Introduction of transcatheter edge-to-edge repair in patients with congenital heart disease at a children's hospital.

BACKGROUND: Atrioventricular valve regurgitation (AVVR) is a devastating complication in children and young adults with congenital heart disease (CHD), particularly in patients with single ventricle physiology. Transcatheter edge-to-edge repair (TEER) is a rapidly expanding, minimally invasive option for the treatment of AVVR in adults that avoids the morbidity and mortality associated with open heart surgery. However, application of TEER in in CHD and in children is quite novel. We describe the development of a peri-procedural protocol including image-derived pre-intervention simulation, with successful application to four patients. AIMS: To describe the initial experience using the MitraClip system for TEER of dysfunctional systemic atrioventricular valves in patients with congential heart disease within a pediatric hospital. METHODS: A standardized screening and planning process was developed using cardiac magnetic resonance imaging, three dimensional echocardiography and both virtual and physical simulation. Procedures were performed using the MitraClip G4 system and patients were clinically followed post-intervention. RESULTS: A series of four CHD patients with at least severe AVVR were screened for suitability for TEER with the MitraClip system: three patients had single ventricle physiology and Fontan palliation, and one had repair of a common atrioventricular canal defect. Each patient had at least severe systemic AVVR and was considered at prohibitively high risk for surgical repair. Each patient underwent a standardized preprocedural screening protocol and image-derived modeling followed by the TEER procedure with successful clip placement at the intended location in all cases. CONCLUSIONS: The early results of our protocolized efforts to introduce TEER repair of severe AV valve regurgitation with MitraClip into the CHD population within our institution are encouraging. Further investigations of the use of TEER in this challenging population are warranted.

Physical Simulation of Transcatheter Edge-to-Edge Repair using Image-Derived 3D Printed Heart Models.

Background: Transcatheter edge-to-edge valve repair (TEER) is a complex procedure requiring delivery and alignment of the device to the target valve, which can be challenging in atypical or surgically palliated anatomy. We demonstrate application of virtual and physical simulation to plan optimal TEER access and catheter path in normal and congenitally abnormal cardiac anatomy. Methods: Three heart models were created from three-dimensional (3D) images and 3D printed, including two with congenital heart disease. TEER catheter course was simulated both virtually and physically using a commercial TEER system. Results: We demonstrate application of modeling in three patients, including two with congenital heart disease and a Fontan circulation. Access site and pathway to device delivery was simulated by members of a multidisciplinary valve team. Virtual and physical simulation were compared. Conclusions: Virtual and physical simulation of TEER using 3D printed heart models is feasible and may be beneficial for planning and simulation, particularly in patients with complex anatomy. Future work is required to demonstrate application in the clinical setting.

Pediatric Genitourinary 3D Modeling and Printing Using Multiphase Postcontrast Imaging Segmentation.

OBJECTIVE: To describe the development and implementation of a process for creating accurate Pediatric genitourinary 3D modeling and printing with multiphase postcontrast imaging for surgical planning. MATERIALS AND METHODS: Additive manufacturing and 3D model present opportunities to support clinical planning, this manuscript's specific process and considerations for creating pediatric genitourinary 3D modeling to support urology. The process for creating the 3D models and prints covers 3 key aspects from image acquisition, imaging review and selection, and segmentation and modification (as needed). Each step is outlined with the key roles and procedures. RESULTS: The described case had digital and printed models prepared with references to the optimized imaging sequence for 3D modeling of Pediatric genitourinary. Case shared include complex genitourinary reconstruction and Kideny with Wilms tumors. CONCLUSION: The processes described have become a standard of practice for complex kidney tumors and exstrophy planning. The team continues to work on ever-changing improvements to make the best possible models to support clinical and surgical planning.

Using human factors principles to redesign a 3D lab workflow during the COVID-19 pandemic.

