Introduction
Acellular dermal matrix allografts are increasingly used in otorhinolaryngology in cases of large soft tissue defects for which primary closure without tension is not feasible, or where regional or free flaps are inadequate without additional soft tissue augmentation. The use of an acellular dermal matrix provides a robust collagen framework for mucosal epithelialisation and neovascularisation, while reducing potential donor site morbidity.
Sheet acellular dermal matrices such as AlloDerm (LifeCell, Branchburg, New Jersey, USA) typically comprise a decellularised dermal layer of collagen and a basement membrane. Acellular dermal matrices may either be allografts derived from human cadavers or xenografts from other mammalian skin. Additionally, acellular dermal matrices may be available in either aseptic freeze-dried forms that require 20–30 minutes of reconstitution, or sterile ‘ready-to-use’ forms that require 2–3 minutes of rehydration or less. Sheet acellular dermal matrices may be peeled, layered, cut, shaped, rolled or folded to tailor the graft to the contour of the surrounding host tissue.Reference Pushpoth, Tambe and Sandramouli 1
Soft tissue reconstruction or repair of the larynx, trachea, nasopharynx, oropharynx and hypopharynx traditionally involves local or pedicled flaps, or free autologous tissue transfer (cartilage, bone, dermis, fat). Although the acellular dermal matrix has been described for other head and neck surgical applications, such as soft tissue augmentation in hemifacial atrophy,Reference Ortega and Sastoque 2 palatoplasty,Reference Hudson and Pickett 3 tympanoplasty,Reference Haynes, Vos and Labadie 4 rhinoplastyReference Gryskiewicz 5 and prevention of post-parotidectomy Frey syndrome,Reference Wang, Fan, Sun, Chen, Zhao and Ma 6 indications for their use in reconstruction of the larynx, trachea and pharynx, beyond the injection of a micronised acellular dermal matrix for vocal fold paralysis,Reference Pearl, Woo, Ostrowski, Mojica, Mandell and Costantino 7 are evolving.
This systematic review aimed to investigate: current uses of sheet acellular dermal matrices in laryngotracheal and pharyngeal reconstruction, including examination of surgical indications, graft thickness and dimensions; use of aseptic versus sterile varieties of acellular dermal matrix; concomitant flaps used; and incidence of associated peri-operative complications.
Materials and methods
A systematic review, aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) standards, was performed of published literature on cases in which acellular dermal matrices were used in tracheolaryngeal and pharyngeal reconstruction. All sources were searched through 1 May 2016.
Search strategy
A literature search of the PubMed, Medline, Embase and Web of Science databases was conducted. The following Boolean search (using Medical Subject Headings (MeSHs)) was performed in PubMed: (((((Alloderm OR “acellular dermal matrix”))) OR ((“Acellular Dermis” OR “Alloderm”)))) AND ((“Larynx”[MeSH] OR “Pharynx”[MeSH] OR “Nasopharynx”[MeSH] OR “Oropharynx”[MeSH] OR “Hypopharynx”[MeSH] OR “Trachea”[MeSH] OR “Glottis”[MeSH] OR “Esophagus”[MeSH] OR laryngeal OR pharyngeal OR tracheal OR laryngotracheal OR hypopharyngeal OR nasopharyngeal OR oropharyngeal OR esophageal OR thyroid)). Similar search terms were applied to Medline and Embase. Search results were limited to articles that analysed human subjects and were written in the English language. Abstracts were analysed and the full-text articles were obtained for literature that fulfilled the inclusion criteria. Additional articles were identified by conducting a screen of the references of the included full-text articles.
Selection criteria
Literature not in English-language publications was excluded. Animal, cadaveric, histological, radiological and in vitro bioengineering studies were also excluded. In addition, studies with unobtainable full text, or with insufficient or aggregate data,Reference Deneve, Turaga, Marzban, Puleo, Sarnaik and Gonzalez 8 or those involving anatomical locations outside of the trachea, nasopharynx, posterior oropharynx or hypopharynx (i.e. inferior to the oesophageal inlet, or cervical skin overlying the pharynx, or hard and soft palate), were excluded. Literature on injectable micronised dermal fillers were also excluded, as these are almost exclusively intended for medialisation laryngoplasty and have been sufficiently reviewed elsewhere.Reference Lisi, Hawkshaw and Sataloff 9 – Reference King and Simpson 11 Articles on the use of acellular dermal matrices in palatal repair were excluded for similar reasons.Reference Aldekhayel, Sinno and Gilardino 12 , Reference Losee and Smith 13 Searches were conducted independently by two investigators (AH and MB) to ensure that all appropriate articles were included in this analysis. Any discrepancies regarding the inclusion of articles were resolved among all authors.
