Auto-crosslinked hyaluronan gel injections in phonosurgery

Otolaryngology–Head and Neck Surgery (2010) 142, 547-553

ORIGINAL RESEARCH–LARYNGOLOGY AND NEUROLARYNGOLOGY

Auto-crosslinked hyaluronan gel injections in phonosurgery Gabriele Molteni, MD, Giuseppe Bergamini, MD, Andrea Ricci-Maccarini, MD, Caterina Marchese, MD, Angelo Ghidini, MD, Matteo Alicandri-Ciufelli, MD, Maria Pia Luppi, ST, and Livio Presutti, MD, Modena and Cesena, Italy No sponsorships or competing interests have been disclosed for this article. ABSTRACT OBJECTIVES: To evaluate the clinical performance of an autocrosslinked gel obtained from hyaluronic acid (ACP-based gel) as an anti-adhesive agent and/or augmentative agent in vocal cord surgery for the treatment of vocal fold (VF) atrophy, sulcus vocalis, and postsurgery scarring as well as its tolerability at short- and long-term follow-up. STUDY DESIGN: This was a prospective multicenter trial conducted between 2007 and 2009. SETTING: Academic center. SUBJECTS AND METHODS: Inclusion criteria were patients with glottic gap due to previous endoscopic phonosurgery, VF scars, vocal cord atrophy, and sulcus vocalis. Forty patients who underwent endoscopic injection of hyaluronic acid under general anesthesia were enrolled. Two different injections sites were used: the thyroarytenoid muscle in cases of glottic gap for augmentative purposes, and the lamina propria for treatment of scars and sulcus vocalis. A voiceevaluation protocol was performed before surgery, at the first follow-up visit (3 mo), and at the final follow-up (12 mo). RESULTS: Follow-up data at three months were available for 38 patients, while data at 12 months follow-up were available for 27 patients. No side effects, hematoma, or infection and allergic reactions were reported in either the perioperative or postoperative period. Patients had statistically significant improvement in voice parameters compared with the baseline data at the first follow-up visit and at the 12-month follow-up. CONCLUSION: ACP-based gel seems to be a new tool in the challenging treatment of VF scarring, functioning as both an antiadhesive product and an augmentation agent. Improvements in all glottal parameters and in both objective and subjective evaluation of voice performance were observed. © 2010 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.

I

njection laryngoplasty is an established surgical procedure first described by Brünings in 1911.1 The choice of material is based not only on its characteristics but also on

different applications of injection laryngoplasty. Glottal insufficiency is usually caused by unilateral vocal fold (VF) paresis, VF atrophy, sulcus vocalis, and postsurgery scar defect. All of these conditions may lead to hoarseness, breathy and weak voice, and sometimes aphonic voice or swallowing disorders.2 Treatment is usually a combination of voice therapy and surgery, but VF scarring and atrophy are difficult diseases that remain a therapeutic challenge. Although previous researches have focused on the treatment of unilateral VF paresis, vocal cord atrophy and scarring are by far the most common cause of glottal insufficiency.3 Optimal biomaterial for VF mucosa injections should have similar viscoelastic properties to the lamina propria (LP). This is because VF scarring disrupts the LP and alters the biomechanical properties of the vocal cord by increasing the viscoelastic strength of the mucosa, thus reducing vibration and hence causing severe disphonia.4 One of the most recent developments in injectable materials demonstrates the aforementioned properties. Hyaluronic acid (HA) is a high molecular weight glycosaminoglycan that is present in the extracellular matrix, including the LP, in VF mucosa.5 It shows the closest match to native VF viscoelasticity of any other injectable material that has been evaluated6 and offers an excellent biocompatibility. Indeed, several authors in many experimental and clinical settings have proposed that deposition of HA around surgically treated tissues reduces postoperative adhesion formation.7,8 An auto-crosslinked hyaluronan gel was used in the present study. It was obtained from HA by an auto-crosslinking process that does not introduce foreign bridge molecules. The purpose of this prospective study was to evaluate the clinical performance of this auto-crosslinked polymer (ACP)-based gel as an anti-adhesive and/or augmentative agent in vocal cord surgery for the treatment of VF atrophy, sulcus vocalis, postsurgical scarring, as well as its tolerability at short-term and long-term follow-up. To the best of our knowledge, this is the first clinical experience with ACP-based gel in phonosurgery.

