|Year : 2019 | Volume
| Issue : 1 | Page : 31-37
The role of growth factors in the treatment of voice disorders: systematic review
Mohamed K. M. El-Sharnoby1, Mohamed A. S. Baraka2, Hossam M El-Dessouky3, Eman E Abd El-Wahed4, Amina G Abd El-Aleem5
1 Department of Otolaryngology, Menoufiya University, Menoufiya, Egypt
2 Phoniatrics Unit, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
3 Phoniatrics Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
4 Phoniatrics Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
5 Phoniatrics at El-Bajur General Hospital, El-Bajur, Egypt
|Date of Submission||03-Jul-2018|
|Date of Acceptance||26-Aug-2018|
|Date of Web Publication||17-Apr-2019|
Amina G Abd El-Aleem
Source of Support: None, Conflict of Interest: None
The aim of this study was to present a review about the role of growth factors (GFs) in the treatment of some voice disorders.
Materials and methods
The data sources consisted of Medline databases (PubMed, Elsevier, and Wily Library) and all materials available in the internet from 1990 to 2017. The initial search presented 150 articles, of which 57 met the inclusion criteria, with level II-2 as the level of evidence. The articles studied the function, uses and the efficacy of basic fibroblast growth factor (bFGF) on vocal outcomes of patients with vocal fold (VF) lesions. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria were specified, appropriate controls were used, adequate information was given and whether the studies defined assessment measures. Significant data were collected. It was heterogeneous. Thus, a structured review was performed with the results tabulated.
VF lesions and paralysis induced severe dysphonia, and the fundamental therapy for these diseases is voice therapy; however, this approach is ineffective for severe dysphonia. Surgical approaches have been attempted, but the outcome varies. The aim of surgical treatment has recently changed to stimulate the regeneration of VF structures. GF therapy is considered to be a 'trigger' for jumpstarting biological processes. One promising GF is bFGF. Cases of severe dysphonia that were treated by the single, transoral bFGF injection method showed significant improvements in the vocal functions after injection. The single injection method is easy to perform as an office procedure. The use of bFGF injection to treat severe VF lesions and VF paralysis is still controversial.
Keywords: basic fibroblast growth factor, growth factors, office procedure, regenerative medicine, superficial lamina propria, unilateral vocal fold paralysis, vocal fold lesions
|How to cite this article:|
El-Sharnoby MK, Baraka MA, El-Dessouky HM, Abd El-Wahed EE, Abd El-Aleem AG. The role of growth factors in the treatment of voice disorders: systematic review. Menoufia Med J 2019;32:31-7
|How to cite this URL:|
El-Sharnoby MK, Baraka MA, El-Dessouky HM, Abd El-Wahed EE, Abd El-Aleem AG. The role of growth factors in the treatment of voice disorders: systematic review. Menoufia Med J [serial online] 2019 [cited 2019 May 27];32:31-7. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/31/256089
| Introduction|| |
Tissue engineering, with significant research inputs over the last decades, has emerged as a potential tool to regenerate damaged and diseased tissues. The use of growth factors (GFs) in the tissue engineering regime has recently gained great interest . Polypeptide GFs are a diverse group of hormone-like agents that regulate growth and differentiation through cell surface receptors. They are generally represented by homologous families containing several members with distinct overlapping receptor interactions and hence responsive tissue specificities. Similarly, their receptors are alsoclustered in family groups of sequence-related proteins . As with the classical hormones, the polypeptide GFs are usually relatively small, highly soluble proteins of compact structure, and, although some are glycosylated, the majority are not. From a functional point of view, polypeptide GFs can conveniently be divided into four categories. Tissue GFs, hemopoietic GFs, neurotrophic factors and cytokines . The neurotrophic factors are a more specialized grouping and are now generally considered to be those entities that act on neurons. The hemopoietic GFs and cytokines act on the circulating cells and those involved in the immune response. Like most proteins, polypeptide GFs can also be subdivided into 'families'. This is well illustrated by the insulin-related growth factors, fibroblast growth factors (FGFs) and, more recently, the neurotrophins . FGF is a representative GF that has shown the potential effects on the repair and regeneration of tissue ,. FGF was originally identified as a protein capable of promoting fibroblast proliferation and is now known to comprise 22 members. FGFs exert multiple functions through the binding into and activation of fibroblast growth factor receptors (FGFRs). With their potential biological functions, FGFs have been utilized for the regeneration of damaged tissues, including skin, blood vessel, muscle, adipose, tendon/ligaments, cartilage, bone, tooth and nerve . The fundamental