Age-related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in old mice.

Fracture healing complications increase with age, with higher rates of delayed unions and nonunions and an associated increase in morbidity and mortality in older adults. Macrophages have a dynamic role in fracture healing, and we have previously demonstrated that age-related changes in macrophages are associated with attenuated fracture repair in old mice. Here, we provide a single cell characterization of the immune cells involved in the early phase of fracture healing. We show that there were multiple transcriptionally distinct macrophage subpopulations present simultaneously within the healing tissue. Fracture healing was attenuated in old mice compared to young, and macrophages from the fracture callus of old mice demonstrated a pro-inflammatory phenotype compared to young. Interestingly, Trem2 expression was decreased in old macrophages compared to young. Young mice lacking Trem2 demonstrated attenuated fracture healing and inflammatory dysregulation similar to old mice. Trem2 dysregulation has previously been implicated in other age-related diseases, but its role in fracture healing is unknown. This work provides a robust characterization of the macrophage subpopulations involved in fracture healing, and further reveals the important role of Trem2 in fracture healing and may be a potential driver of age-related inflammatory dysregulation. Future work may further examine macrophages and Trem2 as potential therapeutic targets for management of fracture repair in older adults.

A Longitudinal Comparison of Telemedicine Versus In-Person Otolaryngology Clinic Efficiency and Patient Satisfaction During COVID-19.

OBJECTIVES: Telemedicine was increasingly adopted in otolaryngology as a result of the COVID-19 pandemic, but how it compares to in-person visits over the longitudinal course of the pandemic has not been characterized. This study compares telemedicine visits to in-person visits on measures of clinical efficiency and patient satisfaction. METHODS: We examined all in-person and telemedicine encounters that occurred during the 13-month period from April 1, 2020 to April 30, 2021 at a pediatric otolaryngology clinic associated with a large tertiary care children's hospital. We compared patient demographics, primary encounter diagnoses, completions, cancellations, no-shows, cycle time, and patient satisfaction. RESULTS: A total of 19 541 (90.5%) in-person visits and 2051 (9.5%) telemedicine visits were scheduled over the study period. There was no difference in patient age or gender between the visit types. There was a difference in race (75% White or Caucasian for in-person and 73% for telemedicine, P = .007) and average travel distance (53.3 miles for in-person vs 71.0 for telemedicine, P = .000). The most common primary diagnosis was Eustachian tube dysfunction for in-person visits (11.8%) and sleep disordered breathing for telemedicine visits (13.7%). Completion rate was greater for telemedicine visits (52.4% in-person vs 62.5% telemedicine). Cancellations were greater for in-person visits (42.6% in-person vs 24.2% telemedicine), but no-shows were greater for telemedicine (5.0% in-person vs 13.3% telemedicine, all P = .000). Average cycle time was shorter for telemedicine visits (56.5 minutes in-person vs 47.6 minutes telemedicine, P = .000). Patient satisfaction with provider interactions and overall care experience was high for both visit types. CONCLUSIONS: Telemedicine was utilized more during months of heightened COVID-19 cases, with higher completion rates, fewer cancellations, shorter cycle times, saved travel distance, and comparable patient satisfaction to in-person visits. Telemedicine has the potential to remain an efficient mode of care delivery in the post-pandemic era.

Age-related changes to macrophages are detrimental to fracture healing in mice.

The elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age-related diseases. Therefore, we investigated age-related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA-seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an up-regulation of M1/pro-inflammatory genes in macrophages from old mice as well as dysregulation of other immune-related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age-matched controls. After preventing infiltration by macrophages, the macrophages remaining within the fracture callus were collected and examined via RNA-seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age-related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.

Fracture healing: A review of clinical, imaging and laboratory diagnostic options.

A fundamental issue in clinical orthopaedics is the determination of when a fracture is united. However, there are no established "gold standards," nor standardized methods for assessing union, which has resulted in significant disagreement among orthopaedic surgeons in both clinical practice and research. A great deal of investigative work has been directed to addressing this problem, with a number of exciting new techniques described. This review provides a brief summary of the burden of nonunion fractures and addresses some of the challenges related to the assessment of fracture healing. The tools currently available to determine union are discussed, including various imaging modalities, biomechanical testing methods, and laboratory and clinical assessments. The evaluation of fracture healing in the setting of both patient care and clinical research is integral to the orthopaedic practice. Weighted integration of several available metrics must be considered to create a composite outcome measure of patient prognosis.

Stimulating Fracture Healing in Ischemic Environments: Does Oxygen Direct Stem Cell Fate during Fracture Healing?

Bone fractures represent an enormous societal and economic burden as one of the most prevalent causes of disability worldwide. Each year, nearly 15 million people are affected by fractures in the United States alone. Data indicate that the blood supply is critical for fracture healing; as data indicate that concomitant bone and vascular injury are major risk factors for non-union. However, the various role(s) that the vasculature plays remains speculative. Fracture stabilization dictates stem cell fate choices during repair. In stabilized fractures stem cells differentiate directly into osteoblasts and heal the injury by intramembranous ossification. In contrast, in non-stable fractures stem cells differentiate into chondrocytes and the bone heals through endochondral ossification, where a cartilage template transforms into bone as the chondrocytes transform into osteoblasts. One suggested role of the vasculature has been to participate in the stem cell fate decisions due to delivery of oxygen. In stable fractures, the blood vessels are thought to remain intact and promote osteogenesis, while in non-stable fractures, continual disruption of the vasculature creates hypoxia that favors formation of cartilage, which is avascular. However, recent data suggests that non-stable fractures are more vascularized than stable fractures, that oxygen does not appear associated with differentiation of stem cells into chondrocytes and osteoblasts, that cartilage is not hypoxic, and that oxygen, not sustained hypoxia, is required for angiogenesis. These unexpected results, which contrast other published studies, are indicative of the need to better understand the complex, spatio-temporal regulation of vascularization and oxygenation in fracture healing. This work has also revealed that oxygen, along with the promotion of angiogenesis, may be novel adjuvants that can stimulate healing in select patient populations.