Received September 14, 2009; revised December 16, 2009; accepted December 16, 2009.

0194-5998/$36.00 © 2010 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2009.12.035

548

Otolaryngology–Head and Neck Surgery, Vol 142, No 4, April 2010

Materials and Methods Patients Between May 2007 and January 2009, a prospective multicenter uncontrolled clinical study was carried out at the Departments of Otorhinolaryngology of the University Hospital of Modena and at the Hospital M. Bufalini in Cesena. Forty patients with voice impairment were enrolled: 22 females and 18 males. Inclusion criteria were patients older than 18 years of age with voice impairment resulting from the following organic laryngeal disorders: sulcus vocalis, VF atrophy, vocal scars, and postcordectomy. All patients underwent speech therapy before injection, except for those with malignant tumors. If results after speech therapy were not sufficient, patients were evaluated for injection of ACPbased gel. Exclusion criteria were pregnant or breast-feeding women, acute inflammatory disease of the larynx, and immunodeficiency or immunosuppressive treatment. All patients underwent at least 10 face-to-face sessions of speech therapy after surgery. Approval for this study was obtained from the institutional review board of our institute.

Assessments and Recordings All patients underwent a general ENT clinical examination, video laryngostroboscopy, and voice evaluation before treatment (T0) and three months (T1) and 12 months (T2) after treatment. Video laryngostroboscopy was performed and recorded using a rigid endoscope (90-degree laryngostroboscope, Karl Storz, Tuttlingen, Germany) connected to a digital laryngostroboscope (Media Stroboscope, Atmos, Germany). The same instruments were used in both hospitals. Three parameters were evaluated: glottal closure, vibratory pattern, and mucosal wave of both VFs. Glottal competence was graded 0 for complete closure, 1 for unstable, 2 for lightly incomplete, and 3 for strongly incomplete. Vibratory pattern and mucosal wave were graded 0 (absent), 1 (small), 2 (moderate), or 3 (normal). Vocal folds were analyzed and reported separately in order to compare results in treated and untreated cords. Sound recordings were made with a digital recorder (Speech Laboratory, Model CSL G300B, Kay, Lincoln Park, NJ) and a microphone placed at a constant distance of 20 cm from the mouth to obtain a digital voice spectrography and perceptual voice evaluation. Patients were asked to read a paper with their own name and surname, numbers from 0 to 10, five vowels, and one verse from a well known Italian song. Digital voice spectrography for prolonged /a/ was classified according to the Yanagihara scale.9 Presence of diplophonia was reported. Maximum phonation time (MPT) was registered as the best out of three recordings of a sustained /a/. MPT was classified as normal (⬎ 10 seconds) or altered (slight, 8-10 seconds; moderate, 5-7 seconds; wide, ⬍ 5 seconds). Perceptual voice evaluation was made using the GIRBAS scale (grade, instability, roughness, breathiness, asthenia, strain). Each part of the GIRBAS scale was graded 0 (normal), 1 (slight change), 2 (moderate change), or 3 (wide

change), and the total score was also reported.10 Subjective evaluation of dysphonia was collected using a reduced version of the Voice Handicap Index (VHI-10). This patientbased self-assessment tool, designed to assess all types of voice disorders, has a score range of 0 to 40: 1-13, slight; 14-27, moderate; ⬎ 27, wide change. The higher the score, the worse the voice handicap as perceived by the patient.11

