Otorhinolaryngology and Diving-Part 1: Otorhinolaryngological Hazards Related to Compressed Gas Scuba Diving: A Review.

IMPORTANCE: Scuba diving is becoming increasingly popular. However, scuba diving is associated with specific risks; 80% of adults and 85% of juvenile divers (aged 6-17 years) have been reputed to have an ear, nose, or throat complaint related to diving at some point during their diving career. Divers frequently seek advice from primary care physicians, diving physicians, and otorhinolaryngologists, not only in the acute setting, but also related to the long-term effects of diving. OBSERVATIONS: The principles underpinning diving-related injuries that may present to the otorhinolaryngologist rely on gas volume and gas saturation laws, and the prevention of these injuries requires both that the diver is skilled and that their anatomy allows for pressure equalization between the various anatomical compartments. The overlapping symptoms of middle ear barotrauma, inner ear barotrauma, and inner ear decompression sickness can cause a diagnostic conundrum, and a thorough history of both the diver's symptoms and the dive itself are required to elucidate the diagnosis. Correct diagnosis and appropriate treatment result in a more timely return to safe diving. CONCLUSIONS AND RELEVANCE: The aim of this review is to provide a comprehensive overview of otorhinolaryngological complications during diving. With the increasing popularity of diving and the frequency of ear, nose, or throat-related injuries, it could be expected that these injuries will become more common and this review provides a resource for otorhinolaryngologists to diagnose and treat these conditions.

Otorhinolaryngology and Diving-Part 2: Otorhinolaryngological Fitness for Compressed Gas Scuba Diving: A Review.

IMPORTANCE: Self-contained underwater breathing apparatus (scuba) diving has become increasingly popular with millions of people diving each year. Otorhinolaryngologists are often consulted either by patients or diving physicians regarding fitness to dive, and at present, the guidelines do not provide comprehensive information regarding the evaluation of this patient cohort. The aim of this review is to provide a comprehensive overview of existing otorhinolaryngological guidelines for fitness to dive recreationally. OBSERVATIONS: There is a paucity of guidelines for assessing otorhinolaryngological fitness to dive in the recreational diver. Comprehensive guidelines exist from US, European, and UK regulatory bodies regarding fitness for commercial diving; however, not all of these can be directly extrapolated to the recreational diver. There are also a variety of conditions that are not covered either by the existing fitness for recreational diving guidelines or the commercial regulatory bodies. CONCLUSIONS AND RELEVANCE: With the paucity of recreational fitness to dive guidelines we must draw on information from the commercial diving regulatory bodies. We have provided our own recommendations on the conditions that are not covered by either of the above, to provide otorhinolaryngologists with the information they require to assess fitness for recreational diving.

The current status of human laryngeal transplantation in 2017: A state of the field review.

OBJECTIVES: Human laryngeal allotransplantation has long been contemplated as a surgical option following laryngectomy, but there is a paucity of information regarding the indications, surgical procedure, and patient outcomes. Our objectives were to identify all human laryngeal allotransplants that have been undertaken and reported in the English literature and to evaluate the success of the procedure. DATA SOURCES: MEDLINE, Embase, Current Index to Nursing and Allied Health Literature, Web of Science and Scopus, and the Gray literature. REVIEW METHODS: A comprehensive search strategy was undertaken across multiple databases. Inclusion criteria were case reports of patients who had undergone human laryngeal allotransplantation. Information regarding indications, operative techniques, complications, graft viability, and functional outcomes were extracted. RESULTS: A total of 5,961 articles, following removal of duplicates, matched the search criteria and were screened, with five case reports relating to two patients, ultimately fulfilling the entry criteria. CONCLUSIONS: Two laryngeal transplants have been reported in the medical literature. Although both patients report improved quality of life relating to their ability to communicate with voice, further research is necessary to shape our understanding of this complicated operation, its indications, and its functional outcomes. Laryngoscope, 127:1861-1868, 2017.

Stem cell approaches for vocal fold regeneration.

