in the past decade , vocal fold injection ( vfi ) has re - emerged as a valuable treatment modality for a variety of laryngeal disorders .
recent advances in injection materials have broadened the indications for this technique , while the increasing capabilities of endoscopic technology have increased the number of available approaches and precision of injection delivery .
the basic indications for vfi have expanded to include treatment for vocal fold paralysis , paresis , atrophy , and scar or sulcus ( 1 ) .
however , the myriad of options in patient selection , injectable materials , and approach to injection has made utilizing this modality increasingly complex for the clinician . in the broadest sense
, vfi can include procedures that target the superficial ( subepithelial space ) aspect of the vocal fold .
useful for mild - to - moderate vocal fold scar and lamina propria defects , superficial injection provides correction of vibratory defects rather than global augmentation . in the stricter sense
, vfi refers to deep or lateral injection , as a means for vocal fold augmentation .
typically , deep injection allows for placement of a filler substance in the lateral aspect of the thyroartyenoid / lateral cricoarytenoid muscle complex ( medial aspect of the paraglottic space ) .
the result is a medially displaced free edge of the vocal fold , akin to laryngeal framework surgery , or type i thyroplasty .
the procedure allows for correction of glottal insufficiency from a variety of causes , and is typically used to treat temporary or permanent mild - to - moderate glottal insufficiency ( < 1 to 3 mm glottal gaps ) . for the purposes of this review , vfi will refer to this latter method of deep vocal fold injection augmentation .
with advancing technology , such as distal chip and flexible working channel laryngoscopes , awake in - office techniques have become viable alternatives to the traditional microsuspension laryngsocopy technique .
available technology , choice of materials , surgeon preference , and patient preference must all dictate the approach used for vfi .
traditionally , microscopic suspension laryngoscopy is performed under general anesthesia with a small endotracheal tube or under jet ventilation , and with an adequately sized laryngoscope in suspension .
the degree of glottic incompetence is assessed through a combination of pre - operative awake stroboscopy and intra - operative visualization with microlaryngoscopy and zero- , thirty- , and seventy - degree angled telescopes . as an alternative , vfi may be done with a combination of conscious sedation and topical anesthesia , without endotracheal intubation , using a smaller slotted laryngoscope with 0-degree telescopic visualization endoscopic vocal fold injection ( 2 ) .
both techniques provide direct access to the vocal fold , and allow for precise needle placement along the superior arcuate line with a direct , linear trajectory .
these techniques prove especially valuable in the patient who is otherwise unable to tolerate an awake procedure .
however , both techniques do not provide real time assessment of vocal fold closure or voice quality .
though vfi in the awake patient was initially described over a century ago , vfi in an in - office setting has re - emerged in the past decade as an attractive alternative to microsuspension laryngoscopy . pointing to the popularity of this technique , a recent multi - institutional review revealed that vfi was performed equally often in an awake patient as one under general anesthesia ( 3 ) .
vfi in the awake setting has the distinct advantages of providing direct feedback of vocal fold closure and voice outcome during the injection , avoiding limitations of difficult exposure , and avoiding general anesthesia with its inherent risks and increased cost ( 4 ) .
technical successes , as well as voice outcomes , as measured by standardized patient - based voice surveys , are similar to injection performed under general anesthesia when performed by an experienced laryngologist ( 4 , 5 ) .
patient selection is critical when choosing vfi in an awake patient ; a cooperative , calm patient without a strong gag reflex is required for successful completion .
one concern about awake vfi lies in the relative decrease in needle control , leading to decrease in precision of injection .
in fact , there is some evidence that minor complications are slightly increased in an in - office setting ( 5 )
. in - office vfi encompasses percutaneous ( trans - cricothryoid membrane , trans - thyroid cartilage , and trans - thyrohyoid membrane ) , per - oral , and trans - nasal endoscopic approaches .
typically the three approaches are performed with a flexible laryngoscope in place , visualizing the larynx for visualization and to monitor injection effects . in most cases ,
optimal visualization is provided with a distal chip laryngoscope with digital , high quality video image output .
