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Wound Healing - Recent Advances and Future Opportunities
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macrophages is negatively affected by the stabilising impact of steroids on lysosomes.
Epithelialisation, which is a critical step in wound healing is inhibited by glucocorticoids such as hydrocorticosterone [57].
Things are further complicated by the low-secretory state induced by corticosteroids due to their effect on the endoplasmic reticulum. Thus, risk of wound dehiscence is consequently enhanced due to the reduced deposition of collagen [58].
. Genetic syndromes associated with abnormal wound healing
5.4.1 Cutis laxa
Defective elastin fibres as evidenced in cutis laxa- an acquired or congenital
disorder, impacts wound healing. Characterised by skin that is loose (lax), wrinkled,
sagging, and lacking elasticity (inelastic). The inelastic skin returns to place abnormally slowly when stretched. The skin around the face, arms and legs etc. are the
predominantly affected parts and give patients a prematurely-aged appearance [59].
5.4.2 Ehlers-Danlos Syndrome
Characterised by deficit in collagen metabolism, it is a group of connective tissue
abnormalities that lead to defects in the inherent strength, elasticity, integrity, and
healing properties of the tissues [60, 61]. Even mild injury in Ehlers-Danlos patients
may lead to severe bruising and the development of wide, ‘open’ wounds due to the
delayed healing [27, 60, 61].
5.4.3 Osteogenesis imperfecta
An inheritable disorder of connective tissue, clinical features of this condition
include bone fragility, neonatal dwarfism, deformities of the long bones, scoliosis,
ligamentous laxity, blue sclerae, defective dentinogenesis, and deafness. While there
are four major forms, mutations in the genes that encode type I collagen is a common
trait that result in the formation of wide scars [27, 62].
. Adjuncts to wound healing
. Bioengineered skin
One of the best examples of Bioengineered skin is the Apligraf: a bi-layered
bioengineered skin substitute composed of ‘bovine type I collagen matrix populated
with human male neonatal fibroblasts and an epidermal sheet derived from male
neonatal epidermal keratinocytes’, that has been approved by the US Food and Drug
Administration (FDA) for cases where standard wound care has failed to treat ulcers.
The mechanism that initiates wound healing by the use of these bioengineered
products is still being researched but it has been revealed that these cells grow and
proliferate, and produce growth factors, collagens, and extracellular matrix proteins,
all of which are known to positively stimulate re-epithelialisation, formation of
granulation tissue, angiogenesis, and neutrophil and monocyte chemotaxis. Thus,
these have the potential to provide a potent cellular remedy and adaptable response in
acute and chronic wounds [63].
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. Electrostimulation
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While the first exploration of electrical current in skin was described as early as
1860 by DuBois-Reymond; the fact that wounds treated with electrostimulation had
a positive potential compared with the surrounding skin was only confirmed in 1945
[64]. It is believed that electro-stimulations aides in wound healing by accelerate the
wound-healing process by tissue increasing the migration of vital cells to the site of
injury i.e., neutrophils, macrophages [64–66] and fibroblasts [67–69] by imitating the
natural electrical current that occurs in skin when it is injured and thereby accelerates
the healing process [70–72].
. Hydrotherapy
One of the oldest adjunct treatment modalities that is still practiced today is
the Whirlpool therapy that accelerates wound healing by wound debridation,
warming the wounded tissue, and providing buoyancy and gentle limb resistance
for physical therapy [73]. However, despite their prevalence, Whirlpool treatments have been subject to disapprobation in recent years because of the enhanced
risk ofnosocomial contamination and transmission of virulent infections associated with them [74–78]. These days, modified forms of the whirlpool therapy,
suchasthe pulsed lavage and the VersaJet are more popular as they provide the
benefits of hydrotherapy without the associated collateral trauma of traditional
methods [78, 79].
. Hyperbaric oxygen
Although hyperbaric oxygen treatment for narcotising soft-tissue infections has
not always been successful, the treatment has been found to be beneficial for a variety
of conditions including amputations, [80] osteoradionecrosis, [81, 82] surgical flaps,
and skin grafts [81, 83, 84]. However, studies have failed to statistically corroborate
significant outcomes regarding differences with respect to mortality rates and length
of hospitalisation [82, 85–88]. Benefits are suspected to primarily originate from the
benefits of the increased nitric oxide levels that are developed by increasing oxygen
pressure as nitric oxide is known to be vital for wound-healing [88].
