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Injectable substances for injection laryngoplasty

last modified on: Tue, 08/03/2021 - 07:32

Injectable substances for injection laryngoplasty

return to: Injection Laryngoplasty for Vocal Fold Paralysis and Glottic IncompetenceInstructions to patients about vocal cord paralysis treatment (injection laryngoplasty and approaches requiring open surgery)

see also:Percutaneous Injection Laryngoplasty;  Vocal Cord Injection with Prolaryn Gel with Videostroboscopy (transoral)

Cymetra Injection to Paralyzed Vocal Cord In the Clinic Technical Points for Percutaneous Injection 

and: Injection laryngoplasty difficulties

Background: 

There are many injectable substances (injectates) used for management of glottic incompetence via Injection Laryngoplasty. An understanding of the properties of these materials is useful to help counsel patients about management options. Review of the following will help in providing realistic expectations in the course of maximizing outcomes and limiting risks.  At this point, no single material is ideal and, as a result, compromises are necessarily made in matching the best material for the patient's specific needs.

General Considerations: 

  1. General Indications: Many of the  injectables used by laryngologists to treat glottic incompetence are used off-label (approved by the FDA for uses outside of the larynx). Injection laryngoplasty when used for glottic incompetence is designed to reposition a vocal cord in the process of adding bulk to it. Many substances have been evaluated for this purpose for diagnoses including vocal cord paralysis/paresis, vocal fold atrophy, vocal scarring, augmentation to subsequent to open medialization thyroplasty, presbylaryngis, and more. 
     
  2. General Contraindications: Injection laryngoplasty is typically contraindicated in the presence of acute laryngeal inflammation/infection, inadequately controlled malignancy or rapidly progressing disease of the upper aerodigestive tract, bilateral laryngeal paralysis or other cause of upper airway obstruction (including unilateral laryngeal paralysis, posterior glottic scarring, other features compromising the airway).  

  3. Long-term vs short-term injectates: Injectable substances used in injection laryngoplasty are classified by anticipated duration. 

    • Note that the duration of benefit following injection is dependent on more than the type of material placed. 
      • The location of the material 
        • Placement in Reinke's space provides anticipated longer effect than in the better vascularized more mobile TA/LCA muscles where reposition commonly occurs more rapidly
      • The altered nature of the recipient bed injected
        • Patients with decreased blood supply to the vocal folds (s/p irradiation) or reduced inflammatory response (on immunosuppressants) may experience longer duration of effect - see Chang 2014
      • The degree of re-innervation to the larynx
        • Some degree of re-innervation is common and may provided tone (bulk) or improved position to the vocal fold
      • The location of the vocal fold during recovery (re-innervation with synkinesis rather than full movement) - potential to also favorably affect location of vocal process 
        • Early injection (shortly after the identification of symptomatic laryngeal paralysis) has found recent support to improve the static location of the vocal fold - that may be maintained after the injectate has resorbed
      • Possible induction of fibrosis to induce lasting fullness to the vocal fold that persists after resorption of the material
        • Fibrosis is one of several hypotheses offered for the observation by Predres et al (2012) that
          • 'treatment with these temporary agents may provide a longer duration of benefit than previously expected'
            and
          • "clinicians should consider counseling UVFP patients that opting for a temporary vocal fold injection may result in lasting voice improvement that may the reduce their subsequent desire for a permanent intervention"
      • Emerging support favoring use of early injection laryngoplasty for longer term benefit likely to decrease the need for a subsequent open 'more permanent' procedure - see references below including:
        • Shen T, Damrose EJ, Morzaria S: A meta-analysis of voice outcome comparing calcium hydroxyapatite injection laryngoplasty to silicone thyropalsty. Otolaryngol Head Neck Surg. 2013 Feb;148(2):197-208
        • Alghonaim et al.: Evaluating the timing of injection laryngoplasty for vocal fold paralysis in an attempt to avoid future type 1 thyroplasty. Journal of Otolaryngology - Head and Neck Surgery 2013 42:24
        • Friedman AD, Burns JA, Heaton JT and Zeitels SM: Early Versus Late Injection Medicalization for Unilateral Vocal Cord Paralysis. Laryngoscope, 120:2042-2046 2010
        • Yung KC, Likhterov I, Courey MS. Effect of temporary vocal fold injection medialization for unilateral vocal cord paralysis. Laryngoscope 2010;120:2042-2046
    • Shorter-term Injectates< >These include carboxymethylcellulose and gelfoamUseful for patients who would like to "test-drive"  before proceeding with injection with longer lasting material or an open procedure such as thyroplasty and/or arytenoid adduction - useful when diagnosis is uncertain (is the muscle tension dysphonia secondary to glottic incompetence from subtle paresis?)
    • Useful for injection to Reinke's space (i.e. for sulcus - see: Sulcus Vocalis case example response to Radiesse voice gel injection)
  • Intermediate-term injectates
    • These include hyaluronic acid derivatives and collagen derivatives
      1. Considered more 'forgiving' substances that require less accuracy in delivery to specific sites in the larynx than the longer term injectables (hence more often used in the clinic where precision of injection and then manipulation of the injectate is not as readily accomplished as in the OR)
      2. Have been (in the past) best for situations where return of vocal function is anticipated or at least possible - more recent support for potential long term benefit, including a series of early injections (see Friedman et al 2010)
      3. Compared to open procedures is much less of an intervention with respect to time, cost and potential morbidity - most commonly now done as an outpatient office procedure
  • Longer-term Injectates:
    • These include calcium hydroxylapetite,  autologous fat, and autologous fascia  
      1. More often done under general anesthesia
  • Potentially permanent injectates 
    • These include autologous fat and fascia
  • Permanent injectates
    • These include Teflon, silicone,
  • Viscoelastic properties of injectates:

