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Objective: To determine the prevalence of jugular bulb and vestibular aqueduct dehiscence (JBVAD) in pediatric patients undergoing temporal bone computed tomography (CT) scans and to assess the relationship between JBVAD and hearing loss. Study Design: Cross-sectional study with chart review. Setting: Tertiary academic medical center. Subjects and Methods: All patients 18 years of age or younger who had undergone temporal bone CT scans and audiometric testing between 2004 and 2009 were retrospectively reviewed. JBVAD was determined by blinded review of CT images. Hearing loss was determined by review of audiometric data and was correlated with imaging findings. Results: CT images and audiometric data were available for review in 927 patients (1854 ears). Overall prevalence of JBVAD was 8.6%, with a prevalence of 6.6% in right ears and 3.6% in left ears. JBVAD was present in 8.3% and 7.1% of patients with and without sensorineural or mixed hearing loss, respectively (95% confidence interval [CI], -2.3% to 4.6%; P = .51). Similarly, JBVAD was present in 5.5% of ears with and 4.6% of ears without sensorineural or mixed hearing loss (95% CI, -1.1% to 2.9%; P = .37). Conclusion: The prevalence of JBVAD is 8.6% in pediatric patients undergoing temporal bone CT scans, 65% of which occur in the right ear. We were unable to identify any relationship between JBVAD and hearing loss. A major contribution to pediatric sensorineural hearing loss from JBVAD is therefore extremely unlikely. [ABSTRACT FROM AUTHOR]

Fetal magnetic resonance imaging (MRI) extends in utero imaging beyond the reach of ultrasound. High field-strength magnets, improved sequences, and rapid imaging techniques continue to increase the technique's utility in ways not before possible. This article describes several intrathoracic abnormalities in the fetus as examples of how MRI techniques enable more confident early diagnosis, facilitate patient counseling, and assist planning for fetal surgery. Fetal MRI enhances the radiologist's ability to diagnose and communicate findings that benefit both patients and professional colleagues. [ABSTRACT FROM AUTHOR]

Preexisting hypertension complicates 5% of all pregnancies. The objective of this study was to evaluate steady-state atenolol pharmacokinetics and pharmacodynamics (n = 17) during the second trimester (2nd T), third trimester (3rd T), and 3 months postpartum. Pregnancy as compared to 3 months postpartum (nonpregnant control) resulted in significant (P < .05) changes, including the following: 42% (2nd T) and 50% (3rd T) increase in creatinine clearance, 38% (2nd T) and 36% (3rd T) increase in atenolol renal clearance, 12% (2nd T) and 11% (3rd T) decrease in atenolol half-life, 20% (2nd T) and 28% (3rd T) increase in cardiac output, 15% (2nd T) and 23% (3rd T) increase in resting heart rate, and 22% (2nd T) and 21% (3rd T) decrease in total peripheral resistance in subjects on steady-state oral atenolol for treatment of hypertension in pregnancy. In conclusion, the renal clearance of atenolol along with creatinine clearance is increased during pregnancy. However, this does not translate into an increase in apparent oral clearance of atenolol, possibly related to the high variability in bioavailability. Atenolol administration did not appear to change the pattern of the increase in cardiac output and the decrease in total peripheral resistance, which normally occurs during pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Mutations in GJB2, a gene that encodes a gap junction protein, Connexin 26 (Cx26), are responsible for approximately one third of sporadic severe-to-profound or profound congenital deafness and half of severe-to-profound or profound autosomal recessive nonsyndromic hearing loss (ARNSHL). Mouse mutants homozygous for knockouts of this gene are nonviable, precluding histopathologic studies of the associated inner ear pathology in this animal model. Therefore, we studied archival temporal bone sections to identify temporal bone donors with Cx26-related deafness.Study Design: Temporal bone donors with a history of congenital severe-to-profound or profound deafness were identified in the registry of the Temporal Bone Library at the University of Iowa. Histological findings were interpreted in a blinded fashion. DNA extracted from two celloidin-embedded mid-modiolar sections from each temporal bone was screened for the 35delG Cx26 mutation. The entire coding region of Cx26 was screened for other deafness-causing mutations if the 35delG mutation was detected.Results: Of five temporal bone donors with congenital severe-to-profound deafness, one donor was found to have Cx26-related deafness. This individual was a Cx26 compound heterozygote, carrying the 35delG mutation and a noncomplementary Cx26 missense mutation on the opposing allele. Microscopic evaluation of this temporal bone showed no neural degeneration, a good population of spiral ganglion cells, near-total degeneration of hair cells in the organ of Corti, a detached and rolled-up tectorial membrane, agenesis of the stria vascularis, and a large cyst in the scala media in the region of the stria vascularis.Conclusion: This study is the first to report the temporal bone histopathology associated with Cx26-related deafness. Preservation of neurons in the spiral ganglion suggests that long-term successful habilitation with cochlear implants may be possible in persons with severe-to-profound or profound Cx26-related deafness. [ABSTRACT FROM AUTHOR]