Data extraction
Data extracted included author, publication year, study type, sample size, clinical indication, concomitant procedures and therapies (chemoradiotherapy), and peri-operative complications. Characteristics of the acellular dermal matrix product used were also recorded, including source (allograft vs xenograft), thickness and shape. Conflict disclosures and level of evidence were also documented based on the Oxford Center for Evidence-Based Medicine.
Results
Our initial search of the PubMed, Web of Science, Medline and Embase databases identified a total of 67 articles (Figure 1). A total of 11 articles and 170 cases were included in this review (Table I).Reference Kucur, Durmus, Gun, Old, Agrawal and Teknos 14 – Reference Persichetti, Aveta and Segreto 24 There were seven case series,Reference Kelly, Plikatitis, Blalock, Argenta and David 16 – Reference Sinha, Chang and Shih 19 , Reference Li, Li, Tang, He, Yin and Wang 21 – Reference Yin, Tang, Wang, Li, He and Liu 23 three case reportsReference Kucur, Durmus, Gun, Old, Agrawal and Teknos 14 , Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15 , Reference Persichetti, Aveta and Segreto 24 and one prospective studyReference Sclafani, Jacono and Dolitsky 20 included in the analysis, with an aggregate level of evidence of 4 based on the Oxford Center for Evidence-Based Medicine. The sole prospective study included was performed with the financial support of the acellular dermal matrix manufacturer.Reference Sclafani, Jacono and Dolitsky 20 Conflicts of interest were not disclosed in 2 of the 11 studies.Reference Tan, Bassiri-Tehrani and Woo 17 , Reference Sinha, Chang and Shih 19
Study selection flow diagram in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement.
Studies meeting criteria for systematic review
Graft characteristics
Of the 11 studies included, 7 detailed the use of AlloDerm,Reference Kucur, Durmus, Gun, Old, Agrawal and Teknos 14 – Reference Sclafani, Jacono and Dolitsky 20 3 described the use of Heal-All Oral Biofilm (Zhenghai Biotech, Yantai, China)Reference Li, Li, Tang, He, Yin and Wang 21 – Reference Yin, Tang, Wang, Li, He and Liu 23 and 1 study outlined the use of Permacol (Covidien, Dublin, Ireland).Reference Persichetti, Aveta and Segreto 24 AlloDerm is an acellular dermis derived from human cadaveric tissue, and is available in freeze-dried or ready-to-use forms. Heal-All is a freeze-dried heterogeneous dermal product purified from bovine skin, and is composed of cross-linked type I and III collagen. Permacol is a ready-to-use, decellularised porcine dermis, comprising cross-linked type I and III collagen and small amounts of elastin, and was initially indicated for abdominal wall defect closure.
Only 6 of the 11 studies provided an indication of graft thickness (Table II).Reference Tan, Bassiri-Tehrani and Woo 17 , Reference Sinha, Chang and Shih 19 , Reference Li, Li, Tang, He, Yin and Wang 21 – Reference Persichetti, Aveta and Segreto 24 Thin acellular dermal matrices (0.30–0.69 mm) were used for hemi-tracheal reconstruction, total laryngectomy and partial hypopharyngectomy. Medium thickness grafts (0.53–1.02 mm) were implanted to bulk up the medial one-third of vocal folds for glottic insufficiency. Thicker implants (0.9–1.5 mm) were used in complex pharyngeal fistula closure and partial pharyngoplasty for advanced carcinomas of the piriform sinuses, tongue base and lateral pharyngeal walls. There were no reports of dermal matrix rolling or folding for volume augmentation.
Description of acellular dermal matrices, defects and flap types in included studies
NR = not reported; 3D = three-dimensional; SCM = sternocleidomastoid
Seven studies reported the dimensions of their implants,Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15 – Reference Zhang, Cheng, Zhang, Li and Anniko 18 , Reference Li, Li, Tang, He, Yin and Wang 21 – Reference Yin, Tang, Wang, Li, He and Liu 23 which ranged from 0.5 cm wide strips when used as a sling to narrow the velopharyngeal space in velopharyngeal insufficiency,Reference Kelly, Plikatitis, Blalock, Argenta and David 16 to 1.5 × 1.5 cm squares for vocal fold augmentation,Reference Tan, Bassiri-Tehrani and Woo 17 to 6 × 8 cm sheets used for total laryngo-hypopharyngeal reconstruction.Reference Persichetti, Aveta and Segreto 24 Only five studies specified defect sizes;Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15 , Reference Zhang, Cheng, Zhang, Li and Anniko 18 , Reference Li, Li, Tang, He, Yin and Wang 21 , Reference Yin, Tang, Wang, Li, He and Liu 23 , Reference Persichetti, Aveta and Segreto 24 these were within the documented dimensions of their overlying acellular dermal matrix grafts (Table II).
