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Vocal Fold Wound Healing: A Review for Clinicians

*Ryan C. Branski, k{Katherine Verdolini, k{Vlad Sandulache,
{Clark A. Rosen, and k{#Patricia A. Hebda
*New York, New York, and k{#Pittsburgh, Pennsylvania

Summary: The basic science of wound healing is largely omitted from the
curriculum of many voice clinicians. This fact is relatively disheartening as
most therapeutic manipulation in the realm of laryngology and voice disorders deals with injured tissue. Therefore, the selection of therapeutic tasks
for persons with vocal injury should ideally be informed by basic science
in wound healing. Recently, several investigators have initiated lines of research to determine the course of vocal fold wound healing and the potential
role of therapeutic agents, including behavioral agents. The current review
seeks to provide a foundation of basic wound healing science and present
the most current data regarding the wound healing process in the vocal folds.
Key Words: InjuryReviewVocal foldWound healing.

the population has some type of voice dysfunction

at any given point in time.1 Although the precise
etiologic factors causing these problems remain relatively unknown, a likely cause is the response to
injurious stimuli in a preponderance of cases. Injuries to the vocal folds, including phonotrauma as
well as mechanical and chemical trauma, often result in changes to the lamina propria, benign vocal
fold lesions, or vocal fold scar. This speculation is
consistent with results from a recent study suggesting that approximately 22% of patients seeking
treatment for voice disorders present with organic
vocal fold lesions, resulting in dysphonia.2 Although vocal fold trauma cannot be implicated in
all cases, there is a high likelihood that the primary
etiology of these lesions is the inherent response to
some sort of injury.
In these cases, the goal of therapy via surgery or
behavioral voice treatment must focus on (1) ceasing
the injurious activity and (2) modulating wound
healing or managing tissue that has undergone reparative processes. The goal of treatment, therefore, is
restoration of the biomechanical function of the

INTRODUCTION
Voice disorders seem to be the most common
communication disorder across the lifespan. Estimates indicate that anywhere from 3% to 9% of
Accepted for publication August 10, 2005.
From the *Department of Head and Neck Surgery, Memorial
Sloan-Kettering Cancer Center, New York, New York;
Department of Communication Science and Disorders, University of Pittsburgh, Pittsburgh, Pennsylvania; Department
of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania; University of Pittsburgh Voice Center, University of
Pittsburgh, Pittsburgh, Pennsylvania; kOtolaryngology Wound
Healing Laboratory, Department of Pediatric Otolaryngology,
Childrens Hospital of Pittsburgh, Pittsburgh, Pennsylvania;
{McGowan Institute for Regenerative Medicine, University
of Pittsburgh, Pittsburgh, Pennsylvania; and the #Department
of Cell Biology and Physiology, University of Pittsburgh,
Pittsburgh, Pennsylvania.
Address correspondence and reprint requests to Ryan C.
Branski, PhD, Head and Neck Surgery, Memorial SloanKettering Cancer Center, New York, New York 10021.
E-mail: branskir@mskcc.org
Journal of Voice, Vol. -, No. -, pp. 0892-1997/$30.00
2005 The Voice Foundation
doi:10.1016/j.jvoice.2005.08.005

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RYAN C. BRANSKI ET AL

tissue. Therefore, treatment should be founded in the

science of wound healing. However, discussion of
wound healing is typically omitted from curricula
of voice care clinicians. The current review seeks
to present up-to-date information regarding the general tenets of wound healing as well as emerging literature regarding wound healing in the vocal folds.

