An Opportunity to See the Heart Defect Physically: Medical Student Experiences of Technology-Enhanced Learning with 3D Printed Models of Congenital Heart Disease.

Three-dimensional (3D) printing is increasingly used in medical education and paediatric cardiology. A technology-enhanced learning (TEL) module was designed to accompany 3D printed models of congenital heart disease (CHD) to aid in the teaching of medical students. There are few studies evaluating the attitudes and perceptions of medical students regarding their experience of learning about CHD using 3D printing. This study aimed to explore senior medical students' experiences in learning about paediatric cardiology through a workshop involving 3D printed models of CHD supported by TEL in the form of online case-based learning. A mixed-methods evaluation was undertaken involving a post-workshop questionnaire (n = 94 students), and focus groups (n = 16 students). Focus group and free-text questionnaire responses underwent thematic analysis. Questionnaire responses demonstrated widespread user satisfaction; 91 (97%) students agreed that the workshop was a valuable experience. The highest-level satisfaction was for the physical 3D printed models, the clinical case-based learning, and opportunity for peer collaboration. Thematic analysis identified five key themes: a variable experience of prior learning, interplay between physical and online models, flexible and novel workshop structure, workshop supported the learning outcomes, and future opportunities for learning using 3D printing. A key novel finding was that students indicated the module increased their confidence to teach others about CHD and recommended expansion to other parts of the curriculum. 3D printed models of CHD are a valuable learning resource and contribute to the richness and enjoyment of medical student learning, with widespread satisfaction. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01840-w.

Multi-Targeting DKK1 and LRP6 Prevents Bone Loss and Improves Fracture Resistance in Multiple Myeloma.

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (µCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Who Benefits From Allowing the Physis to Grow in Slipped Capital Femoral Epiphysis?

BACKGROUND: The globally acknowledged treatment for mild to moderate slipped capital femoral epiphysis (SCFE) is single screw in situ fixation, also used for prophylactic contralateral fixation. The Free-Gliding Screw (FG; Pega Medical) is a 2-part free-extending screw system designed to allow the growth of the proximal femur. We aimed to analyze the relationship between skeletal maturity and potential growth of the proximal physis and remodeling of the femoral neck using this implant. MATERIALS AND METHODS: Females below 12 years and males below 14 years undergoing in situ fixation for stable SCFE or prophylactic fixation were treated using the implant. Three elements of the modified Oxford Bone (mOB 3 ) score were used to measure maturity (triradiate cartilage, head of the femur, and greater trochanter). Radiographs were analyzed immediately postoperatively and at a minimum of 2 years for a change in screw length, posterior-sloping angle, articulotrochanteric distance, α angle, and head-neck offset. RESULTS: The study group comprised 30 (F:M=12:18) of 39 hips treated with SCFE and 22 (F:M=13:9) of 29 hips managed prophylactically using the free-Gliding screw. In the therapeutic group, chronologic age was a less valuable predictor of future screw lengthening than mOB 3 . An mOB 3 of ≤13 predicted future growth of >6 mm but did not reach statistical significance ( P =0.07). Patients with open triradiates showed a mean screw lengthening of 6.6 mm compared with those with closed triradiates (4.0 mm), but this did not reach significance ( P =0.12). In those with mOB 3 ≤13, the α angle reduced significantly ( P <0.01) and the head-neck offset increased significantly, suggesting remodeling. There was no change in these parameters when mOB 3 ≥14. In the prophylactic group, change in screw length was significant with mOB 3 of ≤13 (mean=8.0 mm, P <0.05), as was the presence of an open triradiate cartilage (mean=7.7 mm, P <0.05). In both cohorts, posterior-sloping angle and articulotrochanteric distance did not change, indicating no slip progression in either treatment or prophylactic groups and minimal effect on the proximal physeal growth relative to the greater trochanter. CONCLUSIONS: Growing screw constructs can halt slip progression while allowing proximal femoral growth in young patients with SCFE. Ongoing growth is better when the implant is used for prophylactic fixation. The results in treated SCFE need to be expanded to demonstrate a clinically meaningful cut-off for significant growth, but SCFE patients with an open triradiate remodel significantly more than those where it is closed. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Comparison of multiple 3D scanners to capture foot, ankle, and lower leg morphology.