therapy for vocal fold (VF) lesions and paralysis, which are caused by congenital, postoperative, inflammatory and age-related alterations, is conservative voice therapy; however, this approach is ineffective for severe dysphonia . In a severe VF lesion, such as a VF scar, sulcus and atrophy, superficial lamina propria (SLP) has deposits of disorganized thick collagen bundles with little hyaluronic acid (HA); these histological changes induce VF sclerosis, vibratory suppression and glottal insufficiency. These changes induce severe symptoms such as dysphonia, phonasthenia, and aspiration associated with communication disorders and fatal pneumonia . The aim of surgical treatments for VF lesions has initially been to produce adequate glottal closure in phonation. Several surgical approaches have been attempted, such as the dissection or excision of the lesion, the slicing technique, carbon dioxide laser ablation with collagen injection and fat implant and fascia implant to stimulate regeneration of the SLP, but the surgical outcome varies because it depends on an unpredictable healing process. Thus, it is necessary to develop a new type of treatment . At the end of the 20th century, innovations in tissue engineering and regenerative medicine aimed to regenerate lost organs and recover their function. It was found that the bFGF stimulated the production of HA by VF fibroblasts and reduced collagen production in an animal model . On the basis of these laboratory experiments, the clinical application of bFGF to human patients with VF scar, atrophy, paralysis and sulcus, using a bFGF product was carried out, and showed significant improvement in the voice functions of VFs . The aim of this study was to present a review about the role of GFs in the treatment of voice disorders in order to highlight the efficacy of bFGF on vocal outcomes of patients with VF lesions.
| Materials and Methods|| |
We reviewed papers on the role of GFs in the treatment of voice disorders from Medline databases, which are PubMed, Elsevier, J-STAGE, and Wily Library, and also from materials available on the internet from 1990 to 2017. We used bFGF/VF atrophy and bFGF/VF scar/paralysis/GFs functions and bFGF as search terms.
All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria: Published in the English language, published in peer-reviewed journals, focused on the basic fibroblast growth factor (bFGF) and the clinical application of bFGF in human patients with VF scar, atrophy, paralysis and sulcus. If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.
If the studies did not fulfill the above criteria, they were excluded. The analyzed publications were evaluated according to evidence-based medicine criteria using the classification of the US Preventive Services Task Force, which includes the following:
- Level I: evidence obtained from at least one properly designed randomized controlled trial
- Level II-1: evidence obtained from well-designed controlled trials without randomization
- Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
- Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
- Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.
A structured systematic review was performed with the results tabulated.
| Results|| |
On the basis of our selection criteria, 37 well-designed studies were included. Studies that were not original or poorly designed were excluded from our review. With regard to biology, functions, [Table 1] and general uses of GFs in tissue engineering (10), studies showed data, which illustrated that FGF functions were largely implicated in many types of cells in vitro and in vivo.
However, seven of the studies showed that histopathological changes occur in VF lesions such as VF scar, sulcus and atrophy, which induce VF sclerosis, vibratory suppression and glottal insufficiency, leading to dysphonia, phonasthenia and aspiration.
About five studies concerned with other surgical attempts performed for these lesions showed that a particular treatment had not been established.
With regard to the effect of GF application on VF scar, atrophy, sulcus and paralysis, 15 of the available studies showed that the regenerative treatments by bFGF intracordal injection – even a single injection – effectively improved vocal functions [Table 2]. There were no major side effects, although hyperemia of the VFs and temporal dysphonia did occur for a couple of weeks; however, these effects completely resolved. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force.
|Table 2: Summary of studies showing the outcome of regenerative therapy for some vocal fold lesions and vocal fold paralysis with basic fibroblast growth factor|
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| Discussion|| |
According to Bradshaw et al. , polypeptide GFs are a diverse group of hormone-like agents that regulate growth and differentiation through cell surface receptors. They are generally represented by homologous families containing several members with distinct overlapping receptor interactions and hence responsive tissue specificities. Similarly, their receptors are alsoclustered in family groups of sequence-related proteins .