Fascinatingly, in a study using an ischemic rabbit ear model, hyperbaric
oxygen therapy was used in combination with PDGF or TGF-β1 and was found
to have a synergistic effect that completely reversed the healing issues caused by
ischemia [89].
. Scars
A scar refers to a growth of tissue marking the spot where skin has healed after
an injury. And while scars are used for body modification and ‘body art’ in some
cultures, most take it to be a sign of someone surviving a catastrophic event or a
debilitating disease [2, 3]. They are predominantly of two types:
Keloid scar:
lagen bundles in their midst and being limited in macrophage content but abundant
in eosinophils, mast cells, plasma cells and lymphocytes [90–92].
these are scars that have overgrown their boundaries with large col-
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Hypertrophic scar: Hypertrophic scars do not have collagen bundles, but nodules
of α-smooth muscle actin–staining myofibroblasts that contain cells and collagen [93].
. Treatment
While multiple treatments are promoted/suggested to minimise the development
of scars, none have been proven to be completely effective. Keloid scars especially are
difficult to treat because of their high recurrence rate.
Common scar-treatment modalities include:
Excision: While one of the more popular treatments, excision alone (especially in
the case of keloid scars) has been proven to have a high recurrence rate ranging from
45 to 93 percent.
However, when coupled with other treatment practices, excision has been known
to lower recurrence risk [90–92].
Laser excision: Lasers cause a range of specific thermal tissue reactions in a dry
and bloodless environment and was initially utilised in the hopes of reducing scar
formation, however they are not frequently used in the present date owing to their
high recurrence levels [94, 95].
Radiation Therapy: Radiations have been used in the eradication of this benign
lesion since the 1960s; however current concerns regarding the safety of patients due to increased risks of developing skin cancer; have limited the perpetuity of this
therapeutic modality [94].
Steroids: While steroids themselves are known to interfere with wound healing, they
are used in initial treatment of scars as they suppress the inflammatory stage [95, 96].
Cryo-surgery: Traditionally, cryotherapy have been used for managing hypertrophic scars and keloids, with pre-treatment and post-treatment histological analyses
indicating significant improvement in scar organisation after needle cryosurgery [93].
Interferon: IFN-α-2b normalises the collagen and glycosaminoglycan of the
keloid, thereby interfering with the fibroblasts collagen synthesis [97]. Complications
with IFN-α-2b include flu-like symptoms, headache, fever, and myalgias.
However, till date; prevention is the best keloid therapy.
. Problems with current strategies to reduce scarring
Current strategies for non-surgical therapy for the treatment of keloids and hypertrophic scars include topical therapy and intra-lesional injections of corticosteroids.
While literature has reported a success rate ranging between 50 to 100 percent; these
methods have also been associated with hypopigmentation, dermal atrophy, telangiectasia, widening of the scar, and delayed wound healing [98].
. Prospects being explored to promote scarless-wound healing
8.1.1 Dermal stem cells
While advances in genetic lineage-tracing technologies, cellular assays, and
imaging techniques have revealed important stem and progenitor cell reservoirs in the
inter- follicular epidermis, the eccrine sweat glands, and the hair follicle; given excisional wounds develop into areas lacking sweat and sebaceous glands as well as hair
Scarless Wound Healing
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follicles, further understanding of stem and progenitor cells would aide in achieving
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the ultimate goal of scarless wound healing following injury [99].
8.1.2 Interfollicular epidermis
During wound healing of the interfollicular epidermis, a population of ‘slow-
cycling cells’ is suspected to demonstrate autocrine regulation [100, 101] until mobilised by a wound healing signal. The cell division frequency of these slow-cycling
cells increases following a wound, which provides excess daughter cells that help in
repairing the damage. Further, injured epithelium has been known to demonstrate
behavioural plasticity with progenitors capable of reverting to multipotent states and
multipotent cells differentiating to fill unipotent roles, [102, 103]. Exploring these
avenues may eventually allow us to discover the hitherto undiscovered processes that
would allow regenerative wound healing with negligible scarring.