Tetralogy of Fallot with absent pulmonary valve (ToF-APV) is associated with severe tracheobronchomalacia (TBM) and significant airway compromise. These patients often require early repair with right ventricle-to-pulmonary artery conduit, pulmonary arterioplasty, tracheostomy, and long-term ventilator support. A bioresorbable, 3D-printed airway splint has shown early success in treating severe TBM and has the potential to obviate the need for early repair with conduit and tracheostomy. A retrospective case series analysis was conducted on consecutive patients with ToF-APV and severe TBM who underwent airway splinting between 2012 and 2021. Clinical data was extracted from the medical record. Patients were grouped and analyzed according to their sequence of procedures. Eight patients with ToF-APV and severe TBM underwent airway splinting with a median follow up of 3.6 years (range 1.0-6.4). All patients were alive at the most recent follow-up. Five patients underwent complete cardiac repair first, and one patient underwent concurrent complete cardiac repair and airway splinting. All six of these patients required tracheostomy and long-term ventilator support, even after airway splinting. Five of six remained on ventilator support at the most recent follow up. Two patients underwent airway splinting before complete cardiac repair. Neither required tracheostomy nor prolonged ventilatory support (p = 0.036). Both were discharged home in the neonatal period and returned as infants to undergo elective ToF-APV repair. Patients with TOF-APV and severe TBM may be able to avoid early repair with conduit placement and tracheostomy by undergoing airway splinting prior to complete cardiac repair., (© 2024. The Author(s).)

Additive manufacturing, or 3D printing, of the bioresorbable polymer [Formula: see text]-polycaprolactone (PCL) is an emerging tissue engineering solution addressing patient specific anatomies. Predictively modeling the mechanical behavior of 3D printed parts comprised of PCL improves the ability to develop patient specific devices that meet design requirements while reducing the testing of extraneous design variants and development time for emergency devices. Predicting mechanical behavior of 3D-printed devices is limited by the variability of effective material moduli that are determined in part by the 3D printing manufacturing process. Powder fusion methods, specifically laser sintering, are known to produce parts with internal porosity ultimately impacting the mechanical performance of printed devices. This study investigates the role of print direction and part size on the material and structural properties of laser sintered PCL parts. Solid PCL cylinders were printed in the XY (perpendicular to laser) and Z direction (parallel to laser), scanned using microcomputed tomography, and mechanically tested under compression. Compositional, structural, and functional properties of the printed parts were evaluated with differential scanning calorimetry, gel permeation chromatography, microcomputed tomography, and mechanical testing. Computational models of printed and scanned cylinders were fit to experimental data to derive effective moduli. Effective moduli were used to predict the mechanical behavior of splints used for emergency repair of severe tracheobronchomalacia. Laser sintering did not cause significant differences in polymer material properties compared to unmanufactured powder. Effective moduli (E eff ) were greater for larger part sizes (p < 0.01) and for parts oriented in the XY direction compared to the Z direction (p < 0.001). These dependencies were congruent with the differences in void volumes associated with the print direction (p < 0.01) and part size (p < 0.01). Finite element models of splint parallel compression tests utilizing the E eff dependent on print direction and size agreed with experimental closed compression tests of splints. Evaluating the microstructural properties of printed parts and selecting effective moduli for finite element models based on manufacturing parameters allows accurate prediction of device performance. These findings allow testing of a greater number of device design variants in silico to accomodate patient specific anatomies towards providing higher quality parts while lowering overall time and costs of manufacturing and testing., (© 2021. Biomedical Engineering Society.)

Objective/hypothesis: To assess the use of a three-dimensional (3D) printed, multilayer facial flap model for use in trainee education as an alternative method of teaching surgical techniques of facial reconstruction., Study Design: Cohort study., Methods: A 3D printed facial flap simulator was designed from a computed tomography scan and manufactured out of silicone for low-cost, high-fidelity simulation. This simulator was tested by a group of Otolaryngology-Head and Neck Surgery trainees at a single institution. The simulator group was compared to a control group who completed an exercise on a traditional paper facial flap exercise. Both groups underwent didactic lectures prior to completing their respective exercises. Pre- and post-exercise Likert scale surveys measuring experience, understanding, effectiveness, and realism were completed by both groups. Central tendency, variability, and confidence intervals were measured to evaluate the outcomes., Results: Trainees completing the facial flap simulator reported a statistically significant (p < 0.05) improvement in overall expertise in facial flap procedures, design of facial flaps, and excision of standing cutaneous deformities. No statistically significant improvement was seen in the control group., Conclusions: Trainees found the facial flap simulator to be an effective and useful training tool with a high level of realism in surgical education of facial reconstruction. Surgical simulators can serve as an adjunct to trainee education, especially during extraordinary times such as the novel coronavirus disease 2019 pandemic, which significantly impacted surgical training., Level of Evidence: NA Laryngoscope, 131:E2444-E2448, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc..)