    Calcium Hydroxylapetite

    Hyaluronic Acid Derivatives

    Hylaform (Hyalan B gel): 

    Juvederm / Juvederm Ultra

    Restylane / Perlane

    Tissue-derived Injectates

    Others:

    Suggested Reading:

    Prendes BL, Yung KC, Likhterov I, Schneider SL, Al-Jurf SA, and Courey MS: Long-term effects of injection laryngoplasty with a temporary agent on voice quality and vocal fold position.Laryngoscope. 2012 Oct;122(10):2227-33. 

    Friedman AD, Burns JA, Heaton JT, Zeitels SM. Early versus late injection medicalization for unilateral vocal fold paralysis patients. Laryngoscope 2011;121:2191-2194
  • Bertroche JT, Radder M,Kallogjeri D, Paniello RC and Bradley JP: Patient-Defined Duration of Benefit from Juvederm (Hyaluorinc Acid) Used in Injection Laryngoplasty Laryngoscope, 129:2744-2747, 2019
     
    Yung KC, Likhterov I, Courey MS. Effect of temporary vocal fold injection medialization for unilateral vocal cord paralysis. Laryngoscope 2010;120:2042-2046
    Jiang JJ and Titze IR: A Methodological study of hemilaryngeal phonation Laryngoscope 1993 Aug;103(8):872-82
    Shen T, Damrose EJ, Morzaria S: A meta-analysis of voice outcome comparing calcium hydroxyapatite injection laryngoplasty to silicone thyropalsty. Otolaryngol Head Neck Surg. 2013 Feb;148(2):197-208

    Mallur PS, Rosen CA: Vocal fold injection: review of indications, techniques, and materials for augmentation. Clin Exp otorhinolaryngol 2010, 3(4):177–182. 

    Alghonaim et al.: Evaluating the timing of injection laryngoplasty for vocal fold paralysis in an attempt to avoid future type 1 thyroplasty. Journal of Otolaryngology - Head and Neck Surgery 2013 42:24. 

    Chang J, Courey MS, Al-Jurf SA, Schneider SL and Yung KC: INjection laryngoplasty Outcomes in Irradiated and Nonirradiated Unilateral Vocal Fold Paralysis. Laryngoscope. 124:1895-1899, 2014
    Friedman AD, Burns JA, Heaton JT and Zeitels SM: Early Versus Late Injection Medicalization for Unilateral Vocal Cord Paralysis. Laryngoscope, 120:2042-2046 2010
    -Canton T, Thibeault S, Klemuk S et al. Viscoelasticity of Hyaluronan and Nonhyaluronan Based Vocal Fold Injectables: Implications for Mucosal Versus Muscle Use. Laryngoscope. 117:3 (2007) 516-521
 

    -Hamilton DW, Sachidananda R, Carding PN, et al. Bioplastique injection laryngoplasty: voice performance outcome. J Laryngol Otol. 2007 May;121(5):472-5. 

    -Hertegard 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 Dec; 112(12):2211-2219

    -Lisi C, Hawkshaw MJ, Sataloff RT. Viscosity of Materials for Laryngeal Injection: A Review of Current Knowledge and Clinical Implications. J Voice. 27:1 (2013) 119-123.