the trans - cricothyroid membrane approach typically utilizes a submucosal path ; a 25 g needle bent 45-degrees is inserted below the inferior border of the thyroid cartilage , 3 - 7 mm lateral to midline and subsequently passed cephalad and laterally . applying gentle
pressure medially transmits motion to the vocal fold , allows the surgeon to confirm submusocal location of the needle and thus prevents perforation of the mucosa by the needle .
alternatively , with adequate tracheal anesthesia , the needle can be inserted into the midline in the infra - glottis , and then directed superior and lateral , intraluminally , to the deep aspect of the vocal fold .
anatomic studies using multidetector array computed tomography has confirmed this approximate 45-degree cephalad angle from a typical injection point 7 mm off of the midline ( 6 ) .
the trans - thyroid cartilage approach utilizes a percutaneous approach perpendicular to the thyroid cartilage ala .
a 24- or 25 gauge needle is inserted 3 mm to 5 mm above the lower border of the thyroid cartilage and passed gently through the cartilage . advancing the needle toward midline with gentle pressure transmits motion to the vocal fold , and allows the surgeon to estimate the location of the needle tip .
occasional obstruction of the needle with cartilage may be overcome through pressure on the plunger , with care to avoid excessive pressure and possible overinjection of material .
a trochar - based injection devise has been made to assist tran - thyroid cartilage vfi ( casiano needle , medtronic inc . ,
once through the thyrohyoid membrane , the needle is directed sharply caudal and advanced ; with this maneuver , the needle can be visualized entering the lumen at the petiole of the epiglottis . from this position , with direct visualization using the flexible laryngoscope , the needle can be directed toward the vocal fold for injection . bending the needle , while improving the inferior angle , often makes directing the needle more difficult , and therefore is discouraged . among the percutaneous techniques , the trans - thyrohyoid membrane approach offers the distinct advantage of direct needle placement , increasing precision of the injection ( 7 , 8) .
the per - oral vocal fold injection approach utilizes a direct approach and offers excellent precision and needle visualization .
topical anesthesia of the oropharynx and larynx is critical , as the needle is guided from the mouth to the vocal fold with a per - oral approach .
typically the patient is placed in a seated " sniffing position " , with the neck flexed and the head slightly extended .
a flexible laryngoscope is inserted through the nose while the patient protrudes and holds his or her own tongue .
topical anesthesia may be given via an abrahms cannula passed per - oral to the base of tongue , epiglottis , and true vocal folds .
alternatively , topical anesthetic may be applied through a flexible catheter directed through the working channel of a flexible laryngoscope ; the laryngoscope is used to drip anesthetic onto the base of tongue , epiglottis , and , while the patient is phonating , onto the true vocal folds .
the route of the needle is typically a 90-degree path , though this varies from patient to patient , and may be approximated by comparing with the abrahms cannula passage .
typically , the false vocal fold will be retracted with the shaft of the needle , allowing for a lateral injection .
several commercially available needles , length 220 mm to 250 mm , may be purchased separately or included with injectate materials for per - oral vfi .
a final injection approach is the trans - nasal endoscopic approach to the vocal fold .
this approach utilizes a flexible working channel laryngoscope with a 23- or 25-gauge flexible needle introduced through the working channel . with the needle slightly from the tip of the endoscope
advocates describe utilizing this technique as an alternative to other approaches for its ease of use , patient tolerance , and ability to overcome anatomic and patient limitations .
however , it should be noted that the fine gauge injection needles only accommodate dilute preparations of most substances unless a mechanical injection device is used . this approach has been advocated using a dilute concentration of micronized deep dermal tissue ( cymetra ) , mixed with 2.3 ml of 1% lidocaine for all cases ( 9 ) .
it should also be noted that due to the length and caliber of the injection needle , this approach requires more than the normal amount of injection material to accommodate the relatively large dead space in the needle .
in the past 10 years material sciences have increased the number of injectables with increased safety profile and improved biomechanical profiles .
materials developed have sought to eliminate the deleterious foreign body and inflammatory reactions caused by some of the early injectable materials such as paraffin , silicone , and teflon. recent efforts have focused on matching the biomechanical and viscoelastic properties of the superficial lamina propia .