8.1.3 Sweat glands
Loss of sweat glands in burn patients remains an unsolved problem. However,
recent studies of these epidermal appendages have identified gland-specific progenitors, [104] and indicated the role of these cells in development, homeostasis, and
wound repair [104–107].
8.1.4 Hair follicles
Mammalian hair follicles are known to house numerous progenitor cell popula
tions that might play indispensable role in the repair of injured dermal tissue and
exploring them might give us ground breaking insight towards achieving scarless
wound healing [106, 108, 109].
. Future prospects for scarless wound healing
8.2.1 Gene targets
Genes involved in the scarring response that influence fibrosis by regulating
collagen production and degradation have been identified. If they can be safely
down-regulated by emerging medical techniques, they may provide the answer to the
mechanisms involved in the minimisation of scars [110].
8.2.2 Dermal substitutes
Wound coverage as well as a matrix to encourage engraftment and proliferation of
endogenous cells and the function of transplanted cells is provided by dermal substitutes. These are typically acellular in nature, but biocompatible and morphologically
similar to natural tissue structure with mechanical properties similar to host dermal
tissue [111].
8.2.3 Mechanical offloading
Another alternative to limiting fibrosis in cutaneous injuries is mechanical offload-
ing since mechanical tension plays a significant role in the development of fibrosis,
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activating numerous mechano-responsive signalling pathways such as the focal
adhesion kinase (FAK) [112, 113].
. Cellular targets for scarless wound healing
Identification of populations of cells contributing to scar formation allows us to
explore options that reduce these specific cell populations during wound healing,
thereby minimising scarification.
For instance, Dulauroy and team (2012) successfully distinguished a pro- inflammatory subset of perivascular cells that are activated upon acute injury in muscle and
dermis by transient expression of a disintegrin and metalloprotease (ADAM12) [114].
Knocking down ADAM12 expression or ablating these cells was shown to decrease
fibrosis and resulting scar formation.
This has been concordant with the findings of Rinkevich et al. [115] who found
that fibroblasts originating from En1-lineages were the main culprits in the cutaneous
scarring. These cells majorly contribute to scar formation in connective tissue.
Selective abrogation of the En1-fibroblast lineage with diprotin A by accompanying CD26 (also known as dipeptidyl peptidase-4, DPP4) surface marker has also been
found to reduce cutaneous scarring without compromising the integrity of the healed
tissue [115].
The ability of DPP4 inhibitors to curb the fibrogenic phenotypes of keloid-derived
fibroblasts and normal fibroblasts have been further verified through various in vivo
experiments. Observed decrease in collagen production and TGF-β1 expression have
also been found to be enabled by underlying mechanisms involving the pro-fibrotic
pp38 and pERK1/2 pathways [116].
Further, Myofibroblasts have been identified as the key players in the standard
wound healing response, as they contribute to wound contraction and ECM production [117], making them ideal targets for reducing scar formation [118]. However,
during the maturation phase of normal wound healing, the majority of these cells
undergo apoptosis [119]. Thus, reversal of the myofibroblast phenotype might also
help in decreasing this cell population [120, 121].
Unfortunately, like fibroblasts, myofibroblasts (or myofibroblast-like cells) also
form a functionally heterogeneous population with potential precursors including
fibroblasts, mesenchymal stem cells (MSCs), smooth muscle cells, endothelial cells,
and fibrocytes [122]. Although it is still being determined whether fibroblasts and
adipocytes share a common progenitor, Schmidt and Horsley [123] have demonstrated that dermal adipocytes are essential for fibroblast recruitment during wound
healing mechanisms. Experimental interventions with direct and indirect targeting at
both populations have been demonstrated to be responsible for scar formation.
