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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 disor-

ders 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 re-

search to determine the course of vocal fold wound healing and the potentialrole of therapeutic agents, including behavioral agents. The current review

seeks to provide a foundation of basic wound healing science and presentthe most current data regarding the wound healing process in the vocal folds.

Key Words: Injury—Review—Vocal fold—Wound healing.

INTRODUCTION

Voice disorders seem to be the most common

communication disorder across the lifespan. Esti-mates indicate that anywhere from 3% to 9% of

the population has some type of voice dysfunctionat any given point in time.1 Although the preciseetiologic factors causing these problems remain rel-

atively unknown, a likely cause is the response toinjurious stimuli in a preponderance of cases. Inju-ries to the vocal folds, including phonotrauma aswell as mechanical and chemical trauma, often re-sult in changes to the lamina propria, benign vocalfold lesions, or vocal fold scar. This speculation isconsistent with results from a recent study suggest-ing that approximately 22% of patients seekingtreatment for voice disorders present with organicvocal fold lesions, resulting in dysphonia.2 Al-though vocal fold trauma cannot be implicated inall cases, there is a high likelihood that the primaryetiology of these lesions is the inherent response tosome sort of injury.

In these cases, the goal of therapy via surgery orbehavioral voice treatment must focus on (1) ceasingthe injurious activity and (2) modulating woundhealing or managing tissue that has undergone repar-ative processes. The goal of treatment, therefore, isrestoration of the biomechanical function of the

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, Uni-versity of Pittsburgh, Pittsburgh, Pennsylvania; ‡Departmentof Otolaryngology, University of Pittsburgh, Pittsburgh, Penn-sylvania; §University of Pittsburgh Voice Center, University of Pittsburgh, Pittsburgh, Pennsylvania; kOtolaryngology WoundHealing Laboratory, Department of Pediatric Otolaryngology,Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania;{McGowan Institute for Regenerative Medicine, University

of Pittsburgh, Pittsburgh, Pennsylvania; and the #Departmentof Cell Biology and Physiology, University of Pittsburgh,Pittsburgh, Pennsylvania.

Address correspondence and reprint requests to Ryan C.Branski, PhD, Head and Neck Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.E-mail: [email protected]

Journal of Voice, Vol. -, No. -, pp. -0892-1997/$30.00 2005 The Voice Foundationdoi:10.1016/j.jvoice.2005.08.005

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tissue. Therefore, treatment should be founded in thescience of wound healing. However, discussion of wound healing is typically omitted from curriculaof voice care clinicians. The current review seeks

to present up-to-date information regarding the gen-eral tenets of wound healing as well as emerging lit-erature regarding wound healing in the vocal folds.

WOUND HEALING: AN OVERVIEW

Wound healing is a dynamic, interactive processinvolving cells and extracellular matrix. The woundhealing cascade, when uninterrupted, is typicallyorganized temporally into three major, overlappingphases: inflammation, extracellular matrix (ECM)

deposition and epithelialization, and remodeling.

3

Although a gross oversimplification of the woundhealing process, these phases serve as a basicframework for discussion.

Disruptions in the normal wound healing se-quence can produce less-than-desirable outcomes.In cases of impaired wound healing, reestablish-ment of tissue structure and function is diminished.Excessive and/or prolonged inflammation subse-quent to tissue injury has been shown to result inextended tissue damage in conditions such as oste-oarthritis. Systemic conditions such as diabetes,

Cushing’s syndrome, malnutrition, and sepsis canalso disrupt the normal healing process and leadto nonhealing wounds or, at the other end of thespectrum, excessive fibrosis.3

Inflammation

Injury causes blood vessel disruption leading toleakage of blood into the wound area. Immediatelyafter injury, the inflammatory response is criticalfor (1) stopping blood flow at the site of the wound,(2) filling tissue deficits, (3) providing a provisionalmatrix for subsequent cell migration into the woundbed, (4) sterilization of the wound bed, and (5) sig-naling other cells to come to the wound region andrebuild the ECM. A fibrin-rich clot plugs damagedvessels, fills tissue deficits, and serves as a provi-sional matrix for subsequent cellular invasion.4 In-flammatory cells such as macrophages andneutrophils disinfect the wound site by enzymaticclearance of contaminants. Such cells also

stimulate reepithelization of the wound and encour-age replacement of the extracellular matrix.5

ECM deposition

As inflammation subsides, emphasis is switchedto fibroblast and epithelial cell infiltration of thewound bed and reconstitution of the ECM (deposi-tion of fibronectin and collagen). Fibroblasts mi-grate into the wound area between 48 and 72hours after injury.6 Fibroblasts are responsible forsecreting new matrix materials such as collagenand hyaluronic acid in response to injury. Fibroblastactivity in the wound bed leads to granulation tissueformation in dermal wounds, approximately 4 daysafter injury. Granulation tissue has high myofibro-blast density, a transitional cell type with properties

of both fibroblasts and smooth muscle cells. Myofi-broblasts are responsible for wound contraction.Contraction is required to maintain tissue continuity,to reduce the size of the wound, and to facilitate scarproduction.7 Upon epithelialization (to be describedin the next section), granulation tissue resolves.