From a functional point of view, polypeptide GFs can conveniently be divided into four categories:
- Tissue GFs
- Hemopoietic GFs
- Neurotrophic factors
- Cytokines .
There is considerable overlap in the activities of many of these factors, and many can be listed in more than one category. Like most proteins, polypeptide GFs can also be subdivided into 'families'. This is well illustrated by insulin-related growth factors, FGFs and, more recently, neurotrophins .
According to Hill , the primary role of peptide GFs contributes to the fundamental intercellular signaling within tissues that underlies a complex interaction of cell proliferation, hypertrophy, migration, differentiation, and senescence, which proceeds within strict temporal and anatomical constraints.
According to Andreopoulos and Persaud , FGFs that signal through FGFRs regulate a wide range of biological functions. Organ transplantation or implantation of synthetic devices is the currently available and most used methods to treat loss of tissues and organs in humans. However, there is a continued demand of new solutions and approaches for tissues failure, as the definitive solution is yet to be achieved. For this reason, regenerative medicine and tissue engineering are becoming of great interest, as the alternative strategy to repair or regenerate damaged tissue .
According to Lee et al. , regenerative medicine provides alternatives to organ transplantation, which is limited in applicability owing to immune responses against allografts, and the large disparity between the need for organs and tissues and the number available for transplantation. GFs are critical signaling molecules that instruct cells during development, and one may achieve tissue regeneration in the adult by enabling control over GF delivery .
According to Macri and Clark , the ideal materials are biodegradable, biocompatible, and able to serve as a supporting artificial extracellular matrix until the natural tissue is produced by the neighboring cells, as the biomaterials gradually degrade. The use of GFs has become greatly attractive to achieve the above-mentioned goals because their activity affects and regulates many cellular processes involved during tissue healing .
According to ASHA, the VF is a multilayered vibrator structure, which gives the VFs their mechanical properties. These structures oscillate during the production of sound. According to cover-body complex theory, the layered structure can be classified into three sections:
- Cover: epithelium + superficial layer of lamina propria
- Transition portion: intermediate and deep layers of lamina propria
- Body (core): vocalis muscle and vocal ligament .
According to Pawlak et al.  and Titzeand Sundberg , the SLP is a layer that contains an amorphous substance and microfibrils that allow it to slide over the deep layer and contribute to the viscoelastic and vibratory characteristics of the human VFs. The SLP is normally very loose and contains abundant interstitial proteins such as HA, fibronectin, and proteoglycans such as fibromodulin, decorin, and versican ,.
According to Chan et al. , in a severe VF lesion, such as a VF scar, sulcus and atrophy, the SLP has deposits of disorganized thick collagen bundles with little HA. These histological changes induce VF sclerosis, vibratory suppression and glottal insufficiency. These changes induce severe symptoms such as breathy dysphonia, phonasthenia and aspiration associated with communication disorders and fatal pneumonia .
According to Tsunoda et al. , various surgical attempts have been performed in these cases; however, a particular treatment has not been established, because the wound-healing process for regeneration is unpredictable.
According to Hess and Fleischer  and Pagano et al.  also, UVFP induces not only severe dysphonia but aspiration as well, which leads to a reduction in the patient's quality of life. Various treatments have been used, including laryngeal framework surgery, and injection laryngoplasty ,.
However, for patients with mild symptoms of UVFP and individuals with poorer general health, it is best to receive minimally invasive therapy. Even in severe cases, a 6-month observation period is required from onset to laryngeal framework surgery, because some UVFP patients experience spontaneous recovery during their clinical course. Patients under observation should also receive some type of therapy to mitigate the severity of dysphonia and aspiration during the observation period. Although various surgical strategies have been applied in these cases, a definitive treatment has not been established, because these surgical procedures are sometimes performed under general anesthesia, and phonological problems often remain unresolved .
