VEGFA Promotes Skeletal Muscle Regeneration in Aging.

Aging is associated with loss of skeletal muscle regeneration. Differentially regulated vascular endothelial growth factor (VEGF)A with aging may partially underlies this loss of regenerative capacity. To assess the role of VEGFA in muscle regeneration, young (12-14 weeks old) and old C57BL/6 mice (24,25 months old) are subjected to cryoinjury in the tibialis anterior (TA) muscle to induce muscle regeneration. The average cross-sectional area (CSA) of regenerating myofibers is 33% smaller in old as compared to young (p < 0.01) mice, which correlates with a two-fold loss of muscle VEGFA protein levels (p = 0.02). The capillary density in the TA is similar between the two groups. Young VEGFlo mice, with a 50% decrease in systemic VEGFA activity, exhibit a two-fold reduction in the average regenerating fiber CSA following cryoinjury (p < 0.01) in comparison to littermate controls. ML228, a hypoxia signaling activator known to increase VEGFA levels, augments muscle VEGFA levels and increases average CSA of regenerating fibers in both old mice (25% increase, p < 0.01) and VEGFlo (20% increase, p < 0.01) mice, but not in young or littermate controls. These results suggest that VEGFA may be a therapeutic target in age-related muscle loss.

A Whole-Course-Repair System Based on Neurogenesis-Angiogenesis Crosstalk and Macrophage Reprogramming Promotes Diabetic Wound Healing.

Diabetic wound (DW) therapy is currently a big challenge in medicine and strategies to enhance neurogenesis and angiogenesis have appeared to be a promising direction. However, the current treatments have failed to coordinate neurogenesis and angiogenesis simultaneously, leading to an increased disability rate caused by DWs. Herein, a whole-course-repair system is introduced by a hydrogel to concurrently achieve a mutually supportive cycle of neurogenesis-angiogenesis under a favorable immune-microenvironment. This hydrogel can first be one-step packaged in a syringe for later in situ local injections to cover wounds long-termly for accelerated wound healing via the synergistic effect of magnesium ions (Mg2+ ) and engineered small extracellular vesicles (sEVs). The self-healing and bio-adhesive properties of the hydrogel make it an ideal physical barrier for DWs. At the inflammation stage, the formulation can recruit bone marrow-derived mesenchymal stem cells to the wound sites and stimulate them toward neurogenic differentiation, while providing a favorable immune microenvironment via macrophage reprogramming. At the proliferation stage of wound repair, robust angiogenesis occurs by the synergistic effect of the newly differentiated neural cells and the released Mg2+ , allowing a regenerative neurogenesis-angiogenesis cycle to take place at the wound site. This whole-course-repair system provides a novel platform for combined DW therapy.

Metformin alleviates bone loss in ovariectomized mice through inhibition of autophagy of osteoclast precursors mediated by E2F1.

BACKGROUND: Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague. RESULTS: In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression. CONCLUSION: In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss. Video abstract.

Lights, camera, scalpel: a lookback at 100 years of plastic surgery on the silver screen.

BACKGROUND: The presentation of medical topics in the cinema can greatly influence the public's understanding and perception of a medical field, with regard to the doctors and surgeons, medical diagnosis, and treatment and outcome expectations. This study aims to evaluate the representation of plastic surgery in commercial films that include a character with a link to plastic surgery, either as a patient or surgeon. METHODS: The international film databases Internet Movie Database (IMDb), The American Film Institute (AFI), and British Film Institute (BFI) were searched from 1919 to 2019 to identify feature-length films with a link to plastic surgery. Movies were visualized and analyzed to identify themes, and the portrayal of plastic surgery was rated negative or positive, and realistic or unrealistic. RESULTS: A total of 223 films were identified from 1919 to 2019, produced across 19 countries. Various genres were identified including drama (41), comedy (25), and crime (23). A total of 172 patient characters and 57 surgeon characters were identified as major roles, and a further 102 surgeons as minor roles. Disparities were noted in presentation of surgeons, both in terms of race and gender, with the vast majority of surgeons being white and male. In total only 11 female surgeons were portrayed and only one black surgeon. Thirteen themes emerged: face transplantation, crime, future society, surgeon mental status, body dysmorphic disorder, vanity, anti-aging, race, reconstructive surgery, deformity, scarring, burns, and gender transitioning. The majority of films (146/223) provide an unrealistic view of plastic surgery, painted under a negative light (80/146). Only 20 films provide a positive realistic image (24/77). CONCLUSIONS: There exists a complicated relationship between plastic surgery and its representation on film. Surgical and aesthetic interventions are portrayed unrealistically, with surgeons and patients presented negatively, perpetuating stigma, particularly with regard to cosmetic surgery. Cinema is also characterized by lack of representation of female and non-white surgeons. Recruitment of surgeons as technical advisors would help present a more realistic, representative view, without necessarily sacrificing creativity.Level of evidence: Not ratable.

