vocal fold scars current concepts and future directions

LARYNGOLOGY

Vocal fold scars: current concepts and future directions.Consensus report of the phonosurgery committee of the Europeanlaryngological society

G. Friedrich F. G. Dikkers C. Arens M. Remacle

M. Hess A. Giovanni S. Duflo A. Hantzakos

V. Bachy M. Gugatschka

Received: 1 October 2012 / Accepted: 11 April 2013

Springer-Verlag Berlin Heidelberg 2013

Abstract Scarring of the vocal folds leads to a deterio-

ration of the highly complex micro-structure with consec-

utively impaired vibratory pattern and glottic insufficiency.

The resulting dysphonia is predominantly characterized by

a reduced vocal capacity. Despite the considerable progress

in understanding of the underlying pathophysiology, the

treatment of scarred vocal folds is still an unresolved

chapter in laryngology and phonosurgery. Essential for a

successful treatment is an individual, multi-dimensional

concept that comprises the whole armamentarium of sur-

gical and non-surgical (i.p. voice therapy) modalities. An

ideal approach would be to soften the scar, because the

reduced pliability and consequently the increased vibratory

rigidity impede the easiness of vibration. The chosen

phonosurgical method is determined by the main clinical

feature: Medialization techniques for the treatment of

glottic gap, or epithelium freeing techniques for improve-

ment of vibration characteristics often combined with

injection augmentation or implantation. In severe cases,

buccal mucosa grafting can be an option. New develop-

ments, include treatment with anxiolytic lasers, laser

technology with ultrafine excision/ablation properties

avoiding coagulation (Picosecond infrared laser, PIRL), or

techniques of tissue engineering. However, despite the

promising results by in vitro experiments, animal studies

and first clinical trials, the step into clinical routine appli-

cation has yet to be taken.

Keywords Phonosurgery Vocal fold scars Sulcusvocalis Vergeture Vocal fold medialization Micro-flap

G. Friedrich M. Gugatschka (&)Department of Phoniatrics, ENT University Hospital Graz,

Speech and Swallowing, Medical University Graz,

Auenbruggerplatz 26, 8036 Graz, Austria

e-mail: [email protected]

F. G. Dikkers

Department of Otorhinolaryngology, University of Groningen,

University Medical Center Groningen, Groningen,

The Netherlands

C. Arens

Department of Otorhinolaryngology, University Hospitals

Magdeburg, Otto-von-Guericke University, Magdeburg,

Germany

M. Remacle

Louvain University Hospital of Mont-Godinne, Dinant, Belgium

M. Hess

Department of Voice, Speech and Hearing Disorders, University

Medical Center Hamburg-Eppendorf Hamburg, Hamburg,

Germany

A. Giovanni

Service ORL Et Chirurgie Cervico-Faciale, Centre Hospitalier

Universitaire La Timone, Marseille, France

S. Duflo

Department of Otorhinolaryngology, Head and Neck Surgery,

University Hospital of Pointe A` Pitre, Guadeloupe, France

A. Hantzakos

1st Department of Otolaryngology, Head and Neck Surgery,

University of Athens Medical School, Hippokration General

Hospital, Athens, Greece

V. Bachy

Department of Head and Neck Surgery, Division

Otolaryngology, Catholic University of Louvain at Mont-

Godinne, Louvain, Belgium

123

Eur Arch Otorhinolaryngol

DOI 10.1007/s00405-013-2498-9

HessHervorheben

technique Buccal mucosa grafting Laser Tissueengineering

Introduction

Vocal fold (VF) scarring results from an injury to the lay-

ered structure of the VF and leads to a significant impair-

ment in vibration characteristics. It alters its visco-elastic

properties and leads to a dysphonic, often breathy and little

sustainable voice and has a considerable impact on the

quality of life. Main features of VF scarring are disorga-

nized collagen and elastin bundles, loss of important ECM

(extra-cellular matrix) constituents, volume deficiency,

reduced VF pliability and glottal insufficiency [1]. The

treatment of scarred VFs is still an unresolved chapter in

laryngology and is mainly caused by the highly complex

micro-structure of the VFs, especially the tri-layered

structure of the human lamina propria. Comprehensive

knowledge about this highly specific ultra-structure and the

molecular mechanisms of VF injury are the background for

every profound treatment modality. Research in this field

has emerged the last years, giving deeper insights and new

understandings of the complex interplay between interstitial

proteins (e.g. fibronectin, decorin, fibromodulin), glycos-

aminoglycans (e.g. hyaluronic acid [HA]) and various

extracellular matrix fibers (e.g. collagen, procollagen,

elastin) [1, 2]. The proportions, relationship and organiza-

tion of ECM components determine to a large degree the

biomechanical properties of the VFs. However, main focus

of research and experiments was on animal trials, with only

a handful studies carried out in humans [3, 4].

In his landmark paper, Minoru Hirano described the

body-cover model of phonation as the morphological basis

for self-sustaining periodic VF vibrations and a conse-

quently undisturbed voice sound [5]. Epithelium, basement

membrane zone [6] and the superficial layer of the lamina

propria (SLP) form the cover. They share similar

mechanical properties and behave collectively as one

functional unit. The deep layer of the lamina propria (DLP)

is firmly attached to the vocalis muscle, both are referred to

as body. The transitional zone lies between the two and

consists of the middle or intermediate layer of the lamina

propria (MLP) (Fig. 1a). This specific architecture with

two functional units enables the superficial cover to oscil-

late independently from the deeper lying body. The amount

of tissue in vibration depends on pitch, loudness, but is also

influenced by age [7].