BACKGROUND: Like most hospitals, our hospital experienced COVID-19 pandemic-related supply chain shortages. Our additive manufacturing lab's capacity to offset these shortages was soon overwhelmed, leading to a need to improve the efficiency of our existing workflow. We undertook a work system analysis guided by the Systems Engineering Initiative for Patient Safety (SEIPS) construct which is based on human factors and quality improvement principles. Our objective was to understand the inefficiencies in project submission, review, and acceptance decisions, and make systematic improvements to optimize lab operations. METHODS: Contextual inquiry (interviews and workflow analysis) revealed suboptimal characteristics of the system, specifically, reliance on a single person to facilitate work and, at times, fractured communication with project sponsors, with root causes related to the project intake and evaluation process as identified through SEIPS tools. As interventions, the analysis led us to: 1) enhance an existing but underused project submission form, 2) design and implement an internal project scorecard to standardize evaluation of requests, and 3) distribute the responsibility of submission evaluation across lab members. We implemented these interventions in May 2021 for new projects and compare them to our baseline February 1, 2018 through - April 30, 2021 performance (1184 days). RESULTS: All project requests were submitted using the enhanced project submission form and all received a standardized evaluation with the project scorecard. Prior to interventions, we completed 35/79 (44%) of projects, compared to 12/20 (60%) of projects after interventions were implemented. Time to review new submissions was reduced from an average of 58 days to 4 days. A more distributed team responsibility structure permitted improved workflow with no increase in staffing, allowing the Lab Manager to devote more time to engineering rather than administrative/decision tasks. CONCLUSIONS: By optimizing our workflows utilizing a human factors approach, we improved the work system of our additive manufacturing lab to be responsive to the urgent needs of the pandemic. The current workflow provides insights for labs aiming to meet the growing demand for point-of-care manufacturing.

Clinical 3D modeling to guide pediatric cardiothoracic surgery and intervention using 3D printed anatomic models, computer aided design and virtual reality.

BACKGROUND: Surgical and catheter-based interventions for congenital heart disease require precise understanding of complex anatomy. The use of three-dimensional (3D) printing and virtual reality to enhance visuospatial understanding has been well documented, but integration of these methods into routine clinical practice has not been well described. We review the growth and development of a clinical 3D modeling service to inform procedural planning within a high-volume pediatric heart center. METHODS: Clinical 3D modeling was performed using cardiac magnetic resonance (CMR) or computed tomography (CT) derived data. Image segmentation and post-processing was performed using FDA-approved software. Patient-specific anatomy was visualized using 3D printed models, digital flat screen models and virtual reality. Surgical repair options were digitally designed using proprietary and open-source computer aided design (CAD) based modeling tools. RESULTS: From 2018 to 2020 there were 112 individual 3D modeling cases performed, 16 for educational purposes and 96 clinically utilized for procedural planning. Over the 3-year period, demand for clinical modeling tripled and in 2020, 3D modeling was requested in more than one-quarter of STAT category 3, 4 and 5 cases. The most common indications for modeling were complex biventricular repair (n = 30, 31%) and repair of multiple ventricular septal defects (VSD) (n = 11, 12%). CONCLUSIONS: Using a multidisciplinary approach, clinical application of 3D modeling can be seamlessly integrated into pre-procedural care for patients with congenital heart disease. Rapid expansion and increased demand for utilization of these tools within a high-volume center demonstrate the high value conferred on these techniques by surgeons and interventionalists alike.

Additive manufacturing (3d printing) in response to a pandemic: Lessons learned at the children's hospital of Philadelphia.

The COVID-19 pandemic produced unprecedented challenges to healthcare and medical device manufacturing (e.g. personal protective device and replacement part shortages). Additive manufacturing, 3D printing, and the maker community were uniquely positioned to respond to these needs by providing in-house design and manufacturing to meet the needs of clinicians and hospitals. This paper reviews the pandemic response of Children's Hospital of Philadelphia CHAMP 3D Lab, a point-ofcare3D printing team that supports clinical and research projects across the hospital network. The CHAMP team responded to a variety of COVID-19 healthcare needs including providing protective eyewear and ventilator components, creating a transport hook, and designing a novel transparent facemask. This case series details our response to these needs, describing challenges experienced and lessons learned in overcoming them so that others may learn from our experiences. Challenges to responding to the pandemic included the need to handle urgent pandemic related requests in addition to our standard fare. This required us to not only expand our capacity without additional resources, but also to develop a system of prioritization. Specific changes made included: streamlining workflows, identifying safety review processes, and developing/enlisting a network of collaborators. Further, we consider how to transition to a future, post-pandemic world without losing the cohesive drive of emergency-induced innovation. This paper aims to share what we have learned and to encourage both teams currently engaged in the printing community and those looking to join it.

