Using short-term exposure of embryoid bodies to transforming growth factor-β, the authors directed induced pluripotent stem cells (iPSCs) toward mesenchymal stem cell (MSC) differentiation. Two types of iPSC-derived MSCs were identified: early (aiMSCs) and late (tiMSCs) outgrowing cells. Both types differentiated in vitro in response to osteogenic or adipogenic supplements; aiMSCs demonstrated higher osteogenic potential than tiMSCs. Upon orthotopic injection into radial defects, both types regenerated bone and contributed to defect repair.

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro–computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchy-mal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.

IMPORTANCE A substantial portion of the public is diagnosed with myopia, which increases the risk of potential sight-threatening complications. The association between study style and the development of myopia is unclear. OBJECTIVE To analyze the association between studying in different educational systems and the prevalence and severity of myopia among Jewish male adolescents in Israel. DESIGN, SETTING, AND PARTICIPANTS A nationwide, population-based study was conducted of 22 823 male candidates for military service in Israel aged 17 to 18 years attending the military draft board in 2013 who underwent a medical examination and a visual acuity assessment. Statistical analysis was performed from January 1 to March 31, 2018. EXPOSURES The participants studied in 1 of 3 Israeli educational systems: secular, Orthodox, or ultra-Orthodox. The ultra-Orthodox system and, to a lesser extent, the Orthodox system involve intensive reading starting in early childhood compared with the secular system. MAIN OUTCOMES AND MEASURES The odds ratio (OR) for the association between educational system and the prevalence and severity of myopia. RESULTS Among the 22 823 participants (mean [SD] age, 17.7 [0.6] years), there was a higher proportion of adolescents in the ultra-Orthodox educational system with myopia (1871 of 2276 [82.2%]) compared with adolescents in the Orthodox educational system (1604 of 3189 [50.3%]) and those in the secular educational system (5155 of 17 358 [29.7%]). Compared with adolescents in the secular educational system, those in the Orthodox educational system were more likely to have myopia (OR, 2.3; 95% CI, 2.1-2.5; P < .001), as were those in the ultra-Orthodox educational system (OR, 9.3; 95% CI, 8.2-10.7; P < .001), after adjustment for age, country of origin, socioeconomic status, years of education, and body mass index. The multivariable adjusted OR for high myopia (refractive error of at least −6.0 diopters) was 4.6 (95% CI, 3.8-5.5; P < .001) for adolescents in the Orthodox educational system and 38.5 (95% CI, 30.7-48.2; P < .001) for adolescents in the ultra-Orthodox educational system compared with adolescents in the secular educational system. CONCLUSIONS AND RELEVANCE This study provides evidence of the independent association between educational systems and the prevalence and severity of myopia. Male adolescents in the ultra-Orthodox educational system have higher odds of having myopia and high myopia. These findings suggest that study styles that involve intensive reading and other near-work activities (those done at a short working distance) play a role in the development of myopia and warrant consideration of prevention strategies.