The basement membrane zone serves as junction

between epithelium and lamina propria. Gray et al. [6]

described collagenous anchoring fibers in the basement

membrane zone that help in securing basal cells to the SLP

(Fig. 1b). The SLP is also known as Reinkes space. This

important structure plays a crucial role in decoupling the

mucosal cover from the VF body. Reinkes space is absent

at the anterior commissure and the posterior end of the

VFs. Situated at both extremities of the VFs are the nuclei-

rich centres of proliferation, the anterior and posterior

macula flava [811]. The superficial layer consists mainly

of amorphous material, with only few collagen and elastin

fibers. The intermediate layer is characterized by a higher

amount of elastic, the deep layer by an increased amount of

collagenous fibers [7]. This laminated structure is present

in the freely vibrating membranous mid-part of the VF, but

changes its structure near the attachments of the VF to the

anterior and posterior macula flava (syn.: nodulus elasti-

cus). These transition zones consist of interwoven bundles

of collagen and elastic fibers, having the function of a

cushion ball during vibration [12]. Tillmann et al. [13]

compared these structures with a traction spring that pro-

tects the attachments of the VF and balances the different

elasticities between the vibrating VF and the stiff laryngeal

framework. The lengths of the different zones show sig-

nificant sex related differences [9] (Fig. 2). The delicate

architecture has not only functional consequences in terms

of voice outcome, but has a significant impact on surgery

of the VFs. Phonosurgery of the SLP generally heals better

than surgery that penetrates into the deeper layers [14].

Micro-physiology of vocal fold injury

The cell-rich maculae flavae can be considered as the cell

reservoir of the VFs. These areas play a crucial role during

growth [15, 16], but also in both acute and chronic

inflammation processes. Throughout the VFs, few spindle-

shaped fibroblasts are present. They are mainly inactive

under normal conditions. In contrast, the morphology and

quantity of fibroblasts in the anterior and posterior macula

flava differ significantly: Stellate-formed fibroblasts can be

found here that actively synthesize collagenous, elastic and

reticular fibers, as well as the glycosaminoglycan hyalu-

ronic acid (HA) [17]. More recent studies proved the

presence of stem cells in these areas: Studies in rats VFs

showed that stem cells migrate after injury from the mac-

ulae flavae to the region of the lesion with a peak after

57 days [18, 19]. Ultrastructural studies of scarred ferret

VFs described larger fibroblasts as compared to those

found in normal VFs. These are assumed to be myofibro-

blasts that produce abundant amounts of type I collagen

[20].

Collagen fibers have been regarded as the most impor-

tant constituent in scar tissue [21]. Collagen synthesis was

found to be unregulated between 3 and 6 weeks post-

injury. In contrast to normal VFs, where collagen fibers run

parallel to the epithelial lining, this characteristic


123

organization is lost and replaced by deposits of thick col-

lagen bundles throughout all layers of the lamina propria.

Their density is significantly reduced as compared to nor-

mal VFs [21, 22]. The precursor of collagen, procollagen 1,

was found to be increased in the SLP of injured VFs.

Although levels of procollagen one decreased to pre-injury

levels after 6 months, densities of collagen remained ele-

vated [21]. Native collagen type 3, which is of finer caliber

and the predominant type before injury, is replaced

throughout the healing process by the molecularly and

microscopically different collagen type I [23]. Elastin was

found to be reduced in VF scars with its architecture

scattered [1, 24].

Levels of HA have a significant impact on viscoelastic

properties of the VFs and play a decisive role in wound

healing and scarring [25, 26]. It has been shown that ele-

vated levels of HA favor wound healing and diminish

scarring as can be observed in scarless fetal wounds [27].

HA plays an outstanding role in determining the biome-

chanical properties of the VFs. The removal of HA led to

increased viscosity and reduced stiffness with detrimental

effects on oscillation behavior [26]. Experiments in rabbits

revealed decreased levels of HA during the 1 days after VF

injury, although a relative peak was found after 5 days

when compared with uninjured VFs. This decrease is

thought to play a negative effect on wound healing and

may contribute to formation of scar tissue [27]. However,

one has to keep in mind that in experiments of chronic scar

formation significant differences between various animal

studies can be found [3].

Fibronectin is a glycoprotein of the ECM that acts as an

adhesion and migration molecule during repair processes. It

furthermore acts chemotactic for inflammatory cells and

fibroblasts and contributes to matrix organization [2]. In

Fig. 1 Layered structure of the vocal folds (a) and basement membrane zone according to Gray (b) [6]


123

normal VFs this glycoprotein is usually found in the basement

membrane zone and SLP. Levels of fibronectin remained

elevated as long as 6 months after injury in VF tissue (rabbit

and canine experiments) [28]. Recent studies suggest a com-

plex interplay of numerous other glycoproteins. Increased

levels of fibronectin are associated with elevated levels of

collagen synthesis (due to decreased fibromodulin, which

allows collagen regulation) and disorganized collagen depo-

sition (due to decreased decorin) [2]. Decorin is another

adhesion molecule of the ECM that maintains collagen fibril

organization. It is assumed to inhibit cell adhesion and

migration through interactions with beta-integrins. Decorin

density was significantly reduced in scarred rabbit VFs

60 days after injury [29]. It is currently assumed that adequate

levels of decorin counteract the disorganized structural

regrowth of collagen fibers into scar tissue.

Etiopathogenesis

Origins of VF scarring can be either congenital or acquired,

with the last one to be far more common. Bouchayer and

Cornut published 1985, an elaborated concept of congenital

VF lesions, suggesting epidermoid cysts as a common

cause for different pathologic conditions [30] (Fig. 3).