Translational research in pediatric contrast-enhanced ultrasound.

The role of contrast-enhanced ultrasound (CEUS) imaging is being widely explored by various groups for its use in the pediatric population. Clinical implementation of new diagnostic or therapeutic techniques requires extensive and meticulous preclinical testing and evaluation. The impact of CEUS will be determined in part by the extent to which studies are oriented specifically toward a pediatric population. Rather than simply applying principles and techniques used in the adult population, these studies are expected to advance and augment preexisting knowledge with pediatric-specific information. To further develop this imaging modality for use in children, pediatric-focused preclinical research is essential. In this paper we describe the development and implementation of the pediatric-specific preclinical animal and phantom models that are being used to evaluate CEUS with the goal of clinical translation to children.

Three-dimensional printed realistic pediatric static and dynamic airway models for bronchoscopy and foreign body removal training.

For mastering bronchoscope handling, positioning, and directing of the bronchoscope in response to the intraluminal view provided by the bronchoscope camera, sufficient training is necessary, especially in infants and toddlers who have smaller airways, faster respiratory rates, and higher airway collapsibility. With the use of three-dimensional printing, we aimed to develop a set of anatomically accurate and low-cost airway models for teaching and training of bronchoscopy technique and foreign body removal: a translucent airway box model, a static airway model, and a dynamic airway model consisting of a flexible tree model connected to a pump that allows simulation of airway collapsibility during breathing. Computed tomography (CT) patient data of three different ages (1, 5, and 18 years of age) was imported into Materialise Mimics, segmented, and printed using VisoClear and soft Tango+ material. The models were evaluated by three pediatric pulmonology attendings for anatomical accuracy and usefulness for teaching and training. The translucent airway box model was preferred for the initial presentation of bronchoscope handling and learning anatomy in three dimensions. The static and flexible tree models were used to train bronchoscope handling and foreign body removal. The dynamic model provided the most realistic representation of a pediatric airway throughout the respiratory cycle with increased patency during inspiration and relative collapse during exhalation. Objective verification of anatomical accuracy and physiology of breathing motion was obtained by comparing CT scans of the model with original images and by application of 4D dynamic CT airway imaging protocols, respectively.

Optimization of Mechanical Indices for Clinical Contrast-Enhanced Ultrasound.

The quality of contrast-enhanced ultrasound (CEUS) imaging performed with high-frequency convex and linear transducers is often suboptimal. A common solution to improving the microbubble signal is by increasing the volume of the ultrasound contrast agent being administered. An alternative technique to improve the signal from the contrast agent is to adjust the mechanical index (MI). This study aimed to compare the manufacturer's default MI to an optimal MI (as determined by the best contrast-to-tissue ratio) for improving the CEUS image quality using linear and convex transducers. This study found that in most cases, the default CEUS MI setting by the manufacturer is often suboptimal, and increasing the MI is necessary to improve the contrast-to-tissue ratio and image quality. The MI can be modified by the clinician during the study to improve the quality of the clinical CEUS examination.

A primer for pediatric radiologists on infection control in an era of COVID-19.

Pediatric radiology departments across the globe face unique challenges in the midst of the current COVID-19 pandemic that have not been addressed in professional guidelines. Providing a safe environment for personnel while continuing to deliver optimal care to patients is feasible when abiding by fundamental recommendations. In this article, we review current infection control practices across the multiple pediatric institutions represented on the Society for Pediatric Radiology (SPR) Quality and Safety committee. We discuss the routes of infectious transmission and appropriate transmission-based precautions, in addition to exploring strategies to optimize personal protective equipment (PPE) supplies. This work serves as a summary of current evidence-based recommendations for infection control, and current best practices specific to pediatric radiologists.

Imaging Properties of Additive Manufactured (3D Printed) Materials for Potential Use for Phantom Models.

