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In vitro and in vivo studies are critical for the preclinical efficacy assessment of novel therapies targeting musculoskeletal infections (MSKI). Many preclinical models have been developed and applied as a prelude to evaluating safety and efficacy in human clinical trials. In performing these studies, there is both a requirement for a robust assessment of efficacy, as well as a parallel responsibility to consider the burden on experimental animals used in such studies. Since MSKI is a broad term encompassing infections varying in pathogen, anatomical location, and implants used, there are also a wide range of animal models described modeling these disparate infections. Although some of these variations are required to adequately evaluate specific interventions, there would be enormous value in creating a unified and standardized criteria to animal testing in the treatment of MSKI. The Treatment Workgroup of the 2023 International Consensus Meeting on Musculoskeletal Infection was responsible for questions related to preclinical models for treatment of MSKI. The main objective was to review the literature related to priority questions and estimate consensus opinion after voting. This document presents that process and results for preclinical models related to (1) animal model considerations, (2) outcome measurements, and (3) imaging.

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Disease or trauma of orthopedic tissues, including osteomyelitis, osteoporosis, arthritis, and fracture, results in a complex immune response, leading to a change in the concentration and milieu of immunological cells and proteins in the blood. While C-reactive protein levels and white blood cell counts are used to track inflammation and infection clinically, controlled longitudinal studies of disease/injury progression are limited. Thus, the use of clinically-relevant animal models can enable a more in-depth understanding of disease/injury progression and treatment efficacy. Though longitudinal tracking of immunological markers has been performed in rat models of various inflammatory and infectious diseases, currently there is no consensus on which markers are sensitive and reliable for tracking levels of inflammation and/or infection. Here, we discuss the blood markers that are most consistent with other outcome measures of the immune response in the rat, by reviewing their utility for longitudinal tracking of infection and/or inflammation in the following types of models: localized inflammation/arthritis, injury, infection, and injury + infection. While cytokines and acute phase proteins such as haptoglobin, fibrinogen, and α2 -macroglobulin demonstrate utility for tracking immunological response in many inflammation and infection models, there is likely not a singular superior marker for all rat models. Instead, longitudinal characterization of these models may benefit from evaluation of a collection of cytokines and/or acute phase proteins. Identification of immunological plasma markers indicative of the progression of a pathology will allow for the refinement of animal models for understanding, diagnosing, and treating inflammatory and infectious diseases of orthopedic tissues.

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Gait training via a wearable device in children with cerebral palsy (CP) offers the potential to increase therapy dosage and intensity compared to current approaches. Here, we report the design and characterization of a pediatric knee exoskeleton (P.REX) with a microcontroller based multi-layered closed loop control system to provide individualized control capability. Exoskeleton performance was evaluated through benchtop and human subject testing. Step response tests show the averaged 90% rise was 26 ± 0.2 ms for 5 Nm, 22 ± 0.2 ms for 10 Nm, 32 ± 0.4 ms for 15 Nm. Torque bandwidth of P.REX was 12 Hz and output impedance was less than 1.8 Nm with control on (Zero mode). Three different control strategies can be deployed to apply assistance to knee extension: state-based assistance, impedance-based trajectory tracking, and real-time adaptive control. One participant with typical development (TD) and one participant with crouch gait from CP were recruited to evaluate P.REX in overground walking tests. Data from the participant with TD were used to validate control system performance. Kinematic and kinetic data were collected by motion capture and compared to exoskeleton on-board sensors to evaluate control system performance with results demonstrating that the control system functioned as intended. The data from the participant with CP are part of a larger ongoing study. Results for this participant compare walking with P.REX in two control modes: a state-based approach that provided constant knee extension assistance during early stance, mid-stance and late swing (Est+Mst+Lsw mode) and an Adaptive mode providing knee extension assistance proportional to estimated knee moment during stance. Both were well tolerated and significantly improved knee extension compared to walking without extension assistance (Zero mode). There was less reduction in gait speed during use of the adaptive controller, suggesting that it may be more intuitive than state-based constant assistance for this individual. Future work will investigate the effects of exoskeleton assistance during overground gait training in children with neurological disorders and will aim to identify the optimal individualized control strategy for exoskeleton prescription.