OBJECTIVES/HYPOTHESIS: Current interventions in the management of vocal fold (VF) dysfunction focus on conservative and surgical approaches. However, the complex structure and precise biomechanical properties of the human VF mean that these strategies have their limitations in clinical practice and in some cases offer inadequate levels of success. Regenerative medicine is an exciting development in this field and has the potential to further enhance VF recovery beyond conventional treatments. Our aim in this review is to discuss advances in the field of regenerative medicine; that is, advances in the process of replacing, engineering, or regenerating the VF through utilization of stem cells, with the intention of restoring normal VF structure and function. DATA SOURCES: English literature (1946-2015) review. METHODS: We conducted a systematic review of MEDLINE for cases and studies of VF tissue engineering utilizing stem cells. RESULTS: The three main approaches by which regenerative medicine is currently applied to VF regeneration include cell therapy, scaffold development, and utilization of growth factors. CONCLUSION: Exciting advances have been made in stem cell biology in recent years, including use of induced pluripotent stem cells. We expect such advances to be translated into the field in the forthcoming years. Laryngoscope, 126:1865-1870, 2016.

The Host Immune Response to Tissue-Engineered Organs: Current Problems and Future Directions.

As the global health burden of chronic disease increases, end-stage organ failure has become a costly and intractable problem. De novo organ creation is one of the long-term goals of the medical community. One of the promising avenues is that of tissue engineering: the use of biomaterials to create cells, structures, or even whole organs. Tissue engineering has emerged from its nascent stage, with several proof-of-principle trials performed across various tissue types. As tissue engineering moves from the realm of case trials to broader clinical study, three major questions have emerged: (1) Can the production of biological scaffolds be scaled up accordingly to meet current and future demands without generating an unfavorable immune response? (2) Are biological scaffolds plus or minus the inclusion of cells replaced by scar tissue or native functional tissue? (3) Can tissue-engineered organs be grown in children and adolescents given the different immune profiles of children? In this review, we highlight current research in the immunological response to tissue-engineered biomaterials, cells, and whole organs and address the answers to these questions.

Operating RegenMed: development of better in-theater strategies for handling tissue-engineered organs and tissues.

Tissue engineering ex vivo and direct cellular application with bioscaffolds in vivo has allowed surgeons to restore and establish function throughout the human body. The evidence for regenerative surgery is growing, and consequently there is a need for the development of more advanced regenerative surgery facilities. Regenerative medicine in the surgical field is changing rapidly and this must be reflected in the design of any future operating suite. The theater environment needs to be highly adaptable to account for future significant advances within the field. Development of purpose built, combined operating suites and tissue-engineering laboratories will provide the facility for modern surgeons to treat patients with organ deficits, using bespoke, regenerated constructs without the need for immunosuppression.

Airway tissue engineering: an update.

INTRODUCTION: Prosthetic materials, autologous tissues, cryopreserved homografts and allogeneic tissues have thus far proven unsuccessful in providing long-term functional solutions to extensive upper airway disease and damage. Research is therefore focusing on the rapidly expanding fields of regenerative medicine and tissue engineering in order to provide stem cell-based constructs for airway reconstruction, substitution and/or regeneration. AREAS COVERED: Advances in stem cell technology, biomaterials and growth factor interactions have been instrumental in guiding optimization of tissue-engineered airways, leading to several first-in-man studies investigating stem cell-based tissue-engineered tracheal transplants in patients. Here, we summarize current progress, outstanding research questions, as well as future directions within the field. EXPERT OPINION: The complex immune interaction between the transplant and host in vivo is only beginning to be untangled. Recent progress in our understanding of stem cell biology, decellularization techniques, biomaterials and transplantation immunobiology offers the prospect of transplanting airways without the need for lifelong immunosuppression. In addition, progress in airway revascularization, reinnervation and ever-increasingly sophisticated bioreactor design is opening up new avenues for the construction of a tissue-engineered larynx. Finally, 3D printing is a novel technique with the potential to render microscopic control over how cells are incorporated and grown onto the tissue-engineered airway.

Stem cell-based organ replacements-airway and lung tissue engineering.

