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J Korean Soc Laryngol Phoniatr Logop > Volume 35(1); 2024 > Article
Park and Kim: The Investigation of Hyaluronic Acid (The Chaeum Premium No.2®) to Evaluate the Efficacy and Safety for Injection Laryngoplasty in Unilateral Vocal Cord Paralysis: A Single Center, Phase II Trial


Background and Objectives

This study aimed to evaluate the clinical efficacy and safety of hyaluronic acid (HA) (The Chaeum Premium No.2®) for injection laryngoplasty (IL) in unilateral vocal cord paralysis (UVCP) patients.

Materials and Method

This clinical trial has been registered with the clinical research information service of the Republic of Korea (No. KCT0007597). Ten patients with UVCP were enrolled. Auditory-perceptual evaluation, acoustic analysis, aerodynamic analysis, electroglottography, laryngoscopy, and voice handicap index (VHI)-30 were assessed before injection, at 1, 3, and 6 months after injection.


All auditory-perceptual parameters gradually showed statistically significant improvements at 1, 3, and 6 months after injection. Acoustic, aerodynamic parameters, electroglottography, and VHI-30 showed gradual improvements at 1 and 3 months after injection. Then, they showed slight deterioration 6 months after injection. There were no adverse effects in all patients.


IL using HA is an effective and safe treatment for UVCP patients.


Unilateral vocal cord paralysis (UVCP) usually results in poor quality of life with symptoms such as hoarseness, reduced coughing strength, aspiration, and subsequent pneumonia. Several approaches, including laryngeal framework surgery, re-innervation surgery, and injection laryngoplasty (IL), have been suggested as potential treatments for addressing UVCP [1].
Numerous materials have been introduced for IL in UVCP patients since the early 1990s. However, earlier IL materials such as paraffin and polytetrafluoroethylene (Teflon®) have gradually been phased out given the evidence of foreign body reactions and high extrusion rates. Recently, IL materials are typically described according to their duration as temporary and long-lasting. Hyaluronic acid (HA), collagen, and carboxymethylcellulose (CMC) are temporary materials. Long-acting materials include calcium hydroxyapatite (CaHA), fat, and polymethylmethacrylate (PMMA) microspheres in bovine collagen. CMC and CaHA are currently Food and Drug Administration (FDA)-approved materials for IL [2].
The ideal material for IL should be biocompatible, easily injectable with minimal preparation, and possess a durability that provides patients with a reasonable period of benefit before undergoing reabsorption [3]. HA, serving as a ubiquitous element in the extracellular matrix, is a polysaccharide naturally found in the extracellular matrix of human cells and is plentiful in the lamina propria of the vocal cord. Its chemical molecular structure is simple and consistent across various species, spanning from humans to bacteria. Its non-immunogenic nature is attributed to the absence of amino acids [4]. It has very low tissue reactivity and promotes tissue repair and regeneration in vocal cords by providing synthetic building blocks for the extracellular matrix [2,5]. It was initially presented by Hertegård et al. [6] in 2002 as an injection material for glottic insufficiency resulting from various causes, including UVCP. Several clinical studies have affirmed the safety and effectiveness of HA in UVCP patients [3,7-16]. Therefore, HA is the most used material. However, it is not currently FDA-approved for IL. This study was designed as a preliminary study for approval from the Korean FDA. The purpose of this study is to evaluate the clinical efficacy and safety of HA for IL in UVCP patients.


Trial design and participants

This trial was conducted at two institutions from March 2023 to February 2024. The study was approved by the Institutional Review Boards (No. CHAMC-2022-02-032-004). This clinical trial was approved by the Korean Ministry of Food and Drug Safety (Approval No. 1353) and registered with the Clinical Research Information Service (No. KCT0007597) as international clinical trials registry platform of Korea.
The patients’ inclusion criteria were: 1) adult patients (aged 19 and above) with complaints of breathy or aspiration phonation, where UVCP is observed during laryngoscopy, necessitating vocal fold injection; 2) individuals capable of reading and understanding the guidelines related to the HA’s safety and efficacy and able to complete relevant questionnaires; 3) those who have listened to a detailed explanation of the clinical trial, fully understood it, voluntarily decided to participate, and provided written consent on the informed consent form; and 4) individuals who can adhere to the procedures of the clinical trial and comply with visit schedules. The exclusion criteria were: 1) patients with compromised or suspected compromised immunity; 2) individuals with a history of anaphylaxis, severe complex allergic reactions, or adverse reactions to local anesthetics and HA; 3) patients with clinically significant disorders affecting the cardiovascular, digestive, respiratory, endocrine, or central nervous systems; 4) pregnant or lactating women; 5) children; 6) those unwilling to participate in the study; and 7) patients with interrupting lesions involving the vocal folds, which are the injection route for HA, as observed in the screening neck CT conducted for differential diagnosis of UVCP.
Ten patients with UVCP were initially enrolled, and none of them was lost during the follow-ups. All patients were informed of treatment details and possible side effects and provided written consent to undergo treatment and present regularly for follow-up examinations.