materials for deep augmentation injection are typically described as temporary , and permanent / long lasting .
long lasting , and sometimes , permanent injectable materials include autologous fat , calcium hydroxylapatite ( radiesse ) , polydimethylsiloxane ( pdms or particulate silicone ) , and historically , and polytef paste ( teflon ) .
temporary injection materials include bovine gelatin ( gelfoam , surgifoam ) , collagen - based products ( cymetra , zyplast , cosmoplast / cosmoderm ) , hyaluronic acid ( restylane , hyalaform ) , and carboxymethylcellulose ( radiesse voice gel ) .
the materials vary in the duration of integration and are thought to vary in their specific viscoelastic properties and biocompatibility .
autologous fat typically lasts from one to several years , and is considered a permanent injection by many . though the material is autologous
, may be generously injected , and is readily available , it is typically harvested in the operating suite under sterile conditions . additionally , the survival is highly , which may be due to fat preparation techniques ; indeed , many suggest substantial overinjection of due to this immediate variability .
in addition to global augmentation , autologous lipoinjection has been described for vocal fold scar and vocal fold atrophy ( 10 , 11 ) .
polydimethylsiloxane , or particulate silicone , has been advocated by some for global vocal fold augmentation .
the duration of this substance is likely permanent , as alluded to in follow up of close to 10 years post - injection ( 12 ) .
recent evidence points to safety and efficacy in both the short and long term , though complications of extrusion and foreign body reaction have been reported .
in addition , recent studies comparing this directly to some of the more accepted materials do not exist ( 13 , 14 ) .
polytetrafluoroethylene , or teflon , is another permanent injectable that is of considerable historical significance but has fallen out of favor in the past 20 years .
long - term studies have revealed significant foreign - body inflammatory reactions to this substance , often requiring removal with subsequent significant vocal fold tissue loss .
calcium hydroxylapatite ( caha ) , known by the trade name radiesse voice , is currently a fda approved substance for potentially long - term vocal fold injection . comprised of microspheres of caha in a carboxymethylcellulose carrier
, this substance has been studied in both animal and human studies . in an in vivo canine vocal fold model
, it has been shown that caha injection provided adequate medialization of the canine vocal fold up to 12 month follow up without migration or resorption , and a giant cell reaction without appreciable chronic inflammation ( 15 ) .
a recent multi - institutional clinical trial revealed excellent results of 80% improvement at 12 month follow - up ( 16 ) .
long term clinical results show that persistent medialization after caha injection may be present up to 2 years and more , with an average duration of 18 months ( 17 ) .
bovine - based gelatin products , such as gelfoam and surgifoam , can be used for temporary vocal fold injection augmentation .
an injectable version of this product may be prepared by mixing the powder with saline .
the resulting substance is highly viscous , and may be used for injection by injecting with a pressurized syringe through a 18- or 19-gauge large bore needle .
this has been used extensively for temporary augmentation , lasting 4 - 6 weeks and found to be very safe ( 18 ) . despite the excellent track record
, this material has little utility due to development of new substances that are easier to use and last longer .
bovine - based collagen products , such as zyplast , have been used for longer injection .
thus , the fda advocates skin hypersensitivity testing prior to using this substance . despite this possibility , the rarity of this reaction in laryngeal injection augmentation has led some to question the need for testing ( 19 ) .
atelocollagen , a water - soluble form of bovine dermal collagen , has been used in the past for injection augmentation and for scar and sulcus , though some evidence exists that this may impair normal mucosal wave when injected submucosally .
human based collagen injectables include micronized cadaveric dermis , such as cymetra , and tissue engineered human collagen , such as cosmoplast / cosmoderm .
the former has been used extensively and results have been positive for vocal fold immobility and presbylarynx ( 20 ) .
it has also been used sparingly for scar and sulcus , though this has not been studied extensively .
cymetra is clinically effective for 2 to 3 months , and radiographic evidence of the injectable up to 11 months has been reported ( 21 ) . because this is prepared from human cadaveric tissue , potential for infectious transmission exists , though this has not been documented to date .