Over the last few decades, there has been growing interest in the application of additive manufacturing (AM) or 3D printing for medical research and clinical application. Imaging phantoms offer clear benefits in the way of training, planning, and quality assurance, but the model's availability per catalog tend to be suited for general testing purposes only. AM, on the contrary, offers flexibility to clinicians by enabling custom-built phantoms based on specific interests or even individual patient needs. This study aims to quantify the radiographic properties (ultrasound, magnetic resonance imaging, and computed tomography) of common additive manufacturing technologies and to discuss potential opportunities to fabricate imaging phantoms. Test phantoms were composed of samples from the three most common AM styles, namely PolyJet, fused deposition modeling (FDM), and stereolithography (SLA). Test imaging of the phantoms was performed on ultrasound, MRI, and CT and reviewed and evaluated with radiology software. The ultrasound images showed clearly defined upper and lower edges of the material but did not demonstrate distinct differences in internal echogenicity between materials. The MR scans revealed a distinct signal intensity difference between the model (17 grayscale value) and the printer support (778 grayscale value). Finally, the CT images showed a slight variation between the plastic (82 HU) and rubber (145 HU) materials. The radiographic properties of AM offer a clear opportunity to create basic two- or three-material phantoms. These would be high-accuracy and cost-effective models. Although the materials currently available are not suitable for complex multi-material applications as realistic as true human anatomy, one can easily foresee the development of new materials with broader density in the near future.

Three-dimensional printed models of the rib cage in children with non-accidental injury as an effective visual-aid tool.

Three-dimensional (3-D) printing is gaining terrain in medical education, presurgical evaluation and recently as forensic evidence in court. Physicians, including radiologists, often provide expert testimony in court cases involving children with rib fractures and other injuries concerning for child physical abuse. Effectively communicating the complexities of fractures and other skeletal findings to nonmedical personnel using standard radiology studies can be challenging, especially during medical courtroom testimony. For this reason, we printed two 3-D models of the rib cage from the chest computed tomography (CT) scans of two patients with suspected non-accidental injury. The patients also had available chest radiographs. The DICOM (Digital Imaging and Communications in Medicine) data were 3-D reconstructed and segmented using two attenuation thresholds. We removed unwanted structures and printed them on a commercially available scanner. A pediatric radiologist, blinded to clinical data, reviewed both 3-D models, identified all rib lesions and classified them according to their healing stage. We compared the 3-D models and the chest radiograph against the chest CT as the standard of care. We convened a meeting with the Child Protection Team at out institution to get their feedback and opinions about the models. From our observations of our experts, three spontaneous interactions were observed. Instinctively, the experts picked up and grasped the models, rotating them, feeling them and angling them to better visualize the fractures from multiple angles. The experts expressed a willingness to consider using the models in court.

Comparison of 3D Echocardiogram-Derived 3D Printed Valve Models to Molded Models for Simulated Repair of Pediatric Atrioventricular Valves.

Mastering the technical skills required to perform pediatric cardiac valve surgery is challenging in part due to limited opportunity for practice. Transformation of 3D echocardiographic (echo) images of congenitally abnormal heart valves to realistic physical models could allow patient-specific simulation of surgical valve repair. We compared materials, processes, and costs for 3D printing and molding of patient-specific models for visualization and surgical simulation of congenitally abnormal heart valves. Pediatric atrioventricular valves (mitral, tricuspid, and common atrioventricular valve) were modeled from transthoracic 3D echo images using semi-automated methods implemented as custom modules in 3D Slicer. Valve models were then both 3D printed in soft materials and molded in silicone using 3D printed "negative" molds. Using pre-defined assessment criteria, valve models were evaluated by congenital cardiac surgeons to determine suitability for simulation. Surgeon assessment indicated that the molded valves had superior material properties for the purposes of simulation compared to directly printed valves (p < 0.01). Patient-specific, 3D echo-derived molded valves are a step toward realistic simulation of complex valve repairs but require more time and labor to create than directly printed models. Patient-specific simulation of valve repair in children using such models may be useful for surgical training and simulation of complex congenital cases.

Differential Influence of Early Life and Adult Stress on Urogenital Sensitivity and Function in Male Mice.