Interestingly, Desai and his team [120] have found indications that the myofibroblast differentiation process is not terminal with basic fibroblast growth factor
(bFGF) functioning as a phenotypic reversing agent as it led to diminishing expression of α-Smooth Muscle Actin (SMA), collagen I, and fibronectin, and a loss of focal
adhesions and stress fibres being inversely co-related with tenascin-C and vimentin
upregulation, in agreement with a more fibroblast-like phenotype [120]. These findings are in tune Rinella et al. [124] work that indicate that extracorporeal shockwaves
(ESW), which cause myofibroblast precursors to differentiate into more fibroblastlike cells with lower contractility and higher migration potential, simultaneously
reducing α-SMA and type I collagen expression may play a significant role in scar
reduction.
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. Stem cells
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Stem cells are known to modulate the wound environment and improve healing by
reducing inflammation [125–127]. A recent study by Li et al. [128] has demonstrated
the potential benefits of conditioned media from umbilical cord (UC)-MSC cultures
wherein, dermal fibroblasts under the paracrine influence exhibit characteristics
similar to those of foetal fibroblasts: low myofibroblast forming capacity, decreased
TGF-β1/TGF-β3 ratio, as well as increased expression of enzymes (matrix metalloproteinases or MMPs) involved in ECM remodelling [128]. Other in vitro studies
have indicated that human amniotic-fluid-derived MSC-conditioned media also
has the potential to inhibit the pro-fibrotic actions of TGF-β1 and even reverse the
myofibroblast phenotype to a fibroblast-like state. Conditioned media from ASCs
produced similar results, but to a lesser extent [129]. However, this enhanced healing
mechanism may not always translate to reduced scar-formation as these experiments
do not have similar results when performed in vivo [130, 131]. Additionally, ethical,
legal as well as practical barriers associated with stem-cell- based therapies might
restrict their use in the exploration of scarless wound healing [132].
. Wnt and regeneration
Various signalling pathways, such as the canonical Wnt/
β-catenin have been implicated in the expression of foetal mouse keratinocytes and fibroblasts at embryonic
day (E)16 and E18 time points, straddling the transition from scarless to scar-forming
repair [117, 133]. While Wnt signalling is a key component of embryological development, it is also involved in various wound healing mechanisms with the canonical
Wnt pathway being the most relevant [134]. In this pathway, the Wnt-ligand binding
at the cell surface leads to cytoplasmic β-catenin accumulation, which subsequently
translocates to the nucleus to exert its effects as a transcriptional co-activator [135].
Additionally, a link between TGF-β
and the canonical Wnt/β-catenin pathway has
been observed in the case of fibrosis with analysis of pathological scars (hypertrophic
scars and keloids) revealing upregulated Wnt signalling secondary to TGF-β [136].
β-catenin levels have been shown to double during the proliferative phase in normal
wound healing (with scarring) as well [137]. Keloids in humans also display Wnt-3a
over-expression by inducing fibroblasts of endothelial origin to transition to mesenchymal cells that leads to collagen accumulation [138].
. MicroRNA
MicroRNA (miRNA) gene therapies are a more recent avenue for potential thera-
peutic interventions as these molecules exert an inhibitory role on mRNA transcription within eukaryotic cells, effectively silencing genes at a post- transcriptional level
[139]. Comparison of genome-wide miRNA expression between mid-gestational
(E16) and late-gestational (E19) mouse skin discovered global repression of these
molecules at the earlier time point where scarless healing is the norm [140]. miR-34
family have been established as potential candidates for scarless wound healing in
human foetal keratinocytes, however; expression of these miRNAs was found to be
significantly lower as gestation progressed [103].
Regenerative wound healing using miRNAs has been explored to reduce scarifica-
tion [141–143]. For instance, miR-145 has been found at three times its normal levels
in hypertrophic scars and pro-fibrotic TGF-β1-induced myofibroblasts. However,
Wound Healing - Recent Advances and Future Opportunities
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with the help of a commercial inhibitor of miR-145, Gras et al. (2015) were able to
significantly decrease type I collagen expression, TGF-β1 secretion, and contractility
in skin myofibroblasts [144].
Similarly, miRNAs have been combined with biomimetic scaffolds to enhance
wound healing, and furthering their clinical potential [145]. Future in vivo studies
will hopefully enumerate the clinical potential for other miRNA-based therapies.
. Conclusions
Our current understanding of wound healing and cell subpopulations within
the skin has allowed us to develop scar-reducing therapies, however, they are not as
effective as needed to make them the mainstay of available wound healing modalities.