Objectives/hypothesis: Create a competency-based assessment tool for pediatric esophagoscopy with foreign body removal., Study Design: Blinded modified Delphi consensus process., Setting: Tertiary care center., Methods: A list of 25 potential items was sent via the Research Electronic Data Capture database to 66 expert surgeons who perform pediatric esophagoscopy. In the first round, items were rated as "keep" or "remove" and comments were incorporated. In the second round, experts rated the importance of each item on a seven-point Likert scale. Consensus was determined with a goal of 7 to 25 final items., Results: The response rate was 38/64 (59.4%) in the first round and returned questionnaires were 100% complete. Experts wanted to "keep" all items and 172 comments were incorporated. Twenty-four task-specific and 7 previously-validated global rating items were distributed in the second round, and the response rate was 53/64 (82.8%) with questionnaires returned 97.5% complete. Of the task-specific items, 9 reached consensus, 7 were near consensus, and 8 did not achieve consensus. For global rating items that were previously validated, 6 reached consensus and 1 was near consensus., Conclusions: It is possible to reach consensus about the important steps involved in rigid esophagoscopy with foreign body removal using a modified Delphi consensus technique. These items can now be considered when evaluating trainees during this procedure. This tool may allow trainees to focus on important steps of the procedure and help training programs standardize how trainees are evaluated., Level of Evidence: 5. Laryngoscope, 131:1168-1174, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

The worst complication of cricotracheal resection (CTR) is anastomotic dehiscence, and to limit it, postoperative management at Michigan Medicine included the use of a modified Minerva cervical-thoracic orthosis (MMCTO). To date, there has been no analysis of the risks and benefits of the brace's use following CTR. We analyze this with our retrospective study. A search with the keywords "cricotracheal resection" and "laryngotracheal reconstruction" was performed in the Electronic Medical Record Search Engine to identify patients retrospectively. The Statistical Package for Social Sciences was used for analysis; t test, χ 2 , and Fisher exact tests were used to analyze data. Fifteen males and 13 females with a median age of 4 years were identified, and almost 2/3 had a supra- and/or infrahyoid release performed. Postoperatively, 12 had a Grillo stitch and an MMCTO for a mean of 7 days. Most had no complications, but the most common complications were agitation due to brace discomfort and skin irritation. The worst complication was stroke. Our MMCTO's design allowed for better head and neck control with relative comfortability, and most patients had no complications with its short-term use. Our modification may be useful adjunct in the postoperative management.

Tracheobronchomalacia is a condition of dynamic collapse of the trachea and mainstem bronchi. The clinical significance of tracheobronchomalacia depends on its severity. Mild cases may be medically managed with limited symptomology, while severe cases require advanced therapies, lengthy hospital stays, and carry significant morbidity and mortality. Current therapies for severe tracheobronchomalacia include tracheostomy with prolonged mechanical ventilation, aortopexy, tracheobronchopexy, and intraluminal metallic, silicone, or bioresorbable stents. Three-dimensional (3D)-printed, patient-specific, bioresorbable airway splinting is a novel treatment option that is undergoing investigation in a cohort of critically ill children with severe tracheobronchomalacia. At the time of our last review of our data, 29 splints had been implanted in 15 children with intrathoracic tracheobronchomalacia. The median follow-up was 8.5 months. There were 12 long-term survivors, and all but one lived at home. This article discusses the details of our institution's development and use of 3D-printed, patient-specific, bioresorbable splints for treatment of severe tracheobronchomalacia in the pediatric population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Current limitations in the supply of ventilators during the Covid19 pandemic have limited respiratory support for patients with respiratory failure. Split ventilation allows a single ventilator to be used for more than one patient but is not practicable due to requirements for matched patient settings, risks of cross-contamination, harmful interference between patients and the inability to individualize ventilator support parameters. We hypothesized that a system could be developed to circumvent these limitations., Methods and Findings: A novel delivery system was developed to allow individualized peak inspiratory pressure settings and PEEP using a pressure regulatory valve, developed de novo, and an inline PEEP 'booster'. One-way valves, filters, monitoring ports and wye splitters were assembled in-line to complete the system and achieve the design targets. This system was then tested to see if previously described limitations could be addressed. The system was investigated in mechanical and animal trials (ultimately with a pig and sheep concurrently ventilated from the same ventilator). The system demonstrated the ability to provide ventilation across clinically relevant scenarios including circuit occlusion, unmatched physiology, and a surgical procedure, while allowing significantly different pressures to be safely delivered to each animal for individualized support., Conclusions: In settings of limited ventilator availability, systems can be developed to allow increased delivery of ventilator support to patients. This enables more rapid deployment of ventilator capacity under constraints of time, space and financial cost. These systems can be smaller, lighter, more readily stored and more rapidly deployable than ventilators. However, optimizing ventilator support for patients with individualized ventilation parameters will still be dependent upon ease of use and the availability of medical personnel., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: KVK, GEG and DAZ are founders of MakeMedical LLC, which is the legal manufacturer of this device (provided at cost). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives/hypothesis: Create a competency-based assessment tool for pediatric tracheotomy., Study Design: Blinded, modified, Delphi consensus process., Methods: Using the REDCap database, a list of 31 potential items was circulated to 65 expert surgeons who perform pediatric tracheotomy. In the first round, items were rated as "keep" or "remove," and comments were incorporated. In the second round, experts were asked to rate the importance of each item on a seven-point Likert scale. Consensus criteria were determined a priori with a goal of 7 to 25 final items., Results: The first round achieved a response rate of 39/65 (60.0%), and returned questionnaires were 99.5% complete. All items were rated as "keep," and 137 comments were incorporated. In the second round, 30 task-specific and seven previously validated global rating items were distributed, and the response rate was 44/65 (67.7%), with returned questionnaires being 99.3% complete. Of the Task-Specific Items, 13 reached consensus, 10 were near consensus, and 7 did not achieve consensus. For the 7 previously validated global rating items, 5 reached consensus and two were near consensus., Conclusions: It is feasible to reach consensus on the important steps involved in pediatric tracheotomy using a modified Delphi consensus process. These items can now be considered to create a competency-based assessment tool for pediatric tracheotomy. Such a tool will hopefully allow trainees to focus on the important aspects of this procedure and help teaching programs standardize how they evaluate trainees during this procedure., Level of Evidence: 5 Laryngoscope, 130:2700-2707, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To determine the feasibility of a patient-specific, three-dimensionally (3D)-printed reconstruction plate for repair of lateral skull base defects., Study Design: Prospective case series and cadaveric study., Setting: A university-based, tertiary care hospital., Patients: Three patients with lateral skull base defects and five cadavers., Main Outcome Measure(s): Caliper gauge fit testing was performed in the cadaver temporal bones to determine the fit of the tegmen plate in engaging the tegmen defect. Additionally, three patients underwent standard of care reconstruction of their middle fossa floor using autografts or allografts. Temporary plate insertion during standard operative repair was performed to gauge feasibility and fit. Operative time required for standard grafting compared with placement of the tegmen plate was examined., Results: Real-time, intraoperative placement of the tegmen plate in our patients under 1 minute compared with nearly 60 minutes for standard surgical repair. Tegmen plates covered the defects and locked into place from contour matching without impinging on critical structures. Fit testing revealed flush-fitting plates to the cadaveric temporal bone surface with all gaps less than 500 μm., Conclusions: Computer modeling and 3D printing can design custom fitted tegmen reconstruction plates for temporal bone defects. Versatility in prefabrication and 3D modeling shows potential in allowing the construct to avoid critical structures and adequately cover defects with high precision to the tegmen surface.