The end product of fibroblast activity is an ap-proximation of the preinjury tissue structure andfunction. However, although most ECM compo-nents are present, they are poorly organized. Duringwound healing, fibroblasts produce large amountsof collagen and elastin.8 Glycosaminoglycans and

proteoglycans are also produced.9 Glycosaminogly-cans are large space-filling molecules found in theECM of many organs including the skin and vocalfolds. The specific signals responsible for glycos-aminoglycan and proteoglycan production are rela-tively unknown. However, insight into the stimulusfor proteoglycan production, for example, mightprove to be useful in antifibrotic therapy.

Under certain conditions, wound healing contin-ues unabated with excessive scar formation, result-ing in dermal pathologies such as hypertrophicscars and keloids.10 Both are characterized by anincreased inflammatory response and ECM produc-tion11 as well as an abnormal fibroblastfunction.12,13

Epithelialization

One major goal of wound healing is reconstitu-tion of the epithelium as a functional barrier. Clin-ically, a wound is reepithelialized when a

2 RYAN C. BRANSKI ET AL

Journal of Voice, Vol. -, No. -, 2005

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water-impermeable seal is present at the site of thewound.5 In dermal wound healing, epithelial cellmigration into the site of injury after stimulationby growth factors14,15 begins 24 to 48 hours after

the injury occurs.16

Tissue remodeling

Wound healing and tissue repair continue longafter a functional epidermal barrier has been re-stored. These events are collectively referred to asthe remodeling phase of wound healing and referto the deposition and reorganization of matrix com-ponents over time. Scar remodeling is typicallythought to be the final stage of the wound healingcascade. Early scar, between 1 to 3 months afterinjury, is thick and stiff. In contrast, a more mature

scar is typically more thin and pliable. This obser-vation has significant implications for tissue elastic-ity. The pronounced differences between immatureand mature scar are thought to be due, at least inpart, to the reorganization of collagen fibers alonglines of stress as well as to changes in proteoglycancontent.17 Collagen content has been found tobecome relatively stable approximately 21 daysafter injury. However, both collagen depositionand remodeling are dynamic processes17,18 andare thought to continue up to 12 months after injurydemonstrating increased degradation and deposi-

tion organized along lines of stress.17

VOCAL FOLD WOUND HEALING

The vocal folds, unlike most structures in thebody, are subjected to nearly continuous mechani-cal stresses due to phonation for many wakinghours daily. Given this mechanically stressful state,it is surprising that the vocal folds are not structur-ally and physiologically compromised more often.There are two possible explanations for this appar-ent resistance to mechanical stress. First, the vocalfolds may have an enhanced reparative capacity, bywhich any microstructural damage to the laminapropria and overlying epithelium can be repairedwithout a full-scale wound healing response. Sec-ond, the microstructure of the vocal fold laminapropria may be organized to accommodate moremechanical stress than a tissue such as dermis. Itis likely that both hypotheses are correct given

the microstructural elements present in the vocalfolds that might explain increased vocal fold ac-commodation of mechanical stresses. In addition,if vocal folds can accommodate some level of con-

tinuous mechanical stress, it stands to reason thata threshold would exist, past which a full-scalewound healing response is required for tissuerepair. The current review categorizes vocal foldinjury into four types based on the source and chro-nicity of the injury: acute phonotrauma, chronicphonotrauma, nonphonatory mechanical injury,and chemical injury.

Acute phonotrauma

It is speculated that acute phonotraumatic injurynot only disrupts the vascular network, but it also

causes damage to the basement membrane zoneand ECM. Clinically, acute phonotrauma manifestsas edema of the vocal folds or laryngitis. Many pa-tients may present with focal regions of inflamma-tion at the midpoint of the musculomembranousvocal folds. This site is the region of greatestimpact stress and the most common site of masslesions associated with continued phonotrauma.19

Frequently, edema associated with phonotraumalikely resolves without specific intervention, andvoice quality improves.

Description of the magnitude and temporal pat-

tern of the acute inflammatory process in the vocalfolds may help elucidate the subsequent pathologi-cal events resulting in long-term vocal fold damage.Recent studies have described the acute inflamma-tory response in the vocal folds by measuring levelsof inflammatory mediators. Marked shifts in IL-1b,TNF-a, and matrix metalloproteinase-8 levels in se-cretions collected from the surface of the vocalfolds have been reported after an episode of acutephonotrauma.20 These data may prove useful forfuture investigations into the acute wound healingresponse in the vocal folds.