WOUND HEALING: AN OVERVIEW

Wound healing is a dynamic, interactive process
involving cells and extracellular matrix. The wound
healing cascade, when uninterrupted, is typically
organized temporally into three major, overlapping
phases: inflammation, extracellular matrix (ECM)
deposition and epithelialization, and remodeling.3
Although a gross oversimplification of the wound
healing process, these phases serve as a basic
framework for discussion.
Disruptions in the normal wound healing sequence can produce less-than-desirable outcomes.
In cases of impaired wound healing, reestablishment of tissue structure and function is diminished.
Excessive and/or prolonged inflammation subsequent to tissue injury has been shown to result in
extended tissue damage in conditions such as osteoarthritis. Systemic conditions such as diabetes,
Cushings syndrome, malnutrition, and sepsis can
also disrupt the normal healing process and lead
to nonhealing wounds or, at the other end of the
spectrum, excessive fibrosis.3
Inflammation
Injury causes blood vessel disruption leading to
leakage of blood into the wound area. Immediately
after injury, the inflammatory response is critical
for (1) stopping blood flow at the site of the wound,
(2) filling tissue deficits, (3) providing a provisional
matrix for subsequent cell migration into the wound
bed, (4) sterilization of the wound bed, and (5) signaling other cells to come to the wound region and
rebuild the ECM. A fibrin-rich clot plugs damaged
vessels, fills tissue deficits, and serves as a provisional matrix for subsequent cellular invasion.4 Inflammatory cells such as macrophages and
neutrophils disinfect the wound site by enzymatic
clearance of contaminants. Such cells also
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stimulate reepithelization of the wound and encourage replacement of the extracellular matrix.5
ECM deposition
As inflammation subsides, emphasis is switched
to fibroblast and epithelial cell infiltration of the
wound bed and reconstitution of the ECM (deposition of fibronectin and collagen). Fibroblasts migrate into the wound area between 48 and 72
hours after injury.6 Fibroblasts are responsible for
secreting new matrix materials such as collagen
and hyaluronic acid in response to injury. Fibroblast
activity in the wound bed leads to granulation tissue
formation in dermal wounds, approximately 4 days
after injury. Granulation tissue has high myofibroblast density, a transitional cell type with properties
of both fibroblasts and smooth muscle cells. Myofibroblasts are responsible for wound contraction.
Contraction is required to maintain tissue continuity,
to reduce the size of the wound, and to facilitate scar
production.7 Upon epithelialization (to be described
in the next section), granulation tissue resolves.
The end product of fibroblast activity is an approximation of the preinjury tissue structure and
function. However, although most ECM components are present, they are poorly organized. During
wound healing, fibroblasts produce large amounts
of collagen and elastin.8 Glycosaminoglycans and
proteoglycans are also produced.9 Glycosaminoglycans are large space-filling molecules found in the
ECM of many organs including the skin and vocal
folds. The specific signals responsible for glycosaminoglycan and proteoglycan production are relatively unknown. However, insight into the stimulus
for proteoglycan production, for example, might
prove to be useful in antifibrotic therapy.
Under certain conditions, wound healing continues unabated with excessive scar formation, resulting in dermal pathologies such as hypertrophic
scars and keloids.10 Both are characterized by an
increased inflammatory response and ECM production11 as well as an abnormal fibroblast
function.12,13
Epithelialization
One major goal of wound healing is reconstitution of the epithelium as a functional barrier. Clinically, a wound is reepithelialized when a

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VOCAL FOLD WOUND HEALING

water-impermeable seal is present at the site of the
wound.5 In dermal wound healing, epithelial cell
migration into the site of injury after stimulation
by growth factors14,15 begins 24 to 48 hours after
the injury occurs.16
Tissue remodeling
Wound healing and tissue repair continue long
after a functional epidermal barrier has been restored. These events are collectively referred to as
the remodeling phase of wound healing and refer
to the deposition and reorganization of matrix components over time. Scar remodeling is typically
thought to be the final stage of the wound healing
cascade. Early scar, between 1 to 3 months after
injury, is thick and stiff. In contrast, a more mature
scar is typically more thin and pliable. This observation has significant implications for tissue elasticity. The pronounced differences between immature
and mature scar are thought to be due, at least in
part, to the reorganization of collagen fibers along
lines of stress as well as to changes in proteoglycan
content.17 Collagen content has been found to
become relatively stable approximately 21 days
after injury. However, both collagen deposition
and remodeling are dynamic processes17,18 and
are thought to continue up to 12 months after injury
demonstrating increased degradation and deposition organized along lines of stress.17
VOCAL FOLD WOUND HEALING
The vocal folds, unlike most structures in the
body, are subjected to nearly continuous mechanical stresses due to phonation for many waking
hours daily. Given this mechanically stressful state,
it is surprising that the vocal folds are not structurally and physiologically compromised more often.
There are two possible explanations for this apparent resistance to mechanical stress. First, the vocal
folds may have an enhanced reparative capacity, by
which any microstructural damage to the lamina
propria and overlying epithelium can be repaired
without a full-scale wound healing response. Second, the microstructure of the vocal fold lamina
propria may be organized to accommodate more
mechanical stress than a tissue such as dermis. It
is likely that both hypotheses are correct given