BACKGROUND: 3D scanning of the foot and ankle is gaining popularity as an alternative method to traditional plaster casting to fabricate ankle-foot orthoses (AFOs). However, comparisons between different types of 3D scanners are limited. OBJECTIVES: The aim of this study was to evaluate the accuracy and speed of seven 3D scanners to capture foot, ankle, and lower leg morphology to fabricate AFOs. STUDY DESIGN: Repeated-measures design. METHODS: The lower leg region of 10 healthy participants (mean age 27.8 years, standard deviation [SD] 9.3) was assessed with 7 different 3D scanners: Artec Eva (Eva), Structure Sensor (SS I), Structure Sensor Mark II (SS II), Sense 3D Scanner (Sense), Vorum Spectra (Spectra), Trnio 3D Scanner App on iPhone 11 (Trnio 11), and Trnio 3D Scanner App on iPhone 12 (Trnio 12). The reliability of the measurement protocol was confirmed initially. The accuracy was calculated by comparing the digital scan with clinical measures. A percentage difference of #5% was considered acceptable. Bland and Altman plots were used to show the mean bias and limit of agreement (LoA) for each 3D scanner. Speed was the time needed for 1 complete scan. RESULTS: The mean accuracy ranged from 6.4% (SD 10.0) to 230.8% (SD 8.4), with the SS I (21.1%, SD 6.8), SS II (21.7%, SD 7.5), and Eva (2.5%, SD 4.5) within an acceptable range. Similarly, Bland and Altman plots for Eva, SS I, and SS II showed the smallest mean bias and LoA 21.7 mm (LoA 25.8 to 9.3), 21.0 mm (LoA 210.3 to 8.3), and 0.7 mm (LoA 213 to 11.5), respectively. The mean speed of the 3D scanners ranged from 20.8 seconds (SD 8.1, SS I) to 329.6 seconds (SD 200.2, Spectra). CONCLUSIONS: Eva, SS I, and SS II appear to be the most accurate and fastest 3D scanners for capturing foot, ankle, and lower leg morphology, which could be used for AFO fabrication.

Targeted postnatal knockout of Sclerostin using a bone-targeted adeno-associated viral vector increases bone anabolism and decreases canalicular density.

PURPOSE: The creation of murine gene knockout models to study bone gene functions often requires the resource intensive crossbreeding of Cre transgenic and gene-floxed strains. The developmental versus postnatal roles of genes can be difficult to discern in such models. For example, embryonic deletion of the Sclerostin (Sost) gene establishes a high-bone mass phenotype in neonatal mice that may impact on future bone growth. To generate a postnatal skeletal knockout of Sost in adult mice, this study used a single injection of a bone-targeted recombinant adeno-associated virus (rAAV) vector. METHODS: 8-week-old Sostflox/flox mice were injected with saline (control) or a single injection containing 5 × 1011 vg AAV8-Sp7-Cre vector. Ai9 fluorescent Cre reporter mice were dosed in parallel to confirm targeting efficiency. After 6 weeks, detailed bone analysis was performed via microCT, biomechanical testing, and bone histology on vertebral and long bone specimens. RESULTS: The AAV8-Sp7-Cre vector induced widespread persistent recombination in the bone compartment. Regional microCT analyses revealed significant increases in bone with vector treatment. In the L3 vertebrae, Sostflox/flox:AAV-Cre showed a 22 % increase in bone volume and 21 % in trabecular bone fraction compared to controls; this translated to a 17 % increase in compressive strength. In the tibiae, Sostflox/flox:AAV-Cre led to small but statistically significant increases in cortical bone volume and thickness. These were consistent with a 25 % increase in mineral apposition rate, but this did not translate into increased four-point bending strength. Ploton silver nitrate stain on histological sections revealed an unexpected increase in canalicular density associated with Sost ablation. CONCLUSION: This report demonstrates a proof-of-concept that the AAV8-Sp7-Cre vector can efficiently produce postnatal skeletal knockout mice using gene-floxed strains. This technology has the potential for broad utility in the bone field with existing conditional lines. These data also confirm an important postnatal role for Sost in regulating bone homeostasis, consistent with prior studies using neutralizing Sclerostin antibodies, and highlights a novel role of Sost in canalicular remodeling.