Chronic phonotrauma

Multiple episodes of acute phonotrauma can re-sult in long-standing tissue damage. Although oftentermed chronic phonotrauma, these episodes likelyencompass recurrent acute phonotraumatic (RAP)events. The result is a relatively permanent stateof tissue repair or scarring, which may manifest

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as a benign vocal fold lesion(s) and/or vocal foldscar. It is also likely that there is a continuum of re-sponses associated with RAP whereby focal edemagives way to mass lesions and, finally, vocal fold

scar based on the chronicity of injury. Mass lesionsof the vocal folds are poorly defined. No standard-ized nomenclature system exists to facilitate bothscholarly and clinical communication regardingvoice disorders.21 One particular lesion, a fibrousmass, has not yet been described in the literature,but it has gained clinical popularity. Although thehistology of this lesion has not been characterized,clinically it is referred to as a unilateral lesion of the midpoint of the musculomembranous vocalfolds.22 Entire volumes could be dedicated to thedescription 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 ormucosal scars. Although the dermis and airway mu-cosa are relatively static structures, the vocal foldsare subjected to continuous mechanical stress. Asa result, the process of vocal fold scar formationis likely different from that encountered in othertissues. In addition, a continuum of vocal fold scarexists ranging from focal to diffuse and exophitic toendophitic (sulcus vocalis).

Three general types of long-standing vocal fold

structural abnormalities have been described:nodules, polyps, and cysts. The extent to whicheach of these pathologies is truly a ‘‘scar’’ is yetunclear.21 Furthermore, the lack of standardizednomenclature for organic vocal fold lesionspresents a challenge to describing these entitiesconsistently in the literature.21

Vocal fold nodules are the most commonly diag-nosed lesions of the vocal folds and are thought tobe a consequence of repetitive of vocal trauma.Nodules are a disruption of the basement mem-brane zone with separation of the epithelium fromthe underlying extracellular matrix.23 Kotby et al24

described vocal fold nodules as having intercellular junction gaps, disruption and duplication of thebasement membrane zone, and focal collagen de-position. Increased levels of fibronectin have alsobeen identified at sites of nodular lesions.25 It hasbeen hypothesized that the disruption of the base-ment membrane zone associated with vocal fold

nodules may place the tissue at increased risk forrepeated injury, resulting in stiffening or scarringof the vocal folds over the long term.23

Polyps are thought to be a more acute vascular

injury characterized by less fibronectin depositionand basement membrane zone disruption as com-pared with nodules.25 Kotby et al24 proposed thatnodules and polyps represent a relative continuumof vocal fold injury, with critical variables beingthe chronicity of the wound and the focal or diffusenature of the injury. Furthermore, polyps may rep-resent the result of an arrest in the wound healingprocess involving stasis in the inflammatory phase.In contrast, nodules are likely a result of completewound healing with deposition of fibronectin asa precursor to scar formation.

Vocal fold cysts are typically less commonly en-countered than other benign vocal fold lesions. It isunclear whether cysts are a result of a reparativeprocess associated with phonation. Courey et al25

described cysts as having a basement membranezone thickness between the thickness found for pol-yps and nodules. Varying cell types may line the le-sion. Cysts may be lined with either columnar orsquamous epithelium.26 The implications for thesefindings remain unclear. However, it is speculatedthat cysts located at the midpoint of the membra-nous vocal folds are likely due, at least in part, to

injury associated with high intracordal impactstress.

As with acute vocal fold injury, the use of bio-chemical markers of the wound healing processmay provide some insight into the nature of morelong-standing vocal fold lesions. Patients with ac-tive epithelial disease such as recurrent respiratorypapilloma and squamous cell carcinoma exhibitmarkedly increased levels of IL-1b, suggesting anactive inflammatory response to invasive diseaseprocesses.27 In contrast, patients with chronic path-ological conditions of the vocal folds (cysts andpolyps) do not seem to have significant IL-1b upre-gulation.27 These data suggest that benign vocalfold lesions represent the end product of the woundhealing cascade, or at least an arrest of the processbeyond the acute, active inflammatory phase. In ad-dition, patients with established vocal fold lesionsseem to have increased prostaglandin-E2 (PGE-2)levels. PGE-2 is an inflammatory mediator and is



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The authors, however, did not mention these find-ings in the context of vocal nodules. As mentioned,vocal nodules are characterized by a disruption of the basement membrane zone. Therefore, it is a log-

ical assumption that increased fibronectin deposi-tions at the site of nodules are a component of thereparative 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 theepithelium and lamina propria in a canine model,no significant difference in collagen density wasnoted. Instead, the collagen was arranged in thick bundles of disorganized fibers. At 6 months afterinjury, collagen density was significantly increased

in surgically injured as compared with normalvocal folds.37

Although animal models can be used to investi-gate the sequence of wound healing events thataccompany vocal fold injury, human studies willbe required for subsequent translation to clinicalmanagement choices. For obvious reasons, humanstudies cannot involve a precise examination of vo-cal fold micro-architectural changes during woundhealing. Noninvasive techniques for monitoringwound healing hold the best promise for humanstudies. Recent studies have attempted to monitor

the inflammatory phase of vocal fold repair usinga noninvasive technique. Branski et al38 reporteddifferential temporal expression of IL-1b andPGE-2 after surgical injury in a rabbit model.Maximal expression of IL-1b occurred 1 day afterinjury. Resolution to baseline levels was observedby seven days after injury. In contrast, PGE-2 didnot significantly increase immediately after injury.Maximal PGE-2 expression occurred 7 days afterinjury. Preinjury levels were not achieved by 21days after injury, the endpoint of the study. Thistype of investigation may yield insight into thewound healing process and provide therapeutictargets 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 typeare cigarette smoke, inhaler treatment for asthma,

and laryngopharyngeal reflux. However, severalreports in the laryngology literature also describethermal in juries associated with the aspiration of hot liquid.39,40 In addition, there are emerging re-

ports of upper airway burns from cocaine pipescreen ingestion.41,42 Obviously, vocal function isnot the primary target of therapy in severe casesthat may yield impaired respiratory function. Morecommonly, patients’ voice complaints seem to berelated to exposure to airborne irritants such ascigarette smoke.43