Background: Pediatric-specific difficult airway guidelines include algorithms for 3 scenarios: unanticipated difficult tracheal intubation, difficult mask ventilation, and cannot intubate/cannot ventilate. While rare, these instances may require front-of-neck access (FONA) to secure an airway until a definitive airway can be established. The aim of this study was to develop a pediatric FONA simulator evaluated by both anesthesiology and otolaryngology providers, promoting multidisciplinary airway management., Methods: A 3-dimensional-printed tracheal model was developed using rescaled, anatomically accurate dimensions from a computerized tomography scan using computer-aided design software. The medical grade silicone model was incorporated into a mannequin to create a low-cost, high-fidelity simulator. A multidisciplinary team of anesthesiology, otolaryngology, and simulation experts refined the model. Experts in airway management were recruited to rate the realism of the model's characteristics and features and their own ability to complete specific FONA-related tasks., Results: Six expert raters (3 anesthesiology and 3 otolaryngology) were identified for multidisciplinary evaluation of model test content validity. Analysis of response data shows null variance within 1 or both specialties for a majority of the content validity tool elements. High and consistent absolute ratings for each domain indicate that the tested experts perceived this trainer as a realistic and highly valuable tool in its current state., Conclusions: The ability to practice front-of-neck emergency airway procedures safely and subsequently demonstrate proficiency on a child model has great implications regarding both quality of physician training and patient outcomes. This model may be incorporated into curricula to teach needle cricothyroidotomy and other FONA procedures to providers across disciplines.