Utility of 3D Printed Models Versus Cadaveric Pathology for Learning: Challenging Stated Preferences.

Introduction: 3D printing has recently emerged as an alternative to cadaveric models in medical education. A growing body of research supports the use of 3D printing in this context and details the beneficial educational outcomes. Prevailing studies rely on participants' stated preferences, but little is known about actual student preferences. Methods: A mixed methods approach, consisting of structured observation and computer vision, was used to investigate medical students' preferences and handling patterns when using 3D printed versus cadaveric models in a cardiac pathology practical skills workshop. Participants were presented with cadaveric samples and 3D printed replicas of congenital heart deformities. Results: Analysis with computer vision found that students held cadaveric hearts for longer than 3D printed models (7.71 vs. 6.73 h), but this was not significant when comparing across the four workshops. Structured observation found that student preferences changed over the workshop, shifting from 3D printed to cadaveric over time. Interactions with the heart models (e.g., pipecleaners) were comparable. Conclusion: We found that students had a slight preference for cadaveric hearts over 3D printed hearts. Notably, our study contrasts with other studies that report student preferences for 3D printed learning materials. Given the relative equivalence of the models, there is opportunity to leverage 3D printed learning materials (which are not scarce, unlike cadaveric materials) to provide equitable educational opportunities (e.g., in rural settings, where access to cadaveric hearts is less likely).

Clinical applications of machine learning in predicting 3D shapes of the human body: a systematic review.

BACKGROUND: Predicting morphological changes to anatomical structures from 3D shapes such as blood vessels or appearance of the face is a growing interest to clinicians. Machine learning (ML) has had great success driving predictions in 2D, however, methods suitable for 3D shapes are unclear and the use cases unknown. OBJECTIVE AND METHODS: This systematic review aims to identify the clinical implementation of 3D shape prediction and ML workflows. Ovid-MEDLINE, Embase, Scopus and Web of Science were searched until 28th March 2022. RESULTS: 13,754 articles were identified, with 12 studies meeting final inclusion criteria. These studies involved prediction of the face, head, aorta, forearm, and breast, with most aiming to visualize shape changes after surgical interventions. ML algorithms identified were regressions (67%), artificial neural networks (25%), and principal component analysis (8%). Meta-analysis was not feasible due to the heterogeneity of the outcomes. CONCLUSION: 3D shape prediction is a nascent but growing area of research in medicine. This review revealed the feasibility of predicting 3D shapes using ML clinically, which could play an important role for clinician-patient visualization and communication. However, all studies were early phase and there were inconsistent language and reporting. Future work could develop guidelines for publication and promote open sharing of source code.

Replicating and redesigning ankle-foot orthoses with 3D printing for children with Charcot-Marie-Tooth disease.