Reinke’s edema (RE), a common clinical entity,is associated with prolonged exposure to the irri-tants in cigarette smoke. Clinically, patients withthis condition present with vast, diffuse edemaand erythema of the true vocal folds. RE is associ-

ated with hemorrhage, increased fibrin deposition,edematous lakes, and thickening of the basementmembrane zone. Reinke’s edema likely representsan arrest in the normal reparative process due toprolonged exposure to inflammatory stimuli.44

In addition to smoke inhalation, the vocal foldsare subjected to many other airborne irritants. Mostcommonly, patients experiencing such exposurepresent with vocal fold irritation and inflammationassociated with prolonged use of inhaled b-agonistsand/or steroids for the treatment of restrictive pul-monary disease. Areas of vocal fold hyperemia

with plaque-like changes of the vocal fold surfacehave been noted in patients using combinationcorticosteroid and bronchodilator therapy.45 It isunclear whether the laryngitis is due to medicinaleffects or due to the carrier.

In addition, the literature is fraught with casereports of dysphonia associated with chemicalfume exposure. Dysphonia has been connected toprolonged exposure to Freon, formaldehyde, andmercury among others. Even the performing artscommunity is not immune to exposure. Richteret al46 identified potentially toxic substances that mayaffect professional opera singers. These includeformaldehyde, cobalt, aromatic diisocyanates, andother agents. It seems unclear why certain patientsmay be more susceptible to injury from airborneirritants than others. One hypothesis may be thatindividual thresholds for the elicitation of a woundhealing response in the vocal folds are variableamong humans. This notion is completely



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hypothetical at this point, but it warrants furtherinvestigation.

Likely the most researched source of chemicalvocal fold injury is laryngopharyngeal reflux

(LPR). Approximately 50% of patients with laryn-geal and voice disorders have pH-documentedLPR, gastroesophageal reflux disease, or both.47,48

Clinically, this population presents with diversesymptomology and endoscopic findings. Most com-monly, patients present with local edema, whichranges from mild to severe Reinke’s edema, pseu-docyst, erythema, subglottic edema, and posteriorcommissure hypertrophy.49 There is emerging datato suggest that laryngeal epithelial defenses to re-fluxate are different from those in the esophagus.50

WOUND HEALING THERAPY

Phonation is crucial for oral communication, andproper vocal fold function is a requisite of phona-tion. Therefore, the clinician interested in address-ing a phonation deficit associated with vocal foldtrauma must primarily address the structural issuesassociated with vocal fold injury, or attempt to con-trol the vocal fold wound healing process. To date,no studies or methods have demonstrated a consis-tent method for controlling vocal fold woundhealing.

Historically, rest has been the primary treatmentprescribed for most voice problems. A recent studyhas partially validated this approach. The authorsreported more rapid reestablishment of the base-ment membrane zone in a canine model of surgicalinjury after a voice rest condition as compared witha phonation condition.51 However, poor patientcompliance along with the social ramifications as-sociated with aphonia limit voice rest as a therapeu-tic option in many cases. In addition, there isemerging evidence to suggest that low levels of mechanical stress may attenuate the inflammatoryresponse in other tissue. To address these issues,ongoing studies are attempting to determine wheth-er moderate voice use involving large-amplitude,low-impact stress vocal fold oscillations typicallydescribed as Resonant Voice can result in improvedwound healing outcomes. Specifically, vocalizationunder the direction of a speech pathologist may al-low for the requisite communication while

facilitating optimal tissue mechanics. In additionto the potential antiinflammatory actions, thelong-term tissue organization after injury may bealtered in response to mechanical stress.52 Investi-

gation is currently underway to examine these is-sues in the vocal folds.

In the case of an established scar, the orthopedicliterature suggests utility in prolonged stretching orthe application of tension to the fibrotic region toregain functional mobility at the wound site. Aremand Madden53 were the first to describe scar elon-gation after low-load prolonged stress (LLPS). Sev-eral studies have since attempted to determine theoptimal duration of LLPS in the form of stretchor splinting to yield the best outcomes. Brand54

suggested that holding the tissue in a moderately

lengthened position for a ‘‘significant time’’ shouldinduce functionally positive scar remodeling. Al-though ‘‘significant time’’ is not specific, it hasspawned investigation to determine the durationof tension that yields optimal outcomes. This timeis referred to as total end range time (TERT). Itseems that end range must be maintained for atleast 6 to 12 hours per day in order to receivemaximal improvement.55,56 Specifically, Prosser56

reported that a mean TERT of 10 hours dailyyielded functionally superior results compared withless time spent at end range. These data suggest the

potential for the application of such techniques tothe vocal folds through the use of prolonged vocalfold elongation associated with high pitches.However, the time and specific tasks required foroptimal tissue outcomes remain unknown.