According to Kanazawa et al. , recent progress in regenerative medicine has made it possible to develop tissue engineering techniques by using cells, scaffolds, and GFs. GFs stimulate the growth, proliferation and migration of cells. One promising GF is bFGF, which is a member of the FGF family and a promising agent for regenerative medicine of the larynx. Regenerative treatments using bFGF injection of SLP of the vocal cords effectively improved dysphonia in vocal cord lesions and in UVFP  [Table 2].
Suehiro et al.  presented an in-vivo canine study, which showed that a local injection of bFGF resulted in the recovery of vibration, in scarred VFs.
Histological examination showed recovery of HA with reduced disorganization of collagen bundles. On the basis of these laboratory experiments, Hirano et al.  have established the clinical application of bFGF to human patients with VF sulcus, using a bFGF product.
According to Hirano et al. , the clinical application of bFGF to human cases with VF sulcus, using a bFGF via a local injection of bFGF or regenerative surgery using implant of gelatin sponge and bFGF. The bFGF dissolved in saline was injected transorally into one side of the VF. The injection was performed unilaterally or bilaterally depending on the site of the lesion. The regenerative surgical procedure consisted of dissection of the scar and implant of the gelatin sponge with bFGF .
According to Hirano et al. , injection of bFGF or regenerative surgery with the implant of gelatin sponge and bFGF was performed for 7 human patients with VF scar. Both treatments resulted in the significant improvement of vocal parameters, including maximum phonation time (MPT), voice handicap index-10 (VHI-10) and grade, roughness, breathiness, asthenia, and strain (GRBAS) scale. It is suggested that bFGF has regenerative effects for VF scar .
In atrophy of human VF, the study by Hirano et al.  reported preliminary data of a human clinical trial of bFGF administration for an aged VF. A 63-year-old male patient with aged VFs was recruited for the current trial. He had complained of a dysphonic, breathy voice. Stroboscopic examination showed bilateral VF atrophy with glottic insufficiency and reduction of mucosal wave amplitude. Ten micrograms of bFGF in 0.5 ml saline was transorally injected into the left VF under videolaryngoscopic monitoring, after thorough topical anesthesia by 4% lidocaine spray. The curved injection needle was placed at the lateral portion of the VF, and the bFGF solution was gradually infiltrated into the whole lamina propria .
During a short-period observation from 1 week through 3 months, sufficient regenerative effects on the tissue properties of the treated VF were noted without any adverse effect or toxicity. Videostroboscopic examination revealed an improvement of the mucosal wave with complete glottic closure, and these positive effects were maintained for up to 3 months. Mucosal wave amplitude (normalized mucosal wave amplitude) and glottis closure (normalized glottal gap) also showed improvements after the administration of bFGF. The voice became stronger with less dysphonia. MPT and mean airflow rate (MFR) improved. Acoustic parameters also showed improvements during the period spanning from 1 week to 3 months .
Thereafter, a clinical trial was carried out by Hirano et al.  who examined the regenerative effects of bFGF on aged VFs in 10 patients. All cases showed regenerative effects, indicated by the significant improvements in aerodynamic and acoustic function. Stroboscopic findings also demonstrated better mucosal vibration with a reduction of the glottic gap .
According to Kanazawa et al. , single bFGF injections for cases of severe dysphonia caused by VF atrophy are a novel therapeutic strategy. Fifty micrograms of bFGF dissolved in 0.5 ml saline was injected and spread into the SLP, not into the muscle layer, using a 23-G injection needle (Varixer; TOP Corp., Tokyo, Japan) under the transnasal fiberscopic monitoring of the larynx. In this study, the injection was not repeated. Patients were instructed to rest their voices on the day of the injection but were allowed to phonate the following day. The stroboscopic findings showed improved vibration of the VFs. The MPT improved, and the VHI was reduced. As in the representative patient, most patients improved in every phonologic parameter .
According to Ohno et al. , administration of bFGF into the lamina propria of the VFs significantly improved VHI-10 scores in the patients having age-related VF atrophy. The GRBAS scale, MPT, amplitude perturbation quotient and period perturbation quotient scores were also improved. Stroboscopic examination showed significant improvement of glottis closure and mucosal wave. The VHI-10 was useful for making treatment decisions and assessments of treatment success. The bFGF injection is a promising therapy for treating age-related VF atrophy .
