Vocal Fold Submucosa

The Scar Solution Natural Scar Removal

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Mark S. Courey

Physiologie Considerations

In order to produce efficient normal voice, the vocal folds must be able to achieve a nearly closed, parallel prephonatory position. This ability is regulated by neurologic input to the intrinsic laryngeal muscles, the bulk or mass of the vocal fold body and cover, and the structural and functional integrity of the cricoarytenoid joints. If any one of these systems is impaired, the prephonatory position is less than ideal and vibratory efficiency is compromised. Neurologic input to the thyroarytenoid muscles and the cricothyroid muscles also controls vocal fold tone. Efficiency of vibration is best when the vocal folds are matched in terms of this tone or tension.

If an adequate prephonatory position can be achieved, and the vocal fold mass and tone are nearly symmetric, then the vocal fold cover, the epithelium, and superficial layer of the lamina propria must be of sufficient viscosity to allow vibration. If the cover is stiff or deficient from scarring, air pressures required to initiate and sustain vibration will be increased. Patients will not be able to finely modulate vocal fold tone, their dynamic range will be compromised, and they will complain of increased phonatory effort.

Injection laryngoplasty with collagen, or most currently available substances for that matter, can increase vocal fold bulk, but will not restore the neurologic function required to balance vocal fold tone and cannot reduce the viscosity of the cover to improve its vibratory function. It is important for the surgeon to understand these limitations of injection laryngoplasty to allow better patient selection and better understanding of surgical outcomes.

Historical Considerations

Collagen was first reported for the management of glottic closure defects during the early 1980s [1]. In these original animal models and clinical reports surgeons used available forms of bovine collagen as a xenograft to reshape the vocal fold [2-4]. The reports were innovative and encouraging, but scientific evidence supporting the use of bovine collagen in this manner was scant and other surgeons were not able to achieve the same results.

The original forms of solubilized collagen were produced from bovine species and were intended for use in the management of dermal deficiencies [5]. Specifically for cosmetic dermal application, collagen was isolated from animal dermal material, purified, and then processed for injection into humans in the form of a xenograft. These bovine collagen compounds, with and without glutaraldehyde cross-linkages, were developed to be placed in the region of the mid-reticular dermis known to be deficient in aging skin. The collagen graft was designed to replace the natural deficiency with similar tissue. The addition of the specific concentration of glutaraldehyde cross-linkages to the collagen implant was hypothesized to increase host fibroblast invasion and neovascularization of the graft [6], Multiple reports emphasized ease of placement and the relatively stable results in skin augmentation [7-11]. After clinical trials, collagen compounds received approval of the U.S. Food and Drug Administration (FDA) for use in the correction of skin defects.

Despite the ease of injection and relative tolerance, the main objection to the use of bovine collagen products remained the potential host-vs-graft reaction to the xenograft protein material. A localized reaction to the xenograft was shown to occur in 3.5% of patients. In addition, delayed hypersensitivity was demonstrated in 1.3% of patients [3, 12-14]. These reactions resulted in localized erythema and induration. While less than desirable in dermal applications, this type of reaction could have potentially devastating results in the larynx or airway, an off-label use of bovine collagen products; therefore, it is recommended that patients have a small test dose planted in the forearm and be observed for 6 weeks prior to clinical use. This problem has always tempered the use of bovine collagen products, particularly in the larynx [14]. A comparison of collagen products is given in Table 8.2.1.

To address these concerns and eliminate the main objection to the use of bovine collagen - the unpredictable host/graft reaction - work with purified human forms of collagen was undertaken. During the early 1990s, the initial work was performed for dermal applications and recipients served as their own donors. Skin was harvested and collagen isolated from the dermal tissue. Reinjection into the same patient at another intradermal site revealed the autologous implants to be well tolerated and of 6-month duration [16,17]. Histologic evaluation of implants showed a minimal inflammatory reaction with ingrowth of native fibroblasts. With repeated application to the same region over a 6-month period, skin augmentation for the elimination of fine wrinkles was demonstrated to persist for up to 4years in limited case reports [18,19].

This same process for preparing autologous collagen was then evaluated for use in hu man vocal folds. Initial and subsequent clinical reports were encouraging, both in terms of tolerance and persistence of graft materials. Evaluation of vocal changes with perceptual, aerodynamic, and acoustical measures demonstrated limited improvements over a 6-month follow-up period [20-22]. In addition, limited numbers of animal studies demonstrated persistence of graft material with minimal foreign body reaction and ingrowth of host fibroblasts into the implanted material [23].

Despite promise for dermal and vocal fold augmentation, clinically, objections to the use of allograft material arose from donor site morbidity, the required delay in implant availability due to processing time, and the increased cost associated with individual graft preparation. To overcome these objections, purified forms of human collagen from cadaveric skin were developed during the 1990s [24, 25]. Homologous collagen compounds are currently available in both glutaraldehyde cross-linked forms and non-glutaraldehyde cross-linked forms. In addition, micronized dermis containing both collagen and elastin particles is also available for use [26]. While these substances have been given FDA approval for dermal augmentation, laryngeal application is still regarded as an offlabel application due to the lack of controlled clinical trials.