The management of pediatric airway stenosis has evolved considerably over time. At the outset, dilation was the mainstay of management. In the 1900s, open surgery in the form of cricoid expansion procedures or resection procedures was the primary treatment with subsequent development of the slide tracheoplasty. Now in the twenty-first century, advances in endoscopic management, balloon dilation, and stenting, along with the advent of external scaffolds and tissue replacement continue to advance pediatric airway surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: To report the clinical safety and efficacy of three-dimensional (3D)-printed, patient-specific, bioresorbable airway splints in a cohort of critically ill children with severe tracheobronchomalacia., Study Design: Case series., Methods: From 2012 to 2018, 15 subjects received 29 splints on their trachea, right and/or left mainstem bronchi. The median age at implantation was 8 months (range, 3-25 months). Nine children were female. Five subjects had a history of extracorporeal membrane oxygenation (ECMO), and 11 required continuous sedation, six of whom required paralytics to maintain adequate ventilation. Thirteen were chronically hospitalized, unable to be discharged, and seven were hospitalized their entire lives. At the time of splint implantation, one subject required ECMO, one required positive airway pressure, and 13 subjects were tracheostomy and ventilator dependent, requiring a median positive end-expiratory pressure (PEEP) of 14 cm H 2 O (range, 6-20 cm H 2 0). Outcomes collected included level of respiratory support, disposition, and splint-related complications., Results: At the time of discharge from our institution, at a median of 28 days postimplantation (range, 10-56 days), the subject on ECMO was weaned from extracorporeal support, and the subjects who were ventilated via tracheostomy had a median change in PEEP (discharge-baseline) of -2.5 cm H 2 O (range, -15 to 2 cm H 2 O, P = .022). At median follow-up of 8.5 months (range, 0.3-77 months), all but one of the 12 surviving subjects lives at home. Of the 11 survivors who were tracheostomy dependent preoperatively, one is decannulated, one uses a speaking valve, six use a ventilator exclusively at night, and three remain ventilator dependent., Conclusions: This case series demonstrates the initial clinical efficacy of the 3D-printed bioresorbable airway splint device in a cohort of critically ill children with severe tracheobronchomalacia., Level of Evidence: 4 Laryngoscope, 129:1763-1771, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: Reconstruction of craniofacial cartilagenous defects are among the most challenging surgical procedures in facial plastic surgery. Bioengineered craniofacial cartilage holds immense potential to surpass current reconstructive options, but limitations to clinical translation exist. We endeavored to determine the viability of utilizing adipose-derived stem cell-chondrocyte co-culture and three-dimensional (3D) printing to produce 3D bioscaffolds for cartilage tissue engineering. We describe a feasibility study revealing a novel approach for cartilage tissue engineering with in vitro and in vivo animal data., Methods: Porcine adipose-derived stem cells and chondrocytes were isolated and co-seeded at 1:1, 2:1, 5:1, 10:1, and 0:1 experimental ratios in a hyaluronic acid/collagen hydrogel in the pores of 3D-printed polycaprolactone scaffolds to form 3D bioscaffolds for cartilage tissue engineering. Bioscaffolds were cultured in vitro without growth factors for 4 weeks and then implanted into the subcutaneous tissue of athymic rats for an additional 4 weeks before sacrifice. Bioscaffolds were subjected to histologic, immunohistochemical, and biochemical analysis., Results: Successful production of cartilage was achieved using a co-culture model of adipose-derived stem cells and chondrocytes without the use of exogenous growth factors. Histology demonstrated cartilage growth for all experimental ratios at the post-in vivo time point confirmed with type II collagen immunohistochemistry. There was no difference in sulfated-glycosaminoglycan production between experimental groups., Conclusion: Tissue-engineered cartilage was successfully produced on 3D-printed bioresorbable scaffolds using an adipose-derived stem cell and chondrocyte co-culture technique. This potentiates co-culture as a solution for several key barriers to a clinically translatable cartilage tissue engineering process., Level of Evidence: NA. Laryngoscope, 128:E251-E257, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Fibroblastic reticular cells (FRCs) are stromal cells in secondary lymphoid organs, the major sites for HIV-1 infection of CD4 + T cells. Although FRCs regulate T cell survival, proliferation, and migration, whether they play any role in HIV-1 spread has not been studied. Here, we show that FRCs enhance HIV-1 spread via trans-infection in which FRCs capture HIV-1 and facilitate infection of T cells that come into contact with FRCs. FRCs mediate trans-infection in both two- and three-dimensional culture systems and in a manner dependent on the virus producer cells. This producer cell dependence, which was also observed for virus spread in secondary lymphoid tissues ex vivo, is accounted for by CD44 incorporated into virus particles and hyaluronan bound to such CD44 molecules. This virus-associated hyaluronan interacts with CD44 expressed on FRCs, thereby promoting virus capture by FRCs. Overall, our results reveal a novel role for FRCs in promoting HIV-1 spread.

Objectives/hypothesis: To explore the perioperative utility of three-dimensionally (3D)-printed temporal bone models of patients undergoing repair of lateral skull base defects and spontaneous cerebrospinal fluid leaks with the middle cranial fossa approach., Study Design: Case series., Methods: 3D-printed temporal bone models-based on patient-specific, high-resolution computed tomographic imaging-were constructed using inexpensive polymer materials. Preoperatively, the models demonstrated the extent of temporal lobe retraction necessary to visualize the proposed defects in the lateral skull base. Also preoperatively, Silastic sheeting was arranged across the modeled tegmen, marked, and cut to cover all of the proposed defect sites. The Silastic sheeting was then sterilized and subsequently served as a precise intraoperative template for a synthetic dural replacement graft. Of note, these grafts were customized without needing to retract the temporal lobe., Results: Five patients underwent the middle cranial fossa approach assisted by 3D-printed temporal bone models to repair tegmen defects and spontaneous cerebrospinal fluid leaks. No complications were encountered. The prefabricated dural repair grafts were easily placed and fit precisely onto the middle fossa floor without any additional modifications. All defects were covered as predicted by the 3D temporal bone models. At their postoperative visits, all five patients maintained resolution of their spontaneous cerebrospinal fluid leaks., Conclusions: Inexpensive 3D-printed temporal bone models of tegmen defects can serve as beneficial adjuncts during lateral skull base repair. The models provide a panoramic preoperative view of all tegmen defects and allow for custom templating of dural grafts without temporal lobe retraction., Level of Evidence: 4 Laryngoscope, 127:2347-2351, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Autologous cartilage grafting during open airway reconstruction is a complex skill instrumental to the success of the operation. Most trainees lack adequate opportunities to develop proficiency in this skill. We hypothesized that 3-dimensional (3D) printing and computer-aided design can be used to create a high-fidelity simulator for developing skills carving costal cartilage grafts for airway reconstruction. The rapid manufacturing and low cost of the simulator allow deployment in locations lacking expert instructors or cadaveric dissection, such as medical missions and Third World countries. In this blinded, prospective observational study, resident trainees completed a physical simulator exercise using a 3D-printed costal cartilage grafting tool. Participant assessment was performed using a Likert scale questionnaire, and airway grafts were assessed by a blinded expert surgeon. Most participants found this to be a very relevant training tool and highly rated the level of realism of the simulation tool.

