2017 [21] RCT 3 49 24–90 31/18 Standard of care VLUs
silver-ORCEvidence-Based Complementary and Alternative Medicine 5
Table 1: Continued.
No.
Authors Study design Centres Age Gender (M/F) Test dressing Control dressing Type of wound
of patients
Ovine (sheep-
ORC/collagen/ derived)
Griffin et al., 2019 [23] CCT 1 844 NR NR DFUs
silver-ORC collagen extracellular
matrix
Skin graft
ORC/collagen/ Petrolatum-based
Chowdhry, 2019 [20] CRS 1 59 51.9 ± 14.4 27/32 donor site
silver-ORC gauze dressing
wounds
Note: RCT, randomized clinical trial; CCT, comparative clinical trial; CRS, comparative retrospective study; ORC, oxidized regenerated cellulose; DFU,
diabetic foot ulcer; VLU, venous leg ulcer; PI, pressure injuries; NR, not reported.
Table 2: Interventional characteristics of all included studies.
No. of dressing No. of dressing
No. of No. of
Type of Wound Wound area, Wound area, changes per changes per Follow-
Authors test control
wound duration test control week per week per up
wounds wounds
patient, test patient, control
Veves et al., 6 2.5 12
DFUs 3.1 (0.1–42.4) 138 138 10.1 11.2
2002 [29] months (0.2–27.4) weeks
Vin et al., 2002 12
VLUs NR NR NR 37 36 3.9 + 1.4 d 4.1 + 1.6 d
[30] weeks
Lobmann et al.,
DFUs NR 1237 mm sq 1132 mm sq 18 15 Daily Daily 1 week
2006 [26]
Luis Lazaro-
Martinez et al., DFUs NR NR NR 20 20 Every 2 days Every 2 days 6 weeks
2007 [27]
Kakagia et al., ≥3
DFUs 25.8 ± 15.2 28.4 ± 13.6 17 17 NR NR 8 weeks
2007 [24] months
Smeets et al.,
VLUs NR NR NR 17 10 NR NR 8 weeks
2008 [13]
Motzkau et al.,
DFUs NR NR NR 13 6 7 7 5 days
2010 [15]
Ulrich et al., 12
DFUs NR 12 ± 6 14 ± 5 22 10 NR NR
2011 [28] weeks
Gottrup et al., 2.1 ± 3.1 cm 4.4 ± 6.3 cm
DFUs NR 24 15 NR NR 4 weeks
2013 [22] sq sq
Kloeters et al., More than More than 12
PIs ≥6 weeks 23 10 2–3 days 2–3 days
2015 [25] 1 cm sq 1 cm sq weeks
12 6.9 ± 4.1 5.6 ± 3.0 22 27 Twice in a week Twice in a week
2017 [21] weeks
months
Griffin et al., Once in 2 16
DFUs NR 1.5 cm sq 1.5 cm sq 422 422 Once in 2 weeks
2019 [23] weeks weeks
Skin graft
Chowdhry,
donor site NR 69.67 ± 9.45 69.13 ± 6.81 29 30 1.79 ± 0.73 0.67 ± 0.66 NR
2019 [20]
wounds
Note: DFU, diabetic foot ulcer; VLU, venous leg ulcer; PI, pressure injury; NR, not reported.
4. Discussion included studies did not show any statistical significant differ-
ence. There was no significant difference in adverse events
This systematic review aimed at evaluating the wound healing between ORC/collagen-treated group and comparative group
efficacy and adverse events associated with ORC/collagen (P � 0.19).
dressings in treatment of various chronic skin wounds. Con- The beneficial effect of ORC/collagen can be due to its
solidated data from thirteen comparative clinical studies un- ability to absorb oxygen free radicals, bind excess iron, and
dertaken for management of DFUs, VLUs, and PIs showed protect growth factors present in chronic wound fluid [31].