They hypothesized that epidermoid cysts result from

residuals of the fourth and six branchial arches. According

to their theories sulcus vocalis and what they refer to as

vergeture, results from a rupture of those epidermoid cysts.

If the ruptured VF cyst penetrates on both sides (superior

and below the free margin of the VF) the mucosa between

these two openings turns into a mucosal bridge [30, 31].

They underlined their theory with the typical early onset of

this kind of dysphonia during childhood, familial occur-

rence, simultaneous findings of multiple lesions in both

VFs and association with other malformations, such as

pathological vessels and micro-webs.

Ford classified sulcus vocalis into three subtypes [32]:

type I is a physiologic variant accentuated by atrophy, but

with intact lamina propria and an undisturbed mucosal

wave. Type II (sulcus vergeture) is characterized by dis-

appearance of a functional SLP. In most cases, the bottom

of the vergeture is attached to the vocal ligament and leads

to moderate dysphonia. Type III true sulcus (pouch)

Fig. 2 Absolute and relative dimensions of the glottis and their sex related differences. Zones: I lat wall of the post glottis, II vocal process, IIIpost macula flava, IV freely vibrating midpart, V ant macula flava. Asterisks indicate statistically significant sex related differences (p \ 0.05) [9]


123

extends more deeply into the vocal ligament and may even

penetrate into the thyroarytenoid muscle. It disrupts the

mucosal vibration and leads to severe dysphonia [33]. The

incidence of sulcus vocalis seems to be considerably high:

a recent study performed in 100 cadavers found sulcus

vocalis in 39 cases with a pathological sulcus vocalis rate

of 23 [34].

Other authors have suggested that sulcus vocalis is

acquired and results from local trauma and/or chronic

inflammatory processes [35, 36]. Sato and Hirano [37]

demonstrated that sulcus vocalis is associated with a

degeneration of fibroblasts in the macula flava. Collage-

nous and elastic fibers, synthesized by fibroblasts in the

maculae flavae, were decreased. They described the pres-

ence of many abnormal elastic fibers in the maculae flavae.

This mechanism is similar to the age-related degeneration

of the VFs. Giovanni [33] concluded that congenital and

acquired lesions are complementary and that the decisive

link is a specific weakness in the regulation mechanisms of

fibrous tissue in the VF.

The most common cause for VF scars are sequelae after

traumatic injuries by heterogenic mechanisms including

external laryngeal trauma (fracture), internal laryngeal

trauma (intubation) and phonotrauma as well as phono-

surgery. In cancer surgery extended resection of VF tissue

with consecutive heavy scarring is mostly inevitable.

Surgery for benign VF lesions has to avoid this by any

means by carefully respecting phonosurgical principles, as

inadequate techniques and wrong indications can have

disastrous consequences for the patient [38, 39]. Special

care must be taken of the very trauma-sensitive SLP. A

study by Martinez-Arias et al. [40] reported on adherent

epithelium to the deep VF tissue after laser-assisted surgery

(CO2 laser scanning technology) of benign lesions in 12

patients. Thermal trauma can damage the delicate lamina

propria very easily. On the other hand, carefully conducted

studies by Benninger [41] and Remacle [42] could prove

that there are no differences in the functional outcomes

between CO2 laser and cold instrument surgery in benign

VF lesions when proper settings and techniques are used.

Other causes for acquired VF scars are chronic inflamma-

tory processes due to laryngo-pharyngeal reflux, smoking,

radiotherapy, toxic inhalants etc. The aging process of the

VFs does not necessarily lead to scars, but very often to

similar conditions by a combination of VF atrophy and an

accumulation of lifelong traumas.

One must state, however, that there is no general accepted

classification of VF scars. Benninger et al. [43] distinguished

the following causes of VF scarring: traumatic, neoplastic,

iatrogenic, inflammatory and miscellaneous.

With respect to the severity of scar formation, Arens and

Remacle [44] divided glottic scars into four types:

Type I Mild to moderate glottic insufficiency and

reduced vibrations of the vocal folds. The scar involves the

mucosal and submucosal levels of the vocal fold.

Type II Anterior moderate glottic insufficiency, seen

around the anterior commissure region. The scar involves

the vocalis muscle. No vibrations of the VF.

Type III Considerable glottic insufficiency. The scar

formation is adherent to the inner perichondrium and the

cartilage. The defect extends up to the supraglottic region,

twisted arytenoids may be noticed.

Type IV Considerable glottic insufficiency. Web for-

mation at the anterior commissure region. Bilaterally

reduced vibrations of the VFs.

Diagnosis

Patients usually present clinically with long lasting dys-

phonia, vocal fatigue, loss of vocal control and a breathy,

little sustainable, dysphonic voice. In addition to a thor-

ough medical history, meticulous laryngoscopy and vid-

eolaryngostroboscopy using rigid and/or flexible

endoscopes are indispensible for a proper diagnosis. Some

of the scars can be apparent and evident, thus needing

little effort to identify, as in cases following cordectomy.

Others can be difficult to assess as in cases of sulcus and

subepithelial adhesions.

Fig. 3 Congenital lesions according to the concept of Bouchayer andCornut [30]


123

Two major clinical features are typical for scarring: (1) a

spindle-shaped glottis during phonation with insufficient

glottic closure and air leakage and (2) an impaired VF

vibration with reduced amplitude and reduced or mostly

absent mucosal wave. Vibrations are mostly asymmetric

and irregular. Especially when it comes to planning of

treatment, it is essential to distinguish between two major

findings: rigidity and/or insufficient glottic closure. Addi-

tional signs that should raise attention are: dilated or

pathological vessels on the surface of the VFs, thickening

of the epithelium, chronic inflammatory signs, or supra-

glottic hyperfunction.