Importance: Three-dimensional (3-D) printing is an exponentially growing technology that enables the use of a patient's image data to create patient-specific models, devices, and implants. Three-dimensional printing, developed in the 1980s, has emerged in the past decade with the potential to create new paradigms in personalized medicine., Observations: The field of otolaryngology has advanced many current and evolving future medical applications of 3-D printing. The predominant uses of 3-D printing have rapidly progressed from patient-specific models and simulators to intraoperative guides. Continued advancements now include 3-D-printed implants and future tissue-engineered constructs, which bring new regulatory challenges. This review summarizes the literature and provides a comprehensive guide to the background, applications, and current limitations of 3-D printing across the head and neck., Conclusions and Relevance: Three-dimensional printing enables the rapid production of patient-specific devices for personalized medicine. The field of otolaryngology has pioneered many of the underlying advancements in medical 3-D printing and will continue to remain at the forefront of 3-D printing technology.

Despite significant advances in 3D biomaterial printing, the potential of 3D printing for patient specific implants and tissue reconstruction has not been fully exploited. This is due in part to the lack of integration of image-based patient specific design with 3D biomaterial printing within a relevant regulatory framework, namely design control, required by the FDA. In this manuscript, we describe the integration of image-based, multi-scale patient specific design with 3D biomaterial printing within a design control framework for clinical translation. Specifically, we define design inputs for patient specific implants and scaffolds, and utilize image-based patient specific design to achieve these design inputs. We then illustrate realization of these topology designed patient specific implants by laser sintering of polycaprolactone (PCL). Finally, we present initial results in large animal models using 3D printed PCL implants addressing two challenging problems in tissue reconstruction: 1) designing and 3D printing implantable devices to allow growth in pediatric airway applications and 2) utilizing 3D printed scaffolds as foundations for pre-fabricated flaps to obtain vascularization and bone formation for large volume bone/soft tissue reconstruction. We illustrate these challenging problems as they need to be incorporated in design control, but as of yet there is little data to direct how growth and vascularization should be utilized in design control.

CHARGE syndrome is a dominant disorder characterized by ocular colobomata, heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear abnormalities including deafness and vestibular disorders. The majority of individuals with CHARGE have pathogenic variants in the gene encoding CHD7, a chromatin remodeling protein. Here, we present a 15-year-old girl with clinical features of CHARGE syndrome and a de novo 6.5 Mb gain of genomic material at 2p25.3-p25.2. The duplicated region contained 24 genes, including the early and broadly expressed transcription factor gene SOX11. Analysis of 28 other patients with CHARGE showed no SOX11 copy number changes or pathogenic sequence variants. To our knowledge, this child's chromosomal abnormality is unique and represents the first co-occurrence of duplication 2p25 and clinical features of CHARGE syndrome. We compare our patient's phenotype to ten previously published patients with isolated terminal duplication 2p, and elaborate on the clinical diagnosis of CHARGE in the context of atypical genetic findings., Competing Interests: The authors declare no conflicts of interest., (© 2016 Wiley Periodicals, Inc.)

This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of β-carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose consumed approximately 30-min pre-exposure. There were no group differences in post-exposure TTS or music-induced decreases in distortion product otoacoustic emission (DPOAE) amplitude. Transient tinnitus was more likely to be reported by the treatment group, but there were no group differences in perceived loudness or bothersomeness. All subjects were monitored until auditory function returned to pre-exposure levels. Taken together, this supplement had no effect on noise-induced changes in hearing. Recommendations for future clinical trials are discussed.

Dietary supplements consisting of beta-carotene (precursor to vitamin A), vitamins C and E and the mineral magnesium (ACEMg) can be beneficial for reducing hearing loss due to aminoglycosides and overstimulation. This regimen also slowed progression of deafness for a boy with GJB2 (CONNEXIN 26) mutations. To assess the potential for treating GJB2 and other forms of hereditary hearing loss with ACEMg, we tested the influence of ACEMg on the cochlea and hearing of mouse models for two human mutations: GJB2, the leading cause of childhood deafness, and DIAPH3, a cause of auditory neuropathy. One group of mice modeling GJB2 (Gjb2-CKO) received ACEMg diet starting shortly after they were weaned (4 weeks) until 16 weeks of age. Another group of Gjb2-CKO mice received ACEMg in utero and after weaning. The ACEMg diet was given to mice modeling DIAPH3 (Diap3-Tg) after weaning (4 weeks) until 12 weeks of age. Control groups received food pellets without the ACEMg supplement. Hearing thresholds measured by auditory brainstem response were significantly better for Gjb2-CKO mice fed ACEMg than for the control diet group. In contrast, Diap3-Tg mice displayed worse thresholds than controls. These results indicate that ACEMg supplementation can influence the progression of genetic hearing loss.

CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary anomalies, and Ear malformations, including deafness and vestibular disorders) is a genetic condition characterized by a specific and recognizable pattern of features. Heterozygous pathogenic variants in the chromodomain helicase DNA-binding protein 7 (CHD7) are the major cause of CHARGE syndrome, and have been identified in 70-90% of individuals fulfilling clinical diagnostic criteria. Since 2004, when CHD7 was discovered as the causative gene for CHARGE syndrome, the phenotypic spectrum associated with pathogenic CHD7 variants has expanded. Predicted pathogenic CHD7 variants have been identified in individuals with isolated features of CHARGE including autism and hypogonadotropic hypogonadism. Here, we present genotype and phenotype data from a cohort of 28 patients who were considered for a diagnosis of CHARGE syndrome, including one patient with atypical presentations and a pathogenic CHD7 variant. We also summarize published literature on pathogenic CHD7 variant positive individuals who have atypical clinical presentations. Lastly, we propose a revision to current clinical diagnostic criteria, including broadening of the major features associated with CHARGE syndrome and addition of pathogenic CHD7 variant status as a major criterion., (© 2015 Wiley Periodicals, Inc.)