In paralysis of vocal cords, Motoyoshi et al.  reported that the local application of bFGF at the site of the lesion improves recovery of VF movement after transection and immediate repair of the recurrent laryngeal nerve. It is thought to act by both facilitating the regeneration of the damaged nerve fibers and by preventing denervation-induced atrophy of the laryngeal muscle, thereby improving the contractile force of the intrinsic laryngeal muscles. Another possible explanation is that bFGF minimizes the misdirection on the nerve fibers. No side effects related to the local use of bFGF were noted .
Kanazawa et al.  retrospectively investigated the phonological outcomes of direct bFGF injection into the muscle layer of primary UVFP patients. Injection of bFGF was performed on both VFs. Seven months after the injection, his breathy dysphonia improved demonstrably. The glottal gap was not observed during phonation, and the vibration of the vocal cords improved significantly The MPT in all cases significantly increased, and MFR in all cases decreased. The pitch range (PR) significantly increased. In contrast to aerodynamic parameters and PR, acoustic parameters, such as shimmer, jitter and noise-to-harmonic ratio, were not improved by bFGF injection .
One possibility is that direct bFGF injection into the muscle layer increases muscle volume and induces the medicalization effect of the VFs, but would not affect the SLP, which contributes to the vocal acoustic effect. Kanazawa et al.  previously reported that bFGF injection into the SLP improved jitter, which would support this hypothesis. Although bFGF injection did not improve acoustic parameters, VHI significantly increased, and the injection provided sufficient patient satisfaction .
Suzuki et al.  analyzed the effects of this treatment using high-speed digital imaging in follow-up examinations. High-speed digital imaging allowed making a detailed analysis of the effects of bFGF on the oscillation modes of the VF mucosa. The postinjection improvement in an insufficient glottal closure without a decrease in VF vibration indicates that the viscoelasticity of the VF mucosa was preserved. Intracordal injection of bFGF improved insufficient glottal closure without reducing VF vibrations, resulting in an attendant improvement in vocal quality. Furthermore, this effect was maintained for 12 months. A single injection can yield a sufficient and persistent long-term effect, reducing the number of operations and providing a minimally invasive treatment for insufficient glottal closure .
Drug injection for VF is a low-risk and low-cost therapy suitable for office surgery. A significant difference was observed between the preinjection and postinjection values of MPT, MFR, PR, jitter, speech fundamental frequency, and VHI. These results indicate that the single injection method has a similar effect as the repeated injection method or regenerative surgery used for severe dysphonia due to VF lesions or VF paralysis. GF therapy is considered to be a 'trigger' for jumpstarting biological processes .
There were no major side effects, although hyperemia of the VFs and temporal dysphonia did occur for a couple of weeks; however, these effects completely recovered. Because bFGF has a strong effect on angiogenesis and a blood supply is inevitable for inducing regeneration, hyperemia is a sign of the regenerative effects of bFGF. A dysphonia may occur because of hyperemia or because of the temporal imbalance of tissue property between the two VFs during the healing process .
The single injection method is easy to perform as an office procedure. The bFGF is suitable for office procedures because it is less toxic and readily available as an injectable aqueous solution. Furthermore, bFGF is a type of regenerative medicine that maintains vocal cord-specific structure, which differs from various foreign material injections .
| Conclusion|| |
The bFGF injection would be a useful tool in the treatment of severe dysphonia caused by severe VF lesions and UVFP. It can be performed as a day-surgery procedure, with a 4–5 min operation time, and no infection or allergic reaction to residual foreign substances.
An allergic response or any severe adverse effects were not observed in any patient. Most patients experienced a dysphonic voice and hyperemia of the vocal cord for 2–3 weeks; however, these effects completely recovered.
The bFGF therapies by either local injections or regenerative surgery have favorable outcomes. The glottal gap was not observed during phonation, and vibration of the vocal cords improved significantly; moreover, the vocal function was improved significantly in VF lesions after injection.
The bFGF injection, an easy method and suitable as an office procedure, significantly improved the dysphonia caused by severe VF lesions such as VF sulcus, scars, atrophy and paralysis. It is expected to be widely adopted, and effective adjunctive drugs and procedures are anticipated to be developed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]