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Topic: Current Concepts in Wound Healing

Current concepts in the physiology of adult


wound healing
Friji Meethale Thiruvoth, Devi Prasad Mohapatra, Dinesh Kumar Sivakumar,
Ravi Kumar Chittoria, Vijayaraghavan Nandhagopal
Department of Plastic Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India.
Address for correspondence: Dr.Friji Meethale Thiruvoth, Department of Plastic Surgery, Jawaharlal Institute of Postgraduate Medical
Education and Research, Puducherry 605006, India. Email:frijimt@gmail.com

ABSTRACT
Wound healing requires a complex interaction and coordination of different cells and molecules. Any
alteration in these highly coordinated events can lead to either delayed or excessive healing. This
review provides an overview of adult wound healing physiology. Areview of the literature focused
on wound healing physiology and current advances in wound healing was conducted using the online
MEDLINE/PubMed database. The aim of this review was to inspire further investigation into wound
healing physiology that will ultimately translate into improved patient care.

Key words:
Cytokine, growth factor, inflammation, wound healing

INTRODUCTION collagen remodeling begins, along with vascular maturity


and regression; this process typically lasts 624months
Wound healing without complications is critical to the from the time of injury[1] [Figure 1].
survival, as it restores the integrity of the skin and protects The wound healing cascade may be arrested in
the individual from infection and dehydration. Adult wound any of these phases, leading to the formation of a
healing involves a wellorchestrated series of events leading chronic nonhealing wound. Many mediators including
to the repair of injured tissues, resulting in scar formation. inflammatory cells, growth factors, proteases such as
Healing of acute wounds, triggered by tissue injury, matrix metalloproteinases (MMPs) and cellular and
consists of overlapping and highly coordinated phases of extracellular elements play important roles in the process
hemostasis, inflammation, proliferation and remodeling. of wound healing. Alterations in one or more of these
When a breach of the skins integrity occurs, hemostasis components may lead to the impaired healing.[2] Wound
is initiated by platelets through fibrin clot formation. healing can also be negatively influenced by many
Platelets also release various mediators of wound healing exogenous factors, including concurrent diseases, such as
to attract macrophages and fibroblasts to the site of diabetes, renal failure, malnutrition, smoking, radiation
tissue injury.[1] The inflammatory phase begins with the exposure, infection and an immunocompromised state.
arrival of neutrophils followed later by macrophages and In the presence of these factors, wounds can fail to heal
lymphocytes at the wound site. The proliferative phase is adequately, resulting in chronic wound formation.[3] The
characterized by new blood vessel formation(angiogenesis), wound healing process can occasionally go into overdrive,
synthesis of extracellular matrix(ECM) components and
reepithelialization.[2] Following the proliferative phase, This is an open access article distributed under the terms of the Creative Commons
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How to cite this article: Thiruvoth FM, Mohapatra DP, Sivakumar DK,
Chittoria RK, Nandhagopal V. Current concepts in the physiology of
DOI:
10.4103/2347-9264.158851 adult wound healing. Plast Aesthet Res 2015;2:250-6.
Received: 12-01-2015; Accepted: 27-02-2015

250 2015 Plastic and Aesthetic Research | Published by Wolters Kluwer - Medknow
Figure1: Distinct and overlapping phases of wound healing