BACKGROUND: Children with the most common inherited neuropathy, Charcot-Marie-Tooth disease (CMT), are often prescribed ankle-foot orthoses (AFOs) to improve walking ability and prevent falls by reducing foot drop, postural instability, and other gait impairments. These externally worn assistive devices are traditionally custom-made using thermoplastic vacuum forming. This labour-intensive manufacturing process often results in AFOs which are cumbersome due to limited design options, and are associated with low acceptability, discomfort, and suboptimal impact on gait. The aim of this study was to determine how 3D printing can be used to replicate and redesign AFOs in children with CMT. METHODS: Traditional AFOs, 3D printed replica AFOs (same design as traditional AFOs), 3D printed redesigned AFOs and a shoes only control condition were compared in 12 children with CMT. 3D printed AFOs were manufactured using material extrusion in Nylon-12. 3D gait analysis (temporal-spatial, kinematic, kinetic), in-shoe pedobarography and self-reported satisfaction were used to compare conditions. The primary kinematic and kinetic outcome measures were maximum ankle dorsiflexion in swing and maximum ankle dorsiflexor moment in loading response, to capture foot drop and an absent of heel rocker. RESULTS: The 3D printed replica AFOs were comparable to traditional AFOs for all outcomes. The 3D printed replica AFOs improved foot position at initial contact and during loading response and significantly reduced pressure beneath the whole foot, rearfoot and forefoot compared to the shoes only. The 3D printed redesigned AFOs produced a device that was significantly lighter (mean -35.2, SD 13.3%), and normalised maximum ankle dorsiflexor moment in loading response compared to shoes only and traditional AFOs. SIGNIFICANCE: 3D printing can be used to replicate traditional handmade AFOs and to redesign AFOs to produce a lighter device with improved biomechanics by incorporating novel design features.

Combination treatment with growth hormone and zoledronic acid in a mouse model of Osteogenesis imperfecta.

INTRODUCTION: Osteogenesis imperfecta (OI) or brittle bone disease is a genetic disorder that results in bone fragility. Bisphosphonates such as zoledronic acid (ZA) are used clinically to increase bone mass and reduce fracture risk. Human growth hormone (hGH) has been used to promote long bone growth and forestall short stature in children with OI. The potential for hGH to improve bone quality, particularly in combination with ZA has not been robustly studied. METHODS: A preclinical study was performed using n = 80 mice split evenly by genotype (WT, Col1a2+/G610C). Groups of n = 10 were treated with +/-ZA and +/-hGH in a factorial design for each genotype. Outcome measures included bone length, isolated muscle mass, bone parameters assessed by microCT analysis, dynamic histomorphometry, and biomechanical testing. RESULTS: Treatment with hGH alone led to an increase in femur length in WT but not OI mice, however bone length was increased in both genotypes with the combination of hGH/ZA. MicroCT showed that hGH/ZA treatment increased cortical BV in both WT (+15%) and OI mice (+14.3%); hGH/ZA were also found to be synergistic in promoting cortical thickness in OI bone. ZA was found to have a considerably greater positive impact on trabecular bone than hGH. ZA was found to suppress bone turnover, and this was rescued by hGH treatment in terms of cortical periosteal perimeter, but not by dynamic bone remodeling. Statistically significant improvements in long bone by microCT did not translate into improvements in mechanical strength in a 4-point bending test, nor did vertebral strength improve in L4 compression testing in WT/OI bone. DISCUSSION/CONCLUSION: These data support hGH/ZA combination as a treatment for short stature, however the improvements granted by hGH alone and in combination with ZA on bone quality are modest. Increased periosteal perimeter does show promise in improving bone strength in OI, however a longer treatment time may be required to see effects on bone strength through mechanical testing.

Digital mapping of a manual fabrication method for paediatric ankle-foot orthoses.