IL technique (trans-cricothyroid membrane approach)

The participants underwent percutaneous IL in the outpatient clinic under local anesthesia. Prior to the injection, a 10% xylocaine spray was soaked in nasal packing gauzes to anesthetize the fiberoptic laryngoscope’s nasal pathway. The packing gauze was inserted into both nasal cavities. Next, a 10% xylocaine spray was applied to the oropharynx. The patients were prompted to cough to facilitate the dispersion of the anesthetic solution throughout the larynx. Additional local anesthesia was administered subcutaneously around the cricothyroid membrane by an aseptic injection of 2% lidocaine. After finishing local anesthesia, HA (The Chaeum Premium No.2®, ACROSS CO., Ltd, Chuncheon, Republic of Korea) was percutaneously injected through the cricothyroid membrane using a 25-gauge needle. Once the needle’s location in the vocal fold was confirmed by a fiberoptic laryngoscope, the operator (M-S. K) began to inject HA and stopped IL when the paralyzed vocal cord sufficiently was medialized. After IL, they were examined for any adverse reactions for 30 minutes.

Follow-up and the trial’s endpoints

Patients followed up at 1, 3, and 6 months after IL. Auditoryperceptual evaluation, acoustic analysis, aerodynamic analysis, electroglottography, laryngoscopy, and voice handicap index (VHI)-30 were assessed before IL and 1, 3, and 6 months after IL. This trial’s primary endpoint was to assess its efficacy using the perceptual parameter grade, roughness, breathiness, asthenia, and strain (GRBAS) scale. The secondary endpoints were to evaluate its effectiveness with the use of different parameters such as the acoustic parameter, electroglottography parameter, aerodynamic parameter, and VHI.

Statistical analysis

The Friedman test was used to analyze changes in the measured variables over time. p<0.05 was considered significant. Statistical analyses were performed using SPSS software version 22.0 (IBM Corp., Armonk, NY, USA).


Patient characteristics are summarized in Table 1. Median volume of injected HA was 1.05 mL (range 0.7 to 1.6 mL). All auditory-perceptual parameters of the GRBAS scale showed statistically significant improvements at 1, 3, and 6 months after IL. All acoustic parameters of Jitter, Shimmer, noise-to-harmonic ratio (NHR), and cepstral peak prominence (CPP) showed gradual improvements at 1 and 3 months after IL. Then they showed slight deterioration at 6 months after IL. These changes were not statistically significant in Jitter, Shimmer, and NHR, but statistically significant in CPP. Aerodynamic parameters showed similar patterns. Maximum phonation time (MPT) and mean airflow rate (MFR) showed gradual improvements at 1 and 3 months after IL, and then they showed slight deterioration at 6 months after IL. They were statistically significant. The closed quotient in electroglottography showed gradual improvements at 1 and 3 months after IL, and then it showed slight deterioration at 6 months after IL. This trend was not statistically significant. VHI-30 showed statistically significant improvements at 1 and 3 months after IL. Then it showed statistically significant deterioration at 6 months after IL (Table 2). There were no adverse effects in all patients during follow-up periods.


All patients with UVCP showed persistent improvements after IL using HA for 6 months without any adverse effects. GRBAS showed significantly gradual improvement until 6 months after IL. Acoustic analysis, aerodynamic analysis, electroglottography, and VHI-30 showed improvement after IL compared to those before IL. However, the parameters gradually improved until 3 months after IL but slightly worsened by 6 months after IL. Acoustic parameters can be judged to represent the objective voice quality of patients with UVCP [17-19]. Among the acoustic parameters, CPP was the only statistically significant parameter. This is consistent with the recent studies that present CPP as an important indicator for UVCP [2,5,20]. Aerodynamic parameters are measures of objective voice intensity in patients with UVCP. Like acoustical parameters, aerodynamic parameters showed similar trends according to the timing after IL. This finding tended to be precisely consistent with the closed quotient (the ratio between the closed glottal phase duration and the fundamental period) and the VHI-30 (self-assessment questionnaire that evaluates the level of handicap caused by hoarseness) [21,22]. These results demonstrated that subjective satisfaction, voice quality, and intensity peak around 3 months after IL, which is the estimated half-life of HA in vocalis muscles.
Some studies showed similar results for the peak of the IL effect to our results. Wen et al.’s [12] study evaluated MPT and VHI-10 at 1, 3, and 6 months posttreatment. They gradually improved until 3 months after IL but slightly worsened by 6 months after IL. Lee et al. [23] reported that many parameters improved 3 months after IL but slightly worsened by 6 months after IL in 19 patients with permanent UVCP after thyroidectomy. The Upton’s study to examine the use of HA for IL demonstrated that 12 patients’ voice outcome measures trended back toward baseline at 4 months, indicating that the beneficial effects of HA are temporary [13]. Interestingly, there was a study comparing small and large particle-size HA in IL for UVCP. Restylane® (small particle-size HA) and Perlane® (large particlesize HA) were two used products with respective particle sizes of 547±280 µm/mL and 1024±547 µm/mL. The small particlesize HA group starts to show VHI’s deterioration by 3 months, whereas the large particle-size HA group demonstrates continued VHI’s improvement right up to 6 months [16]. This study’s used HA (The Chaeum Premium No.2®)’s particle size was 473± 242 µm/mL [24]. It is a smaller particle-size HA than Restylane®, which is consistent with the result that starts to show VHI’s deterioration by 3 months after IL.
The duration of HA is generally believed to be 3–6 months [2,7,25]. However, some studies showed that its clinical benefits may persist for up to 24 months. Pei et al. [11] evaluated voice analysis baseline and at 1, 3, and 6 months after IL with HA. Most measurements showed immediate improvements after HA injection, with a persisting effect at the 3 or 6 months follow-up. Halderman’s research reported the average patient’s self-reported length of benefit to be 12.2 weeks (range 0–52 weeks) [3]. In the study by Bertroche, the patient-defined longevity of HA for IL in patients with UVCP or vocal cord atrophy was investigated. Longevity was defined as the time between IL and the date that a patient first noted subjective deterioration of their voice. Fifty-nine patients revealed a mean longevity of 10.6 months (95% confidence interval: 9.1–12.0 months) [10]. Miaśkiewicz et al. [7] showed that GRBAS and acoustic parameters improved at 6, 12, and 24 months after IL under general anesthesia.
In this study, no specific complications were observed after IL. A recent systematic review for IL with HA revealed that the overall number of reported complications in the included studies was low (none to 7.8%). Complications are mostly mild such as edema and/or inflammation. Complications can be managed with antibiotics and corticosteroids [5]. This study had several limitations. First, the number of study subjects was small (n=10), which means that our conclusion may not be reliable. Second, we did not test various types of HA in terms of particle size, crosslinking rate, gel type, concentration, viscosity, and elasticity. In the future, prospective studies with a larger sample size, a longer follow-up period, and various types of HA are necessary to further determine the best efficacy and safety of HA for IL in UVCP patients.