Tissue engineering requires the use of cells seeded onto scaffolds, often in conjunction with bioactive molecules, to regenerate or replace tissues. Significant advances have been made in recent years within the fields of stem cell biology and biomaterials, leading to some exciting developments in airway tissue engineering, including the first use of stem cell-based tissue-engineered tracheal replacements in humans. In addition, recent advances within the fields of scaffold biology and decellularization offer the potential to transplant patients without the use of immunosuppression.

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model.

Decellularized (acellular) scaffolds, composed of natural extracellular matrix, form the basis of an emerging generation of tissue-engineered organ and tissue replacements capable of transforming healthcare. Prime requirements for allogeneic, or xenogeneic, decellularized scaffolds are biocompatibility and absence of rejection. The humoral immune response to decellularized scaffolds has been well documented, but there is a lack of data on the cell-mediated immune response toward them in vitro and in vivo. Skeletal muscle scaffolds were decellularized, characterized in vitro, and xenotransplanted. The cellular immune response toward scaffolds was evaluated by immunohistochemistry and quantified stereologically. T-cell proliferation and cytokines, as assessed by flow cytometry using carboxy-fluorescein diacetate succinimidyl ester dye and cytometric bead array, formed an in vitro surrogate marker and correlate of the in vivo host immune response toward the scaffold. Decellularized scaffolds were free of major histocompatibility complex class I and II antigens and were found to exert anti-inflammatory and immunosuppressive effects, as evidenced by delayed biodegradation time in vivo; reduced sensitized T-cell proliferative activity in vitro; reduced IL-2, IFN-γ, and raised IL-10 levels in cell-culture supernatants; polarization of the macrophage response in vivo toward an M2 phenotype; and improved survival of donor-derived xenogeneic cells at 2 and 4 wk in vivo. Decellularized scaffolds polarize host responses away from a classical TH1-proinflammatory profile and appear to down-regulate T-cell xeno responses and TH1 effector function by inducing a state of peripheral T-cell hyporesponsiveness. These results have substantial implications for the future clinical application of tissue-engineered therapies.

Alternative injectable materials for vocal fold medialisation in unilateral vocal fold paralysis.

BACKGROUND: Patients with unilateral vocal fold paralysis (UVFP) usually present with dysphonia, but can also be breathless and have problems with their swallowing. Speech and language therapy forms the initial mainstay of management in cases of UVFP, since up to 60% of cases will resolve spontaneously. If vocal fold paralysis persists surgery, in the form of injection medialisation, has been shown to be an effective intervention. What is currently unclear is which is the most effective material available for injection. OBJECTIVES: To assess the effectiveness of alternative injection materials in the treatment of UVFP. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 23 March 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) of injectable materials in patients with UVFP. The outcomes of interest were patient and clinician-reported improvement, and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies from the search results and extracted data. We used the Cochrane 'Risk of bias' tool to assess study quality. MAIN RESULTS: We identified no RCTs which met the inclusion criteria for this review. We excluded 18 studies on methodological grounds: 16 non-randomised studies; one RCT due to inadequate randomisation and inclusion of non-UVFP patients; and one RCT which compared two different particle sizes of the same injectable material. AUTHORS' CONCLUSIONS: There is currently insufficient high-quality evidence for, or against, specific injectable materials for patients with UVFP. Future RCTs should aim to provide a direct comparison of the alternative materials currently available for injection medialisation.

Decellularized rabbit cricoarytenoid dorsalis muscle for laryngeal regeneration.

OBJECTIVES: Although considerable progress has been made in regenerative medicine, a quantum step would be the replacement and/or regeneration of functional muscle tissue. For example, although patients' airways can now be successfully replaced with stem cell-based techniques, a much greater patient need would be addressed by regeneration of the muscles required for engineering a functional larynx, in which active movement is critical. The rabbit cricoarytenoid dorsalis muscle was chosen for the present study because it is equivalent to the posterior cricoarytenoid muscle, the only significant abductor muscle in human larynges. METHODS: Rabbit cricoarytenoid dorsalis muscles were harvested, and different decellularization methods were compared by use of a combination of histologic, immunohistochemical, and molecular techniques. Decellularized scaffolds were implanted into Sprague-Dawley rats as part of a 2-week biocompatibility study to assess immunogenicity. RESULTS: Decellularization with a combination of latrunculin B, potassium iodide, potassium chloride, and deoxyribonuclease resulted in total DNA clearance and reduced levels of major histocompatibility complex class II expression, with relative preservation of the scaffold's structural integrity (collagen, elastin, and glycosaminoglycan content). The scaffolds showed minimal signs of rejection at 2 weeks in a cross-species (xenotransplantation) study. CONCLUSIONS: Decellularized laryngeal muscles, which are nonimmunogenic, may provide the optimal scaffold source for the generation of a fully functional tissue-engineered larynx.