Ankle-foot orthoses (AFOs) are devices prescribed to improve mobility in people with neuromuscular disorders. Traditionally, AFOs are manually fabricated by an orthotist based on a plaster impression of the lower leg which is modified to correct for impairments. This study aimed to digitally analyse this manual modification process, an important first step in understanding the craftsmanship of AFO fabrication to inform the digital workflows (i.e. 3D scanning and 3D printing), as viable alternatives for AFO fabrication. Pre- and post-modified lower limb plaster casts of 50 children aged 1-18 years from a single orthotist were 3D scanned and registered. The Euclidean distance between the pre- and post-modified plaster casts was calculated, and relationships with participant characteristics (age, height, AFO type, and diagnosis) were analysed. Modification maps demonstrated that participant-specific modifications were combined with universally applied modifications on the cast's anterior and plantar surfaces. Positive differences (additions) ranged 2.12-3.81 mm, negative differences (subtractions) ranged 0.76-3.60 mm, with mean differences ranging from 1.37 to 3.12 mm. Height had a medium effect on plaster additions (rs = 0.35). We quantified the manual plaster modification process and demonstrated a reliable method to map and compare pre- and post-modified casts used to fabricate children's AFOs.

Content analysis of child user and carer perspectives of ankle-foot orthoses.

BACKGROUND: The evaluation of ankle-foot orthoses is primarily focused on biomechanical performance, with comparatively less studies pertaining to users' quality of life and experiential factors. OBJECTIVES: To investigate how child users regard acquisition and use of ankle-foot orthoses through the perspectives of child users, parents/carers and practitioners. STUDY DESIGN: Inductive content analysis of secondary data. METHODS: Child user and parent/carer perspectives, as communicated by them and by practitioners, were collected from online platforms and formal publications. Data and themes were analysed through an inductive approach. Investigator triangulation was used to increase trustworthiness and reduce bias. RESULTS: We found and analysed 223 data points from 30 informal online platforms and 15 formal publications. These data clustered into five key themes relating to user experience with ankle-foot orthoses, including materials, structure, aesthetics, service and impact. Child users had mixed opinions about ankle-foot orthoses, reporting satisfaction with the functional improvements resulting from ankle-foot orthosis wear, while noting negative feelings from the experience of acquiring and using the device. CONCLUSION: This research suggests that considering the five themes in ankle-foot orthosis provision could improve the child user experience, inform future ankle-foot orthosis design, and improve clinical outcomes.

3D printed models can guide safe halo pin placement in patients with diastrophic dysplasia.

PURPOSE: To trial the use of three-dimensional (3D) printed skull models to guide safe pin placement in two patients with diastrophic dysplasia (DTD) requiring prolonged pre-fusion halo-gravity traction (HGT). METHODS: Two sisters aged 8 (ML) and 4 (BL) with DTD were planned for staged fusion for progressive kyphoscoliosis. Both sisters were admitted for pre-fusion HGT. Models of their skulls were generated from computer tomography (CT) scans using Mimics Innovation Suite and printed on a Guider II in polylactic acid. The 3D models were cut axially proximal to the skull equator, in-line where pins are usually inserted, allowing identification of the thickest skull portion to guide pin placement. RESULTS: Eight pins were inserted into each patient's skull. Postoperative CT scans demonstrated adequate pin position. Pre-traction Cobb angles were 122° and 128° for ML and BL, improving to 83° and 86° following traction. Duration of HGT was 182 and 238 days for ML and BL. Prior to fusion, both patients returned to theatre twice for exchange of loose pins and there was one incidence of pin site infection. Surgery was performed via a posterior instrumented fusion. Postoperatively, both patients remained in their halos for 3 months. One pin in BL was removed for loosening. Both patients achieved fusion union by 9 months. CONCLUSION: 3D models of the skull can be a useful tool to guide safe pin placement in patients with skeletal dysplasias, who require prolonged pre-fusion HGT for severe deformity correction.

Comparison of 3D scanning versus traditional methods of capturing foot and ankle morphology for the fabrication of orthoses: a systematic review.