    -Luu Q, Tsai V, Mangunta V, Berke GS, Chhetri DK. Safety of percutaneous injection of bovine dermal crosslinked collagen for glottis insufficiency. Otolaryngol Head Neck Surg . 2007; 136(3) :445-9. 

    -Mallur PS, Rosen CA. Vocal Fold Injection: Review of Indications, Techniques, and Materials for Augmentation. Clin Exp Otorhinolaryngol. 2010 Dec; 3(4): 177–182.

    -McCulloch TM, Andrews BT, Hoffman HT, et al. Long-term follow-up of fat injection laryngoplasty for unilateral vocal cord paralysis. Laryngoscope. 2002 Jul;112(7 Pt 1):1235-8.

    -Molteni G, Bergamini G, Ricci-Maccarini A et al. Auto-crosslinked hyaluronan gel injectionsin phonosurgery. Otolaryngol Head Neck Surg. 2010 Apr; 142(4):547-53.

    -Phua CQ, Mahalin-Gappa Y, Homer J, et al. Injection Laryngoplasty. The Otorhinolaryngologist. 2013; 6(2): 111–118

    -Reijonen P. Injection laryngoplasty with autologous fascia for treatment of unilateral vocal fold paralysis (Doctoral dissertation). 

    -Wen MH, Cheng PW, Liao LJ, et al. Treatment Outcomes of Injection Laryngoplasty Using Cross-Linked Porcine Collagen and Hyaluronic Acid.Otolaryngol Head Neck Surg. 149:6 (2013) 900-906

    • Note that the ex vivo measured viscosity of a substance is anticipated to be altered by biological processes as the recipient incorporates it in vivo. 
    • Increased stiffness to a medialized paralyzed vocal fold is considered by many to be desirable 
      • A greater pitch range is anticipated to result from a normal vocal fold striking the properly positioned and stiffened paralyzed vocal fold – see Jiang JJ and Titze IR (1993)
      •  A narrow pitch range is anticipated to result from the limited frequencies entraining a normal vocal fold with a well medialized by 'floppy' paralyzed vocal fold
    • Normal vocal fold mucosa has a very low viscosity at phonatory frequencies of vibration
    • Substances with viscosities similar to normal mucosa are thought less likely to impair mucosal wave and therefore are more likely to be used for superficial injection 
    • The higher the viscosity of the substance the more likely it is to impair mucosal wave. The more viscous a substance the more lateral (or deep) it should be injected< >Low viscosity injectates (for sub-mucosal injection) include: carboxymethylcellulose, hyaluronic acid hydrogels and autologous fatIntermediate viscosity injectates (for deep layer of lamina propria injection) include: Collagen derivatives, autologous fascia, calcium hydroxyapetiteHigh-viscosity injectates (for thyroarytenoid muscle injection) include: Teflon, siliconeProlaryn Gel (Formerly Radiesse Voice Gel) 
      1. Composition: carboxymethylcellulose and glycerin water based gel
      2. Reported Duration: Rapid reabsorbtion results in 1-2 month duration
      3. Injection: 25-27 guage needle placed lateral to vocal ligament
      4. Outcomes in literature
        • Superior vibratory mucosal outcomes compared to Gelfoam
        • Low viscosity approximates that of vocal fold mucosa making superficial injection safe
        • No reported allergic complications
      1. Prolaryn Plus (Formerly Radiesse Voice) 
        1. Composition: microspheres of calcium hydroxyapetite in Prolaryn Gel
        2. Reported duration: 1-2 years
        3. Injection: 25-27 guage needle to be placed lateral to vocal ligament. Over inject 10% in anticipation of gel reabsorption
        4. Outcomes in literature:
          • Prolaryn Plus had superior vibratory mucosal outcomes compared to gelfoam and worse compared to hyaluronate-based injectates
          •  No significant difference in voice outcomes compared to silicone medialization thyroplasty
          • Very low allergic potential. (Single case reports of severe systemic allergic reaction and giant cell allergic reaction)
          • Animal studies indicate that calcium hydroxylappetite may stimulate tissue ingrowth resulting in neo-cartliage and collagen deposition (which may account for the prolonged effect)
      1. Composition: this group of injectates is composed of various chemical modifications of hyaluronic acid, a glycosaminoglycan naturally abundant in the laryngeal extracellular matrix
      2. Reported duration: Reports vary widely. The average reported duration of effect is 4 months. (Hartegard et al and Molteni et al have both reported good effect up to 12 months). 
      3. Injection 25-28 gauge needle which can be placed in the superficial or deep layers of the lamina propria with good effect. 
      4. Outcomes in literature:
        • Superior patient-reported and videostroboscopic outcomes compared to collagen at 4, 6, and 12 months
        • Superior voice outcomes and duration of effect at 4 months compared to porcine collagen
        • Widely studied viscoelastic properties in animal models have repeatedly demonstrated a near-perfect viscosity match with normal vocal fold mucosa
        • No reports of serious adverse effect 
        • Animal histologic studies have noted increase in connective tissue surrounding hyaluronic acid implants with mild surrounding inflammatory reaction, but no tissue necrosis or foreign body reaction. 
      •  Intermediate-sized cross-linked molecules of hyaluronic acid derived from an avian source (rooster combs) in a hydrogel.
      • Theoretical potential for allergic cross-reaction to avian-derived protein, consider alternative for patients with documented allergies to avian proteins
      • Synthetic hyaluronic acid with the most extensive cross-linking of all of the hyaluronic acid derivatives. Absorbs 1000 times its weight in water. Longest lasting of the hyaluronic acids.
      • Non-animal source results in a theoretically very low risk for allergic reaction
      • Juvederm has not been widely studied. 1 study reported good vocal outcomes but with follow-up of only 4 months. 1 case of delayed glottic inflammation was noted.
      • Hyaluronic acid derived from fermented equine streptococci. There is extensive intermolecular cross-linking with ether bonds resulting in the most viscous of all the hyaluronic acid derivatives. Restylane is suspended in a small-particled hydrogel. Perlane is suspended in a large-particled hydrogel.
      • The most widely studied of the hyaluronic acid injectates
      • Found to have at least some effect on voice up to 12 months
      • Several studies report superior results with Restylane if pre-injection glottic gap is < 2 mm. 
      • Randomized controlled trial showed longer duration of effect in Perlane compared to Restylane; thought to be secondary to larger particle size
      • "Hyaluroinc acid gel (RESTYLANE) 20 mg/ml injection syringe 2 cc"
      1. Cymetra
        1. Composition: Micronized AlloDerm. Tissu is a micronized allograft of cadaveric human dermis which is aseptically pocessed to remove cells but preserve the dermal extracellular matrix. Labelled that it may contains traces of antibiotics with individual labelling on each container often including gentamycin, polymixin B, neomycin