favorable outcomes towards use of ORC/collagen compared to The above mechanism may explain how ORC/collagen can
other traditional and hydrocolloid foam dressings in terms of redress the imbalance of the chronic wound environment
wound healing rate and percentage wound relative reduction. and therefore may have a beneficial effect in the treatment of
The time taken to achieve complete wound healing in the chronic skin wounds.6 Evidence-Based Complementary and Alternative Medicine
ORC/collagen Control Weight Odds ratio Odds ratio
Study or subgroup Events Total Events Total (%) M-H, random, 95% CI Year M-H, random, 95% CI
Vin 2002 18 37 12 36 15.4 1.89 [0.74, 4.88] 2002
Veeves 2002 51 138 37 138 25.5 1.60 [0.96, 2.67] 2002
Lazaro-Martinez 2007 12 19 3 19 8.0 9.14 [1.95, 42.90] 2007
Gottrup 2013 12 33 4 33 10.7 4.14 [1.17, 14.65] 2013
Culien 2017 14 22 22 27 10.3 0.40 [0.11, 1.46] 2017
Griffin 2019 346 422 315 422 30.2 1.55 [1.11, 2.15] 2019
Total (95% CI) 671 675 100.0 1.79 [1.09, 2.94]
Total events 453 393
Heterogeneity: tau2 = 0.18; chi2 = 11.58, df = 5 (P = 0.04); I2 = 57% 0.02 0.1 1 10 50
Test for overall effect : Z = 2.30 (P = 0.02) Favours control Favours ORC/collagen
Figure 2: Forest plot showing comparison of complete wound healing rate between ORC/collagen and control groups.
ORC/collagen Control Weight Mean difference Mean difference
Study or subgroup Mean SD Total Mean SD Total (%) IV, random, 95% CI Year IV, random, 95% CI
Vin 2002 65.9 23.9 18 63.8 25.2 12 28.5 2.10 [−15.93, 20.13] 2002
Veeves 2002 49 2.8 51 40 2.8 37 36.2 9.00 [7.81, 10.19] 2002
Lazaro-Martinez 2007 23.3 9.9 12 40.6 1.15 3 35.3 −17.30 [−23.05, −11.55] 2007
Total (95% CI) 81 52 100.0 −2.25 [−22.95, 18.46]
Heterogeneity: tau2 = 307.47; chi2 = 77.48, df = 2 (P < 0.00001); I2 = 97% −20 −10 0 10 20
Test for overall effect : Z = 0.21 (P = 0.83) Control ORC/collagen
Figure 3: Forest plot showing comparison of time taken to achieve complete wound healing between ORC/collagen and control groups.
ORC/collagen Control Weight Mean difference Mean difference
Study or subgroup Mean SD Total Mean SD Total (%) IV, random, 95% CI IV, random, 95% CI
Culien 2017 45 26 22 40 30 10 23.6 5.00 [−16.54, 26.54]
Kloeters 2015 65 13 23 41 11 10 63.9 24.00 [−15.36, 32.64]
Ulrich 2011 85.6 28.6 22 72.5 77.8 27 12.6 13.10 [−18.59, 44.79]
Total (95% CI) 67 47 100.0 18.15 [6.09, 30.21]
2
Heterogeneity: tau = 39.85; chi2 = 2.82, df = 2 (P = 0.24); I2 = 29%
−100 −50 0 50 100
Test for overall effect : Z = 2.95 (P = 0.003)
Control ORC/collagen
Figure 4: Forest plot showing comparison of percentage wound relative reduction between ORC/collagen and control groups.
ORC/collagen Control Weight Risk difference Risk difference
Study or subgroup Events Total Events Total (%) M-H, random, 95% CI Year M-H, random, 95% CI
Vin 2002 3 37 5 36 30.0 −0.06 [−0.20, 0.09] 2002
Veeves 2002 37 138 34 138 36.9 0.02 [−0.08, 0.12] 2002
Gottrub 2013 0 23 4 13 16.6 −0.31 [−0.56, −0.06] 2013
Culien 2017 5 22 10 27 16.5 −0.14 [−0.40, 0.11] 2017
Total (95% CI) 220 214 100.0 −0.08 [−0.21, 0.04]
Total events 45 53
Heterogeneity: tau2 = 0.01; chi2 = 6.48, df = 3 (P = 0.09); I2 = 54%
−1 −0.5 1 0.5 1
Test for overall effect : Z = 1.31 (P = 0.19)
Control ORC/collagen
Figure 5: Forest plot showing comparison of adverse events in wound healing between ORC/collagen and control groups.Evidence-Based Complementary and Alternative Medicine 7
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Random sequence generation (selection bias)
Incomplete outcome data (attrition bias)
Allocation concealment (selection bias)
Selective reporting (reporting bias)
Other bias
Chowdhry 2019 ? ? + + + + +
Cullen 2017 + + + ? + + +
Gottrup 2013 + ? + + + + +
Griffin 2019 − ? + + + + +
Kakagia 2007 + ? + + + + +
Kloeters 2015 + ? + + + + +
Lazaro- Martinez 2007 + ? ? ? + + +
Lobmann 2006 + ? + + + + +
Motzkau 2010 + ? + − + + +
Smeets 2008 + ? ? ? + + +
Ulrich 2011 ? ? ? ? + + +
Veeves 2002 ? ? ? ? + + +
Vin 2002 + ? + + + + +
(a)
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
0 25 50 75 100
%
Low risk of bias
Unclear risk of bias
High risk of bias
(b)
Figure 6: Risk of (a) bias summary and (b) bias graph of all included studies.8 Evidence-Based Complementary and Alternative Medicine
It is proven that there exists a complex intrinsic interaction and silver-ORC/collagen was similar to that of the materials
between cells and its mediators in response to tissue injury. used as controls for wound healing.