Injection Procedure The injected material is a sterile, transparent, and highly viscous gel. ACP-based gel (Fidia Advanced Biopolymers, Abano Terme, Padova, Italy) is obtained from a low-molecular weight HA by an auto-crosslinking process that does not introduce foreign bridge molecules. The HA in this gel is derived from a bacterial fermentation process. All injections were performed, with the patient under general anesthesia, through a rigid laryngoscope (Kleinsasser, Storz, Germany) using an oro-tracheal 27 G needle (Oro-Tracheal Laryngeal Injector, Medtronic, Minneapolis, MN) in order to achieve high accuracy in injecting the material. Two injection sites were used: in cases of glottic gap, injections were made in the thickest part of the LP into the thyroarytenoid muscle; in cases of scarring and sulcus vocalis, injections were made in the space just below the epithelium of a surgical scar to get the disrupted and unplayable VF mucosa unstuck. One or both VFs were injected. For anti-adherent purposes, 0.1 to 0.2 mL were injected, while the mean dose for filling purposes was 0.8 mL.

Statistical Analysis Descriptive analysis was performed using mean, standard deviation, median, and minimum-maximum range for qualitative variables, and absolute values and percentages were reported for quantitative variables. All variables were calculated at baseline and at follow-up visits, first by analyzing the whole population, then by analyzing subgroups on the basis of baseline pathology and aim of the surgical approach. Variations in objective and subjective parameters among T0, T1, and T2 were analyzed with univariate analysis using the Wilcoxon signed-rank test. Qualitative categorical parameters (dicotomic yes/no) were analyzed using the ␹2 test. Multivariate variance analysis (ANOVA) was performed to estimate a possible correlation between observed dependent variables with independent variables, such as basal value and baseline pathology or aim of the surgery (anti-adhesion effect and/or augmentation volume). Significance levels were P ⬍ 0.05. Statistical analysis was done with SAS statistical software, version 9.1.3 (SAS Institute, Cary, NC).

Results Forty patients were included in the study. Two of them dropped out of the study because they failed to attend follow-up visits. All patients were observed overnight and

Molteni et al

Auto-crosslinked hyaluronan gel injections in phonosurgery

disorders: sulcus vocalis (16 patients, 42.1%), VF atrophy (6 patients, 15.8%), vocal scars (9 patients, 23.7%), and previous cordectomies (5 patients, 13.2%). Two patients (5.3%) received a bilateral treatment because of a different pathology in each cord (vocal scar and atrophy in one patient; previous cordectomy and VC atrophy in the other patient). ACP-based gel was injected in one vocal cord in 16 patients (42.1%) and in both vocal cords in 22 patients (57.9%) (Table 1). Injections were performed for three different purposes: augmentative effect in 12 patients (31.6%), adhesion prevention or treatment in 16 patients (42.1%), and both in 10 patients (26.3%). Short-term follow-up data (1-3 mo) were available for 38 patients. Long-term follow-up data (12 mo) were available for 27 patients (Tables 2 and 3). At the first follow-up visit, patients had statistically significant improvement in voice parameters compared with the baseline data: glottal competence moved from a mean score of 1.87 ⫾ 0.84 to 0.66 ⫾ 0.91, with an improvement in 71.1 percent of patients (P ⬍ 0.0001); vibratory pattern of the right and left vocal cords improved in 45.5 percent (P ⬍ 0.0001) and 58.6 percent of patients (P ⫽ 0.0005),

Table 1 Patient demographics Patients Total Male Female Mean age (yrs) Etiology Sulcus vocalis VF atrophy VF scar Cordectomy Different organic lesions associated Unilateral Bilateral

38 17 21 49.4 ⫾ 13.3

44.70% 55.30%

16 6 9 5

42.10% 15.80% 23.70% 13.20%

2 16 22

5.20% 42.10% 57.90%

549

discharged the day after. No side effects, hematoma, or infection and allergic reactions were reported in our series. We included 21 women and 17 men, with a mean age of 49.4 years (SD ⫾ 13.3 yrs), in the study. Baseline voice impairment was related to the following organic laryngeal