the microstructural elements present in the vocal

folds that might explain increased vocal fold accommodation of mechanical stresses. In addition,
if vocal folds can accommodate some level of continuous mechanical stress, it stands to reason that
a threshold would exist, past which a full-scale
wound healing response is required for tissue
repair. The current review categorizes vocal fold
injury into four types based on the source and chronicity of the injury: acute phonotrauma, chronic
phonotrauma, nonphonatory mechanical injury,
and chemical injury.
Acute phonotrauma
It is speculated that acute phonotraumatic injury
not only disrupts the vascular network, but it also
causes damage to the basement membrane zone
and ECM. Clinically, acute phonotrauma manifests
as edema of the vocal folds or laryngitis. Many patients may present with focal regions of inflammation at the midpoint of the musculomembranous
vocal folds. This site is the region of greatest
impact stress and the most common site of mass
lesions associated with continued phonotrauma.19
Frequently, edema associated with phonotrauma
likely resolves without specific intervention, and
voice quality improves.
Description of the magnitude and temporal pattern of the acute inflammatory process in the vocal
folds may help elucidate the subsequent pathological events resulting in long-term vocal fold damage.
Recent studies have described the acute inflammatory response in the vocal folds by measuring levels
of inflammatory mediators. Marked shifts in IL-1b,
TNF-a, and matrix metalloproteinase-8 levels in secretions collected from the surface of the vocal
folds have been reported after an episode of acute
phonotrauma.20 These data may prove useful for
future investigations into the acute wound healing
response in the vocal folds.
Chronic phonotrauma
Multiple episodes of acute phonotrauma can result in long-standing tissue damage. Although often
termed chronic phonotrauma, these episodes likely
encompass recurrent acute phonotraumatic (RAP)
events. The result is a relatively permanent state
of tissue repair or scarring, which may manifest
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as a benign vocal fold lesion(s) and/or vocal fold

scar. It is also likely that there is a continuum of responses associated with RAP whereby focal edema
gives way to mass lesions and, finally, vocal fold
scar based on the chronicity of injury. Mass lesions
of the vocal folds are poorly defined. No standardized nomenclature system exists to facilitate both
scholarly and clinical communication regarding
voice disorders.21 One particular lesion, a fibrous
mass, has not yet been described in the literature,
but it has gained clinical popularity. Although the
histology of this lesion has not been characterized,
clinically it is referred to as a unilateral lesion of
the midpoint of the musculomembranous vocal
folds.22 Entire volumes could be dedicated to the
description and nomenclature of benign mass
lesions of the vocal folds.
A vocal fold scar should not be thought of in
terms of more commonly encountered dermal or
mucosal scars. Although the dermis and airway mucosa are relatively static structures, the vocal folds
are subjected to continuous mechanical stress. As
a result, the process of vocal fold scar formation
is likely different from that encountered in other
tissues. In addition, a continuum of vocal fold scar
exists ranging from focal to diffuse and exophitic to
endophitic (sulcus vocalis).
Three general types of long-standing vocal fold
structural abnormalities have been described:
nodules, polyps, and cysts. The extent to which
each of these pathologies is truly a scar is yet
unclear.21 Furthermore, the lack of standardized
nomenclature for organic vocal fold lesions
presents a challenge to describing these entities
consistently in the literature.21
Vocal fold nodules are the most commonly diagnosed lesions of the vocal folds and are thought to
be a consequence of repetitive of vocal trauma.
Nodules are a disruption of the basement membrane zone with separation of the epithelium from
the underlying extracellular matrix.23 Kotby et al24
described vocal fold nodules as having intercellular
junction gaps, disruption and duplication of the
basement membrane zone, and focal collagen deposition. Increased levels of fibronectin have also
been identified at sites of nodular lesions.25 It has
been hypothesized that the disruption of the basement membrane zone associated with vocal fold
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nodules may place the tissue at increased risk for