Although voice therapy may be able to influencethe acute inflammatory component of vocal foldwound healing, such therapy still relies heavily onappropriate patient compliance. An alternative ap-proach to behavioral exercises is the chemical inhi-bition of the inflammatory phase of acute vocal foldinjury. A long-standing technique in this regard in-volves the use of steroids. Systemic corticosteroids,either intramuscular or oral, are commonly pre-scribed to reduce vocal fold inflammation associat-ed with prolonged phonotrauma in high-calibervoice users whose careers may be limited by thepresence of subtle vocal fold edema. A case reportin 2001 found marked improvement in vocal func-tion after a 6-day course of oral methyl

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prednisolone in a male professional singer.57 Sever-al investigators have shown a marked reduction invocal fold inflammation after either steroid injec-tion into the lamina propria or even topical treat-

ment with inhalation aerosol.58,59

There may alsobe some utility for steroid injection in the presenceof established vocal fold lesions. In one study, 27patients underwent endoscopic injection of triam-cinolone acetonide to the site of bilateral vocal foldlesions. Postprocedure examination (1 to 3 weeks)revealed complete lesion resolution in 17 patientsand marked decrease in lesion size in the remaining10.60 The described study was poorly controlledand defined, but it supports the concept of targetedtherapy to reduce the inflammatory phase after vo-cal fold injury.

However, steroid use, particularly in the pediatricpopulation, remains a controversial issue. As a re-sult, various soluble mediators of wound healingare currently under investigation for their potentialfor vocal fold therapy. Hepatocyte growth factor(HGF), a powerful antifibrotic agent that modulatescollagen formation and TGF-b expression has beenconsidered as a potential therapeutic agent for vocalfold scar.61,62 Investigators have characterized thetherapeutic potential of HGF in vivo after acutesurgical injury to the vocal folds in a rabbit model.Histological investigation revealed improved

wound healing with decreased fibrosis. Rheologicalassessment revealed that HGF treatment decreasedvocal fold stiffness, improved mucosal wave prop-agation, phonation threshold pressure, vocal effi-ciency, and glottal closure.63 These findings arethought to be due to the antifibrotic effects of HGF on vocal fold fibroblast activity. In addition,HGF increases hyaluronic acid synthesis and de-creases collagen type I synthesis in vocal fold fibro-blasts in vitro.64–66

Mitomycin-C, a chemotherapeutic agent, hasbeen used to improve the results of vocal foldwound healing. In addition to chemotherapeuticindications, mitomycin-C has also been shown tolimit fibroblast activity and limit fibrosis associatedwith tracheal injury. This agent is gaining wide-spread use to prevent restenosis of the upper airwayafter airway-expanding surgery.67 However, topicalapplication to the vocal folds after surgical injuryhad negative consequences on vocal fold vibratory

behavior as assessed via laryngeal videostrobo-scopy. As expected, mitomycin-C reduced fibro-blast proliferation within the wound area, limitingthe connective tissue response after injury.68

Although theoretically sound, the use of mytomy-cin-C does not seem to yield nonfibrotic, bio-mechanically sound tissue.

Rosen69 suggested that the vocal fold scar is oneof the most challenging voice problems cliniciansface. The treatment of the scar is difficult due tothe significant communication deficits associatedwith the pathology as well as the inherent difficul-ties associated with rehabilitation.70 In cases of anestablished vocal fold scar, several surgical techni-ques rely primarily on implantation of biomaterialsthat alter vocal fold pliability, compliance, and vol-

ume. A concern is that treatment does not directlyaugment the wound healing process, and moreover,implantation not only yields a localized vocal foldinjury, but also it may elicit an inherent immune re-sponse to the injected material. For example, theforeign body response to Teflon injection into thevocal fold has been well documented.71 However,the use of autologous fat seems to elicit a minimalinflammatory response, little epithelial reaction,and minimal unexpected fibrosis.72 Numerousaugmentation materials have been described inthe literature. Augmentation materials should not

only attempt to restore the biomechanical integrityof scarred vocal folds but also elicit a limited im-mune response that may alter the long-term func-tion of the vocal folds.

CONCLUSION

Wound healing is a complex process that ispartially directed by the structural and functionalrequirements placed on the tissue type in question.In the vocal fold, wound healing typically occursin the context of exposure to pathogenic agentsand continuous mechanical stresses associated withphonation. In addition, the precise architectural ar-rangement of the layered ECM presents a uniquewound healing scenario. Each of these factors is im-portant in determining the outcome of vocal foldwound healing. Appropriate management of vocalfold injury must account for each of these factors.Specifically, inflammation must be controlled and



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mechanical injury reduced. Cellular activity result-ing in appropriate ECM restoration must be closelymonitored and directed. Appropriate therapeuticcontrol of each of these processes should result in

optimal vocal fold wound healing. Although theexisting vocal fold literature does not offer preciseclinical management strategies, great strides havebeen made in recent years toward developing a com-prehensive approach to vocal fold wound healing.Future approaches in the clinic must be based ona thorough understanding of the underlying cellularand molecular processes associated with vocal foldrepair. This review offers a small insight into avail-able data regarding the basic science of vocal foldrepair.