It is important to take into consideration that minimal

lesions maybe easily overseen in indirect laryngoscopy or

by stroboscopy and that these patients are often misdiag-

nosed with functional dysphonia. Especially in cases of a

very aperiodic voice signal, high-speed cinematography or

kymography can provide valuable additional information.

For exact diagnosis and therapeutic planning, a direct mi-

crolaryngoscopy with palpation of the VFs with microin-

struments is a prerequisite [33] (Fig. 4a, b). A full voice-

lab work up including voice recordings, auditory percep-

tual analysis and patient-perceived outcome measures (i.e.

voice handicap index VHI) is regarded standard before

treatment [45].

Treatment

Because surgical treatment is usually very difficult and the

therapeutic outcome is to some extent unpredictable, con-

servative therapy should be the first line of treatment.

Voice therapy alone can be effective and satisfactory, but it

might also be given as a supplementary postoperative

treatment modality. It is usually based on the traditional

holistic concepts primarily focusing on resonatory voice

and breath supported voice coordination. Anti-reflux ther-

apy, antibiotics and steroids occasionally play a role in

prophylaxis and early management of scarring [43]. A

variety of treatment options have been developed in the last

decades. Despite all efforts, it has not been possible to date

to completely restore an unaltered VF structure and oscil-

lation. From a functional view, the SLP is the crucial

structure of the VF and the creation of a new gliding zone

remains one of the major unsolved problems in

phonosurgery.

The patient has to be informed meticulously that the

options for improving the voice sound are very limited and

that the major aim of all therapeutic procedures is primarily

to increase loudness and vocal endurance and furthermore

to reduce air loss and vocal fatigue [38]. Surgery should not

be performed within 6 months after the formation of scar

when the healing process is not yet complete [40]. As the

objective of surgery is to improve glottic closure and pli-

ability of the VFs, the treatment facilities should be ori-

entated towards the main clinical feature, either glottic gap

and/or rigidity.

Medialization procedures

In cases, where an insufficient glottic closure is the pre-

dominant finding, medialization procedures proved to be

very effective. These can either be performed with medi-

alization thyroplasty or injection augmentation.

Medialization thyroplasty

The principle of medialization thyroplasty is to excise a

thyroid cartilage window corresponding to the position of

the VF in the endolarynx and to insert an implant through

this window which medializes the VF (Fig. 5). The main

advantage of these techniques is to achieve a spatial reor-

ganization of the glottic framework without touching the

VFs directly thus avoiding any trauma to the VFs with

potential scarring and stiffening. This is of special impor-

tance in previously scarred VFs, as thyroplasty usually are

Fig. 4 Vergeture (a) and mucosal bridge (b) during explorative direct laryngoscopy (not visible in indirect laryngoscopy)


123

reversible and hence the danger of postoperative voice

deterioration is minimal as compared to direct VF surgery.

Isshiki [4648] introduced a hand-carved silastic bloc

which is still widely used. Nevertheless, a variety of sur-

gical modifications and different implants regarding

material and shape has been developed over time [4953].

The major indication for medialization thyroplasty is a

unilateral VF paralysis, but its effectiveness has also been

proven in glottic insufficiency due to atrophy and/or scar-

ring [33, 5458]. In cases of bilateral VF bowing, the

implantation procedures can be performed bilaterally. The

implant stays in place and ensures a permanent improve-

ment even in larynges with normal mobility, where injec-

ted materials usually tend to spread [47, 59]. In very stiff,

VFs a combination of medialization thyroplasty and

relaxation laryngoplasty can lead to further voice

improvement. A special advantage of laryngeal framework

surgery under local anesthesia is that it allows a fine tuning

by listening to the positive change happening to the voice

of the patient on table while performing different frame-

work surgery procedures in combination [47, 55].

Especially for VF medialization after chordectomy,

Sittel et al. [60] developed a procedure where after resec-

tion of the upper rim of the thyroid cartilage a subper-

icondral pouch is created. The harvested cartilage is re-

implanted in that pocket to achieve a VF augmentation and

consequent voice improvement.

Injection augmentation

Injection augmentation was introduced by Brunings [39] in

1911 and was the first real phonosurgical procedure ever. It

was primarily designed for the treatment of unilateral VF

paralysis. A large number of injectable fillers have been in

use over time, which indicates that there is still no ideal

substance for injection augmentation available [61]. Usu-

ally, fillers are injected under general anesthesia during

microlaryngoscopy, but office-based procedures become

increasingly popular particularly for temporary injections.

In a multi-institutional retrospective study, Sulica et al.

[62] reviewed 460 patients with regard to the current

practice in injection augmentation in the US. Out of the

460 patients, nearly half were treated in the operating

room, whilst the other half were treated unsedated in

office-based procedures (transcricothyroid approach, per-

oral approach, transthyrohyoid approach, or transthyroid

cartilage approach). The indications were paralysis in 75 %

VF, VF atrophy in 15 % and scar formation in 10 %. Scar

was more likely to be treated in the operating room.

Basically, two groups of fillers can be distinguished: allo-

plastic and autologous/xenogenic materials.

In general, alloplastic materials are non-biodegradable

fillers aimed to stay in place permanently. They have the

disadvantage that in case of an unfavorable postoperative

result (e.g. by inadvertent placement) the removal of the

injected substance is difficult and leads to severe trauma of

the VF. In addition, long-term side-effects, such as foreign

body reactions, or granuloma formation cannot be totally

excluded, as observed in cases of silicone injections or of

the meanwhile obsolete Teflon [63]. These substances have

to be injected far lateral near to the thyroid cartilage

(internal thyroplasty). A superficial injection must be

strictly avoided as this might lead to a stiffening of the VFs

with resultant dysphonia (Fig. 6a, b). Alloplastic fillers

currently approved for VF medialization are Vox Implant

on a silicon basis (polydimethylsiloxane particles) [64] and

Radiesse on a calcium hydroxylapatite basis [65]. Allo-

plastic fillers did not show promising results in the treat-

ment of VF scars, where laryngeal framework surgery

proved to be superior [66].