Incised urethral diversion reduces the rate of fistula after one-stage hypospadias repair: a single-center retrospective controlled study.

OBJECTIVE: Urethrocutaneous fistula is the most prevalent complication after hypospadias repair. The aim of this study was to evaluate whether incised urethral diversion was superior to traditional transurethral diversion in minimizing complications. PATIENTS AND METHODS: We retrospectively collected and analyzed 113 cases with proximal penile or penoscrotal hypospadias that were repaired by one-stage transverse preputial island flap urethroplasty between January 2016 and January 2020. Of those cases, 60 used incised urethral diversion (group A), whereas the remaining 53 were managed by transurethral diversion (group B) for urinary drainage after surgery. Postoperative complications in both groups were assessed for fistula, urethral diverticulum, meatal stenosis, wound infection, and distal urethral breakdown. RESULTS: Fistula was reported in 2 patients (3.3%) in group A, while it was observed in 15 patients (28.3%) in group B (p < 0.001). Wound infection occurred in one patient (1.7%) in group A, compared with six patients (11.3%) in group B (p < 0.05). The incidence rates of distal urethral breakdown were 1.7% (1/60) and 11.3% (6/53) for group A and group B, respectively (p < 0.05). One patient (1.7%) in group A and three patients (5.7%) in group B had a meatal stenosis (p > 0.05). There were two patients who developed urethral diverticulum in either group (p > 0.05). CONCLUSIONS: The use of incised urethral diversion for urinary drainage had an advantage over transurethral diversion in one-stage hypospadias repair with respect to the post-operational fistula occurrence, wound infection, and distal urethral breakdown.

In Vivo Printing of Nanoenabled Scaffolds for the Treatment of Skeletal Muscle Injuries.

Extremity skeletal muscle injuries result in substantial disability. Current treatments fail to recoup muscle function, but properly designed and implemented tissue engineering and regenerative medicine techniques can overcome this challenge. In this study, a nanoengineered, growth factor-eluting bioink that utilizes Laponite nanoclay for the controlled release of vascular endothelial growth factor (VEGF) and a GelMA hydrogel for a supportive and adhesive scaffold that can be crosslinked in vivo is presented. The bioink is delivered with a partially automated handheld printer for the in vivo formation of an adhesive and 3D scaffold. The effect of the controlled delivery of VEGF alone or paired with adhesive, supportive, and fibrilar architecture has not been studied in volumetric muscle loss (VML) injuries. Upon direct in vivo printing, the constructs are adherent to skeletal muscle and sustained release of VEGF. The in vivo printing of muscle ink in a murine model of VML injury promotes functional muscle recovery, reduced fibrosis, and increased anabolic response compared to untreated mice. The in vivo construction of a therapeutic-eluting 3D scaffold paves the way for the immediate treatment of a variety of soft tissue traumas.

Miniaturized Needle Array-Mediated Drug Delivery Accelerates Wound Healing.

A major impediment preventing normal wound healing is insufficient vascularization, which causes hypoxia, poor metabolic support, and dysregulated physiological responses to injury. To combat this, the delivery of angiogenic factors, such as vascular endothelial growth factor (VEGF), has been shown to provide modest improvement in wound healing. Here, the importance of specialty delivery systems is explored in controlling wound bed drug distribution and consequently improving healing rate and quality. Two intradermal drug delivery systems, miniaturized needle arrays (MNAs) and liquid jet injectors (LJIs), are evaluated to compare effective VEGF delivery into the wound bed. The administered drug's penetration depth and distribution in tissue are significantly different between the two technologies. These systems' capability for efficient drug delivery is first confirmed in vitro and then assessed in vivo. While topical administration of VEGF shows limited effectiveness, intradermal delivery of VEGF in a diabetic murine model accelerates wound healing. To evaluate the translational feasibility of the strategy, the benefits of VEGF delivery using MNAs are assessed in a porcine model. The results demonstrate enhanced angiogenesis, reduced wound contraction, and increased regeneration. These findings show the importance of both therapeutics and delivery strategy in wound healing.