Technical Considerations

Due to the relative success of collagen for the management of dermal deficiencies, the rela-

Table 8.2.1 Comparison of collagen products

Substance

Source

Glutaraldehyde cross-linkages

Characteristics

Zyderm

Bovine

No

Superficial injection, relatively more rapid resorption

Zyplast

Bovine

Yes

Deeper injection, potentially longer lasting

Cosmoderm

Human

No

Superficial injection, relative rapid resorption

Cosmoplast

Human

Yes

Deeper injection, potentially longer lasting

Micronized alloderm, Cymetra

Human

No

Powdered form, reconstituted in clinic or OR. Contains elastin fibers

tivelylow risk of adverse reactions, particularly if human preparations are utilized, and the continued difficulty with other substances for the management of glottal insufficiency, otolaryngologists have continued to experiment with collagen as a substance for laryngeal augmentation by injection. For cosmetic applications, collagen preparations are injected into the midreticular dermis under direct visualization through a 27-G needle. By expanding the volume of the intradermal region, superficial wrinkles are filled in. Unlike the skin, however, laryngeal mucosal tissue must be supple to vibrate during voice production. In addition, vocal fold mucosa does not have a region analogous to the midreticular dermis. Due to these two technical problems, intramucosal laryngeal injection is different from intradermal injection. The simple addition of a filler substance to augment the vocal fold, while it may result in improved glottic closure, does not result in significant improvements in the viscosity of the mucosal membrane for voicing [27].

The original investigators of collagen for laryngeal augmentation suggested that placement of the collagen graft material within specific layers of the vocal fold significantly affected the results and longevity of the injection. They specified that the attempt should be made to place the collagen graft into the deeper layers of the vocal fold lamina propria, which they termed a superficial injection [4]. This was consistent with the concept for skin injections in which the goal was to place the collagen graft within the midreticular dermis. The vocal fold submucosa is roughly divided into three layers by variations in the concentration of the extracellular matrix proteins. The two deeper layers, termed the intermediate and deep layer, form the vocal ligament and are composed of primarily elastin fibers and collagen fibers, respectively. Morphometric evaluation from cadaver specimens in multiple studies reveals that the combined thickness of the intermediate and deep layers is less than 1 mm [28-30]. Injecting a region that is only 1 mm thick or less is technically challenging under any circumstances. The region can only be reached with a 400-mm needle placed transorally or a shorter needle inserted percutaneously through or under the thyroid cartilage, and this restricted access to a small site further complicates accurate placement.

Cadaver vocal folds were injected with collagen under direct visualization using 27-G needles to evaluate the ability to accurately place the collagen graft [31]. The goal was to place the collagen within the plane of the vocal ligament as had been suggested. Manufacturers' standards indicate that these needles are produced with a 400- to 6oo-^m-long bevel which represents roughly 50% of the size of the region to be injected. Histologic analysis revealed that the collagen material flowed either into the superficial layer of the lamina propria above the vocal ligament or between the thyroarytenoid muscle bundles just below the vocal ligament. In several cases, a tract of collagen could be seen extending through the vocal ligament. Reviewing these results and comparing the needle size and bevel configuration with the actual sizes of the vocal ligament region, one can appreciate the difficulty in exact placement of the graft into the vocal ligament. The vocal ligament itself is relatively dense with increased numbers of cross-linkages between the collagen fibers in comparison with the other surrounding tissues. If the needle is only slightly outside of the desired region, the injected material will flow more readily into the less viscous tissue found in the superficial region of the lamina propria or between the thyroarytenoid muscle bundles. In addition, if the target region is composed primarily of scar tissue, it is equally unlikely that the injection will dissect between scar bundles rather than flow into the less viscous surrounding tissue; therefore, it is unlikely that injected material can be placed into "the plane of the vocal ligament."

With regard to influencing viscosity of the vocal fold vibratory membrane, the initial experience with bovine collagen in both skin and vocal folds suggested that the xenograft collagen fibers stimulated activity of host fibroblasts. This host fibroblast activity was theorized to increase both native collagen production and host collagenase activity to remodel the existing scar and decrease its viscosity. The laboratory evidence in support of this hypothesis consisted of the study of small numbers of animals in a few models. No rheologic evaluation of tissue after injection was undertaken. In addition, in the 1990s, when otolaryngologists switched to using mostly human forms of collagen, this theory about the xenograft stimulation of collagenase activity was abandoned.