repeated injury, resulting in stiffening or scarring
of the vocal folds over the long term.23
Polyps are thought to be a more acute vascular
injury characterized by less fibronectin deposition
and basement membrane zone disruption as compared with nodules.25 Kotby et al24 proposed that
nodules and polyps represent a relative continuum
of vocal fold injury, with critical variables being
the chronicity of the wound and the focal or diffuse
nature of the injury. Furthermore, polyps may represent the result of an arrest in the wound healing
process involving stasis in the inflammatory phase.
In contrast, nodules are likely a result of complete
wound healing with deposition of fibronectin as
a precursor to scar formation.
Vocal fold cysts are typically less commonly encountered than other benign vocal fold lesions. It is
unclear whether cysts are a result of a reparative
process associated with phonation. Courey et al25
described cysts as having a basement membrane
zone thickness between the thickness found for polyps and nodules. Varying cell types may line the lesion. Cysts may be lined with either columnar or
squamous epithelium.26 The implications for these
findings remain unclear. However, it is speculated
that cysts located at the midpoint of the membranous vocal folds are likely due, at least in part, to
injury associated with high intracordal impact
stress.
As with acute vocal fold injury, the use of biochemical markers of the wound healing process
may provide some insight into the nature of more
long-standing vocal fold lesions. Patients with active epithelial disease such as recurrent respiratory
papilloma and squamous cell carcinoma exhibit
markedly increased levels of IL-1b, suggesting an
active inflammatory response to invasive disease
processes.27 In contrast, patients with chronic pathological conditions of the vocal folds (cysts and
polyps) do not seem to have significant IL-1b upregulation.27 These data suggest that benign vocal
fold lesions represent the end product of the wound
healing cascade, or at least an arrest of the process
beyond the acute, active inflammatory phase. In addition, patients with established vocal fold lesions
seem to have increased prostaglandin-E2 (PGE-2)
levels. PGE-2 is an inflammatory mediator and is

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VOCAL FOLD WOUND HEALING

relatively ubiquitous in wound healing. Markers of
wound healing such as PGE-2 be valuable in the description and differentiation of vocal fold lesions.27
Nonphonatory mechanical injury
The vocal folds typically withstand regular
mechanical trauma associated with phonation.
However, the folds are also subjected to nonphonatory mechanical trauma. Examples include endotracheal intubation, phonomicrosurgery, and external
laryngeal trauma.
Phonomicrosurgery is common for the removal
of vocal fold lesions and can result in disruption
of the epithelium, basement membrane, and underlying lamina propria depending on the depth of the
incision and horizontal involvement of the procedure. In the most severe case that involves complete
ablation of the mucosa, a fibrinous clot forms at the
site of the wound within 1 day after injury, in a rabbit model. By 3 days after injury, sparse epithelial
coverage is present. More importantly, massive cellular infiltration and neo-lamina propria deposition
is noted by 3 days after injury. Complete epithelial
coverage is achieved by 5 days after injury. Neolamina propria deposition increases significantly 7
days after injury. By 21 days after surgical injury,
the trilayered structure of the lamina propria is
not yet regained.28
The precise sequence of events that follows surgical injury of the vocal fold can only be elucidated
using animal models. Decreased collagen density in
the scarred vocal fold as compared with control
folds was reported 60 days after forcep biopsy
taken from the midpoint of the membranous vocal
folds, in a rabbit model.29 The relevant study suggested that scar in the vocal folds was associated
with a loss of normal collagen architecture, not
increased collagen density. However, that investigation may describe immature scar, as new matrix
materials may not be stable until after 60 days
postinjury.
The concentration of many ECM components
has been described after vocal fold surgical injury
in an animal model. Decreased elastin content has
been reported 60 days after surgical injury. Elastin
in scarred vocal folds is composed of short, compact fibers. Although hyaluronic acid (HA) was
found predominately in the deep lamina propria