The Effect of Arm Position on Breast Volume Measurement Using Three-dimensional Imaging.

BACKGROUND: Three-dimensional (3D) imaging offers an objective and quantitative way to evaluate the breast volume. In this study, we aimed to investigate whether arm position can be a factor influencing the measurement of breast volume and which arm position is more stable when using 3D breast imaging in evaluating the fat volume retention rate in autologous fat grafting for breast augmentation. METHODS: Patients undergoing breast augmentation with autologous fat grafting in our department were selected for the first part of this study. Preoperative 3D breast imaging was performed at three different arm positions: at the sides, akimbo and with hands on the head. Scans on each arm position were repeated on the first day after surgery, taking six scans in total. Breast volume change (BVC) was compared before and after surgery. The patients planning to receive bilateral mammaplasty in our department were selected for the second part of this study. Two repeated 3D scans were performed at the sides, akimbo and hands on the head, and then, the breast volume change error (BVCE) was compared. RESULTS: Twenty-five patients (n = 50 breasts) were included in the first part of study. For the patients who received 100-200 ml fat injection, compared with hands on the head, a statistically significant difference in the average BVC was found at the sides and akimbo (p = 0.02). For the patients receiving more than 200 ml fat injection, there was no statistically significant difference between the groups (p > 0.05). Twenty-six patients (n = 52 breasts) were enrolled in the second part. For the average BVCE, there was no significant difference between the groups (p = 0.11). CONCLUSIONS: The arm position during 3D breast imaging, to some extent, affects the evaluation of BVC after breast augmentation using autologous fat grafting, particularly for patients receiving less fat grafting. The arm position should be kept consistent when using 3D breast imaging in evaluating the fat volume retention rate. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266.

LncRNA KCNQ1OT1 accelerates fracture healing via modulating miR-701-3p/FGFR3 axis.

Emerging evidence highlights the role of the long noncoding RNA (lncRNA) KCNQ1OT1 in fracture healing. Osteoblast proliferation, migration, and survival are pivotal during this process. In this study, we aimed to improve our understanding of the regulatory role of lncRNA KCNQ1OT1 during osteoblast proliferation, migration, and survival. We searched the gene expression omnibus databases and LncBase Experimental V.2 to identify key microRNAs (miRNAs) targets of KCNQ1OT1. MiR-701-3p was selected as a differentially expressed miRNA and RNA immunoprecipitation assays were performed to verify its interaction with KCNQ1OT1. Fibroblast growth factor receptor 3 (FGFR3) was also identified as a target of miR-701-3p. We further identified KCNQ1OT1 as a competing endogenous RNA of miR-701-3p that could influence osteoblast proliferation, migration, and apoptosis in vitro and in vivo. Taken together, our results indicate that the KCNQ1OT1/miR-701-3p/FGFR3 axis is an important regulator of osteoblast proliferation, migration, and apoptosis, and provide a new therapeutic avenue for fracture healing.

Circulating Exosomal miR-20b-5p Inhibition Restores Wnt9b Signaling and Reverses Diabetes-Associated Impaired Wound Healing.

At present, developing therapeutic strategies to improve wound healing in individuals with diabetes remains challenging. Exosomes represent a promising nanomaterial from which microRNAs (miRNAs) can be isolated. These miRNAs have the potential to exert therapeutic effects, and thus, determining the potential therapeutic contributions of specific miRNAs circulating in exosomes is of great importance. In the present study, circulating exosomal miRNAs are identified in diabetic patients and assessed for their roles in the context of diabetic wound healing. A significant upregulation of miR-20b-5p is observed in exosomes isolated from patients with type 2 diabetes mellitus (T2DM), and this miRNA is able to suppress human umbilical vein endothelial cell angiogenesis via regulation of Wnt9b/ß-catenin signaling. It is found that the application of either miR-20b-5p or diabetic exosomes to wound sites is sufficient to slow wound healing and angiogenesis. In diabetic mice, it is found that knocking out miR-20b-5p significantly enhances wound healing and promotes wound angiogenesis. Together, these findings thus provide strong evidence that miR-20b-5p is highly enriched in exosomes from patients with T2DM and can be transferred to cells of the vascular endothelium, where it targets Wnt9b signaling to negatively regulate cell functionality and angiogenesis.

A porous collagen-GAG scaffold promotes muscle regeneration following volumetric muscle loss injury.