While research regarding this elusive therapeutic modality is underway, successful scarless wound healing would require not only an understanding of signalling
molecules and growth factors but also a thorough understanding of lineage-specific
cellular origin and function during both foetal and adult stages.
Acknowledgements
I would sincerely like to thank Priya Ashrit and Dr. Shweta Sharma for their assistance and encouragement during the preparation of this chapter. I also acknowledge
the kind aid of Mr. Subhasis Bhattacharjee in the design of the images that have been
used in this chapter.
Conflict of interest
The author declares that there is no conflict of interest.
List of abbreviations/acronyms
ADAM a disintegrin and metalloprotease
ASC acellular stem cell (bioengineered cells)
ATP adenosine triphosphate
ECM extra-cellular matrix
ERK extra-cellular related kinase
ESW extracorporeal shockwaves
FAK focal adhesion kinase
FDA Food and Drug Administration (of the USA)
HIF hypoxia inducible factor
IFN interferon
IL interleukin
KGF keratinocyte growth factor
MCP monocyte chemo-attractant protein
MMPs matrix metalloproteinases
MSCs mesenchymal stem cells
PDGF platelet derived growth factor
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PF platelet factor
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SMA smooth muscle actin
TGF transforming growth factor
TNF tumour necrosis factor
bFGF basic fibroblast growth factor
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References
[1] Rodrigues AD, editor. Scarless Wound
Healing. Florida, United States: CRC
Press; 2000
[2] Covino DC. Amending the Abject
Body: Aesthetic Makeovers in Medicine
and Culture. Illustrated. Research
foundation for the State University of
New York: SUNY Press; 2012
[3] Beswick C, Coombs K. More Than
Skin Deep: Managing the Psychological
Impact of Scars. Scar Prevention and
Treatment; 2018
[4] Sanyal S, Law A, Law S. Chronic
pesticide exposure and consequential
keratectasia & corneal
neovascularisation. Experimental Eye
Research. 2017;:1-7
[5] Sanyal S, Law S. Chronic pesticide
exposure induced aberrant Notch
signalling along the visual pathway in a
murine model. Environmental Pollution.
2021;:117077
[6] Sanyal S, Law S. Ocular surface and
chronic pesticide exposure: Evaluating
the alterations in corneal cellular
turnover concerning cell cycle and
apoptosis. Experimental Eye Research.
2019;:122-132
[9] Broek LJ, Limandjaja GC, Niessen FB,
Gibbs S. Human hypertrophic and
keloid scar models: Principles,
limitations and future challenges
from a tissue engineering perspective.
Experiment in Dermatology.
2014;(6):382-386
[10] Broughton G, Janis JE, Attinger CE.
Wound healing: An overview. Plastic and
Reconstructive Surgery. 2006;:1-32
[11] Walmsley GG, Maan ZN, Wong VW,
Duscher D, Hu MS, Zielins ER, etal.
Scarless wound healing. Plastic
and Reconstructive Surgery.
2015;(3):907-917
[12] Witte MB, Barbul A. Role of nitric
oxide in wound repair. American Journal
of Surgery. Apr 2002;(4):406-412
[13] Wong VW, Rustad KC,
Akaishi S, Sorkin M, Glotzbach JP,
Januszyk M, et al. Focal adhesion kinase
links mechanical force to skin fibrosis
via inflammatory signaling. Nature
Medicine. 2012;(1):148-152
[14] Hof W, Veerman ECI, Nieuw
Amerongen A V., Ligtenberg AJM.
Antimicrobial defense systems in saliva.
2014;:40-51
[7] Sanyal S, Das P, Law S. Effect of
chronic pesticide exposure on murine
cornea: A histopathological, cytological
and flow cytometric approach to study
ocular damage by xenobiotics. Cell
Biology and Toxicology.
2016;(1):7-22
[8] El Ayadi A, Jay JW, Prasai A. Current
approaches targeting the wound healing
phases to attenuate fibrosis and scarring.
International Journal of Molecular
Science. 2020;(3):1105
[15] Longaker MT, Whitby DJ,
Ferguson MWJ, Lorenz HP,
Harrison MR, Adzick NS. Adult skin
wounds in the fetal environment heal
with scar formation. Annals of Surgery.