resulting in excessive healing and the formation of released by platelets after injury. Thrombin, released by
fibroproliferative scarlike keloids and hypertrophic scars.[4] platelets at the wound site, is an early mediator of clot
This review provides a general overview of the physiology development.[8] Thrombin also induces the release of
of adult wound healing, focusing specifically on how proinflammatory cytokines like CCL2, interleukin6(IL6)
recent advances could translate into improved clinical and IL8 by endothelial cells. These cytokines induce
outcomes. monocyte chemotaxis.[9] Of the injury response chemokines,
chemokine(CXC motif) ligand 4(CXCL4) participates
HEMOSTASIS in the coagulation process and prevents the premature
development of blood vessels.[10] The degradation of fibrin
Acute wounds cause vascular injury and bleeding from and subsequent activation of the complement system play
the wound, and the immediate priority is to prevent a crucial role in mounting the inflammatory process, as
blood loss by vasoconstriction and formation of a blood well as in facilitating wound angiogenesis and stromal
clot to seal the vessel. Hemostasis is initiated by the cell proliferation. Fibrin binds to integrin CD11b/CD18
exposure of blood components to the subendothelial on infiltrating monocytes and neutrophils. It also binds
layers of the vessel wall. Platelets adhere, aggregate to fibroblast growth factor2(FGF2) and VEGF that help
and form the initial hemostatic plug. The coagulation the wound tissue vascularize. In addition, fibrin binds to
and complement cascades are then initiated. Within the insulinlike growth factor1(IGF1) and promotes stromal
tissue, prothrombin is activated to form thrombin, which cell proliferation.[5,11,12] Under thrombocytopenic conditions,
then cleaves fibrinogen to generate fibrin. Along with macrophages and T cells at the wound site compensate
platelets and the plasma fibronectin, fibrin forms the clot. for the lack of PDGFs and initiation of the inflammatory
The blood clot is made up primarily of crosslinked phase.[13]
fibrin, cells such as erythrocytes and platelets, as well
as other ECM proteins such as fibronectin, vitronectin INFLAMMATION
and thrombospondin.[5] In addition to containment
of blood loss, the blood clot serves as a first defense The inflammatory process involves the recruitment
against microbial invasion and a provisional matrix for of neutrophils, macrophages, and lymphocytes. After
the homing of inflammatory cells.[5] The adhesiveness hemostasis, local vessels dilate secondarily to the effects
of platelets is mediated by activated integrin receptors of the coagulation and complement cascades. Bradykinin
on their surface.[6,7] The platelets in the clot undergo (generated by the coagulation cascade) and C3a and C5a
degranulation, releasing potent chemoattractants for anaphylatoxins (generated by the complement cascade)
inflammatory cells, activation factors for local fibroblasts and increase blood vessel permeability and attract neutrophils
endothelial cells and vasoconstrictors, such as chemokine and monocytes to the wound.[14] The C3a and C5a
(CC motif) ligand 5 (CCL5), thrombin, transforming growth anaphylatoxins also stimulate the release of histamine and
factorb (TGFb), plateletderived growth factor (PDGF) leukotrienes from mast cells. The local endothelial cells
and vascular endothelial growth factor (VEGF).[5] CCL5 then break celltocell contact and increase permeability,
is one of the most potent monocyte chemoattractants enhancing the margination of inflammatory cells at the

Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015 251


wound site.[15] The initial population of white blood cells elicited by injury are only helpful to the healing process if
in the wound is composed of neutrophils. Thrombin they are timely and transient. However, the inflammation
and IL8 stimulate endothelial permeability through is not essential for skin wound healing. Martin et al.[34] has
the modulations of adherensjunction endothelial cell shown that the PU.1 null mouse, which is devoid of both
adhesion and cell contraction, thereby facilitating macrophages and neutrophils, healed both incisional and
leukocyte exit from the circulation.[16,17] Within the excisional wounds at statistically similar rates to wildtype
wound, neutrophils employ various strategies to kill littermates, but without scar formation. The cytokine and
bacteria and decontaminate the wound, including the growthfactor profiles at the wound site in the PU.1 null
secretion of proteases and antimicrobial peptides, as well mouse differed from those of the wildtype. As a result, cell
as the generation of reactive oxygen intermediates via death was reduced, and scar formation did not occur.[34]
the respiratory burst.[18] In the absence of inflammatory Studies have focused on platelets and mast cells as targets,
mediators, neutrophils will undergo spontaneous and have shown that neither of these mediators is essential
apoptosis. The apoptosis is mediated by cathepsin D to effective wound repair. This further suggests that a
release from neutrophil granules, which then facilitates dampened or modified inflammatory response could reduce
the cleavage and activation of caspase 8, ultimately scar formation.[13,35] Impairment of macrophage function
resulting in caspase 3 activation, DNA fragmentation and at the wound site derails the resolution of inflammation.
apoptosis.[19] In the absence of neutrophils, wound site A persistent inflammatory state of diabetic wound
macrophages lack guidance in conducting the healing macrophages is caused by impairment in the ability of these
process.[20] Although neutrophils play a role in decreasing cells to phagocytose apoptotic cells at the wound site, in
infection during wound healing, their absence does not turn preventing the switch from M1 to M2 phenotype.[36]
prevent the overall progress of wound healing.[21] However, Prolonged inflammation may not only compromise wound
their prolonged presence in the wound may be a factor in closure but may also worsen scar outcomes.[37,38] Lipid
the conversion of acute wounds into nonhealing chronic mediators, such as the lipoxins, resolvins, protectins and
wounds. maresins, have emerged as a novel genus of potent and
Within two to three days, monocytes become the stereoselective players that counter regulate excessive
predominant inflammatory cell population in the wound. acute inflammation and stimulate molecular and cellular
Monocyte chemotaxis to the wound occurs via CC events that define resolution.[39] The production and
chemokines like CCL2. The chemokines can be released activity of several proteases including metalloproteinase,
by neutrophils, by the monocytes themselves and by serine proteases and neutrophil elastases which are tightly
keratinocytes at different stages of healing.[2224] Circulating regulated in acute wound healing may be altered in
monocytes and mast cells are attracted to and infiltrate the chronic wounds.[1] For example, non-healing human wound
wound site.[1,25] Within the wound, monocytes differentiate fluid and tissue have increased protease activity, which
into macrophages. Macrophages in turn remove rapidly degrades exogenously applied peptide growth
apoptotic neutrophils and other dead cells, function as factors.[40,41] Products targeting excessive protease activity
antigenpresenting cells, and secrete cytokines and multiple such as proteasescavenging matrices(e.g.Promogran),
peptide growth factors.[10] Phagocytosis of the apoptotic selective inhibitors or specific antibodies may be useful in
neutrophils by macrophages then leads to removal of the treatment of chronic wounds refractory to conventional
chemokines from the area of inflammation, preventing treatments.[42,43]
further leukocyte influx.[10] Several cytokines and growth The lymphocytes are the last type of leukocytes to arrive
factors are known to be secreted by macrophages.[26] Such at the wound site. The lymphocytes exert a specific
growth factors include TGF, TGF, basic FGF(bFGF), response against microbes and other foreign material
VEGF and PDGF. These growth factors activate and attract in the wound: Blymphocytes via antibodies and the
local endothelial cells, fibroblasts and keratinocytes, and Tlymphocytes through production of cytokines and
enable wound healing by causing cell proliferation and stimulation of cytolytic activity. Lymphocyteinduced
synthesis of ECM and inducing angiogenesis VEGF,[2730] inflammation is then resolved by apoptosis when
which stimulates angiogenesis, also stimulates the interferon (IFN)-c and TNF are produced at the wound
macrophages to express LIGHT, a member of the tumor site.[10] Mast cells also appear during the later part of the
necrosis factor alpha(TNF) family of cytokines, which inflammatory phase, but their function remains unclear.
binds to lymphotoxin receptor and induces macrophage Impaired wound healing has been reported in mast
death.[31] celldeficient mice.[44] Mast cells have also been implicated
Macrophages play a crucial role in enabling wound healing. in skin wound fibrosis.[45,46] Recently, the role of mast cells
Macrophage depletion is known to markedly impair wound in wound healing has become an area of intense research
closure.[27,32] In a landmark study, Leibovich and Ross[33] because of a correlation between mast cells and both
demonstrated that the antimacrophage serum combined keloids and hypertrophic scars.[45,46]
with hydrocortisone diminished the accumulation of
macrophages in healing skin wounds of adult guinea pigs. PROLIFERATION PHASE
Such depletion resulted in impaired disposal of damaged
tissue and provisional matrix, compromised fibroblast The proliferative phase of wound healing is accepted to
count, and delayed healing. Inflammatory responses start around twodays after injury and typically lasts up