Table 2 Results of voice parameters T0

Glottal closure 0 1 2 3 Right vibratory pattern 0 1 2 Left vibratory pattern 0 1 2 Right mucosal wave 0 1 2 Left mucosal wave 0 1 2 Diplophonia Absent Present MPT Normal Slight changed Moderate changed Hard changed Absolute numeric value

T1

Patients (n ⫽ 38)

Patients (n ⫽ 38)

7.90% 18.40% 52.60% 21.10%

63.20% 7.90% 28.90% 0.00%

18.2% 63.60% 18.2%

3.00% 42.40% 54.60%

17.20% 72.40% 10.40%

3.50% 37.90% 58.60%

39.40% 51.50% 9.10%

12.10% 39.40% 48.50%

35.50% 62.10% 3.40%

17.20% 41.40% 41.40%

76.30% 23.70%

92.10% 7.90%

21.10% 28.90% 36.80% 13.20%

55.30% 21.10% 18.40% 5.20%

T2

Improvement

P

71.10%

⬍0.0001

45.50%

⬍0.0001

Patients (n ⫽ 27)

Improvement 66.70%

0.0002

62.50%

⬍0.0001

76.20%

⬍0.0001

62.50%

⬍0.0001

71.40%

⬍0.0001

63.00% 0.00% 33.30% 3.70% 0.00% 37.50% 62.50%

58.60%

54.50%

0.0005

⬍0.0001

0.00% 19.00% 81.00% 4.20% 50.00% 45.80%

55.20%

0.001

P

0.00% 61.90% 38.10% 0.6821 52.60%

⬍0.0001

0.5573 74.10% 25.90% 51.90% 51.90% 22.20% 22.20% 3.70%

68.40%

77.80%

0.0124

550

Otolaryngology–Head and Neck Surgery, Vol 142, No 4, April 2010

Table 3 Results of voice parameters T0 GIRBAS total score G 0 1 2 3 I 0 1 2 3 R 0 1 2 3 B 0 1 2 3 A 0 1 2 3 S 0 1 2 3 VHI-10 0 1-13 14-27 ⬎27 Absolute numeric value (0-40) Spectrography Type 0 Type I Type II Type III Type IV

T1

0.00% 10.50% 55.30% 34.20%

18.40% 60.50% 18.40% 2.70%

23.70% 31.60% 31.60% 13.10%

65.80% 31.60% 2.60% 0.00%

5.30% 31.60% 44.70% 18.40%

50.00% 39.50% 7.90% 2.60%

5.30% 42.10% 39.50% 13.10%

36.80% 50.00% 10.60% 2.60%

39.50% 28.90% 18.40% 13.20%

63.20% 31.60% 5.20% 0.00%

47.40% 23.70% 26.30% 2.60%

63.20% 31.60% 5.20% 0.00%

0.00% 24.30% 51.40% 24.30%

11.40% 68.60% 20.00% 0.00%

Improvement

P

89.50% 84.20%

⬍0.0001 ⬍0.0001

60.50%

73.70%

71.10%

52.60%

77.10%

respectively; the mucosal wave improved in 54.4 percent of patients on the right side (P ⬍ 0.0001) and in 55.2 percent of patients on the left side (P ⫽ 0.0010). GIRBAS total score decreased from 8.84 ⫾ 2.48 to 3.68 ⫾ 2.66, with 89.5 percent of patients showing improvement (P ⬍ 0.0001): 84.2 percent of patients showed improvement for G value (P ⬍ 0.0001), 60.5 percent for I value (P ⬍ 0.0001), 73.7 percent for R value (P ⬍ 0.0001), 71.1 percent for B value (P ⬍ 0.0001), 52.6 percent for A value (P ⬍ 0.0001), and 44.7 percent for S value (P ⫽ 0.0158). Digital voice spectrography was significantly better in 71.1 percent of patients (P ⬍ 0.0001). VHI-10 subjective evaluation of the voice decreased from a mean score of 20.6 ⫾ 8.74 at baseline to 8.8 ⫾ 6.32 at the first follow-up visit, with a statistically