The most commonly used flaps for coverage were the pectoralis major myocutaneous flap for circumferential laryngectomies and/or hypopharyngectomies,Reference Zhang, Cheng, Zhang, Li and Anniko 18 , Reference Yin, Tang, Wang, Li, He and Liu 23 and strap muscle flaps for partial tracheal and hypopharyngeal reconstruction.Reference Li, Li, Tang, He, Yin and Wang 21 , Reference He, Tian, Wu, Liao, Quan and Kang 22 Closure using local pharyngeal mucosal or tonsillar wall myomucosal flaps were also described in two studies in which tension-free closure was possible.Reference Kucur, Durmus, Gun, Old, Agrawal and Teknos 14 , Reference Kelly, Plikatitis, Blalock, Argenta and David 16 Supraclavicular artery island and sternocleidomastoid flaps were also described for closure.Reference Persichetti, Aveta and Segreto 24 No flaps were used for vocal fold augmentation or for coverage of exposed post-tonsillectomy defects.Reference Tan, Bassiri-Tehrani and Woo 17 , Reference Sclafani, Jacono and Dolitsky 20 One study described the use of an AlloDerm-wrapped Montgomery T-tube as a tracheal prosthetic stent for structural support.Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15
Clinical indications
The majority of reports examined the use of acellular dermal matrices in primary reconstruction following squamous cell carcinoma resection (Table III). AlloDerm was used for mucosal flap reinforcement post-oropharyngectomy, and for reconstruction of partial and total laryngo-hypopharyngectomy defects resulting from resection of stage II–IVa squamous cell carcinomas. Similarly, Heal-All was described for closure augmentation of hemi-circumferential tracheal defects following adenoid cystic carcinoma resection, and following partial and total laryngo-hypopharyngectomies for stage I–IVa carcinomas. Two instances of acellular dermal matrix use in secondary oncological reconstructions were identified. These included: repeat tracheoplasty and Montgomery T-tube framing with AlloDerm implantation after failed sternocleidomastoid flap reconstruction of a post-medullary thyroid cancer resection defect,Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15 and Permacol implantation for complex oropharyngeal fistula closure in a patient with recurrent fistulisation and necrotising fasciitis secondary to chemoradiotherapy.Reference Persichetti, Aveta and Segreto 24
Indications and complications in included studies
CRT = chemoradiotherapy; post-op = post-operative; SCC = squamous cell carcinoma; SCM = sternocleidomastoid; N/A = not applicable; mth = month; RT = radiotherapy; wk = week
Non-malignancy applications included revision sling pharyngoplasty for tertiary treatment of persistent velopharyngeal insufficiencyReference Kelly, Plikatitis, Blalock, Argenta and David 16 and vocal fold augmentation for glottic insufficiency.Reference Tan, Bassiri-Tehrani and Woo 17 The single prospective study identified examined rates of post-tonsillectomy pain in bilateral cases in which the tonsillar bed was treated with or without the use of an acellular dermal matrix.Reference Sclafani, Jacono and Dolitsky 20 There were no reports of nasopharyngeal or thyroidectomy-associated applications of acellular dermal matrices. Only 1 of 11 studies explored acellular dermal matrix use in the paediatric population.Reference Kelly, Plikatitis, Blalock, Argenta and David 16
Graft complications
Follow-up duration varied widely between reports. For cases in which an acellular dermal matrix was used during primary post-oncological reconstruction, follow up ranged from 3 to 42 months.Reference Kucur, Durmus, Gun, Old, Agrawal and Teknos 14 , Reference Zhang, Cheng, Zhang, Li and Anniko 18 , Reference Sinha, Chang and Shih 19 , Reference Li, Li, Tang, He, Yin and Wang 21 – Reference Yin, Tang, Wang, Li, He and Liu 23 The two reports on acellular dermal matrix use in secondary reconstruction had an average follow-up duration of two to three months.Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15 , Reference Persichetti, Aveta and Segreto 24 In the 3 non-oncological studies, post-operative follow-up duration ranged from 2 weeks, for post-tonsillectomy pain assessment,Reference Sclafani, Jacono and Dolitsky 20 to 40 months, for clinical speech outcomes and evidence of improved glottic closure.Reference Kelly, Plikatitis, Blalock, Argenta and David 16 , Reference Tan, Bassiri-Tehrani and Woo 17