REFERENCES

1. Berry DA, Verdolini K, Montequin DW, Hess MM,

Chan RW, Titze IR. A quantitative output-cost ratio in voice

production. J Speech Lang Hear Res. 2001;44:29–37.

2. Coyle SM, Weinrich BD, Stemple JC. Shifts in relative

prevalence of laryngeal pathology in a treatment-seeking

population. J Voice. 2001;15:424–440.

3. Clark RAF. Wound repair. Overview and general consider-

ations. In: Clark RAF, ed. The Molecular and Cellular

Biology of Wound Repair . New York: Plenum Press; 1998.

4. Trowbridge HO, Emling RC. Inflammation. 5th ed. Chica-go, IL: Quintessence Publishing Co, Inc.; 1997.

5. Hackam DJ, Ford HR. Cellular, biochemical, and clinical

aspects of wound healing. Surg Infect . 2002;3:S23–S35.

6. VanLis JM, Kalssbeek GL. Glycosaminoglycans in human

skin. Br J Dermatol. 1973;88:355–361.

7. Gabbiani G. The myofibroblast in wound healing and

fibrocontractive diseases. J Pathol. 2003;200:500–503.

8. Woodley DT, O’Keefe EJ, Prunieras M. Cutaneous wound

healing: a model for cell-matrix interactions. J Am Acad

Dermatol. 1985;12:420–433.

9. Kirsner RS, Eaglstein WH. The wound healing process.

Dermatologic Clin. 1993;11:629–640.

10. Tredget EE, Nedelec B, Scott PG, Ghahary A. Hypertro-

phic scars, keloids, and contractures. The cellular andmolecular basis for therapy. Surg Clin North Am. 1997;

77:701–730.

11. Bettinger DA, Yager DR, Diegelmann RF, Cohen IK. The

effect of TGF-beta on keloid fibroblast proliferation and

collagen synthesis. Plast Reconstr Surg. 1996;98:827–833.

12. Gadson PF, Russell JD, Russell SB. Glucocorticoid recep-

tors in human fibroblasts derived from normal dermis and

keloid tissue. J Biol Chem. 1984;259:11236–11241.

13. Bettinger DA, Yager DR, Diegelmann R, Cohen IK. The

effect of TGF-B on keloid fibroblast proliferation and

collagen synthesis. Plast Reconstr Surg. 1996;98:827–833.

14. Martin P. Wound healing—aiming for perfect skin. Sci-

ence. 1997;276:75–81.

15. Werner S. Keratinocyte growth factor: a unique player inepithelial repair processes. Cytokine Growth Factor Rev.

1998;9:153–165.

16. O’Toole EA. Extracellular matrix and keratinocyte migra-

tion. Experiment Dermatol. 2001;26:525–530.

17. Ehrlich HP. Collagen considerations in scarring and regen-

erative repair. In: Longaker MT, ed. Scarless Wound Heal-

ing. New York: Marcel Dekker; 2000:99–113.

18. Martins-Green M. The dynamics of cell-ECM interactions

with implications for tissue engineering. In: Lanza R,

Langer R, Chick W, eds. Principles of Tissue Engineering.

New York: R.G. Landes Company; 1997.

19. Jiang JJ, Titze IR. Measurement of vocal fold intraglottal

pressure and impact stress. J Voice. 1994;8:132–144.

20. Verdolini K, Rosen CA, Branski RC, Hebda PA. Cytokineand protease shifts in laryngeal secretions associated with

phonotrauma. Presented at: Combined Otolaryngology

Spring Meetings, American Bronchoesophageal Associa-

tion; Nashville, TN; 2003.

21. Rosen CA, Murry T. Nomenclature of voice disorders and

vocal pathology. In: Rosen CA, Murry T, eds. The Otolar-

yngologic Clinics of North America. Philadelphia, PA:

W.B. Saunders Company; 2000.

22. Rosen CA, Simpson CB, Postma GA, Courey MA,

Sataloff RT. Lumps and bumps: a paradigm for vocal fold

pathology. Presented at: Annual Meeting of the Academy

of Otolaryngology, Head and Neck Surgery; Orlando,

FL; 2003.

23. Gray SD, Hammond EH, Hanson D. Benign pathologicresponse of the larynx. Ann Otol Rhinol Laryngol. 1995;

104:8–13.

24. Kotby MN, Nassar AM, Seif EI, Helal EH, Saleh MM.

Ultrastructural features of vocal fold nodules and polyps.

Acta Otolaryngol. 1988;105:477–482.

25. Courey MS, Shohet JA, Scott MA, Ossoff RH. Immuno-

histochemical characterization of benign laryngeal lesions.

Otol Rhinol Laryngol. 1996;105:525–531.