of the uninjured vocal folds at 60 days, HA was distributed throughout the scarred lamina propria. No
significant difference was found between HA density of scarred versus normal vocal folds.29
Thibeault et al30 found significantly decreased
levels of decorin 60 days after surgical injury in
a rabbit model. Decorin, a proteoglycan found primarily in the superficial layer of the lamina propria,
binds collagen and alters the kinetics of fibril formation.31 Decreased levels of decorin have been
reported in the hypertrophic scar in the skin.32,33
Decreased decorin levels may be responsible for
the altered collagen structure associated with vocal
fold scar. In skin, decorin levels increase to subnormal levels over time after burn injuries.32 It is
unclear whether this process takes place in vocal
folds injury. However, it is likely that decorin levels
increase with time as well as tissue motion. Decorin
content in other tissues has been shown to increase
with exercise.34 Decorin is an interesting vocal fold
protein that warrants investigation as a potential
antifibrotic agent.
In addition, decreased levels of fibromodulin
have been found in vocal fold scar (60 days after injury).30 Fibromodulin has been shown to inhibit
transforming growth factor-beta (TGF-b)-induced
collagen synthesis. Decreased levels of fibromodulin have been implicated in scar formation in the
skin.35 However, the findings in the vocal fold are
puzzling as an increase in collagen synthesis should
correspond with decreased fibromodulin expression. Sixty days after injury, this is not the case,
suggesting a potential imbalance in the wound healing response associated with vocal fold scar formation.29 Like decorin, the role of fibromodulin in the
scar formation deserves investigation and may be
a target for antifibrotic therapies.
Not surprisingly, increased levels of fibronectin
were reported in immature scar as described by
Thibeault et al.30 This increase corresponds with
the previous investigation regarding the role of fibronectin in dermal scar formation.36 Fibronectin has
been implicated in the formation of adhesion
proteins required for epidermal cell/basement
membrane attachment as well as epidermal cell migration and replication. Therefore, Thibeault et al30
suggested that increased fibronectin would be
expected after injury, supporting epithelialization.
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The authors, however, did not mention these findings in the context of vocal nodules. As mentioned,
vocal nodules are characterized by a disruption of
the basement membrane zone. Therefore, it is a logical assumption that increased fibronectin depositions at the site of nodules are a component of the
reparative process associated with reattachment of
the epidermal/basement membrane zone complex.
Rousseau et al37 described the development of
a vocal fold scar 6 months after surgical injury.
As early as 2 months after surgical removal of the
epithelium and lamina propria in a canine model,
no significant difference in collagen density was
noted. Instead, the collagen was arranged in thick
bundles of disorganized fibers. At 6 months after
injury, collagen density was significantly increased
in surgically injured as compared with normal
vocal folds.37
Although animal models can be used to investigate the sequence of wound healing events that
accompany vocal fold injury, human studies will
be required for subsequent translation to clinical
management choices. For obvious reasons, human
studies cannot involve a precise examination of vocal fold micro-architectural changes during wound
healing. Noninvasive techniques for monitoring
wound healing hold the best promise for human
studies. Recent studies have attempted to monitor
the inflammatory phase of vocal fold repair using
a noninvasive technique. Branski et al38 reported
differential temporal expression of IL-1b and
PGE-2 after surgical injury in a rabbit model.
Maximal expression of IL-1b occurred 1 day after
injury. Resolution to baseline levels was observed
by seven days after injury. In contrast, PGE-2 did
not significantly increase immediately after injury.
Maximal PGE-2 expression occurred 7 days after
injury. Preinjury levels were not achieved by 21
days after injury, the endpoint of the study. This
type of investigation may yield insight into the
wound healing process and provide therapeutic
targets to minimize scar formation.
Chemical/thermal injury
Given their role of gatekeepers to the airway,
the vocal folds are exposed to numerous irritants.
Clinically, the most common agents of this type
are cigarette smoke, inhaler treatment for asthma,
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and laryngopharyngeal reflux. However, several

reports in the laryngology literature also describe
thermal injuries associated with the aspiration of
hot liquid.39,40 In addition, there are emerging reports of upper airway burns from cocaine pipe
screen ingestion.41,42 Obviously, vocal function is
not the primary target of therapy in severe cases
that may yield impaired respiratory function. More
commonly, patients voice complaints seem to be
related to exposure to airborne irritants such as
cigarette smoke.43
Reinkes edema (RE), a common clinical entity,
is associated with prolonged exposure to the irritants in cigarette smoke. Clinically, patients with
this condition present with vast, diffuse edema
and erythema of the true vocal folds. RE is associated with hemorrhage, increased fibrin deposition,
edematous lakes, and thickening of the basement
membrane zone. Reinkes edema likely represents
an arrest in the normal reparative process due to
prolonged exposure to inflammatory stimuli.44
In addition to smoke inhalation, the vocal folds
are subjected to many other airborne irritants. Most
commonly, patients experiencing such exposure
present with vocal fold irritation and inflammation
associated with prolonged use of inhaled b-agonists
and/or steroids for the treatment of restrictive pulmonary disease. Areas of vocal fold hyperemia
with plaque-like changes of the vocal fold surface
have been noted in patients using combination
corticosteroid and bronchodilator therapy.45 It is
unclear whether the laryngitis is due to medicinal
effects or due to the carrier.
In addition, the literature is fraught with case
reports of dysphonia associated with chemical
fume exposure. Dysphonia has been connected to
prolonged exposure to Freon, formaldehyde, and
mercury among others. Even the performing arts
community is not immune to exposure. Richter
et al46 identified potentially toxic substances that may
affect professional opera singers. These include
formaldehyde, cobalt, aromatic diisocyanates, and
other agents. It seems unclear why certain patients
may be more susceptible to injury from airborne
irritants than others. One hypothesis may be that
individual thresholds for the elicitation of a wound
healing response in the vocal folds are variable
among humans. This notion is completely