Following the application in urology, Sittel et al. [64]

introduced, among others, the use of textured poly-

dimethylsiloxane particles (PDMS particles: Vox

Implant) in the human larynx for injection augmentation.

With the desirable viscoelastic properties near to Teflon,

PDMS particles did not show the detrimental tendency of

implant migration and foreign body reaction. This is due to

their biomechanical properties of a particle size of about

200 lm that prevents from being phagocytosed. As theimplant procedure is irreversible, injection under general

anesthesia is generally recommended. Improvement of

voice outcome and acoustic parameters were described

similar to those of framework surgery [67]. However, long-

term studies dealing with persistence are lacking in this

field.

Synthetic calcium hydroxylapatite (CaHA: Radiesse

Voice) is available as Radiesse Voice [65]. Among its

favorable characteristics are its biological inertia and easy

application even through a small-gauge needle. Carroll and

Rosen [63] proved its excellent rheological properties, as

well its longevity. Average length of benefit was

19 months in 108 patients. Complications included theo-

retically (as in most fillers) implant migration, granuloma

formation, VF mucosa irregularities, allergic reactions and

Fig. 5 Principle of vocal fold medialization by medializationthyroplasty


123

ectopic calcifications. In the aforementioned study, only

one case of implant migration was described in 108

injections, which required surgical removal. As with other

permanent fillers, only patients with permanent paralysis of

the VFs are supposed to be treated. In cases, where a nerve

recovery is suspected, short-term treatment (suitable for

12 months) by an injectable consisting of synthetic

polymers (carboxymethylcellulose) without CaHA micro-

spheres became recently very popular (Radiesse Voice

Gel) [68].

Autologous materials have the big advantage of pro-

viding usually excellent biocompatibility, but are charac-

terized by a certain resorption rate depending on the

material and site of injection.

The most common autologous fillers used so far for

treatment of VF scarring are autologous fat and fascia.

Numerous papers have been published dealing with fat

injection, with a strong preference on lateral fat injection

compared to implantation near the vibratory margin [69].

Fat autografts are easy to harvest and show only minimal

immunological reactivity [70]. Animal studies demon-

strated improved (decreased) threshold pressures of pho-

nation, increased sound intensity and more effective

acoustic output [71]. Furthermore, Titze et al. [72] showed

that fat injections are favorable to collagen, or Gel-Foam

because its viscoelastic properties are closer to human

mucosa. A retrospective literature review from 2009

proved this method to be very safe, with over-injection of

fat as a reversible complication in only three, and only one

single case of granuloma formation out of totally 88

patients [73]. One single paper reported neck abscess fol-

lowing lipoinjection [74].

Glottic gap insufficiency diminishes after injection as

the VF is placed medially and additional bulk is added to

the VF. Videostroboscopic studies underline this

significantly [7577]. Videostroboscospic parameters of

the aforementioned studies included mucosal wave propa-

gation, stiffness (both improved), length of scar and ectasia

(both no improvement). In addition, acoustic and percep-

tual improvements were reported by the same authors. The

results showed an overall mean increase in fundamental

frequency and phonatory time, whereas jitter and shimmer

values decreased. Breathiness improved in most studies [2,

77].

Rihkanen [78, 79] introduced in 1998 the injection of

minced autologous fascia primarily for treatment of VF

paralysis. Fascia [80] is either used alone as an implant, or in

combination with fat [81]. Here again, satisfying results

have been described stroboscopically regarding a sufficient

glottic closure, mucosal wave, amplitude, breathiness and

overall voice rating. Nevertheless, a laterally placed over-

injection of about 30 % was recommended as fat is reab-

sorbed to a certain degree [75, 82, 83]. In contrast to fat

injection, fascia grafts seem to survive longer as shown by

good voice results even after 36 months [80]. Reijonen et al.

[80] showed stable results after injection over 310 years.

Collagen-based fillers were introduced in the late 1980s

[84, 85]. Due to its bovine basis, potential immunologic and

infectious reactions remained the main objective to use these

fillers. Later on injectable, autologous collagen derived from

human skin from cadavers was introduced (Cymetra).

These were classified as level IV human allografts by the

World Health Organization. However, Hertegard et al. [83]

found comparable outcomes for collagen and hyaluronic

acid in terms of voice improvement, resorption rates and

side-effects. At the moment, collagen is no longer com-

mercially available in the majority of countries.

Hyaluronic acid (HA) is a glycosaminoglycan that is

present in the extra-cellular matrix of most tissues

throughout the body, including the VF mucosa. Several HA

Fig. 6 Lateral injection for vocal fold augmentation (a), situation after false medial injection of polydimethylsiloxane causing vocal foldstiffness during surgical removal (b)


123

derivatives have been developed and some are in laryng-

ological use mostly in Europe. Modern HA products are of

bacterial origin and chemically cross-linked to ensure low

antigenicity and long residence time. The grade of cross-

linking can be tuned bio-chemically thus determining the

rate of degradation and hence durability and viscoelasticity

[86]. Minimal inflammation could be seen after injection,

although durability in tissue can be up to 1 year with cer-

tain products. Furthermore, HA showed to have positive

effects on viscoelasticity of scarred VFs in rabbit trials [87,

88]. First in vivo trials in humans showed that auto-

crosslinked hyaluronan gel injections into the lamina pro-

pria not only act as an augmentation agent, but also as an

anti-adhesive product. Postoperative adhesion and scar

formation was significantly reduced by deposition of HA

derivatives in the lamina propria [8991].