A rat decellularized small bowel scaffold that preserves villus-crypt architecture for intestinal regeneration.

Management of intestinal failure remains a clinical challenge and total parenteral nutrition, intestinal elongation and/or transplantation are partial solutions. In this study, using a detergent-enzymatic treatment (DET), we optimize in rats a new protocol that creates a natural intestinal scaffold, as a base for developing functional intestinal tissue. After 1 cycle of DET, histological examination and SEM and TEM analyses showed removal of cellular elements with preservation of the native architecture and connective tissue components. Maintenance of biomechanical, adhesion and angiogenic properties were also demonstrated strengthen the idea that matrices obtained using DET may represent a valid support for intestinal regeneration.

Esophageal tissue engineering: a new approach for esophageal replacement.

A number of congenital and acquired disorders require esophageal tissue replacement. Various surgical techniques, such as gastric and colonic interposition, are standards of treatment, but frequently complicated by stenosis and other problems. Regenerative medicine approaches facilitate the use of biological constructs to replace or regenerate normal tissue function. We review the literature of esophageal tissue engineering, discuss its implications, compare the methodologies that have been employed and suggest possible directions for the future. Medline, Embase, the Cochrane Library, National Research Register and ClinicalTrials.gov databases were searched with the following search terms: stem cell and esophagus, esophageal replacement, esophageal tissue engineering, esophageal substitution. Reference lists of papers identified were also examined and experts in this field contacted for further information. All full-text articles in English of all potentially relevant abstracts were reviewed. Tissue engineering has involved acellular scaffolds that were either transplanted with the aim of being repopulated by host cells or seeded prior to transplantation. When acellular scaffolds were used to replace patch and short tubular defects they allowed epithelial and partial muscular migration whereas when employed for long tubular defects the results were poor leading to an increased rate of stenosis and mortality. Stenting has been shown as an effective means to reduce stenotic changes and promote cell migration, whilst omental wrapping to induce vascularization of the construct has an uncertain benefit. Decellularized matrices have been recently suggested as the optimal choice for scaffolds, but smart polymers that will incorporate signalling to promote cell-scaffold interaction may provide a more reproducible and available solution. Results in animal models that have used seeded scaffolds strongly suggest that seeding of both muscle and epithelial cells on scaffolds prior to implantation is a prerequisite for complete esophageal replacement. Novel approaches need to be designed to allow for peristalsis and vascularization in the engineered esophagus. Although esophageal tissue engineering potentially offers a real alternative to conventional treatments for severe esophageal disease, important barriers remain that need to be addressed.

Airway tissue engineering.

INTRODUCTION: Prosthetic replacements, autologous tissue transfer and allografts have so far failed to offer functional solutions for the treatment of long circumferential tracheal defects and loss of a functioning larynx. Interest has therefore turned increasingly to the field of tissue-engineering which applies the principles and methods of bioengineering, material science, cell transplantation and life sciences in an effort to develop in vitro biological substitutes able to restore, maintain or improve tissue and organ function. AREAS COVERED: This article gives an overview of the tissue-engineering approach to airway replacement and will describe the encouraging results obtained so far in tracheal regeneration. The recent advances in the field of tissue-engineering have provided a new attractive approach towards the concept of functional substitutes and may represent an alternative to the shortage of suitable grafts for reconstructive airway surgery. We summarize fundamental questions, as well as future directions in airway tissue engineering. EXPERT OPINION: The replacement of active movement, as would be necessary to replace an entire larynx introduces another order of magnitude of complexity, although progress in this area is starting to bear fruit. In addition, the stem cell field is advancing rapidly, opening new avenues for this type of therapy.