        2. Reported duration: 2 - 12 months
        3. Injection: 18-22 guage needle to be placed in deep layer of lamina propria or deeper
        4. Contraindications: Mixed connective tissue diease, gentamycin allergy
        5. Complications: Case reports of intralaryngeal abscess (per manufacturer, non-pathogenic bacteria may remain viable in the graft after processing)
        6. Outcomes in literature:
          • High viscosity compared to vocal fold mucosa
          • Good patient-reported outcomes up to 12 months in several studies
          • Poorer patient-reported voice outcomes compared to hyaluronic acid, but longer duration of effect.
          • Collagen injections inadvertantly (and some intentionally) placed into Reinke's space have resulted in poor outcomes with small submucosal nodules requiring microsurgical excision, loss of mucosal wave and permanent ballooning of the vocal fold.
          • Histologically there is minimal tisuse response to Cymetra, there have been no reports of serious allergic reaction in laryngoplasty
             
      2. Bovine-derived collagen: Zyderm I, Zyderm II and Zyplast 
        1. Composition: Bovine dermal collagen suspension. Zyderm II has a higher concentration of collagen than Zyderm I (and is therefore more viscous and slower rate of resorption). Zyplast has the same collagen concentration of Zyderm I, but has a very high rate of glutaraldehyde cross-linking (resulting in even slower rate of resorption).
        2. Reported duration: 4 - 8 months
        3. Injection: 22-26 gauge needle into deep layer of lamina propria or deeper
        4. Contraindications: Documented-bovine allergy
        5. Complications: 2% risk of allergy, FDA recommends allergy testing on all patients. 
        6. Outcomes in literature: 
          • Luu et al (2007) studied the safety of bovine collagen injection and their data supported selective allergy testing rather than testing all patients
          • Viscoelastic studies show higher viscosity of bovine collagen compared to vocal fold mucosa
          • Collagen injections inadvertantly (and some intentionally) placed into Reinke's space have resulted in poor outcomes with small submucosal nodules requiring microsurgical excision, loss of mucosal wave and permanent ballooning of the vocal fold.
          • We have reported the case of superficial injection into Reinke's space in a patient with unilateral vocal fold paralysis who continues to have significant improvement in voice and glottic closure at 4.5 years
             