BACKGROUND: In the production of ankle-foot orthoses and in-shoe foot orthoses, lower leg morphology is traditionally captured using a plaster cast or foam impression box. Plaster-based processes are a time-consuming and labour-intensive fabrication method. 3D scanning is a promising alternative, however how these new technologies compare with traditional methods is unclear. The aim of this systematic review was to compare the speed, accuracy and reliability of 3D scanning with traditional methods of capturing foot and ankle morphology for fabricating orthoses. METHODS: PRISMA guidelines were followed and electronic databases were searched to March 2020 using keywords related to 3D scanning technologies and traditional foot and ankle morphology capture methods. Studies of any design from healthy or clinical populations of any age and gender were eligible for inclusion. Studies must have compared 3D scanning to another form of capturing morphology of the foot and/or ankle. Data relating to speed, accuracy and reliability as well as study design, 3D scanner specifications and comparative capture techniques were extracted by two authors (M.F. and Z.W.). Study quality was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN). RESULTS: Six articles met the inclusion criteria, whereby 3D scanning was compared to five traditional methods (plaster cast, foam impression box, ink footprint, digital footprint and clinical assessment). The quality of study outcomes was rated low to moderate (GRADE) and doubtful to adequate (COSMIN). Compared to traditional methods, 3D scanning appeared to be faster than casting (2 to 11 min vs 11 to 16 min). Inter-rater reliability (ICC 0.18-0.99) and intra-rater reliability (ICCs 0.25-0.99) were highly variable for both 3D scanning and traditional techniques, with higher agreement generally dependent on the foot parameter measured. CONCLUSIONS: The quality and quantity of literature comparing the speed, accuracy and reliability of 3D scanning with traditional methods of capturing foot and ankle morphology is low. 3D scanning appears to be faster especially for experienced users, however accuracy and reliability between methods is variable.

The Universal Entry Point with oblique screw is superior to fixation perpendicular to the physis in moderate slipped capital femoral epiphysis.

PURPOSE: Stable slipped capital femoral epiphysis (SCFE) is often treated with in situ pinning, with the current gold standard being stabilization with a screw perpendicular to the physis. However, this can lead to impingement and a potentially unstable construct. In this study we model the biomechanical effect of two screw positions used for SCFE fixation. We hypothesize that single screw fixation into the centre of the femoral head from the anterior intertrochanteric line (the Universal Entry Point or UEP) provides a more stable construct than single screw fixation perpendicular to the physis with an anterior starting point. METHODS: Sawbone models of moderate SCFE were used to mechanically test the two screw constructs and an unfixed control group. Models were loaded to failure with a shear load applied through the physis in an Instron mechanical tester. The primary outcomes were maximum load, stiffness and energy to failure. RESULTS: Screw fixation into the centre of the femoral head from the UEP resulted in a greater load to failure (+19%), stiffness (+13%) and energy to failure (+45%) than screw fixation perpendicular to the physis. CONCLUSIONS: In this sawbone construct, screw fixation into the centre of the femoral head from the UEP provides greater biomechanical stability than screw fixation perpendicular to the physis. This approach may also benefit by avoiding an intracapsular entry point in soft metaphyseal bone and subsequent risk of impingement and loss of position.

Validity and reliability of smartphone inclinometer applications for measurement of elbow range of motion in paediatric patients.

PURPOSE: Precise measurement of elbow range of motion (ROM) post-injury or surgery forms an important part of determining prognosis and the need for further intervention. Clinicians are increasingly incorporating smartphone use in our medical practice; we sought to determine if a smartphone goniometer application is a valid and reliable tool for assessment of elbow ROM in the paediatric patient, compared to visual and goniometer assessment. METHODS: In total, 20 paediatric patients (40 elbows) between six and 15 years of age with an elbow or forearm injury were included in this prospective series. Elbow flexion, extension, pronation and supination were measured independently by two orthopaedic clinicians. Measurements were taken from injured as well as unaffected side using a standardized technique, first with visual estimation and then using a universal goniometer (UG) and smartphone goniometer application Angle Meter via Google Play store (Smart Tool Factory, Istanbul, Turkey). RESULTS: There was excellent interobserver reliability for all three modalities, with average intraclass correlation coefficient (ICC) values greater than 0.90. Visual estimation had the lowest average ICC of 0.92, compared to 0.97 for UG and smartphone. Overall, there was excellent intraobserver reliability between the smartphone application and the gold standard UG for all elbow movements with ICCs ranging between 0.98 to 0.99 and mean absolute difference ranging from 1.1 ± 1.0° to 2.6 ± 1.9°. The smartphone application showed superior agreement over visual estimation when compared to the gold standard UG with lower mean differences and 95% limits of agreement (LOA) falling within 10°. CONCLUSIONS: Our study demonstrates that a smartphone application is a valid and reliable assessment tool for measurement of elbow ROM in paediatric patients, and better than visualization alone. LEVEL OF EVIDENCE: III.