HA is an effective and safe material in IL for patients with UVCP. The effect of HA may peak around 3 months after IL and then gradually decrease.




Funding Statement

This study was financially supported by the “Young Investigator Award (YIA)” of the Korean Society of Laryngology, Phoniatrics, and Logopedics and Hugel, Inc.

Conflicts of Interest

The authors have no financial conflicts of interest.

Authors’ Contribution

Conceptualization: Min-Su Kim. Data curation: JunHo Park. Formal analysis: JunHo Park, Min-Su Kim. Funding acquisition: Min-Su Kim. Investigation: JunHo Park, Min-Su Kim. Methodology: JunHo Park, Min-Su Kim. Project administration: Min-Su Kim. Resources: Min-Su Kim. Software: JunHo Park, Min-Su Kim. Supervision: Min-Su Kim. Validation: JunHo Park, Min-Su Kim. Visualization: JunHo Park, Min-Su Kim. Writing—original draft: Min-Su Kim. Writing—review & editing: JunHo Park, Min-Su Kim. Approval of final manuscript: JunHo Park, Min-Su Kim.

Table 1.
Patient characteristics (n=10)
Variable Value
Age (yr) 52.7±13.0
 Male 6 (60)
 Female 4 (40)
 Thyroid operation 6 (60)
 Idiopathic 2 (20)
 Cervical spine operation 1 (10)
 Viral meningitis 1 (10)

Data are presented as mean±standard deviation or n (%).

Table 2.
Analysis of various parameters
Before 1 month 3 months 6 months p-value
 G 1.5±0.8 1.1±0.5 0.7±0.5 0.6±0.6 0.006
 R 1.4±0.7 1.0±0.5 0.6±0.5 0.5±0.5 0.002
 B 1.5±0.8 1.0±0.6 0.6±0.5 0.6±0.6 0.005
 A 1.3±0.9 0.4±0.6 0.3±0.4 0.3±0.4 0.003
 S 1.2±0.7 0.8±0.6 0.4±0.5 0.3±0.4 <0.001
 Jitter 2.0±1.8 1.3±1.3 1.1±0.9 1.4±2.0 0.188
 Shimmer 6.2±4.8 5.7±4.2 3.5±1.4 4.9±5.0 0.222
 NHR 0.6±1.2 0.3±0.6 0.1±0.0 0.2±0.1 0.306
 CPP 5.4±1.0 6.1±0.8 6.0±0.9 5.1±0.7 0.008
 MPT 11.7±8.3 13.4±4.3 16.6±7.3 15.1±5.6 0.026
 MFR 0.3±0.3 0.2±0.2 0.1±0.1 0.4±0.4 0.022
Closed quotient 40.3±10.4 47.5±5.7 48.9±8.5 44.7±5.5 0.107
VHI-30 67.4±33.3 45.3±29.7 39.6±24.5 41.0±31.2 0.006

G, grade; R, roughness; B, breathiness; A, asthenia; S, strain; NHR, noise harmonic ratio; CPP, cepstral peak prominence; MPT, maximum phonation time; MFR, mean airflow rate; VHI, voice handicap index


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