Congenital airway obstruction poses a life-threatening challenge to the newborn. We present the first case of three-dimensional (3D) modeling and 3D printing of complex fetal maxillofacial anatomy after prenatal ultrasound indicated potential upper airway obstruction from a midline mass of the maxilla. Using fetal MRI and patient-specific computer-aided modeling, the craniofacial anatomy of the fetus was manufactured using a 3D printer. This model demonstrated the mass to be isolated to the upper lip and maxilla, suggesting the oral airway to be patent. The decision was made to deliver the infant without a planned ex utero intrapartum treatment procedure. The neonate was born with a protuberant cleft lip and palate deformity, without airway obstruction, as predicted by the patient-specific model. The delivery was uneventful, and the child was discharged without need for airway intervention. This case demonstrates that 3D modeling may improve prenatal evaluation of complex patient-specific fetal anatomy and facilitate the multidisciplinary approach to perinatal management of complex airway anomalies., (Copyright © 2015 by the American Academy of Pediatrics.)

Three-dimensional (3D) printing, or additive manufacturing, technology has rapidly penetrated the medical device industry over the past several years, and innovative groups have harnessed it to create devices with unique composition, structure, and customizability. These distinctive capabilities afforded by 3D printing have introduced new regulatory challenges. The customizability of 3D-printed devices introduces new complexities when drafting a design control model for FDA consideration of market approval. The customizability and unique build processes of 3D-printed medical devices pose unique challenges in meeting regulatory standards related to the manufacturing quality assurance. Consistent material powder properties and optimal printing parameters such as build orientation and laser power must be addressed and communicated to the FDA to ensure a quality build. Postprinting considerations unique to 3D-printed devices, such as cleaning, finishing and sterilization are also discussed. In this manuscript we illustrate how such regulatory hurdles can be navigated by discussing our experience with our group's 3D-printed bioresorbable implantable device., (© 2015 Wiley Periodicals, Inc.)

Objectives/hypothesis: The mechanical properties of normal auricular cartilage provide a benchmark against which to characterize changes in auricular structure/function due to genetic defects creating phenotypic abnormalities in collagen subtypes. Such properties also provide inputs/targets for auricular reconstruction scaffold design. Several studies report the biomechanical properties for septal, costal, and articular cartilage. However, analogous data for auricular cartilage are lacking. Therefore, our aim in this study was to characterize both whole-ear and auricular cartilage mechanics by mechanically testing specimens and fitting the results to nonlinear constitutive models., Study Design: Mechanical testing of whole ears and auricular cartilage punch biopsies., Methods: Whole human cadaveric ear and auricular cartilage punch biopsies from both porcine and human cartilage were subjected to whole-ear helix-down compression and quasistatic unconfined compression tests. Common hyperelastic constitutive laws (widely used to characterize soft tissue mechanics) were evaluated for their ability to represent the stress-strain behavior of auricular cartilage., Results: Load displacement curves for whole ear testing exhibited compliant linear behavior until after significant displacement where nonlinear stiffening occurred. All five commonly used two-term hyperelastic soft tissue constitutive models successfully fit both human and porcine nonlinear elastic behavior (mean R(2) fit >0.95)., Conclusions: Auricular cartilage exhibits nonlinear strain-stiffening elastic behavior that is similar to other soft tissues in the body. The whole ear exhibits compliant behavior with strain stiffening at high displacement. The constants from the hyperelastic model fits provide quantitative baselines for both human and porcine (a commonly used animal model for auricular tissue engineering) auricular mechanics., Level of Evidence: NA, (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Three-dimensional (3D) printing offers the potential for rapid customization of medical devices. The advent of 3D-printable biomaterials has created the potential for device control in the fourth dimension: 3D-printed objects that exhibit a designed shape change under tissue growth and resorption conditions over time. Tracheobronchomalacia (TBM) is a condition of excessive collapse of the airways during respiration that can lead to life-threatening cardiopulmonary arrests. We demonstrate the successful application of 3D printing technology to produce a personalized medical device for treatment of TBM, designed to accommodate airway growth while preventing external compression over a predetermined time period before bioresorption. We implanted patient-specific 3D-printed external airway splints in three infants with severe TBM. At the time of publication, these infants no longer exhibited life-threatening airway disease and had demonstrated resolution of both pulmonary and extrapulmonary complications of their TBM. Long-term data show continued growth of the primary airways. This process has broad application for medical manufacturing of patient-specific 3D-printed devices that adjust to tissue growth through designed mechanical and degradation behaviors over time., (Copyright © 2015, American Association for the Advancement of Science.)