⬍0.0001

⬍0.0001

P

100.00% 88.90%

⬍0.0001 ⬍0.0001

74.10%

⬍0.0001

92.60%

⬍0.0001

70.40%

⬍0.0001

48.10%

0.0028

40.70%

0.0220

79.20%

⬍0.0001

87.50% 63.00%

0.0010

18.50% 70.40% 11.10% 0.00% 70.40% 29.60% 0.00% 0.00% 59.30% 37.00% 0.00% 3.70% 40.70% 55.60% 3.70% 0.00%

0.0158

⬍0.0001

59.30% 40.70% 0.00% 0.00% 12.50% 62.50% 25.00% 0.00%

94.30% 71.10% 15.80% 42.20% 36.80% 2.60% 2.60%

⬍0.0001

Improvement

74.10% 22.20% 3.70% 0.00% 44.70%

0.00% 23.70% 44.70% 23.70% 7.90%

⬍0.0001

T2

⬍0.0001 14.80% 44.40% 33.30% 7.40% 0.00%

significant improvement for 94.3 percent of patients (P ⬍ 0.0001). The preoperative MPT value was 8.16 seconds and increased postoperatively to 10.55 seconds; significant improvement was seen in 68.4 percent of patients (P ⬍ 0.0001). Diplophonia was present in 23.7 percent (n ⫽ 9) of patients at baseline, and this was reduced to 7.9 percent (n ⫽ 3) of patients at the first follow-up visit. At the second follow-up visit, patients confirmed the improvements recorded at short-term follow-up in comparison to baseline results in almost all voice parameters. Comparative analysis was possible for 27 patients. Glottal competence improved in 66.7 percent of patients (P ⫽ 0.0002); vibratory pattern improved on the right side in 62.5 percent of patients (P ⬍ 0.0001) and on the left side in 76.2 percent

Molteni et al

Auto-crosslinked hyaluronan gel injections in phonosurgery

of patients (P ⬍ 0.0001); and mucosal wave improved in the right cord in 62.5 percent of patients (P ⬍ 0.0001) and in the left cord in 71.4 percent of patients (P ⬍ 0.0001). GIRBAS scale findings were as follows: 88.9 percent of patients showed improvement for G (P ⬍ 0.0001), 74.1 percent for I (P ⬍ 0.0001), 92.6 percent for R (P ⬍ 0.0001), 70.4 percent for B (P ⬍ 0.0001), 48.1 percent for A (P ⫽ 0.0028), 40.7 percent for S (P ⫽ 0.0220), and the GIRBAS total score improved in 100 percent of patients (P ⬍ 0.0001). Digital voice spectrography and MPT showed significant improvement in 63 percent of patients (P ⫽ 0.0010) and 51.9 percent of patients (P ⫽ 0.0124), respectively. VHI-10 subjective evaluation of voice decreased from a mean score of 21.1 ⫾ 8.63 at baseline to 8.33 ⫾ 6.32, with a statistically significant improvement in 79.2 percent of patients (P ⬍ 0.0001). Only diplophonia, which showed improvement at short-term follow-up, revealed a slight decrease at long-term follow-up, at which time it was present in 25.9 percent of patients. These comparative analyses, which showed that statistical improvements obtained from the injection of an ACP-based gel were maintained for up to 12 months, confirmed our preliminary clinical observations in these patients. Additionally, to evaluate for a possible correlation between observed dependent variables and independent variables, such as basal value and baseline pathology or aim of the surgical treatment (anti-adhesion prevention or treatment and/or augmentation volume), a multivariate analysis was performed. No correlation was found between the voice parameters and the two independent variables, except for with glottal competence, which was shown to have better improvement at the first follow-up in cases of vocal fold atrophy and sulcus vocalis (P ⫽ 0.0002) and when the aim of the surgery was anti-adhesive prevention (P ⫽ 0.0214).