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Thermosensitive chitosan hydrogels-renewable, biocompatible materials-have many applications as injectable biomaterials for localized drug delivery in the treatment of a variety of diseases. To combat infections such as Staphylococcus aureus osteomyelitis, localized antibiotic delivery would allow for higher doses at the site of infection without the risks associated with traditional antibiotic regimens. Fosfomycin, a small antibiotic in its own class, was loaded into a chitosan hydrogel system with varied beta-glycerol phosphate (ß-GP) and fosfomycin (FOS) concentrations. The purpose of this study was to elucidate the interactions between FOS and chitosan hydrogel. The Kirby Bauer assay revealed an unexpected concentration-dependent inhibition of S. aureus, with reduced efficacy at the high FOS concentration but only at the low ß-GP concentration. No effect of FOS concentration was observed for the planktonic assay. Rheological testing revealed that increasing ß-GP concentration increased the storage modulus while decreasing gelation temperature. NMR showed that FOS was removed from the liquid portion of the hydrogel by reaction over 12 h. SEM and FTIR confirmed gels degraded and released organophosphates over 5 days. This work provides insight into the physicochemical interactions between fosfomycin and chitosan hydrogel systems and informs selection of biomaterial components for improving infection treatment.

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INTRODUCTION: Wearable robotic exoskeletons offer the potential to move gait training from the clinic to the community thereby providing greater therapy dosage in more naturalistic settings. To capitalize on this potential, intuitive and robust interfaces are necessary between robotic devices and end users. Such interfaces hold great promise for research if they are also designed to record data from the robot during its use. METHODS: We present the design and validation of an open source graphical user interface (GUI) for wireless operation of and real-time data logging from a pediatric robotic exoskeleton. The GUI was designed for trained users such as an engineer or clinician. A simplified mobile application is also provided to enable exoskeleton operation by an end-user or their caretaker. GUI function was validated during simulated walking with the exoskeleton using a motion capture system. RESULTS: Our results demonstrate the ability of the GUI to wirelessly operate and save data from exoskeleton sensors with high fidelity comparable to motion capture. CONCLUSION: The GUI code, available in a public repository with a detailed description and step-by-step tutorial, is configurable to interact with any robotic device operated by a microcontroller and therefore represents a potentially powerful tool for deployment and evaluation of community based robotics.

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BACKGROUND: Orthopaedic boots with wedging are commonly used in the treatment of individuals with Achilles tendon rupture to immobilize the foot in plantar flexion and approximate tendon ends. RESEARCH QUESTION: To describe changes in muscle activity of the triceps surae and gait mechanics with the use of wedges in an orthopaedic boot immediately and after an accommodation period. METHODS: Muscle activity of the triceps surae and gait parameters (vertical ground reaction force, knee extension power, gait speed) were collected using surface electromyography and motion capture in 12 healthy individuals. Participants walked in an instrumented orthopaedic boot with 0, 3, and 5 wedges tested in random order. Participants were provided a one hour accommodation period where time spent walking was collected. This was followed by a repeat assessment of triceps surae activity and gait. RESULTS: Peak and integrated EMG in the medial gastrocnemius (p = 0.001, p < 0.001) and soleus (p = 0.010, p < 0.001) significantly decreased with increasing number of wedges. Peak and integrated EMG had a slight but non-significant decrease with increasing number of wedges in the lateral gastrocnemius (p = 0.151, p = 0.077). Vertical ground reaction force decreased (p = 0.019) and peak knee extension power increased (p = 0.003) with increasing number of wedges. There were no statistically significant differences in gait speed with wedges (p = 0.450). There were no significant changes in EMG or gait parameters from pre- to post-accommodation period. SIGNIFICANCE: A combination of factors yield decreased triceps surae activity in individuals wearing an orthopaedic boot with wedges - decreasing loading on the immobilized limb and shifting power generation proximally.

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