Implantation augmentation

This kind of surgery is indicated when glottic or transglottic

scars with a huge substance gap are present (see thyro-

plasty). The connective tissue underlying the mucosa may

be adherent to the thyroid cartilage. During microlaryn-

goscopy or transcervically, a vocal pouch at the inner sur-

face of the thyroid with its maximum at the glottis level is

created. Scars can be freed or dissected. The pouch is filled

up with cartilage (nasal septum, thyroid cartilage) or fascia

lata. After sufficient augmentation, the pouch is closed with

microsutures to stabilize the implant. The procedure can be

performed in several steps to get a sufficient glottis closure

and improvement of the patients voice [44].

Epithelium freeing techniques and combined

approaches

When rigidity is the major feature, the mucosal wave can

beat least theoreticallyrestored by lysing the scarred

mucosa and creating a new lose layer between the epithe-

lium and the vocal ligament to restore the bodycover

relationship. The introduction of the microflap and later

mini-microflap has revolutionized microphonosurgery as it

respects the layered structure of the VF [92, 93]. A sub-

epithelial saline injection prior to surgery can be very

helpful in this respect to define a dissection plane [94, 95].

Especially for treating sulcus vergeture Bouchayer and

Cornut [96, 97] introduced the freeing of the mucosa

(better: epithelium) technique. After careful dissection of

the epithelium and resection of pathologic tissue, the flap is

turned back and fixated with fibrin glue [30]. With the help

of locally injected cortisone and long-term voice therapy,

they reported good functional results with a re-appearance

of mucosal wave in a high percentage of cases.

Using a micro-flap technique, the flap is usually fixed by

with fibrin glue or micro-sutures (Fig. 7ac). In general,

both methods are considered to be equal in outcome and

the choice is mostly the surgeons individual preference.

Application of commercially available fibrin glue, such as

Tissucol, is impossible in the USA, as it is not FDA (food

and drug administration)approved. Fleming et al. [98]

could show in an animal study that primary closure of

micro-flaps with micro-sutures resulted in less scarring

compared to not closed wounds. This result does not nec-

essarily mean that suturing is superior to glueing, but

proves the importance of covering all denuded areas with

epithelium especially near the vibratory margin. The major

disadvantages of this technique are on the one hand

unpredictable re-adhesion or even the creation of new scars

as no filler or tissue is used for replacement of SLP. On the

other hand, this treatment does not address the glottic gap,

which usually also is present and adds substantially to the

degree of dysphonia. To overcome these shortcomings and

to improve the results, freeing techniques are mostly

combined with injections or implantations that should not

only medialize the VFs but also restore the SLP.

Fig. 7 Freeing of the epithelium: Incision (a) and subepithelial removal of the scars (b), flipping back the epithelium and wound closure withfibrin glue and/or micro-sutures (c)


123

Injections are performed superficially (medial injection)

and the injectables should not only act as fillers, but also

create a new soft and pliable layer for restoration of the

mucosal wave propagation (Fig. 8). Predominately, autol-

ogous fat and low-grade crosslinked HA are used for this

purpose. Recently developed substances in this regard

seem to be Extracel [90] or Carbylan-GSX. The latter is a

filler composed of modified HA and gelatine. The presence

of Carbylan-GSX in the wound bed during the early

stages of repair amplified the normal VF wound-healing

response over a short period of time in rabbit studies [99].

Martinez-Arias et al. [40] follow the same principles but

prefer the CO2 laser scanning technology for raising the

microflap and inject collagen into the deep layer of the

lamina propria. Promising results were reported by Zhang

et al. [100] by implantation of a gelatine sponge combined

with autologous fat for treatment of sulcus vocalis.

Although the absorbable gelatine was used to fill the SLP

to prevent re-adhesion of the detached epithelium, the fat

diminished the glottic gap. With a new laser technology on

the horizon, it is possible to apply ultrafine dissections and

excisions on a cellular level with a pulsed infrared laser at

3 lm. In excised tissue experiments, pulses in the range of100 picoseconds showed tissue destruction only a few

microns from the dissection line away with virtually no

coagulation zone [101].

Because liquid substances do not remain in the micro-

dissected SLP, Finck introduced esterified hyaluronic acid

as implant into the elevated pocket with excellent results

regarding pliability and mucosal wave [102]. To bring a

healthy and autologous tissue layer between the pathologic

body and cover, which should provide enough cells to

proliferate and renew the pathologic space, Tsunoda et al.

[103] considered the implantation of autologous veins or

fascia as most promising (Figs. 9, 10ad). Based on their

experiences with implantation of autologous fascia,

Tsunoda et al. [104] found that 6 months after the opera-

tion there was a consistently improved glottic closure and a

further improvement was recognized after 1 year. At that

time, stroboscopy showed excellent glottic closure

including satisfactory mucosal wave propagation during

phonation. After 3 years of surgery, the presence of

mucosal waves remained at those excellent levels. No

critical complications of the procedure could be observed.

Autologous transplantation of fascia can induce not only

survival but also regrowth of the epithelium. In summary,

they concluded that autologous transplantation of fascia is

a successful surgical procedure for sulcus vocalis and

scarred VFs.