Discussion Many materials have been used over the last few decades for injection laryngoplasty, but the perfect material remains elusive. This perfect material would be biocompatible; easily injectable; readily available, with minimal preparation required; have biomechanical properties that were the same as or similar to the VF component being augmented; be resistant to resorption and migration; and easily removable, in case of the need for revision surgery.12 When choosing the right injectable, one should consider the viscoelasticity of the material and the purpose of the treatment. Once injected into the VF, the material should have the same rheological properties, because if the viscoelasticity is different, it might interfere with vocal cord vibration and mucosal wave propagation. Hallen performed the first study on the use of HA in VFs in 1998 using a rabbit model.13 HA has recently received widespread attention in laryngology because it is an important extracellular matrix component of the LP. In vitro and in vivo studies showed that it contributes to the maintenance of an optimal viscosity and

551

stiffness in the VF, which may facilitate phonation and may be important in determining fundamental frequency.14 HA has not been found in the vocal cord epithelium layer, but it is widely expressed in the LP, and some authors assumed that it might play a role in the formation of the mucosal wave.15 It has been proven that the hyaluronan-based biomaterials have elastic values comparable to those of the vocal mucosa. They offer less resistance to flow and less stiffness, and may be the best material, to date, for injections into the LP.16 HA-based gel received widespread attention for its viscoelasticity, which is similar to that of human vocal cord mucosa. Results of several histologic studies suggested that increasing the content of hyaluronan-based gel, elastin, and decorin, or decreasing the levels of collagens and/or fibronectin might be a new strategy in the approach to VF scarring.4 Many reports in animal models or in vitro studies have been published on this topic, but few outcome data for human vocal fold scarring are available to date. The first human VF study with a long follow-up time showed a low resorption of hyaluronan and stable results after 12 months. There were no severe side effects, and an early, slight inflammation rate of only 3.8 percent was reported with Hylaform Hylan B Gel (INAMED Aesthetics, Santa Barbara, CA), and all of the patients with inflammation recovered within 30 days. Hertegård et al reported on only three patients treated for scarring, with just one completing 12month follow-up. The patient showed improvement in all glottal parameters.2 The safety of HA was also confirmed by Perazzo et al. They used Restylane HA (Medicis, Scottsdale, AZ) in a rabbit model and found only slight inflammatory reactions, the complete absence of foreign body reaction, absence of necrosis and granuloma formation, and low fibrogenesis. They also demonstrated good integration between HA and host tissues, with collagen regeneration of connective tissue, mild fibrosis, and, hence, VF augmentation. Their results showed that fibrosis diminished with time, which is important to allow sliding of the LP to create a mucosal wave.17 Furthermore, cross-linked hyaluronan seems to bind water once injected, hence it can maintain its volume in the injection area for a longer period of time than other materials, including autologous HA.18 A recent prospective randomized trial by Lau et al reported a large series of patients treated with HA injections for unilateral VF paralysis. They compared two different particle sizes of HA in 41 patients; follow-up data, which were available for only 17 patients, showed that the effect of medialization using HA of larger particle size was more durable. No side effects were reported in the study.19 On the basis of these previous experiences with HA injection as an adhesion prevention adjuvant and/or augmentative agent, we decided to explore the use of the autocrosslinked hyaluronan polymer in vocal surgery. ACPbased gel is obtained from HA by an auto-crosslinking process that does not introduce foreign chemical bridge molecules, but it is made of an inter- and intra-molecular