cosmoplast / cosmoderm has recent use as a dermal filler , though the experience as an augmentation filler for vocal folds is limited .
hyaluronic acid gels , such as restylane , hyalaform , and juvederm , are animal or bacterial derived variations of the naturally occurring extracellular matrix glycosaminoglycan found in various human tissues , including the vocal fold lamina propia .
clinical studies have supported the safety and efficacy of this injectable for deep vocal fold augmentation ( 22 , 23 ) .
some clinical studies , supported by rheologic studies and animal model work suggest hyaluronic acid derivatives may be useful as a lamina propia replacement for vocal fold scar and sulcus .
however , our clinical experience has been very disappointing and has even worsened vocal fold vibration when placed superficially ( 23 - 25 ) .
the substance is believed to last 4 - 6 months , though clinical effects may last up to 12 months ( 22 , 23 ) .
carboxymethylcellulose , sold as radiesse voice gel , is the carrier substance used in the longer lasting radiesse voice injectable .
this has been utilized extensively for temporary vocal fold paralysis and for trial vocal fold injection augmentation for a variety of causes of glottic incompetence .
though each approach has advantages and drawbacks , no formal algorithm exists in the considerable circumstances where either approach may be acceptable . in general , vocal fold augmentation is used for the temporary correction of incompetence due to unilateral vocal fold paralysis / paresis , permanent correction of mild - to - moderate glottic insufficiency , and glottic insufficiency from soft tissue loss of the vocal fold ( 27 ) .
temporary vocal fold injection is currently the treatment of choice for the treatment of glottic incompetence when prognosis for recovery is unclear .
this is best illustrated in the case of acute unilateral vocal fold paralysis or paresis . during the time for potential recovery of function , usually up to 6-months post - onset , vocal fold injection with a shorter duration substance has been shown to alleviate voice symptoms and improve swallowing until function recovers or the patient is a candidate for a more permanent treatment option . in this setting , injection with collagen , ha , or radiesse voice gel provides the best treatment option ( 20 , 26 , 28 ) .
vocal fold injection may also be used to treat permanent causes of mild - to - moderate glottic insufficiency .
specifically , this has been successfully used to treat vocal fold atrophy , paralysis , paresis , and augmentation after previous framework surgery .
specifically , results with calcium hydroxyapatite ( 3 , 29 ) and autologous fat injections ( 30 ) have proven acceptable in the treatment of atrophy , paralysis , and paresis . though some have reported inconsistent results with fat when compared to type i thyroplasty in cases of unilateral vocal fold paralysis ( 10 ) , many may find better results with the ability to " fine tune " serial injections for progressive vocal fold atrophy and presbylarynx .
additionally , results are promising for those requiring injection augmentation for recalcitrant glottic insufficiency after type i thyroplasty with or without arytenoid adduction ( 31 ) . though studies purport vocal fold injection is comparable to laryngeal framework surgery in many clinical scenarios , the former modality has several advantages over the latter .
patients with very mild forms of glottic gap ( less than 1 mm ) may be better suited for injection than framework surgery . additionally , the ability to perform vocal fold injection in the awake setting has numerous distinct advantages over framework surgery ; patient preference not to undergo an operation , and the ability to obtain direct voicing and vocal fold vibration feedback during the procedure are particularly desirable .
ease of performing the procedure with limited experience is greater in the case of vocal fold injection performed under general anesthesia , when compared with laryngeal framework surgery .
finally , significant cost benefit has been found in the case of in - office awake injection when compared to those performed in the operating room ( 4 ) .
it is generally considered feasible for a glottic gap up to 3 mm , after which the insufficiency becomes increasingly difficult to correct . in cases of posterior glottic gap or significantly foreshortened vocal fold ,
one limitation is the ability to permanently correct for glottic incompetence ; autologous lipoinjection may be inconsistent due to the variability in viability within the first several weeks and calcium hydroxyapatite typically lasts 1 to 2 years , with an average of 18 months ( 17 ) .
currently , three clinical scenarios exist to guide the timing of vocal fold injection augmentation .
the options for trial injection , temporary injection , or permanent injection should guide the timing and material selection for injection .