26. Shvero J, Koren R, Hadar T, Yaniv E, Sandbank J,

Feinmesser R, Gal R. Clinicopathologica study and classi-

fication of vocal cord cysts. Pathol Res Pract . 2000;196:

95–98.

27. Branski RC, Verdolini K, Rosen CA, Hebda PA. Markers

of wound healing in vocal fold secretions from patientswith laryngeal pathology. Ann Otol Rhinol Laryngol.

2004;113:23–29.

28. Branski RC, Rosen CA, Verdolini K, Hebda PA. Acute vo-

cal fold wound healing in a rabbit model. Ann Otol Rhinol

Laryngol. 2005;114:19–24.

29. Thibeault SL, Gray SD, Bless DM, Chan RW, Ford CN.

Histologic and rheologic characterization of vocal fold

scarring. J Voice. 2002;16:96–104.



ARTICLE IN PRESS

8/20/2019 hl3

10/11

30. Thibeault SL, Bless DM, Gray SD. Interstitial protein

alterations in the rabbit vocal fold with scar. J Voice.

2003;17:376–382.

31. Pawlak AS, Hammond T, Hammond E, Gray SD. Immu-

nocytochemical study of proteoglycans in vocal folds.

Ann Otol Rhinol Laryngol. 1996;105:6–11.32. Sayani K, Dodd CM, Nedelec B, Shen YJ, Ghahary A,

Tredget EE, Scott PG. Delayed appearance of decorin in

healing burn scars. Histopathology. 2000;36:262–272.

33. Scott PG, Dodd CM, Tredget EE, Ghahary A,

Rahemtulla F. Immunohistochemical localization of the

proteoglycans decorin, biglycan and versican and trans-

forming growth factor-beta in post-burn hypertrophic and

mature scars. Histopathology. 1995;26:423–431.

34. Visser NA, de Koning MH, Lammi MJ, Hakkinen T,

Tammi M, van Kampen GP. Increase of decorin content

in articular cartilage following running. Connect Tissue

Res. 1998;37:295–302.

35. Soo C, Hu FY, Zhang X, Wang Y, Beanes SR,

Lorenz HP, et al. Differential expression of fibromodulin,a transforming growth factor-B modulator, in fetal skin

development and scarless repair. Am J Pathol. 2000;

157:423–433.

36. Kirscher CW, Hendrix MJC. Fibronectin in hypertrophic

scars and keloids. Cell Tissue Res. 1983;231:29–37.

37. Rousseau B, Hirano S, Scheidt TD, Welham NV,

Thibeault SL, Chan RW, Bless DM. Characterization of

vocal fold scarring in a canine model. Laryngoscope.

2003;113:620–627.

38. Branski RC, Rosen CA, Hebda PA, Verdolini K. Cytokine

analysis of acute wound healing in the larynx: A rabbit

model. Presented at: The Voice Foundation’s 32nd Annual

Symposim: Care of the Professional Voice; Philadelphia,

PA; 2003.39. Rosen D, Avishai-Eliner S, Borenstein A, Leviav A,

Tabachnik E. Life-threatening burns in toddlers following

hot liquid aspiration. Acta Pediatr . 2000;89:1018–1020.

40. Einav S, Braverman I, Yatsiv I, Avital A, Rothschild M.

Airway burns and atelectasis in an adolescent following

aspiration of molten wax. Ann Otol Rhinol Laryngol.

2000;109:687–689.

41. Haim DY, Lippmann ML, Goldberg SK, Walkenstein MD.

The pulmonary complications of crack cocaine. A compre-

hensive review. Chest . 1995;107:233–240.

42. Ludwig WG, Hoffner RJ. Upper airway burn from crack

cocaine pipe screen ingestion. Am J Emerg Med . 1999;

17:108–109.

43. Marcotullio D, Magliulo G, Pezone T. Reinke’s edema andrisk factors: clinical and histopathologic aspects. Am J

Otolaryngol. 2002;23:81–84.

44. Dikkers FG, Nikkels PG. Benign lesions of the vocal folds:

histopathology and phonotrauma. Ann Otol Rhinol

Laryngol. 1995;104:698–703.

45. Mirza N, Kasper Schwartz S, Antin-Ozerkis D. Laryngeal

findings is users of combination corticosteroid and bron-

chodilator therapy. Laryngoscope. 2004;114:1566–1569.

46. Richter B, Lohle E, Knapp B, Weikert M, Schlomicher-

Thier J, Verdolini K. Harmful substances on the opera

stage: possible negative effects on singers’ respiratory

tracts. J Voice. 2002;16:72–80.

47. Koufman JA. The otolaryngologic manifestations of gas-

troesophageal reflux disease (GERD): a clinical investiga-tion of 225 patients using ambulatory 24-hour pH

monitoring and an experimental investigation of the role

of acid and pepsin in the development of laryngeal injury.

Laryngoscope. 1991;101:1–78.

48. Koufman JA, Amin MR, Panetti M. Prevalence of reflux

in 113 consecutive patients with laryngeal and voice dis-

orders. Otolaryngol Head Neck Surg. 2000;123:385–388.

49. Belafsky PC. Abnormal endoscopic pharyngeal and laryn-

geal findings attributable to reflux. Am J Med . 2003;115:

90S–96S.