CSA-90 reduces periprosthetic joint infection in a novel rat model challenged with local and systemic Staphylococcus aureus.

Infection of orthopedic implants is a growing clinical challenge to manage due to the proliferation of drug-resistant bacterial strains. In this study, we aimed to investigate whether the treatment of implants with ceragenin-90 (CSA-90), a synthetic compound based on endogenous antibacterial peptides, could prevent infection in a novel rat model of periprosthetic joint infection (PJI) challenged with either local or systemic Staphylococcus aureus. A novel preclinical model of PJI was created using press-fit porous titanium implants in the distal femur of male Wistar rats. Sterile implants were pre-treated with 500 µg CSA-90 in saline. S. aureus was applied either directly at the time of surgery or administered via tail vein injection immediately afterward. Animals were monitored daily for clinical and radiographic evidence of infection for a total of 6 weeks. Post-study microbiological, radiographic, and histological analysis were performed to determine the incidence of PJI and assess osseointegration. CSA-90 treated groups demonstrated a reduced rate of PJI as confirmed by deep tissue swab culture at the time of cull compared with untreated groups with both local (33% vs 100%; P = .009) and systemic (10% vs 90%; P < .0001) S. aureus inoculation. Median survival time also increased from 8 to 17 days and from 8 to 42 days, respectively. In conclusion, this study describes a novel preclinical model of local and hematogenous PJI using a porous metal implant. CSA-90 reduced the incidence of PJI in this model supporting its further development as an antimicrobial coating for orthopedic implants.

A Bioactive Coating Enhances Bone Allografts in Rat Models of Bone Formation and Critical Defect Repair.

Bone allografts are inferior to autografts for the repair of critical-sized defects. Prior studies have suggested that bone morphogenetic protein-2 (BMP-2) can be combined with allografts to produce superior healing. We created a bioactive coating on bone allografts using polycondensed deoxyribose isobutyrate ester (PDIB) polymer to deliver BMP-2 ± the bisphosphonate zoledronic acid (ZA) and tested its ability to enhance the functional utility of allografts in preclinical Wistar rat models. One ex vivo and two in vivo proof-of-concept studies were performed. First, PDIB was shown to be able to coat bone grafts (BGs). Second, PDIB was used to coat structural allogenic corticocancellous BG with BMP-2 ± ZA ± hydroxyapatite (HA) microparticles and compared with PDIB-coated grafts in a rat muscle pouch model. Next, a rat critical defect model was performed with treatment groups including (i) empty defect, (ii) BG, (iii) collagen sponge + BMP-2, (iv) BG + PDIB/BMP-2, and (v) BG + PDIB/BMP-2/ZA. Key outcome measures included detection of fluorescent bone labels, microcomputed tomography (CT) quantification of bone, and radiographic healing. In the muscle pouch study, BMP-2 did not increase net bone volume measured by microCT, however, fluorescent labeling showed large amounts of new bone. Addition of ZA increased BV by sevenfold (p < 0.01). In the critical defect model, allografts were insufficient to promote reliable union, however, union was achieved in collagen/BMP-2 and all BG/BMP-2 groups. Statement of clinical significance: These data support the concept that PDIB is a viable delivery method for BMP-2 and ZA delivery to enhance the bone forming potential of allografts. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2278-2286, 2019.

