Robert J. Morrison

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.

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.

Antenatal Three-Dimensional Printing of Aberrant Facial Anatomy

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.

Hemiglossectomy tongue reconstruction: Modeling of elevation, protrusion, and functional outcome using receiver operator characteristic curve.

The purpose of this study was to model >12 month speech and the oral phase of swallowing outcomes with the reconstructive metrics of tongue elevation and protrusion in patients reconstructed with the rectangle tongue template for a hemiglossectomy defect.

Computer-Aided Design and 3-Dimensional Printing for Costal Cartilage Simulation of Airway Graft Carving

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.

Treatment of Severe Acquired Tracheomalacia With a Patient-Specific, 3D-Printed, Permanent Tracheal Splint

Treatment of Severe Acquired Tracheomalacia With a Patient-Specific, 3D-Printed, Permanent Tracheal Splint Tracheobronchomalacia (TBM) is a disease of excessive collapse of the primary airways resulting from intrinsic weakness or extrinsic compression. While infantile TBM typically regresses in severity over time, adult-phenotype TBM is more often persistent and progressive.1 Severe TBM carries substantial morbidity and mortality, and interventions such as surgical excision, stenting, and tracheotomy have all been associated with life-threatening complications.2,3

Human and porcine vocalizations after creation of a human larynx

Corresponding Author: gegreen@med.umich.edu Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI, U.S.A. Department of Otolaryngology – Head and Neck Surgery, University of Michigan, Ann Arbor, MI, U.S.A. Department of Animal Sciences, University of Illinois at Urbana-Champaign, Champaign, IL, U.S.A. Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, U.S.A

Pathologic Fibroblasts in Idiopathic Subglottic Stenosis Amplify Local Inflammatory Signals

Objective To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A). Study Design Basic science. Setting Laboratory. Subjects and Methods Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A. Results Mechanistically, IL-17A drives iSGS scar fibroblast proliferation (P < .01), synergizes with transforming growth factor ß1 to promote extracellular matrix production (collagen and fibronectin; P = .04), and directly stimulates scar fibroblasts to produce chemokines (chemokine ligand 2) and cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor) critical to the recruitment and differentiation of myeloid cells (P < .01). Glucocorticoids abrogated IL-17A-dependent iSGS scar fibroblast production of granulocyte-macrophage colony-stimulating factor (P = .02). Conclusion IL-17A directly drives iSGS scar fibroblast proliferation, synergizes with transforming growth factor ß1 to promote extracellular matrix production, and amplifies local inflammatory signaling. Glucocorticoids appear to partially abrogate fibroblast-dependent inflammatory signaling. These results offer mechanistic support for future translational study of clinical reagents for manipulation of the IL-17A pathway in iSGS patients.

Co-culture of adipose-derived stem cells and chondrocytes on three-dimensionally printed bioscaffolds for craniofacial cartilage engineering

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.

Design and Quality Control for Translating 3D-Printed Scaffolds

Abstract 3D printing has become widely utilized for regenerative medicine research due to its ability to fabricate patient-specific scaffolds with well-controlled porous architecture and the capability of printing cells in 3D configurations. These characteristics, combined with the unique capability of producing implants and scaffolds for small, specific patient populations not feasible with other manufacturing techniques, have generated significant interest in using 3D printing to transplant implants and scaffolds for clinical use. However, like any clinically translated device, 3D printed scaffolds are subject to design control and quality control requirements to achieve regulatory approval. 3D printing, with its ability to make patient-specific and custom scaffolds; however, brings a number of challenges for design and quality control. In this chapter, we present an example design and quality control for a laser-sintered 3D-printed, resorbable polycaprolactone splint to treat tracheobronchalmalacia (TBM). This splint has been used clinically to save three children with life threatening TBM. We specifically describe a design control for the PCL resorbable splint, detailing design requirements for surgical, mechanical, and biomaterial needs of the splint. Design control entails not only the design requirements for the device, but also the tests to verify that the final device meets the design inputs (design verification) and the preclinical and clinical tests to verify that the fabricated device meets the clinical requirements (design validation). Finally, since design verification and validation are dependent on the laser sintering fabrication process, we detail the parameters of the laser sintering process as well as the methods used to assess devices made using the laser sintering process.