252 Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015


to three weeks in a healing cutaneous wound. This phase PDGF, TNF, FGF, keratinocyte growth factor and CXCL8
overlaps with the inflammatory phase, beginning with produced by neutrophils, macrophages, endothelial
the degradation of the initial fibrinplatelet matrix and cells and fibroblasts, maintain the proliferation and
invasion of fibroblasts and endothelial cells. Proteases migration of keratinocytes which in turn induces wound
of the serine, cysteine and MMP families are secreted reepithelialization.[22,6466] During reepithelialization, the
to facilitate cellular migration through the fibrin clot keratinocytes migrate beneath the provisional ECM.
and provisional matrix.[4750] The major events of this MMP release keratinocytes from their substratum and
phase include the influx of fibroblasts, ECM deposition, help in the migration through the matrix and promotion
formation of new blood vessels and reepithelialization. of reepithelialization.[6769] Wound treatment with a
broadspectrum metalloproteinase inhibitor significantly
Fibroblasts are the key type of cells in this phase of
delays reepithelialization invitro and in vivo.[70,71] Wound
healing and become the predominant cell type by three to
reepithelialization also requires the activity of various
five days after injury. Macrophages and mast cells release
proteases, including the serine protease plasmin.
growth factors, including PDGF and TGF, that stimulate
Reepithelialization is delayed in plasminogendeficient
fibroblast activation.[25] The fibroblasts proliferate and
mice, due to the inability of keratinocytes to degrade and
produce the matrix proteins fibronectin, hyaluronic
thus migrate through the fibrin matrix and the underlying
acid, collagen and proteoglycans, all of which help to
dermal tissue, whereas mice deficient in both plasminogen
construct the new ECM and a platform for keratinocyte
and fibrinogen exhibit more normal healing.[72,73] After the
migration.[1,14] The provisional fibrin matrix is gradually
reestablishment of the epithelial layer, keratinocytes and
replaced by granulation tissue.
fibroblasts secrete typeIV collagen to form the basement
Granulation tissue is a dense conglomeration of blood membrane.[74] The keratinocytes undergo division and
vessels, macrophages and fibroblasts embedded within a become columnar to restore the epidermal layer and
loose matrix of fibronectin, hyaluronic acid and collagen. reform a barrier to infection and moisture loss.
Granulation tissue begins to appear in human wounds
The dysregulation of the proliferative phase is believed
by about four days after injury. During granulation
to underlie the pathophysiology of chronic wound and
tissue formation, new blood vessels develop from
fibrotic disorders such as hypertrophic scarring and
preexisting vessels (angiogenesis). Angiogenic factors are
keloids. Arandomized controlled trial in patients with
secreted by fibroblasts and macrophages (e.g. VEGF, basic
diabetic neuropathic foot ulcers showed topical PDGF to
FGF, angiopoietin1 and thrombospondin), keratinocytes
be superior to placebo in promoting healing.[75] VEGF gene
(e.g. CXCL8 and VEGF) and endothelial cells themselves
transfer was effective in increasing vascularity in ischemic
(e.g. CXCL8 and VEGF).[5154] Integrin av3 at the leading
leg ulcers.[76] Among cytokines and growth factors, the
capillary tipis a prerequisite for endothelial growth, and
possible targets for promotion of wound healing include
is a promising therapeutic target for angiogenesis.[55]
TNF, PDGF, FGF, VEGF, IGF1 and EGF.[7780] Understanding
Blocking these processes with angiogenesis inhibitors
the signals for halting the proliferative phase will help
impairs wound healing and can be corrected with growth developing new therapeutics for acute wound healing.[51]
factors such as VEGF.[51] Over time, the fibrin provisional
matrix is replaced with typeIII collagen, which in turn
is replaced by the typeI collagen during the remodeling
REMODELING PHASE
phase. At least twenty-eight different types of collagen
The remodeling of wound tissue occurs over a prolonged
are currently known.[56] Most collagen types in the ECM
time and may last up to 1 year.[51] It involves ECM
are synthesized by fibroblasts, however, some types are
turnover coupled with a significant decrease in cellularity.
synthesized by keratinocytes.[57]
The decline in cellularity results from the apoptosis of
Approximately four days after injury, myofibroblasts residual inflammatory cells and myofibroblasts as well as
appear in the wound.[58] TGF and CXCL8 promote the regression of the neovasculature.[59] In humans, remodeling
differentiation of fibroblasts in the granulation tissue into is characterized by both wound contraction and collagen
myofibroblasts.[48,59,60] Myofibroblast differentiation also remodeling. The balance of collagen metabolism is in
requires an interaction with cellular fibronectin containing the part determined by the regulation of MMP activity.[81]
extra domain-A domain. Inhibition of either fibronectin or the The process of wound contraction is produced by wound
corresponding integrin receptors prevents TGF1mediated myofibroblasts. While remodeling, wounds gradually
myofibroblast differentiation.[61,62] Myofibroblasts exert their become stronger with time. Wound tensile strength
contractile forces by focal adhesion contacts that link the increases rapidly from 1 to 8weeks after wounding and
intracellular cytoskeleton to the ECM. In vitro experiments correlates with collagen crosslinking by lysyl oxidase.[82]
have shown higher contractile forces of keratinocytes The tensile strength of wounded skin reaches at best only
compared with fibroblasts.[63] approximately 80% that of unwounded skin, but can be
increased by synthetic MMP inhibitors.[83,84] Scar formation
Reepithelialization is an important process during wound
is the final outcome of wound repair in children and adults.
healing that starts in the early phase of healing. Platelets
in the early wound release epidermal growth factor (EGF) New therapeutic strategies can be tried to reduce an
and TGF stimulate the keratinocytes at the wound edge esthetically unacceptable scar appearance. Treatment
to proliferate and migrate to cover the wound. Cytokines with TGF3 formulations and neutralizing antibodies

Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015 253


to TGF as well as solutions that decrease the activity availability and fewer ethical issues, adult stem cells are
of connexin 43, a mediator of TGF signaling, has been the most commonly used type of stem cells in medical
shown to reduce the inflammatory response and scar practice.
formation.[85,86] Evidence of success using TGFrelated Mesenchymal stem cells are derived from bone marrow,
strategies was provided by a study showing that adipose tissue, umbilical cord, periosteum, tendons,
the exogenous addition to wounds of fibromodulin, muscle and skin.[96] The most commonly used source
a TGF modulator, reduces scar.[87] Decorin is a small is adipose tissue. Stem cells affect all stages of wound
chondroitin/dermatan sulfate proteoglycan that limits the healing. They have significant antiinflammatory and
duration of TGF influence on inflammation and tissue immunomodulatory effects in the inflammation phase of
repair, promoting regenerative repair and limiting tissue healing.[97] In the proliferative phase, they also stimulate
fibrosis.[88] Other novel strategies include the application fibroblasts, keratinocytes and endothelial cells, thereby
of antifibrotic human recombinant growth factors accelerating wound closure. Uysal et al.[98] demonstrated
and cytokines, antiinflammatory substances, protease that wound healing time was reduced in rats treated
inhibitors and molecules that interfere with profibrotic by patchy skin grafts and mesenchymal stem cells. In
cytokine function (e.g. TGF) and collagen synthesis at addition, wound contraction was reduced, angiogenesis
the wound site.[89] was increased, epithelialization progressed rapidly.[99]
Stem cell therapy can be administered either topically
FETAL WOUND HEALING
or systemically. Falanga et al.[100] demonstrated a topical
application of mesenchymal stem cells with either
Fetal wound healing is an area of great interest because it
fibrinogen or thrombin applied to chronic wounds in the
is characterized by scarless, regenerative wound healing.
form of a spray. This spray is converted into a gel form
This process is agedependent, like postnatal healing,
over the wound and helps in retaining the stem cells
wounds in thirdtrimester cause scarring.[90] The exact
over the wound.[100] To improve the retention of stem
mechanism responsible for scarless healing in the first
cells in the wound, cells are now applied on an adequate
and second trimesters is not yet clearly understood. The support/scaffoldlike collagen, skin substitutes. This helps
proposed mechanisms include decreased inflammation, in maintaining the viability of the cells and facilitates
unique properties of fetal cells, altered cytokine milieu, migration in the wound bed.[101]
variable gene expression and ECM deposition.[91] Recent
fields of research revolve around the role of TGF, IL10 and
CONCLUSION
mast cells. King etal.[92] described a major role for IL10 in
scarless wound healing. The authors propose a cytokine
Cutaneous wound healing is a complex and dynamic
hypothesis centered on the antiinflammatory properties
biological process requiring the interaction and
of IL10. IL10 protects against excess deposition of coordination of many different cell types and molecules,
collagen, maintains elevated hyaluronic levels, enhances including growth factors and cytokines. Tremendous
fibroblast function, prevents differentiation of fibroblast strides have been made in delineating the myriad of
to myofibroblasts and increases survival of endothelial factors involved in normal and delayed/excessive healing.
progenitor cells and angiogenesis.[92] Research in a mouse However, this increased understanding has not led to
model demonstrated the scarring potential of mast cells in significant advances in patient care. Administration of
fetal wounds. In early fetal life(day 15), scarless wounds exogenous growth factors and cytokines has shown
were associated with a lesser number of mast cells with promise in improving healing results in wounds. As wound
reduced degranulation as compared to later scarring healing involves multiple molecular mechanisms, no single
wounds.[93] Another factor implicated in fetal wound agent therapy is likely to be successful in accelerating or
healing is the growth factor TGF. Of the three isoforms, modulating wound healing.
TGF1 is responsible for fibrosis. TGF3 isoform is the
predominant isotype in fetal wound healing, and altered Financial support and sponsorship
profiling of the isoform may be a factor responsible for Nil.
scarless healing. Other additional mechanisms include Conflicts of interest
mediators of TGF pathway such as connective tissue There are no conflicts of interest.
growth factor, proteoglycan, decorin and P311.[94]
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