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hypothetical at this point, but it warrants further
investigation.
Likely the most researched source of chemical
vocal fold injury is laryngopharyngeal reflux
(LPR). Approximately 50% of patients with laryngeal and voice disorders have pH-documented
LPR, gastroesophageal reflux disease, or both.47,48
Clinically, this population presents with diverse
symptomology and endoscopic findings. Most commonly, patients present with local edema, which
ranges from mild to severe Reinkes edema, pseudocyst, erythema, subglottic edema, and posterior
commissure hypertrophy.49 There is emerging data
to suggest that laryngeal epithelial defenses to refluxate are different from those in the esophagus.50
WOUND HEALING THERAPY
Phonation is crucial for oral communication, and
proper vocal fold function is a requisite of phonation. Therefore, the clinician interested in addressing a phonation deficit associated with vocal fold
trauma must primarily address the structural issues
associated with vocal fold injury, or attempt to control the vocal fold wound healing process. To date,
no studies or methods have demonstrated a consistent method for controlling vocal fold wound
healing.
Historically, rest has been the primary treatment
prescribed for most voice problems. A recent study
has partially validated this approach. The authors
reported more rapid reestablishment of the basement membrane zone in a canine model of surgical
injury after a voice rest condition as compared with
a phonation condition.51 However, poor patient
compliance along with the social ramifications associated with aphonia limit voice rest as a therapeutic option in many cases. In addition, there is
emerging evidence to suggest that low levels of
mechanical stress may attenuate the inflammatory
response in other tissue. To address these issues,
ongoing studies are attempting to determine whether moderate voice use involving large-amplitude,
low-impact stress vocal fold oscillations typically
described as Resonant Voice can result in improved
wound healing outcomes. Specifically, vocalization
under the direction of a speech pathologist may allow for the requisite communication while