552

Otolaryngology–Head and Neck Surgery, Vol 142, No 4, April 2010

ester of HA in which a proportion of the carboxyl groups are esterified with hydroxyl groups belonging to either the same and/or different molecules of the HA, thus forming a mixture of lactones and inter-molecular ester bonds. The absence of foreign bridge molecules ensures the safety profile of this auto-crosslinked hyaluronan gel, with the simple release of native HA during degradation. The autocrosslinking process improves the viscoelastic properties of the gel compared to unmodified HA solutions of the same molecular weight. Owing to its viscosity, it adheres to the tissue surface and separates apposing tissues.20 ACP-based gel satisfies many of the characteristics of the ideal injectable material. No postoperative safety concerns arose in the 40 treated patients, the 38 patients who attended follow-up between one and three months after surgery, or in the 27 patients who completed long-term follow-up visits. In our series, ACP-based gel was used as an anti-adhesion agent in 26 patients and in 12 patients for augmentative purposes. In many of the patients who underwent injection for augmentative purposes, adhesion prevention was a secondary goal (for example, after a cordectomy procedure). To the best of our knowledge, this is the first series of patients with vocal fold pathologies to be treated with autocrosslinked hyaluronan gel for anti-adhesion purposes. The present study was designed to assess short- and long-term results of ACP-based gel injection in the human larynx in terms of objective and subjective evaluations. All parameters evaluated showed a statistically significant improvement at three and 12 months after injection. Multivariate analysis showed that better results were obtained when ACP-based gel was used as scar prevention or a treatment device (P ⫽ 0.0214). Both objective and subjective evaluations improved at follow-up and remained stable: patients had a better perception of their voice, and this was confirmed by acoustic, aerodynamic, and laryngostroboscopic examinations. Our 12-month results confirmed Hertegård et al’s2 findings at one-year follow-up. This is of particular interest for the use of ACP-based gel for anti-adherent indications, which might be the principle indication for use of this material in vocal fold injection in the near future. ACP-based gel injection can be performed as an in-office procedure, in the operating room setting with local or general anesthesia, with a trans-nasal or trans-oral injection, and even through a trans-thyroid cartilage injection. The choice of how to perform the procedure is strictly related to the ability and confidence of the surgeons.

Conclusion Patients treated with vocal fold injection of ACP-based gel showed that it was well tolerated. Improvement in all glottal parameters and in both objective and subjective evaluation of voice performance was observed. Long-term efficacy of this material has been statistically demonstrated by our results; the gel remained stable for 12 months. ACP-based gel seems to be a new tool in the challenging treatment of

VF scarring that can be used as both an anti-adhesion product and augmentation agent, but further studies are desirable to better assess its anti-adherent effects in vocal fold scarring and to confirm long-term results. ACP-based gel satisfies many of the characteristics of the ideal injectable material. This preliminary study with ACP-based gel injection is promising in terms of treating what is perhaps the most challenging pathology in phonosurgery.

Author Information From the Department of Otolaryngology-Head and Neck Surgery (Drs. Molteni, Bergamini, Marchese, Ghidini, Alicandri-Ciufelli, and Presutti, and Ms. Luppi), University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy; and the Department of Otolaryngology (Dr. RicciMaccarini), Ospedale Bufalini di Cesena, Cesena, Italy. Corresponding author: Gabriele Molteni, MD, Department of OtolaryngologyHead and Neck Surgery, University of Modena and Reggio Emilia, Policlinico di Modena, via del Pozzo 71, 41100 Modena, Italy. E-mail: [email protected]. This article was presented at the 2009 AAO–HNSF Annual Meeting & OTO EXPO, San Diego, CA, October 4-7, 2009.

Author Contributions Gabriele Molteni, conception and design, draft, final approval; Giuseppe Bergamini, conception and design, final approval; Andrea Ricci-Maccarini, conception and design; Caterina Marchese, draft, acquisition of data; Angelo Ghidini, acquisition of data; Matteo Alicandri-Ciufelli, acquisition of data; Maria Pia Luppi, acquisition of data; Livio Presutti, conception and design, final approval.

