Glenn E. Green

Bioresorbable Airway Splint Created with a Three-Dimensional Printer

An infant with localized bronchial malacia was treated with a computer-printed bioresorbable three-dimensional splint. Placement of the splint resulted in improved ventilation.

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13)

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric patients

Patient-specific, image-based design coupled with 3D biomaterial printing produced personalized implants for treatment of collapsed airways in patients with tracheobronchomalacia. Printing in 4D: Personalized implants The 3D printing revolution is in full swing, with frequent reports of printed kidneys and jaws, dolls and cars, food, and body armor. The new challenge is to make 3D materials evolve in the fourth dimension: time. Such “4D” materials could change in response to temperature, light, or even stress, making them adaptable and enduring. In pediatric medicine, 4D implants become particularly relevant; as the patient grows, so, too, should the material. Morrison et al. used 3D printing technology with a safe, bioresorbable polymer blend to create splints for three pediatric patients with tracheobronchomalacia (TBM)—a condition of excessive collapse of the airways during normal breathing. Currently available fixed-size implants can migrate and require frequent resizing. Thus, the authors used imaging and computational models to design the splints for each TBM patient’s individual geometries, structuring the implants to accommodate airway growth and prevent external compression over a period of time, before being resorbed by the body. In all three patients (one with two airways splinted), the 4D devices were implanted without issue. All four implants were stable and functional after 1 month, and one implant has remained in place, keeping the airway open for over 3 years. This pilot trial demonstrates that the fourth dimension is a reality for 3D-printed materials, and with continued human studies, 4D biomaterials promise to change the way we envision the next generation of regenerative medicine. 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.

Temporal bone histopathology in connexin 26-related hearing loss

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.

Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3

Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.

Obesity and risk of peri-operative complications in children presenting for adenotonsillectomy

BACKGROUND Adenotonsillectomy (T&A) is a very common surgical procedure in children. With the rising prevalence of childhood overweight and obesity, our goal was to describe the prevalence of overweight/obesity in children presenting for T&A in our institution. We also sought to compare the frequency of peri-operative complications and the likelihood of being admitted following T&A between overweight/obese and normal weight children. METHODS We examined our peri-operative database and extracted clinical, demographic and anthropometric information on 2170 children who underwent T&A between January 2005 and February 2008. Children were classified into normal weight, overweight and obese using published body mass index (BMI) criteria. The incidences of peri-operative complications were compared between the BMI categories. We also examined factors contributing to the likelihood of admission following T&A. RESULTS The overall prevalence of overweight and obese was 20.7%. Overweight/obese children were more likely to have intra-operative desaturation (p=0.004), multiple attempts at laryngoscopy (p<0.001), difficult mask ventilation (p=0.001), and post-induction and post-anesthesia care unit (PACU) upper airway obstruction (p<0.001). Additionally, overweight and obese children were more likely to be admitted following T&A. BMI showed a moderate positive correlation with post-operative length of stay (LOS). Multiple logistic regression analysis showed that BMI and presence of medical co-morbidities were independent predictors of LOS. CONCLUSION Overweight and obese children presenting for T&A have a higher incidence of peri-operative complications and are more likely to be admitted and stay for longer than their healthy weight peers.

Regulatory Considerations in the Design and Manufacturing of Implantable 3D‐Printed Medical Devices

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 groups 3D‐printed bioresorbable implantable device.

Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects.

Objectives: One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is the availability of an established clinical paradigm with real-world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal-hearing human subjects. Design: Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93 to 95 (n = 10), 98 to 100 (n = 11), or 100 to 102 (n = 12) dBA in-ear exposure level for a period of 4 hr. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured before and after music exposure. Postmusic tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and 1 week later. Results: Changes in thresholds after the lowest-level exposure were difficult to distinguish from test–retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a “notch” configuration, with the largest changes observed at 4 kHz (mean = 6.3 ± 3.9 dB; range = 0–14 dB). Recovery was largely complete within the first 4 hr postexposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1 week postexposure. Conclusions: These data provide insight into the variability of TTS induced by music-player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function after digital music-player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in future TTS studies, including protective agent evaluations, that some noise exposures have resulted in neural degeneration in animal models, even when both audiometric thresholds and DPOAE levels returned to pre-exposure values.

Treatment of severe porcine tracheomalacia with a 3-dimensionally printed, bioresorbable, external airway splint.

IMPORTANCE The study demonstrates use of a novel intervention for severe tracheobronchomalacia (TBM). OBJECTIVE To test a novel, 3-dimensionally (3D) printed, bioresorbable airway splint for efficacy in extending survival in a porcine model of severe, life-threatening TBM. DESIGN AND PARTICIPANTS A randomized, prospective animal trial was used to evaluate an external airway splint as treatment of severe, life-threatening TBM in a multi-institutional, multidisciplinary collaboration between a biomedical engineering department and an academic animal surgery center. Six 2-month-old Yorkshire pigs underwent tracheal cartilage division and inner tracheal lumen dissociation and were randomly assigned to splint treatment (n = 3) or control groups (n = 3). Two additional pigs had the splint placed over their normal trachea. INTERVENTIONS A 3D-printed, bioresorbable airway splint was assessed in a porcine animal model of life-threatening TBM. The open-cylindrical, bellow-shaped, porous polycaprolactone splint was placed externally and designed to suspend the underlying collapsed airway. Two additional animals were splinted without model creation. MAIN OUTCOMES AND MEASURES The observer-based Westley Clinical Croup Scale was used to assess the clinical condition of animals postoperatively. Animal survival time was noted. RESULTS Complete or nearly complete tracheal lumen collapse was observed in each animal, with resolution of symptoms in all of the experimental animals after splint placement. Using our severe TBM animal model, survival was significantly longer in the experimental group receiving the airway splint after model creation than in the control group (P = .0495). CONCLUSIONS AND RELEVANCE A multidisciplinary effort producing a computer-aided designed, computer-aided manufactured bioresorbable tracheobronchial splint was tested in a porcine model of severe TBM and was found to extend survival time. Mortality in the splinted group was ascribed to the TBM model based on the lack of respiratory distress in splinted pigs, long-term survival in animals implanted with the splint without TBM, and necropsy findings.

Computer Aided–Designed, 3-Dimensionally Printed Porous Tissue Bioscaffolds for Craniofacial Soft Tissue Reconstruction

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.