1994;(1):65-72
[16] Glim JE, Everts V, Niessen FB,
Ulrich MM, Beelen RHJ. Extracellular
matrix components of oral mucosa
differ from skin and resemble that of
foetal skin. Archives of Oral Biology.
2014;(10):1048-1055
Scarless Wound Healing
DOI: http://dx.doi.org/10.5772/105618
[17]
40
https://t.me/med1917
Ho S, Marçal H, John L, Foster R.
Towards Scarless Wound Healing: A
Comparison of Protein Expression
between Human, Adult and Foetal
Fibroblasts. 2014. Available from: http://
dx.doi.org/10.1155/2014/676493
[24] Whitby DJ, Longaker MT,
Harrison MR, Adzick NS, Ferguson MW.
Rapid epithelialisation of fetal wounds
is associated with the early deposition
of tenascin. Journal of Cell Science.
1991;(3):583-586
[18]
Siebert JW, Burd AR, McCarthy JG,
Weinzweig J, Ehrlich HP. Fetal wound
healing: A biochemical study of scarless
healing. Plastic and Reconstructive
Surgery. 1990;(4):495-504
[19]
Whitby DJ, Ferguson MWJ.
Immunohistochemical localization
of growth factors in fetal wound
healing. Developmental Biology.
1991;(1):207-215
[20]
Longaker MT, Scott Adzick N,
Hall JL, Stair SE, Crombleholme TM,
Duncan BW, et al. Studies in fetal
wound healing, VII. Fetal wound
healing may be modulated by hyaluronic
acid stimulating activity in amniotic
fluid. Journal of Pediatric Surgery.
1990;(4):430-433
[21]
Longaker MT, Harrison MR,
Crombleholme TM, Langer JC,
Decker M, Verrier ED, et al. Studies
in fetal wound healing: I. A factor in
fetal serum that stimulates deposition
of hyaluronic acid. Journal of Pediatric
Surgery. 1989;(8):789-792
[22]
Longaker MT, Whitby DJ,
Adzick NS, Crombleholme TM, Langer JC,
Duncan BW, et al. Studies in fetal wound
healing VI. Second and early third
trimester fetal wounds demonstrate
rapid collagen deposition without scar
formation. Journal of Pediatric Surgery.
1990;(1):63-69
[23]
Bruce A, Diegelmann RF,
Krummel TM, Cohen K. scarless
wound healing in the mammalian fetus.
Surgery, Gynecology & Obstetrics.
1992;:441-450
[25] Luomanen M, Virtanen I.
Distribution of tenascin in healing
incision, excision and laser wounds.
Journal of Oral Pathology & Medicine.
1993;(1):41-45
[26] Senel O, Cetinkale O, Ozbay G,
Ahçioğlu F, Bulan R. Oxygen free radicals
impair wound healing in ischemic
rat skin. Annals of Plastic Surgery.
1997;(5):516-523
[27] Steinbrech DS, Longaker MT,
Mehrara BJ, Saadeh PB, Chin GS,
Gerrets RP, et al. Fibroblast response
to hypoxia: The relationship between
angiogenesis and matrix regulation.
The Journal of Surgical Research.
1999;(2):127-133
[28] Kadota Y, Nishida K, Hashizume K,
Nasu Y, Nakahara R, Kanazawa T, et al.
Risk factors for surgical site infection and
delayed wound healing after orthopedic
surgery in rheumatoid arthritis patients.
Modern Rheumatology. 2016;(1):68-74
[29] Robson MC. Wound infection: A
failure of wound healing caused by an
imbalance of bacteria. The Surgical Clinics
of North America. 1997;(3):637-650
[30] Bang RL, Gang RK, Sanyal SC,
Mokaddas EM, Lari AR. Beta-haemolytic
Streptococcus infection in burns. Burns.
1999;(3):242-246
[31] Riou J-PA, Cohen JR, Johnson H.
Factors influencing wound dehiscence.
American Journal of Surgery.
1992;(3):324-330
[32] Lingen MW, M. Role of leukocytes
and endothelial cells in the development
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