Disclosures Competing interests: None. Sponsorships: None.

References ¨ ber eine neue behandlungsmethode der rekurrenslh¨1. Brünings W. U mung. Verh Ver Laryngol 1911;18:93–151. 2. Hertegård S, Hallen L, Laurent C, et al. Cross-linked hyaluronan used as augmentation substance for treatment of glottal insufficiency: safety aspects and vocal fold function. Laryngoscope 2002;112:2211–9. 3. Reulbach TR, Belafsky PC, Blalock PD, et al. Occult laryngeal pathology in a community-based co-hort. Otolaryngol Head Neck Surg 2001;124:448 –50. 4. Hirano S. Current treatment of vocal fold scarring. Curr Opin Otolaryngol Head Neck Surg 2005;13:143–7. 5. Butler JE, Hammond TH, Gray SD. Gender related differences of hyaluronic acid distribution in the human vocal fold. Laryngoscope 2001;111:907–11. 6. Hertegård S, Dahlqvist A, Laurent C, et al. Viscoelastic properties of rabbit vocal folds after augmentation. Otolaryngol Head Neck Surg 2003;128:401– 6. 7. Burns JW, Skinner K, Colt J, et al. Prevention of tissue injury and postsurgical adhesion by precoating tissue with hyaluronic acid solution. J Surg Res 1996;59:644 –52. 8. Chen WY, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen 1999;7:79 – 89. 9. Yanagihara N. Significance of harmonic changes and noise components in hoarseness. J Speech Hear Res 1967;10:531– 41.

Molteni et al

Auto-crosslinked hyaluronan gel injections in phonosurgery

10. Dejonckere PH, Remacle M, Fresnel-Elbaz E, et al. Differentiated perceptual evaluation of pathological voice quality: reliability and correlations with acoustic measurements. Rev Laryngol Otol Rhinol (Bord) 1996;117:219 –24. 11. Rose CA, Lee AS, Osborne J, et al. Development and validation of the voice handicap index-10. Laryngoscope 2004;114:1549 –56. 12. Kwon T, Buckmire R. Injection laryngoplasty for management of unilateral vocal fold paralysis. Curr Opin Otolaryngol Head Neck Surg 2004;12:538 – 42. 13. Hallen L, Dahlqvist A, Laurent C. Dextranomeres in hyaluronan (DiHA): a promising substance in treating vocal fold insufficiency. Laryngoscope 1998;108:393–7. 14. Jia X, Yeo Y, Clifton RJ, et al. Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration. Biomacromolecules 2006;7:3336 – 44. 15. Chan RW, Gray SD, Titze IR. The importance of hyaluronic acid in vocal fold biomechanics. Otolaryngol Head Neck Surg 2001;124:607–14.

553

16. Caton T, Thibeault SL, Klemuk S, et al. Viscoelasticity of hyaluronan and nonhyaluronan based vocal fold injectables: implications for mucosal versus muscle use. Laryngoscope 2007;117:516 –21. 17. Perazzo PS, Duprat Ade C, Lacellotti CL. Histological behavior of the vocal fold after hyaluronic acid injection. J Voice 2009;23: 95– 8. 18. Lim JY, Kim HS, Kim YH, et al. PMMA (polymethylmetacrylate) microspheres and stabilized hyaluronic acid as in injection laryngoplasty material for the treatment of glottal insufficiency: in vivo canine study. Eur Arch Otorhinolaryngol 2008;265:321– 6. 19. Lau DP, Lee GA, Wong SM, et al. Injection laryngoplasty with hyaluronic acid for unilateral vocal cord paralysis: randomized controlled trial comparing two different particle sizes. J Voice 2009 Jun 15; [Epub ahead of print]. 20. Renier D. Pharmacokinetic behaviour of HA gel, an autocrosslinked hyaluronan derivative, after intraperitoneal administration. Biomaterials 2005;26:5368 –74.