specific laryngeal pathology , patient expectations , and adjunctive diagnostics will all aid in choosing the proper timing of injection when considering the type of injection performed .
trial injection augmentation consists of injection of temporary substance in patients for whom injection benefits are unclear . in the case of bilateral vocal fold
atrophy , voice results with injection may be unpredictable , and in these cases trial injection may reasonably predict the results of a more permanent augmentation ( vfi or thyroplasty ) . in another subset , patients with dysphonia with a significant dysarthria component may undergo trial augmentation to predict if articulation difficulties do or do not preclude improved communication outcomes with permanent augmentation . finally , in a subset of patients , apprehension or unrealistic expectations exist
; in these patients , trial injection will give an idea of realistic expectations after injection ( 32 ) .
a temporary vocal fold injection may be performed for acute unilateral vocal fold paralysis or paresis . in these cases of uncertain recovery , laryngeal electromyogram ( lemg )
sensitivity for lemg in predicting no recovery in the case of a " poor " or " fair " prognosis is 91% .
specificity for predicting adequate recovery in the case of " excellent " prognosis for recovery is only 44% , however ( 33 ) .
recent evidence suggests that the presence of laryngeal synkinesis can effect the prognosis for recovery .
specificity of lemg with synkinesis analysis increases to 64% , while accuracy is increased from 59% to 84% ( 34 ) .
given this , lemg with synkinesis testing can play a major role in assessing the prognosis for recovery .
, early permanent injection may be considered in the lemg - determinedcase of poor prognosis for recovery with or without synkinesis .
alternatively , it may be performed after 6-month duration in the case of persistent vocal fold immobility . as discussed previously ,
currently , no optimal materials exist for superficial lamina propia replacements ; injectable materials that improve or enhance mucosal wave would prove to be immensely useful in the treatment of vocal fold scar and sulcus vocalis .
improvements in the delivery methods or the viscosity of materials would allow for improved injection delivery through a trans - nasal endoscopic approach .
finally , improvements in instrumentation , such as articulating cannulas may aid in performing injections in the awake , in - office setting .
currently , much research concentrates on optimizing the biomechanical matches of injectables with the host tissue .
the thyroarytenoid / lateral cricoarytenoid muscle complex as well as the superficial lamina propria have specific rheologic properties affecting mucosal wave characteristics , vocal fold vibration , and ultimately voice quality
. studies examining the effects of injection on the viscoelastic properties of the specific host site exist .
future development of vocal fold injectable materials will likely focus on providing a product that is not only safe , but functionally matches host viscoelastic properties .
this is important both in the short - term and in the long - term , where tissue incorporation may alter the typical characteristics of the material / vocal fold interactions .
vocal fold injection is a proven technique with favorable results for the treatment of mild - to - moderate glottic insufficiency due to a variety of causes .
the technique has the advantages of ability to perform in an in - office , awake setting and may be easier to master than laryngeal framework surgery . in select cases of temporary paralysis or paralysis with uncertain prognosis
, temporary vocal fold injection may be considered the standard of care for treating glottic insufficiency .
recent advances in material engineering and digital imaging technology have made this an attractive alternative to laryngeal framework surgery that must be considered in a variety of clinical scenarios .
 vocal fold injection is a procedure that has over a 100 year history but was rarely done as short as 20 years ago . 
 a renaissance has occurred with respect to vocal fold injection due to new technologies ( visualization and materials ) and new injection approaches . 
 awake , un - sedated vocal fold injection offers many distinct advantages for the treatment of glottal insufficiency ( vocal fold paralysis , vocal fold paresis , vocal fold atrophy and vocal fold scar ) . 
 a review of materials available and different vocal fold injection approaches is performed . 
 a comparison of vocal fold injection to laryngeal framework surgery is also undertaken . with proper patient and material selection , 
 vocal fold injection now plays a major role in the treatment of many patients with dysphonia . 
INTRODUCTION
INJECTION APPROACHES
INJECTION MATERIALS
INDICATIONS
TIMING OF INJECTION
FUTURE DIRECTIONS
CONCLUSION