Dedo [105] introduced the concept of fat grafting for

construction of a neo-vocal fold after hemilaryngectomy

and reported good results. Sataloff et al. [75, 106] devel-

oped a minimal invasive technique with the creation of

subepithelial tunnels by elevating the scarred mucosa using

blunt and sharp microinstruments. The fat is inserted into

these pockets with a forceps or a laryngeal syringe with a

large diameter needle. The procedure itself resolves the

scar by elevating the mucosa which restores the cover-body

relationship to the VF by the low-viscosity characteristics

of fat. They found an improved wavelike vibration pattern

with more regular periodicities at the free margins.

In an experimental canine study Woo et al. [107]

implanted fat into a submucosal pocket and closed the flap

with microsutures. Larynges were harvested after 6 weeks.

Endoscopic placement of fat into Reinkes space served as

a filler that increased the VF bulk and showed good

vibratory characteristics with restoration of Reinkes layer.

A novel and different approach for the treatment of

sulcus was introduced by Pontes et al. [108] with the

slicing mucosa technique which interrupts the longitudinal

fibrotic tension lines by multiple transverse incisions.

Mucosa grafting

In cases, where the loss of tissue and the amount of scar

formation is so significant that there is no chance forFig. 8 Medial injection into the lamina propria for medialization andrestoration of a new gliding zone

Fig. 9 After freeing of the epithelium, a subepithelial implantation offascia is performed followed by a wound closure with a micro-suture


123

restoration using one of the aforementioned techniques free

buccal mucosa grafting can be an option. Neumann [109]

has used this transplant technique in the 1970s with an

open technique for the treatment of various scar-induced

lesions. Isshiki [110] described in his textbook one similar

case with an open technique via a laryngofissure. The

transplant was fixed in the endolarynx with a rubber stent

for 10 days. In 1990, the first author developed an endo-

laryngeal technique to fixate an autogenous buccal mucosa

graft that does not require a tracheostomy like the afore-

mentioned techniques [111, 112]. This technique can be

used for restoration of the anterior commissure and/or

replacing the VF mucosa. The rationale behind this tech-

nique is to bring healthy, unscarred tissue into the scarred

endolarynx with the aim to create a new vibrating structure

and to fill up tissue defects. First, the area of acceptance has

to be de-epithelialized, favorably using the CO2 laser in the

scanner mode. Oral mucosa is harvested from the inner

cheek. The thickness of the transplant can be chosen

according to the requirements: very thin when only epi-

thelium has to be replaced or full thickness mucosa for

filling up defects. To secure the transplant in the larynx, the

buccal mucosa graft (raw surface outside) is sutured on a

silastic sheet (0.5 mm, fabric reinforced) with Vicryl rapid

3/0. The entire sandwich-graft is attached with one or

two endo-extralaryngeal suture(s) with the Lichtenberger

needle carrier using Prolene 2/0 onto the raw surfaces of

the larynx. The suture is knotted on the skin over an elastic

bolster made out of a folded sheet of silastic which ensures

a good contact of the transplant with the recipient area

(Figs. 11ac, 12ad). After 3 weeks, the silastic sheet is

removed under general anesthesia and granulation tissue

formation can be removed in the same session with the

CO2 laser. It usually takes a few weeks to get a smooth

endolaryngeal surface. Reappearance of vibration takes

several months, but is not guaranteed in every case. If

necessary an additional augmentation or medialization

thyroplasty can be performed after 612 months.

Angiolytic laser

A novel and promising approach for the treatment of scars

is the use of angiolytic lasers i.e. PDL (pulse dye laser) and

PTP (potassium-titanyl phosphate) [113, 114]. A growing

number of papers demonstrated a beneficial effect in

treating cutaneous scars. Although the exact underlying

mechanisms are not fully understood to date, experimental

trials described potential mechanisms of the laser effect,

which includes the development of a sub-basement mem-

brane cleavage plane, as well as up-regulation of proteins

which may actively modulate mature fibrosis [113]. One

prospective pilot study of 11 patients with VF scarring

Fig. 10 Implantation of fascia in a patient: incision and freeing of the epithelium (a), strip of fascia (b), implantation of fascia (c), micro-sutures(d)


123

treated with the PDL showed statistically significant

improvement in subjective and objective voice measure-

ments, as well as in laryngeal stroboscopy findings [115].

Tissue engineering

Newer therapeutic approaches aim to restore function on a

cellular basis. These studies are often still under experi-

mental investigation, but larger preclinical studies have

been performed, e.g. in the case of hepatic growth factor

(HGF) and treatment is to be expected soon [116, 117].

Modern clinical treatment facilities should not distinguish

between conventional surgery and state-of-the-art bioen-

gineered materials, but are supposed to combine both

approaches. As mentioned before, HA plays a central role

for both maintenance of biomechanical properties and

regeneration after VF injury. HA is degraded enzymatically

by hyaluronidases and has a half-life time of 0.54 days

Fig. 11 Buccal mucosa grafting (schematically): resection of the epithelium with laser (scanner mode) (a), situation after resection of theepithelium and scars (b), sandwich-graft (silastic sheets outside and buccal mucosa graft inside) fixated with an endo-extralaryngeal suture (c)

Fig. 12 Buccal mucosa grafting in a patient: situation after laserchordectomy (type V) with an anterior synechia and scarred substitution vocalfold (a); situation after resection of the synechia and epithelium with laser (b), sandwich-graft inserted and secured with (blue) endo-extralaryngeal sutures (c), 3 month postoperative, synechia is resolved and the fresh mucosa is vital and well integrated, glottic closure and voicesignificantly improved (d)


123

[118]. Experimental attempts tried to interfere chemically

with the enzymatic degradation of endogenous HA. Both

in vitro and in vivo experiments examined stimulation of

endogenous HA production by administration of external

growth factors; namely, epidermal growth factor (EGF),

basic fibroblast growth factor (bFGF), transforming growth

factor beta 1 (TGFb1) and the aforementioned hepatocytegrowth factor (HGF) [28, 117, 119, 120]. A significant

decrease in collagen deposition and an increase in HA were

noted in acute and chronic settings of VF injury after

injection of HGF in rabbits [116]. Noteworthy, also normal

rat VFs were found to express HGF. In injured rabbit VFs

elevated levels of HGF were detected peaking at day 10 in

the regenerative epithelium [121]. The previous studies

showed that also single administrations of EGF, bFGF and

TGF b1 raised significantly levels of HA for at least 7 days[119]. In fact, treating VF atrophy (with decreased levels of

HA) with fibroblast growth factor has already been applied

in humans with considerable success [122].