The primary thrust of tissue engineering is the clinical translation of scaffolds and/or biologics to reconstruct tissue defects. Despite this thrust, clinical translation of tissue engineering therapies from academic research has been minimal in the 27 year history of tissue engineering. Academic research by its nature focuses on, and rewards, initial discovery of new phenomena and technologies in the basic research model, with a view towards generality. Translation, however, by its nature must be directed at specific clinical targets, also denoted as indications, with associated regulatory requirements. These regulatory requirements, especially design control, require that the clinical indication be precisely defined a priori, unlike most academic basic tissue engineering research where the research target is typically open-ended, and furthermore requires that the tissue engineering therapy be constructed according to design inputs that ensure it treats or mitigates the clinical indication. Finally, regulatory approval dictates that the constructed system be verified, i.e., proven that it meets the design inputs, and validated, i.e., that by meeting the design inputs the therapy will address the clinical indication. Satisfying design control requires (1) a system of integrated technologies (scaffolds, materials, biologics), ideally based on a fundamental platform, as compared to focus on a single technology, (2) testing of design hypotheses to validate system performance as opposed to mechanistic hypotheses of natural phenomena, and (3) sequential testing using in vitro, in vivo, large preclinical and eventually clinical tests against competing therapies, as compared to single experiments to test new technologies or test mechanistic hypotheses. Our goal in this paper is to illustrate how design control may be implemented in academic translation of scaffold based tissue engineering therapies. Specifically, we propose to (1) demonstrate a modular platform approach founded on 3D printing for developing tissue engineering therapies and (2) illustrate the design control process for modular implementation of two scaffold based tissue engineering therapies: airway reconstruction and bone tissue engineering based spine fusion.

In this article, the authors describe an initiative that established an infrastructure to manage quality and safety efforts throughout a complex health care system and that improved performance on core measures for acute myocardial infarction, heart failure, pneumonia, surgical care, and children's asthma. The Johns Hopkins Medicine Board of Trustees created a governance structure to establish health care system-wide oversight and hospital accountability for quality and safety efforts throughout Johns Hopkins Medicine. The Armstrong Institute for Patient Safety and Quality was formed; institute leaders used a conceptual model nested in a fractal infrastructure to implement this initiative to improve performance at two academic medical centers and three community hospitals, starting in March 2012. The initiative aimed to achieve ≥ 96% compliance on seven inpatient process-of-care core measures and meet the requirements for the Delmarva Foundation and Joint Commission awards. The primary outcome measure was the percentage of patients at each hospital who received the recommended process of care. The authors compared health system and hospital performance before (2011) and after (2012, 2013) the initiative. The health system achieved ≥ 96% compliance on six of the seven targeted measures by 2013. Of the five hospitals, four received the Delmarva Foundation award and two received The Joint Commission award in 2013. The authors argue that, to improve quality and safety, health care systems should establish a system-wide governance structure and accountability process. They also should define and communicate goals and measures and build an infrastructure to support peer learning.

Objective: To determine the potential of an integrated, image-based computer-aided design (CAD) and 3-dimensional (3D) printing approach to engineer scaffolds for head and neck cartilaginous reconstruction for auricular and nasal reconstruction., Study Design: Proof of concept revealing novel methods for bioscaffold production with in vitro and in vivo animal data., Setting: Multidisciplinary effort encompassing 2 academic institutions., Subjects and Methods: Digital Imaging and Communications in Medicine (DICOM) computed tomography scans were segmented and utilized in image-based CAD to create porous, anatomic structures. Bioresorbable polycaprolactone scaffolds with spherical and random porous architecture were produced using a laser-based 3D printing process. Subcutaneous in vivo implantation of auricular and nasal scaffolds was performed in a porcine model. Auricular scaffolds were seeded with chondrogenic growth factors in a hyaluronic acid/collagen hydrogel and cultured in vitro over 2 months' duration., Results: Auricular and nasal constructs with several types of microporous architecture were rapidly manufactured with high fidelity to human patient anatomy. Subcutaneous in vivo implantation of auricular and nasal scaffolds resulted in an excellent appearance and complete soft tissue ingrowth. Histological analysis of in vitro scaffolds demonstrated native-appearing cartilaginous growth that respected the boundaries of the scaffold., Conclusion: Integrated, image-based CAD and 3D printing processes generated patient-specific nasal and auricular scaffolds that supported cartilage regeneration., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Objective: To determine whether patients with semicircular canal dysplasia have mutations in CHD7., Background: CHARGE syndrome is a nonrandom clustering of congenital anomalies, including ocular coloboma, heart defects, choanal atresia or stenosis, retarded growth and development, genital hypoplasia, and inner and outer ear anomalies including deafness. Semicircular canal dysplasia has been included as a major diagnostic criterion for CHARGE syndrome. Mutations in the gene CHD7 on chromosome 8q12.1 are a major cause of CHARGE syndrome, but the extent to which patients with semicircular canal dysplasia have CHD7 mutations is not fully understood., Study Design: Cross-sectional analysis of CHD7 in 12 patients with semicircular canal dysplasia and variable clinical features of CHARGE syndrome., Results: We identified 6 CHD7 mutations, 5 of which occurred in patients who fulfilled Verloes' diagnostic criteria for typical CHARGE syndrome, and three of which were previously unreported. Of the 3 remaining CHD7 mutation-positive patients, one had atypical CHARGE by diagnostic criteria. Four MRI records were available, which revealed 2 patients with cochlear nerve aplasia and 1 patient with Chiari 1 malformation., Conclusion: These data provide additional evidence that CHD7 mutations are a significant cause of semicircular canal atresia in children with full or partial CHARGE syndrome.