50. Johnston N, Bulmer D, Gill GA, Panetti M, Ross PE,

Pearson JP, et al. Cell biology of laryngeal epithelial

defenses in health and disease: further studies. Ann Otol

Rhinol Laryngol. 2003;112:481–491.51. Cho SH, Kim HT, Lee IJ, Kim MS, Park HJ. Influence of

phonation on basement membrane zone recovery after

phonomicrosurgery: a canine model. Ann Otol Rhinol

Laryngol. 2000;109:658–666.

52. Xu Z, Buckley MJ, Evans CH, Agarwal S. Cyclic tensile

strain acts as an antagonist of IL-1B actions in chrondro-

cytes. J Immunol. 2000;165:453–460.

53. Arem A, Madden J. Effects of stress on healing wounds:

intermittent noncyclical tension. J Surg Res. 1976;20:

93–102.

54. Brand P. Clinical Mechanics of the Hand . St. Louis, MO:

Mosby; 1985.

55. Glasgow C, Wilton J, Tooth L. Optimal daily total end

range time for contracture: Resolution in hand splinting. J Hand Ther . 2003;16:207–218.

56. Prosser R. Splinting in the management of proximal inter-

phalangeal joint flexion contracture. J Hand Ther . 1996;9:

378–386.

57. Watts CR, Clark R, Early S. Acoustic measures of phona-

tory improvement secondary to treatment by oral cortico-

steriods in a professional singer: a case report. J Voice.

2001;15:115–121.

58. Moesgaard NV, Hojslet PE. Topical treatment of Reinke’s

oedema with beclomethasone dipropionate (BDP) inhala-

tion aerosol. J Laryngol Otol. 1987;101:921–924.

59. Tateya I, Omori K, Kojima H, Hirano S, Kaneko K, Ito J.

Steroid injection for Reinke’s edema using fiberoptic

laryngeal surgery. Acta Otolaryngol. 2003;122:417–420.60. Tateya I, Omori K, Kojima H, Hirano S, Kaneko K, Ito J.

Steroid injection to vocal nodules using fiberoptic laryn-

geal surgery under topical anesthesia. Eur Arch

Oto-rhino-laryngol. 2004;261:489–492.

61. Matsumoto K, Nakamura T. Hepatocyte growth factor

(HGF) as a tissue organizer for organogenesis and re-

generation. Biochem Biophys Res Comm. 1997;239:

639–644.



ARTICLE IN PRESS

8/20/2019 hl3

11/11

62. Bataller R, Brenner DA. Hepatic stellate cells as a target

for the treatment of liver fibrosis. Semin Liver Dis. 2001;

21:437–451.

63. Hirano S, Bless DM, Rousseau B, Welham N,

Montequin D, Chan RW, Ford CN. Prevention of vocal

fold scarring by topical injection of hepatocyte growth fac-tor in a rabbit model. Laryngoscope. 2004;114:548–556.

64. Hirano S, Bless D, Heisey D, Ford C. Roles of hepatocyte

growth factor and transforming growth factor B1 in pro-

duction of extracellular matrix by canine vocal fold fibro-

blasts. Laryngoscope. 2003;113:144–148.

65. Hirano S, Bless DM, Heisey D, Ford CN. Effect of growth

factors on hyaluronan production by canine vocal fold fi-

broblasts. Ann Otol Rhinol Laryngol. 2003;112:617–624.

66. Hirano S, Bless DM, Massey RJ, Hartig GK, Ford CN.

Morphological and functional changes of human vocal

fold fibroblasts with hepatocyte growth factor. Ann Otol

Rhinol Laryngol. 2003;112:1026–1033.

67. Hartnick CJ, Hartley BE, Lacy PD, Liu J, Bean JA,

Willging JP, et al. Topical mitomycin application after lar-yngotracheal reconstruction: a randomized, double-blind,

placebo-controlled trial. Arch Otolaryngol Head Neck

Surg. 2001;127:1260–1264.

68. Garrett CG, Soto J, Riddick J, Billante CR, Reinisch L.

Effect of mitomycin-C on vocal fold healing in a canine

model. Ann Otol Rhinol Laryngol. 2001;110:25–30.

69. Rosen CA. Vocal fold scar. In: Rosen CA, Murry T, eds.The Otolaryngologica Clinics of North America. Voice

Disorders and Phonosurgery. Philadelphia, PA: W.B.

Saunders; 2000.

70. Benninger MS, Alessi D, Archer S, Bastian R, Ford C,

Koufman J, et al. Vocal fold scarring: current concepts

and management. Otolaryngol Head Neck Surg. 1996;

115:474–482.

71. Lewy RB, Millet D. Immediate local tissue reactions

to Teflon vocal cord implants. Laryngoscope. 1978;88:

1339–1342.

72. Duprat Ade AC, Costa HO, Lancelotti C, Ribeiro de

Almeida R, Caron R. Histologic behavior of the in-

flammatory process in autologous fat implantation in

rabbit vocal folds. Ann Otol Rhinol Laryngol. 2004;113:636–640.



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