What can regenerative medicine offer for infants with laryngotracheal agenesis?

BACKGROUND: Laryngotracheal agenesis is a rare congenital disorder but has devastating consequences. Recent achievements in regenerative medicine have opened up new vistas in therapeutic strategies for these infants. OBJECTIVE: To provide a state-of-the-art review concerning recent achievements in tissue engineering as applied to fetal airway reconstruction and to discuss the use of autologous human amniotic stem cells to prepare organs in advance for babies with laryngotracheal agenesis. DATA SOURCES AND REVIEW METHODS: A structured search of the current literature (up to and including June 2011). The authors searched PubMed, EMBASE, CINAHL, Web of Science, BIOSIS Previews, Cambridge Scientific Abstracts, ICTRP, and additional sources for published and unpublished trials. RESULTS: Over the past 15 years, progress has been made in advancing the boundaries of regenerative medicine from the laboratory to the clinical setting through translational research. Most experience has been gained with adult stem cells and synthetic materials or decellularized scaffolds. The optimal cell source for fetal tissue engineering remains to be determined, but a combination of decellularized scaffolds and amniotic fluid stem cells holds great promise for fetal tissue engineering. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Current treatment strategies for laryngotracheal agenesis are suboptimal, and fetal tissue engineering offers an alternative to conventional treatments. Use of human amniotic fluid stem cells for preparing autologous tissue-engineered organ constructs prenatally is an attractive concept. Although this approach is still in its experimental stages, further preclinical and clinical studies are encouraged to define its exact role in the pediatric laryngological setting.

Corticosteroids for the treatment of idiopathic acute vestibular dysfunction (vestibular neuritis).

BACKGROUND: Idiopathic acute vestibular dysfunction (vestibular neuritis) is the second most common cause of peripheral vertigo after benign paroxysmal positional vertigo (BPPV) and accounts for 7% of the patients who present at outpatient clinics specialising in the treatment of dizziness. The exact aetiology of the condition is unknown and the effects of corticosteroids on the condition and its recovery are uncertain. OBJECTIVES: To assess the effectiveness of corticosteroids in the management of patients with idiopathic acute vestibular dysfunction (vestibular neuritis). SEARCH STRATEGY: We searched the Cochrane ENT Group Trials Register; CENTRAL; PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 28 December 2010. SELECTION CRITERIA: Randomised controlled trials comparing corticosteroids with placebo, no treatment or other active treatments, for adults diagnosed with idiopathic acute vestibular dysfunction. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies from the search results and extracted data. Three authors independently assessed risk of bias. MAIN RESULTS: Four trials, involving a total of 149 participants, compared the effectiveness of oral corticosteroids against placebo. All the trials were small and of low methodological quality. Although there was an overall significant effect of corticosteroids compared with placebo medication on complete caloric recovery at one month (risk ratio (RR) of 2.81; 95% confidence interval (CI) 1.32 to 6.00, P = 0.007), no significant effect was seen on complete caloric recovery at 12 months (RR 1.58; 95% CI 0.45 to 5.62, P = 0.48), or on the extent of caloric recovery at either one month (mean difference (MD) 9.60%; 95% CI -20.66 to 39.86, P = 0.53) or at 12 months (MD 6.83%; 95% CI -27.69 to 41.36, P = 0.70). In addition, there was no significant difference between corticosteroids and placebo medication in the symptomatic recovery of vestibular function following idiopathic acute vestibular dysfunction with respect to vertigo at 24 hours (RR 0.39; 95% CI 0.04 to 3.57, P = 0.40) and use of the Dizziness Handicap Inventory score at one, three, six and 12 months. AUTHORS' CONCLUSIONS: Overall, there is currently insufficient evidence from these trials to support the administration of corticosteroids to patients with idiopathic acute vestibular dysfunction. We found no trials with a low risk of methodological bias that used the highest level of diagnostic criteria and outcome measures. We recommend that future studies should include health-related quality of life and symptom-based outcome measures, in addition to objective measures of vestibular improvement, such as caloric testing and electronystagmography.