In vitro measurements of available collagen preparations have shown that these preparations are significantly more viscous than the normal superficial layer of the lamina propria. Cadaver models demonstrate that if the collagen preparation is injected into the deep region of the superficial layer of the lamina propria, vibration of the membrane cannot be produced. If, however, the collagen substance is placed just beneath the vocal ligament into the superficial portion of the thyroarytenoid muscle, the forces required to adduct the vocal folds into a position for phonation are significantly reduced and the vibratory patterns are relatively unchanged [31]. Finally, injecting the collagen substance into the lateral portion of the thyroarytenoid muscles, as advocated for Teflon and other substances in the original descriptions of injection laryngoplasty, allows the development of normal vibratory patterns but requires significantly more substance to medialize the vocal fold than injection into the medial or superficial portion of the thyroarytenoid muscle.

Clinical Applications

Most surgeons agree that collagen-containing substances produce temporary medialization of the vocal fold through a mass effect. For the reasons stated above, the injection should be placed into the thyroarytenoid muscle. In this position, the collagen substances last for 2-6 months before resorption. The clinical indications for collagen injection include the management of unilateral vocal fold paralysis, unilateral or bilateral vocal fold paresis, pres-byphonia, or glottal insufficiency secondary to scarring of the mucosal membrane [32].

For the management of unilateral vocal fold paralysis, collagen injections usually produce only temporary benefit and are resorbed without significant adverse reactions. For this reason collagen can be used in the acute situation for patients who cannot tolerate the dysphonia, need an improved cough for pulmonary toilet, or are having significant dysphagia with aspiration. The injection can be performed either percutaneously or transorally in the clinic or in the operating room. The percutaneous injection route can either be accomplished by passing the needle under the thyroid cartilage through the cricothyroid membrane or trans-cartilaginously directly through the thyroid lamina. Cadaver models have demonstrated that if the collagen is deposited into the lateral portion of the thyroarytenoid muscle, approximately 0.7 ml of substance will be required to move the vocal fold to midline. Injection into the medial portion of the thyroarytenoid muscle requires about 0.2 ml to bring the vocal fold medial surface to midline. This difference is statistically significant [31]. When determining the amount of over-injection, the surgeon must consider the concentration of the collagen in the solution that is being injected and the rate of resorption of the carrier vehicle. The vehicle is either saline or glycerine. Usually saline is resorbed within the first 48 h [31]. Glycerine resorption, however, may take longer and is dependent on the compounds with which it is injected. Micronized alloderm (Cymetra) is usually mixed into a 50% solution with injectable xylocaine or saline; therefore, a 50% over injection is indicated to produce significant vocal improvements. In clinical experience, the over-injection is somewhat less with the glycerine-based compounds due to the longer resorption time of the carrier.

For the management of paresis or presby-phonia, injections can be accomplished with the same techniques. The injection can be performed bilaterally during the same intervention if needed. Airway obstruction has not been reported as a significant problem if caution is used in the amount of over-medialization.

Scar tissue on the vibratory surface of the vocal fold does not respond well to injection laryngoplasty. This is due to the fact that the injected material usually flows around the dense/viscous scar tissue into the less viscous surrounding tissue. In addition, the scarred epithelial surface does not hold the injected material well as it tends to be friable and easily disrupted.

Conclusion

Collagen-based compounds have been used over the past 25 years for treatment of glottal insufficiency. These compounds were originally developed for augmentation of skin and were intended to be injected into the midretic-ular dermis. Through distention of the dermal tissues, the implant decreased small wrinkles. Repeated applications into the skin have been shown to produce stable reductions in facial lines. Due to the lack of a vocal fold structure comparable to the midreticular dermis and the need for the vocal fold mucosa to be supple to vibrate, vocal fold augmentation results with collagen compounds have been less than ideal. The collagen can be used as a filler substance to increase the bulk of the vocal fold. If the collagen is placed above the vocal ligament, it will result in increased viscosity of the mucosal membrane and loss of the normal vibratory characteristics. The collagen compounds, therefore, need to be injected below the vocal ligament. In this position they increase the bulk of the vocal fold and lessen the forces required to produce vocal fold adduction. When injected into the thyroarytenoid muscle, either medially or laterally, the collagen compounds are most likely resorbed by the host. There are only scant reports of long-term vocal improvements after collagen injection and most surgeons regard collagen compounds as a temporary method of vocal fold medialization.

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24. Scalafani AP, Romo T III, Jacono AA, McCormick S, Cocker R, Parker A (2000) Evaluation of Acellu-lar dermal graft in sheet (Alloderm) and injectable (micronized Alloderm) forms for soft tissue augmentation. Clinical observations and histological analysis. Arch Facial Plast Surg 2:130-136

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27. Kriesel KJ, Thiebault SL, Chan RW, Suzuki T, Van Groll PJ, Bless DM, Ford CN (2002) Treatment of vocal fold scarring: rhéologie and histological measures of homologous collagen matrix. Ann Otol Rhinol Laryngol 111:884-889

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