Experiences of adverse childhood events have been associated with improper output of the hypothalamic-pituitary-adrenal (HPA) axis in adulthood, as well as development of comorbid functional pain disorders. Symptoms of chronic prostatitis/chronic pelvic pain syndrome frequently overlap with those of interstitial cystitis/painful bladder syndrome and symptom severity is often triggered by stress. The objective of this study was to investigate the influence early life stress and acute adult stress on (1) perigenital sensitivity, (2) micturition, (3) anhedonia, and (4) HPA axis regulation and output in male C56Bl/6 mice. Neonatal maternal separation (NMS) was performed for 3 h a day from postnatal day 1 to 21 and naïve pups remained unhandled during this time. As adults, male mice were tested for referred prostate sensitivity and micturition patterning prior to and 1 and 8 days after exposure to 1 h of water avoidance stress (WAS). Following testing, prostate and bladder tissues were used for mast cell and Western blot analysis and RT-PCR was performed on mRNA from hypothalamus, amygdala, and hippocampus. Serum corticosterone (CORT) was also measured by enzyme-linked immunosorbent assay (ELISA). A significant increase in perigenital sensitivity and micturition frequency was observed in NMS mice and these measures were exacerbated by WAS exposure. Exposure to NMS significantly increased mast cell degranulation in both the bladder and prostate. Mast cell degranulation was also increased in naïve prostate tissue following WAS exposure. Cytokine mRNA levels were influenced by both NMS and WAS exposure, though WAS had a larger impact on central gene expression. Protein levels of CRF1 were differentially regulated by NMS and WAS in the bladder and prostate and serum CORT levels were significantly diminished following stress exposure. Taken together, these data suggest that NMS results in neurogenic inflammation and hypersensitivity within the urogenital organs, coupled with diminished gene expression and output from the HPA axis. Future studies of NMS in male mice may provide a useful tool as a preclinical model of male chronic urological pain syndromes for investigating potential pharmacological and interventional therapies.

Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress.

Early adverse events have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. Despite high clinical relevance and reports of stress-related symptom exacerbation, animal models investigating the contribution of early life stress to female urological pain are lacking. We examined the impact of neonatal maternal separation (NMS) on bladder sensitivity and visceral neuroimmune status both prior-to, and following, water avoidance stress (WAS) in adult female mice. The visceromotor response to urinary bladder distension was increased at baseline and 8d post-WAS in NMS mice, while colorectal sensitivity was transiently increased 1d post-WAS only in naïve mice. Bladder micturition rate and output, but not fecal output, were also significantly increased following WAS in NMS mice. Changes in gene expression involved in regulating the stress response system were observed at baseline and following WAS in NMS mice, and WAS reduced serum corticosterone levels. Cytokine and growth factor mRNA levels in the bladder, and to a lesser extent in the colon, were significantly impacted by NMS and WAS. Peripheral mRNA levels of stress-responsive receptors were differentially influenced by early life and adult stress in bladder, but not colon, of naïve and NMS mice. Histological evidence of mast cell degranulation was increased in NMS bladder, while protein levels of protease activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) were increased by WAS. Together, this study provides new insight into mechanisms contributing to stress associated symptom onset or exacerbation in patients exposed to early life stress.

Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice.

Experiencing early life stress can result in maladjusted stress response via dysregulation of the hypothalamic-pituitary-adrenal axis and serves as a risk factor for developing chronic pelvic pain disorders. We investigated whether neonatal maternal separation (NMS) would increase susceptibility to experimental colitis or exposure to acute or chronic stress. Male mice underwent NMS from postnatal day 1-21 and as adults were assessed for open field behavior, hindpaw sensitivity, and visceromotor response (VMR) to colorectal distension (CRD). VMR was also measured before and after treatment with intracolonic trinitrobenzene sulfonic acid (TNBS) or exposure to acute or chronic water avoidance stress (WAS). Myeloperoxidase (MPO) activity, proinflammatory gene and corticotropin-releasing factor (CRF) receptor expression were measured in distal colon. Baseline VMR was not affected by NMS, but undergoing CRD increased anxiety-like behaviors and mechanical hindpaw sensitivity of NMS mice. Treatment with TNBS dose-dependently decreased body weight and survival only in NMS mice. Following TNBS treatment, IL-6 and artemin mRNA levels were decreased in the distal colon of NMS mice, despite increased MPO activity. A single WAS exposure increased VMR during CRD in NMS mice and increased IL-6 mRNA and CRF2 protein levels in the distal colon of naïve mice, whereas CRF2 protein levels were heightened in NMS colon both at baseline and post-WAS exposure. Taken together, these results suggest that NMS in mice disrupts inflammatory- and stress-induced gene expression in the colon, potentially contributing towards an exaggerated response to specific stressors later in life.