Graft exposure or extrusion was not reported in any of the oncological reconstruction cases. In the largest series reported, graft mucosalisation was reported to be complete by three to six months post-operatively.Reference He, Tian, Wu, Liao, Quan and Kang 22 Three studies reported no complications.Reference Kucur, Durmus, Gun, Old, Agrawal and Teknos 14 , Reference Cheng, Folch, Brik, Gangadharan, Mallur and Wilson 15 , Reference Persichetti, Aveta and Segreto 24 Two studies reported mild stricture or stenosis, which either resolved with dilation or remained stable.Reference Zhang, Cheng, Zhang, Li and Anniko 18 , Reference Li, Li, Tang, He, Yin and Wang 21 Rates of infection and secondary fistulisation in the included studies (which used acellular dermal matrices) did not differ significantly from previously reported complication rates in studies where acellular dermal matrices were not used.Reference Sinha, Chang and Shih 19 , Reference He, Tian, Wu, Liao, Quan and Kang 22 , Reference Yin, Tang, Wang, Li, He and Liu 23 Not surprisingly, scarring, atresia and fistula incidence rates were reported to be higher in patients who received prior radiotherapy.Reference Yin, Tang, Wang, Li, He and Liu 23
Among the 20 patients who underwent sheet acellular dermal matrix vocal fold augmentation, 5 cases of resorption were detected, with 3 of these being reported more than 1 year post-operatively.Reference Tan, Bassiri-Tehrani and Woo 17 A cumulative rate of graft extrusion or failure of 19.6 per cent was observed in non-oncological applications. There were no reports of acellular dermal matrix scarring or contractures, post-operative bleeding, delayed healing, or unsatisfactory mucosal integration in instances of successful graft takes across all 11 studies.
Discussion
The use of acellular dermal matrices in laryngotracheal and pharyngeal reconstruction is a relatively new development, and offers theoretical advantages over the use of synthetic prostheses and autologous split-thickness skin grafts. Acellular dermal matrices are commercially available in a variety of thicknesses for good epithelialisation, vascularisation and incorporation into host mucosa.Reference Zhang, Cheng, Zhang, Li and Anniko 18 They are thin and flexible, while myocutaneous flaps are bulkier and associated with greater risk of pharyngocutaneous fistulas and strictures.Reference Piazza, Taglietti and Nicolai 25 Compared to harvesting split-thickness skin grafts or raising flaps, which may necessitate microsurgery, acellular dermal matrices generally cost less and eliminate donor site complications.Reference Kontos, Qian, Urato, Hassanein and Proper 26 , Reference Girod, Sykes, Jorgensen, Tawfik and Tsue 27 Some surgeons describe a reduction in total operative time with the use of acellular dermal matrices;Reference Zhang, Cheng, Zhang, Li and Anniko 18 , Reference Sinha, Chang and Shih 19 however, this has not been objectively assessed.
Previous reports have endorsed the use of thin acellular dermal matrices in oral mucosal reconstructionReference Sinha, Chang and Shih 19 , Reference Girod, Sykes, Jorgensen, Tawfik and Tsue 27 and partial pharyngeal reconstruction.Reference Chiu and Friedlander 28 The application of thicker acellular dermal matrix implants in the neck had not been explored until Sinha et al. investigated the use of 0.9 mm thick AlloDerm in reconstructing partial pharyngeal defects, reporting a complication-free rate of 86 per cent.Reference Sinha, Chang and Shih 19 The authors suggested that extensive pharyngeal defects, such as those that are circumferential or larger than one-third of the base of the tongue, should be closed using thick grafts,Reference Sinha, Chang and Shih 19 but they did not offer data to support this statement. Although the total number of cases included in our review was limited, a trend could be identified, whereby thin acellular dermal matrices were more frequently used for partial superficial defects of the trachea, larynx and hypopharynx, while thicker implants were used in complex pharyngeal fistula closure and partial pharyngoplasty for more extensive stage III–IV carcinomas. Unfortunately, 5 of the 11 articles in our review failed to report the graft thickness used, potentially skewing our appraisal of how acellular dermal matrix thickness consideration plays into head and neck reconstruction.