facilitating optimal tissue mechanics. In addition

to the potential antiinflammatory actions, the
long-term tissue organization after injury may be
altered in response to mechanical stress.52 Investigation is currently underway to examine these issues in the vocal folds.
In the case of an established scar, the orthopedic
literature suggests utility in prolonged stretching or
the application of tension to the fibrotic region to
regain functional mobility at the wound site. Arem
and Madden53 were the first to describe scar elongation after low-load prolonged stress (LLPS). Several studies have since attempted to determine the
optimal duration of LLPS in the form of stretch
or splinting to yield the best outcomes. Brand54
suggested that holding the tissue in a moderately
lengthened position for a significant time should
induce functionally positive scar remodeling. Although significant time is not specific, it has
spawned investigation to determine the duration
of tension that yields optimal outcomes. This time
is referred to as total end range time (TERT). It
seems that end range must be maintained for at
least 6 to 12 hours per day in order to receive
maximal improvement.55,56 Specifically, Prosser56
reported that a mean TERT of 10 hours daily
yielded functionally superior results compared with
less time spent at end range. These data suggest the
potential for the application of such techniques to
the vocal folds through the use of prolonged vocal
fold elongation associated with high pitches.
However, the time and specific tasks required for
optimal tissue outcomes remain unknown.
Although voice therapy may be able to influence
the acute inflammatory component of vocal fold
wound healing, such therapy still relies heavily on
appropriate patient compliance. An alternative approach to behavioral exercises is the chemical inhibition of the inflammatory phase of acute vocal fold
injury. A long-standing technique in this regard involves the use of steroids. Systemic corticosteroids,
either intramuscular or oral, are commonly prescribed to reduce vocal fold inflammation associated with prolonged phonotrauma in high-caliber
voice users whose careers may be limited by the
presence of subtle vocal fold edema. A case report
in 2001 found marked improvement in vocal function after a 6-day course of oral methyl
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prednisolone in a male professional singer.57 Several investigators have shown a marked reduction in
vocal fold inflammation after either steroid injection into the lamina propria or even topical treatment with inhalation aerosol.58,59 There may also
be some utility for steroid injection in the presence
of established vocal fold lesions. In one study, 27
patients underwent endoscopic injection of triamcinolone acetonide to the site of bilateral vocal fold
lesions. Postprocedure examination (1 to 3 weeks)
revealed complete lesion resolution in 17 patients
and marked decrease in lesion size in the remaining
10.60 The described study was poorly controlled
and defined, but it supports the concept of targeted
therapy to reduce the inflammatory phase after vocal fold injury.
However, steroid use, particularly in the pediatric
population, remains a controversial issue. As a result, various soluble mediators of wound healing
are currently under investigation for their potential
for vocal fold therapy. Hepatocyte growth factor
(HGF), a powerful antifibrotic agent that modulates
collagen formation and TGF-b expression has been
considered as a potential therapeutic agent for vocal
fold scar.61,62 Investigators have characterized the
therapeutic potential of HGF in vivo after acute
surgical injury to the vocal folds in a rabbit model.
Histological investigation revealed improved
wound healing with decreased fibrosis. Rheological
assessment revealed that HGF treatment decreased
vocal fold stiffness, improved mucosal wave propagation, phonation threshold pressure, vocal efficiency, and glottal closure.63 These findings are
thought to be due to the antifibrotic effects of
HGF on vocal fold fibroblast activity. In addition,
HGF increases hyaluronic acid synthesis and decreases collagen type I synthesis in vocal fold fibroblasts in vitro.6466
Mitomycin-C, a chemotherapeutic agent, has
been used to improve the results of vocal fold
wound healing. In addition to chemotherapeutic
indications, mitomycin-C has also been shown to
limit fibroblast activity and limit fibrosis associated
with tracheal injury. This agent is gaining widespread use to prevent restenosis of the upper airway
after airway-expanding surgery.67 However, topical
application to the vocal folds after surgical injury
had negative consequences on vocal fold vibratory
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behavior as assessed via laryngeal videostroboscopy. As expected, mitomycin-C reduced fibroblast proliferation within the wound area, limiting
the connective tissue response after injury.68
Although theoretically sound, the use of mytomycin-C does not seem to yield nonfibrotic, biomechanically sound tissue.
Rosen69 suggested that the vocal fold scar is one
of the most challenging voice problems clinicians
face. The treatment of the scar is difficult due to
the significant communication deficits associated
with the pathology as well as the inherent difficulties associated with rehabilitation.70 In cases of an
established vocal fold scar, several surgical techniques rely primarily on implantation of biomaterials
that alter vocal fold pliability, compliance, and volume. A concern is that treatment does not directly
augment the wound healing process, and moreover,
implantation not only yields a localized vocal fold
injury, but also it may elicit an inherent immune response to the injected material. For example, the
foreign body response to Teflon injection into the
vocal fold has been well documented.71 However,
the use of autologous fat seems to elicit a minimal
inflammatory response, little epithelial reaction,
and minimal unexpected fibrosis.72 Numerous
augmentation materials have been described in
the literature. Augmentation materials should not
only attempt to restore the biomechanical integrity
of scarred vocal folds but also elicit a limited immune response that may alter the long-term function of the vocal folds.
CONCLUSION
Wound healing is a complex process that is
partially directed by the structural and functional
requirements placed on the tissue type in question.
In the vocal fold, wound healing typically occurs
in the context of exposure to pathogenic agents
and continuous mechanical stresses associated with
phonation. In addition, the precise architectural arrangement of the layered ECM presents a unique
wound healing scenario. Each of these factors is important in determining the outcome of vocal fold
wound healing. Appropriate management of vocal
fold injury must account for each of these factors.
Specifically, inflammation must be controlled and

ARTICLE IN PRESS

VOCAL FOLD WOUND HEALING

mechanical injury reduced. Cellular activity resulting in appropriate ECM restoration must be closely
monitored and directed. Appropriate therapeutic
control of each of these processes should result in
optimal vocal fold wound healing. Although the
existing vocal fold literature does not offer precise
clinical management strategies, great strides have
been made in recent years toward developing a comprehensive approach to vocal fold wound healing.
Future approaches in the clinic must be based on
a thorough understanding of the underlying cellular
and molecular processes associated with vocal fold
repair. This review offers a small insight into available data regarding the basic science of vocal fold
repair.

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