Feasibility of designing, manufacturing and delivering 3D printed ankle-foot orthoses: a systematic review.

BACKGROUND: Ankle-foot orthoses (AFO) are prescribed to manage difficulty walking due to foot drop, bony foot deformities and poor balance. Traditional AFOs are handmade using thermoplastic vacuum forming which provides limited design options, is labour-intensive and associated with long wait times. 3D printing has the potential to transform AFO production and health service delivery. The aim of this systematic review was to determine the feasibility of designing, manufacturing and delivering customised 3D printed AFOs by evaluating the biomechanical outcomes, mechanical properties and fit of 3D printed compared to traditionally manufactured AFOs. METHOD: Electronic databases were searched from January 1985 to June 2018 according to terms related to 3D printing and AFOs. Studies of any design from healthy or pathological populations of any age were eligible for inclusion. Studies must have investigated the effect of customised 3D printed AFOs using any 3D printing technique on outcomes related to walking ability, biomechanical function, mechanical properties, patient comfort, pain and disability. Any other orthotic type or AFOs without a 3D printed calf and foot section were excluded. The quality of evidence was assessed using the GRADE process. RESULTS: Eleven studies met the eligibility criteria evaluating 3D printed AFOs in healthy adults, and adults and children with unilateral foot drop from a variety of conditions. 3D printing was used to replicate traditional AFOs and develop novel designs to optimise the stiffness properties or reduce the weight and improve the ease of use of the AFO. 3D printed custom AFOs were found to be comparable to traditional custom AFOs and prefabricated AFOs in terms of temporal-spatial parameters. The mechanical stiffness and energy dissipation of 3D printed AFOs were found to be similar to prefabricated carbon-fibre AFOs. However, the sample sizes were small (n = 1 to 8) and study quality was generally low. CONCLUSION: The biomechanical effects and mechanical properties of 3D printed AFOs were comparable to traditionally manufactured AFOs. Developing novel AFO designs using 3D printing has many potential benefits including stiffness and weight optimisation to improve biomechanical function and comfort.

Effect of rapamycin on bone mass and strength in the α2(I)-G610C mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant-containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations.

Bone Marrow Transplantation for Treatment of the Col1a2+/G610C Osteogenesis Imperfecta Mouse Model.

Bone marrow transplantation (BMT) of healthy donor cells has been postulated as a strategy for treating osteogenesis imperfecta (OI) and other bone fragility disorders. The effect of engraftment by tail vein injection and/or marrow ablation by 6 Gy whole body irradiation were tested in Col1a2+/G610C (OI) mice as a model of mild-moderate OI. Dual-emission X-ray absorptiometry, microCT, and 4-point bending were used to measure bone volume (BV), bone mineral density (BMD), and biomechanical strength. BV, BMD, and mechanical strength were reduced in OI mice compared to wild type (WT) controls. BMT with and without irradiation yielded no difference in BV and BMD outcomes for both OI and WT mice, at 3 weeks. Transplantation of OI cells into OI mice to test for paracrine effects of BMT also showed no difference with non-transplanted OI mice. In a parallel cell tracking study, donor marrow was taken from transgenic mice constitutively expressing tdTomato and transplanted into WT mice. Lineage tracking demonstrated that irradiation considerably enhanced engraftment of tdTomato+ cells. However, tdTomato+ cells predominantly expressed TRAP and not AP, indicating engrafted donor cells were chiefly from the hematopoietic lineages. These data show that whole marrow transplantation fails to rescue the bone phenotype of Col1a2+/G610C (OI) mice and that osteopoietic engraftment is not significantly enhanced by irradiation. These findings are highly relevant to modern approaches focused on the gene repair of patient cells ex vivo and their subsequent reintroduction into the osteopoietic compartment via the circulation.