Wounds that do not progress beyond the inflammatory phase The moderate to high heterogeneity among the studies
often demonstrate an increased activity of proteases such as analyzing time to achieve complete healing, healing rate, and
MMPs and elastase, as well as the persistence of inflammatory adverse events could be explained by the fact that there had
cells [32]. There is also a downregulation of tissue inhibitor of been variation in systemic status of the patients, wound size
matrix metalloproteinase activity. In particular, the inflam- and duration, and follow-up period. The diabetic foot ulcers
matory response seems to be high in chronic skin wounds, are difficult to heal compared to other chronic skin wounds
characterized by increased levels of proinflammatory cytokines due to intrinsic impairment of wound healing response [35].
and proteases [33]. While controlling levels of inflammation The limitation of this review includes difficultly in con-
and protease expression is a critical part of normal wound ducting subgroup analysis based on type of wounds (DFUs,
healing, elevated and prolonged expression of proteases pro- VLUs, PIs, etc.) and between silver-ORC and ORC/collagen
duced during the inflammatory phase of healing can lead to dressing, due to lack of sufficient studies.
excessive ECM degradation associated with impaired healing
[11]. Therefore, use of a collagen-based MMP inhibiting bio- 5. Conclusions
material as wound dressing has been popular nowadays.
The protease inhibitory role of ORC/collagen is well ORC/collagen wound dressings are beneficial in terms of
established in many in vitro and in vivo studies. Smeets et al. in improved wound healing rate and percentage wound relative
2008 [13] showed that the patients treated with ORC/collagen reduction compared to already existing traditional standard of
matrix showed a significant decrease in elastase, plasmin, and care with non-MMP, inhibiting biomaterials such as traditional
gelatinase activity as compared with the control group, with no moistened gauze or petrolatum and modern dressings in-
significant difference in the MMP-2 concentrations between cluding foams, alginates, hydrofibers, hydrogels, hydrocolloids,
the two groups. However, the results showed a significant and films, and biological agents such as ovine collagen. Future
immediate reduction in protease activity in wound exudates comparative studies of high quality evidence are required to
from VLUs treated with ORC/collagen. further establish the beneficial and protective effect of ORC/
Apart from this, ORC/collagen was also found to promote collagen dressings in the treatment of chronic skin wounds.
fibroblast migration and proliferation in vitro [34]. The in vivo
effects of ORC/collagen on wound of diabetic mice were also Data Availability
investigated in terms of wound closure and histological analysis
and concluded that the ORC/collagen accelerated wound The datasets used and/or analyzed during the current study
closure and histological appearance by promoting fibroblastic are available from the corresponding author on reasonable
activity and thereby supporting complete epithelialization [34]. request.
This could be a reason which could explain our favorable
results towards ORC/collagen dressing in terms of faster Conflicts of Interest
wound healing rate and improved percentage wound relative
reduction. However, no significant difference was noted in the The authors declare that they have no conflicts of interest.
time to complete wound closure between ORC/collagen and
comparative dressings. Indeed, complete wound healing does Acknowledgments
not often require just one dressing and at the reepithelialization
This study was supported by the Project of Hunan Education
stage or when exudate disappears, the dressing needs to be
Department (20C1586) “Study of Diabetic Foot Wounds
discontinued. This is an important reason for the nonsignifi-
Exudate Proteomics and Its Application in “DAVIC Medical
cant difference between the two groups of our review.
Sterlizing Liquid Dressing” Mechanism Research.”
Many of the included studies [13, 15, 24–26] in this review
estimated the protease, elastase, and other MMP levels in the
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