Another possible molecular target are factors that con-

trol the phenotype transformation from fibroblasts to

myofibroblasts. One important key molecule is TGF-b, afactor that is released by inflammatory cells, triggering the

Smad signaling pathway of fibroblasts [123]. Numerous

models targeting inactivation of this pathway have been

established to date [124]. Cell therapy might be the most

powerful tool for treatment of VF scarring. Recent studies

showed highly promising results in the treatment of scarred

rabbits VFs with human mesenchymal stem cells in a

xenograft model. The injected stem cells did not survive

longer than 3 months, but showed beneficial effects in

acute and chronic settings. Improved vibration character-

istics with reduced lamina propria thickness and decreased

amounts of type I collagen deposits were found in these

series [87, 125]. But also autologous stem cells derived

from the bone marrow proved their feasibility in wound-

healing models in canines [126]. One has to mention,

however, that certain ethical considerations have to be

cleared up before the clinical use of stem cells. Further-

more, the risk of malignant transformation has to be

excluded before implantation of stem cells in humans.

Chhetri went one step further and injected autologous

fibroblasts into scarred VFs of five patients. They observed

improved outcomes after 12 months for mucosal wave

grade and VHI [127].

Conclusion

Because treatment of VF scarring still is a challenge, pre-

vention of scars especially after VF surgery for benign

lesions is of utmost importance. This has to be done by a

meticulous surgical technique carefully respecting the

principles of phonosurgery, which means improvement/

maintenance of the functional structure of the VFs by

respecting its layered structure, minimal excision of tissue,

no epithelial defects especially on the vibratory margin,

minimal trauma to the SLP.

An optimal result does not only require a skilled surgeon

with a broad armamentarium of surgical techniques and

procedures, but a multidisciplinary treatment approach

where phonosurgery must be combined with various non-

surgical methods in a complex treatment program. Most

authors agree that voice therapy should be mandatory not

only postoperatively but also as first-line treatment. Espe-

cially in the treatment of VF scars one should always

remember that phonosurgical interventions should never

simply focus on the appearance of the VFs, but aiming at

an improvement of voice adapted to the individual requests

and needs of the patient. As every surgery, it always bears

the risk of an unfavorable outcome with even worsening

the situation by additional scarring. Comprehensive coun-

seling and informed consent are therefore of outstanding

importance.

Because of the unpredictability of the results of the

surgical intervention, it is recommended to start always

with the least traumatizing procedure whenever possible.

This is usually injection augmentation using a re-absorb-

able material. It allows a good pre-estimation about the

result following a permanent medialization procedure and

has no substantial risk. Carroll and Rosen [128] described

this strategy as trial VF injection. Patients with a good

response to the temporary injectables went on to have

permanent augmentation more often than patients with a

lesser response. In unclear situations it is a good option to

inject saline solution directly in the office which gives an

immediate impression of the result of a medialization

procedure. It takes usually several months to restore a

minimal mucosal wave propagation and long-term post-

operative voice therapy is mandatory at least until

inflammatory processes are over. The maximum benefit is

not apparent until 45 months postoperatively [129].

Although complete restoration with a clear and sonorous

voice may not be achieved, surgery does improve glottic

closure reducing the air loss and increasing the loudness

and vocal endurance. Most of these patients feel an

improvement due to decreased voice fatigue and dysthesia

in the throat and an increased voice intensity. Although

improvement of glottic closure can be considered a realistic

goal addressing rigidity by restoration of a new SLP is one

of the future issues in phonosurgery. New developments

include the treatment with softening angiolytic lasers,

ultrafine excisional laser and especially, techniques of tis-

sue engineering including injection of various growth

factors, stem cells or implanting scaffolds. Despite the

promising results by in vitro experiments, animal studies


123

and first clinical trials, the step into routine clinical appli-

cation has yet to be done.

The literature dealing with treatment of VF scars is often

based on personal experience and there is a strong need for

prospective studies. One example in this regard is a work

published by Welham et al. [130]. In this multi-arm eval-

uation, they compared clinical effectiveness of type I thy-

roplasty, injection laryngoplasty, and graft implantation

(fascia). Despite significant improvements in all groups, he

concluded that no single treatment modality is successful

for the majority of patients and that there is a need for the

identification of predictive clinical features that can drive

an evidence-based treatment assignment.

Acknowledgments The authors would like to acknowledge ClausGerstenberger, PhD for his contribution in all graphic-design related

works.

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Vocal fold scars: current concepts and future directions. Consensus report of the phonosurgery committee of the European laryngological societyAbstractIntroductionMicro-physiology of vocal fold injuryEtiopathogenesisDiagnosisTreatmentMedialization proceduresMedialization thyroplastyInjection augmentationImplantation augmentation

Epithelium freeing techniques and combined approachesMucosa graftingAngiolytic laserTissue engineering

ConclusionAcknowledgmentsReferences

vocal fold scars current concepts and future directions

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