      3. Cosmoplast / Cosmoderm
        1. Composition: Human-derived fibroblasts cultured in a synthetic extracellular matrix 
        2. Reported duration: 4 - 6 months
        3. Location of injection: 22-26 gauge needle in the deep layer of lamina propria or deeper
        4. Contraindications: Mixed connective tissue disease
        5. Outcomes in literature:
          • Very low rate of allergic reaction (in facial plastic surgery literature)
          • Very limited data on use in injection laryngoplasty
              
      4. Autologous Fat
        1. Composition: operatively harvested autologous fat grat
        2. Reported duration: Results vary widely; classically lasts at least 1 year but is often permanent
        3. Injection: 18 gauge needle (on Brunning's syringe) place submucosally for scar/sulcus or deeper to acheive medialization 
        4. Complications: Donor site morbidity is not insignificant (pain, swelling, scar and infection). Fat is losing favor as it is generally considered as an unpredicatable graft (see below), donor site morbidity is not insignificant
        5. Outcomes in literature
          • There is a high rate of failure to achieve desired results. Hsiung et al. described these as Early failures: failure of fat to soften or fill scarring and atrophy as well as unintended migration of fat. Late failures: resorption of the fat.
          • Our long-term follow-up of fat injection laryngoplasty showed good results in the short-term with very unpredictable results in the long-term. "The role of fat in injection laryngoplasty in the modern era is limited. 
          • Viscoelastic studies show that fat has nearly identical viscosity to true vocal fold mucosa and does not limit mucosal wave.
             
      5. Autologous fascia
        1. Composition: operatively harvested fascia (fascia lata, rectus sheath, temporal fascia)
        2. Reported duration: up to 1 year
        3. Injection: 18 gauge needle (on Brunning's syringe) place in vocalis muscle
        4. Complications: Donor site morbidity is not insignificant (pain, swelling, scar and infection)
        5. Outcomes in literature: 
          • Histologically there is a minimal inflammatory reaction, no foreign body reaction, a discernible mass with its own blood supply was present at 2 years in animal models
          • Viscoelastic studies show a significantly higher viscosity compared to vocal fold mucosa
          • Histologically there is a minimal inflammatory reaction, no foreign body reaction, a discernible mass with its own blood supply was present at 1 year in animal models
      1.  Gelfoam:
        1. Composition: Purified bovine gelatin powder (requires reconstistution)
        2. Reported duration: 4-10 weeks
        3. Injection: requires 18 gauge needle placed submucosally
        4. Contraindications:
        5. Complications: 2% risk of allergy, FDA once recommended allergy testing Luu study
        6. Outcomes in literature:
          • Viscoelastic studies show viscosity comparable to normal vocal fold mucosa
          • Frequently used as injectate in "trial laryngoplasty" 
          • Low rate of allergic reaction
          • Patient-reported and videostroboscopic outcomes superior compared to calcium hydroxylapetite up to 3 months
             
      2. Bioplastique (Commonly used in Europe, not approved for use in USA)
        1. Composition: Solid injectable silicone
        2. Reported duration: Considered permanent (longest follow-up in the literature is 7 years)
        3. Injection: 18 gauge needle (on Brunning's syringe) into thyroarytenoid muscle
        4. Outcomes in literature
          • No significant difference in clinically measured or patient-reported voice outcomes compared to medialization thyroplasty
          • Several reports of significant granulomatous foreign body reaction requiring microsurgical resection
          • Viscoelastic studies show significantly higher viscosity compared to normal vocal fold mucosa
             
      3. Teflon 
        1. Composition: polytetrafluoroethylene
        2. Reported duration: Permanent
        3. Location of injection: 22 gauge needle (on Brunning's syringe) into thyroarytenoid muscle
        4. Outcomes in literature:
      4. Partial list of injectables with trade names come from an excellent discussion in ref Mallur and Rosen (2010)

        calcium hydroxylapatite (RadiesseTM), polydimethylsiloxane (PDMS or particulate silicone), polytef paste (TeflonTM), bovine gelatin (GelfoamTM, SurgifoamTM), collagen-based products (CymetraTM, ZyplastTM, Cosmoplast/CosmodermTM), hyaluronic acid (RestylaneTM, PerlaneTM, HyalaformTM,Juvederm), and carboxymethylcellulose (Radiesse Voice GelTM)