Previously, Shi et al. documented transient mild acellular dermal matrix graft contracture in 7 of 36 patients with buccal mucosal defects (19.4 per cent), and graft failure in 2 of 36 patients who underwent hard palate closure using an acellular dermal matrix (5.6 per cent).Reference Shi, Wang, Yang and Jiang 29 Our review showed a similarly high rate of acellular dermal matrix survival in laryngotracheal and pharyngeal reconstruction, with concomitant low rates of infection, graft rejection or failure. There were no reports of delayed healing, or poor graft epithelialisation or neovascularisation, other than those secondary to graft extrusion or infection. Graft failure was observed in two cases of tonsillar fossa implantationReference Sclafani, Jacono and Dolitsky 20 and in one case of medialisation laryngoplasty.Reference Tan, Bassiri-Tehrani and Woo 17 In the former cases, graft failure may have occurred because the acellular dermal matrix was applied as an onlay, with no mucosal coverage, while in the latter case ongoing laryngeal movement could have led to more rapid resorption or extrusion. Similarly, mild and progressive acellular dermal matrix resorption was reported as early as 2.5 months following sling pharyngoplasty for persistent velopharyngeal insufficiency.Reference Kelly, Plikatitis, Blalock, Argenta and David 16
Based on the limited number and heterogeneity of cases included in our review, it is impossible to draw any conclusions regarding the impact of acellular dermal matrix use on post-operative stricture and stenosis rates in tracheal or pharyngeal reconstruction. The use of adjuvant external-beam radiation for pharyngeal cancer treatment further complicates the interpretation of current literature. As well as affecting native pharyngeal tissue, external-beam radiation has been shown to adversely affect angiogenesis and rates of recellularisation in animal models of acellular dermal matrix engraftment.Reference Ibrahim, Kwiatkowski, Montone, Evans, Rosenthal and Chalian 30 , Reference Dubin, Feldman, Ibrahim, Tufano, Evans and Rosenthal 31 Although others have pointed to a correlation between post-operative radiation and negative acellular dermal matrix graft outcomes, complication rates have not been shown to be significantly different when compared to split-thickness skin grafts in oral cavity reconstruction.Reference Girod, Sykes, Jorgensen, Tawfik and Tsue 27 In our review, a similarly inconsistent picture emerged. Zhang et al. reported mild stenosis and stricture following AlloDerm reconstruction of the larynx and hypopharynx in all seven patients in their series; however, all patients had undergone pre-operative radiotherapy.Reference Zhang, Cheng, Zhang, Li and Anniko 18 Similarly, Yin et al. documented a case of pharyngeal fistula formation following acellular dermal matrix grafting in a patient with a history of hypopharyngeal scarring and atresia secondary to prior adjuvant radiotherapy.Reference Yin, Tang, Wang, Li, He and Liu 23 Conversely, in the study by Sinha et al., neither of the two patients who developed a post-operative pharyngeal fistula received pre-operative radiotherapy, while the sole patient who did receive pre-operative radiation did not develop a fistula.Reference Sinha, Chang and Shih 19
The current review points to the need for adequately powered randomised controlled trials, to effectively determine the potential benefit of acellular dermal matrix use in tracheolaryngeal and pharyngeal reconstruction. A greater understanding of how adjuvant chemoradiotherapy might alter acellular dermal matrix engraftment and subsequent morbidity in human head and neck reconstruction would help shape management guidelines with regard to post-operative recovery time prior to radiotherapy, radiation dose and schedule. Other areas for future investigation include a comparison of various thicknesses or sources (xenogeneic vs allogeneic) of acellular dermal matrices head-to-head for similar defects, or a comparison of differences in operative time and costs for reconstructions with or without acellular dermal matrices.
Conclusion
Current literature on acellular dermal matrix use in laryngotracheal and pharyngeal reconstruction is limited to case reports, retrospective chart reviews and a single industry-funded prospective cohort study. In general, the available studies provide incomplete descriptive detail concerning: peri-operative radiation dosing and scheduling, the surgeon's experience using dermal grafts, graft thickness, and defect size. Prospective randomised studies are needed to make stronger recommendations regarding sheet acellular dermal matrix use in laryngopharyngeal reconstruction. Potential variables for future studies to investigate include graft outcomes in the setting of pre- and post-operative chemoradiotherapy, differences in operative time, and complication rates of different acellular dermal matrix forms.