Volumetric muscle loss (VML) is a segmental loss of skeletal muscle which commonly heals with fibrosis, minimal muscle regeneration, and loss of muscle strength. Treatment options for these wounds which promote functional recovery are currently lacking. This study was designed to investigate whether the collagen-GAG scaffold (CGS) promotes functional muscle recovery following VML. A total of 66 C57/Bl6 mice were used in a three-stage experiment. First, 24 animals were split into three groups which underwent sham injury or unilateral quadriceps VML injury with or without CGS implantation. Two weeks post-surgery, muscle was harvested for histological and gene expression analysis. In the second stage, 18 mice underwent bilateral quadriceps VML injury, followed by weekly functional testing using a treadmill. In the third stage, 24 mice underwent sham or bilateral quadriceps VML injury with or without CGS implantation, with tissue harvested six weeks post-surgery for histological and gene expression analysis. VML mice treated with CGS demonstrated increased remnant fiber hypertrophy versus both the VML with no CGS and uninjured groups. Both VML groups showed greater muscle fiber hypertrophy than non-injured muscle. This phenomenon was still evident in the longer-term experiment. The gene array indicated that the CGS promoted upregulation of factors involved in promoting wound healing and regeneration. In terms of functional improvement, the VML mice treated with CGS ran at higher maximum speeds than VML without CGS. A CGS was shown to enhance muscle hypertrophy in response to VML injury with a resultant improvement in functional performance. A gene array highlighted increased gene expression of multiple growth factors following CGS implantation. This suggests that implantation of a CGS could be a promising treatment for VML wounds.

CircRNA AFF4 promotes osteoblast cells proliferation and inhibits apoptosis via the Mir-7223-5p/PIK3R1 axis.

Fracture healing is a complex process involving various cell types, cytokines, and mRNAs. Here, we report the roles of the circRNA AFF4/miR-7223-5p/PIK3R1 axis during fracture healing. We found that increased expression of PIK3R1 during fracture healing is directly associated with augmented proliferation and decreased apoptosis of MC3T3-E1 cells. Furthermore, miR-7223-5p targeted PI3KR1 and inhibited MC3T3-E1 proliferation while promoting apoptosis. CircRNA AFF4 acted as a sponge of miR-7223-5p, thereby promoting MC3T3-E1 cell proliferation and inhibiting apoptosis. Local injection of circRNA AFF4 into femoral fracture sites promoted fracture healing in vivo while the injection of miR-7223-5p delayed healing. These findings suggest that CircRNA AFF4 promotes fracture healing by targeting the miR-7223-5p/PIK3R1 axis, and suggests miR-7223-5p, CircRNA AFF4, and the miR-7223-5p/PIK3R1 axis are potential therapeutic targets for improving fracture healing.

A comparative study of the efficacy of ultrasonics and extracorporeal shock wave in the treatment of tennis elbow: a meta-analysis of randomized controlled trials.

BACKGROUND: Tennis elbow or lateral epicondylitis is a common source of pain among craftsmen. Although it cannot be completely resolved, extracorporeal shock wave therapy (ESWT) and ultrasonics (US) have been found to be effective for tennis elbow as highlighted in previously published randomized controlled trials (RCTs) and reviews. However, the efficacy of these two therapies in treating tennis elbow is unknown. This meta-analysis compares the effectiveness of ESWT and US in relieving pain and restoring the functions of tennis elbow following tendinopathy. METHODS: RCTs published in the PubMed, Embase, Cochrane Library, and SpringerLink databases comparing ESWT and US in treating tennis elbow were identified by a software and manual search. The risk of bias and clinical relevance of the included studies were assessed. Publication bias was explored using funnel plot and statistical tests (Egger's test and Begg's test). The major outcomes of the studies were analyzed using the Review Manager 5.3. RESULTS: Five RCTs comprising five patients were included in the present meta-analysis. The results revealed a significantly lower VAS score of pain in the ESWT group (1 month: MD = 4.47, p = 0.0001; 3 months: MD = 20.32, p < 0.00001; and 6 months: MD = 4.32, p < 0.0001) compared to US. Besides, the grip strength was markedly higher 3 months after the intervention in ESWT (MD = 8.87, p < 0.00001) than in the US group. Although no significant difference was observed in the scores of the elbow function after 3 months of treatment (SMD = 1.51, p = 0.13), the subjective scores of elbow functions were found to be better in the ESWT group (SMD = 3.34; p = 0.0008) compared to the US group. CONCLUSIONS: Although there was no significant difference in the elbow function evaluation scores between ESWT and US, the superiority of the ESWT group in the VAS of pain (both at 1 month, 3 months, and 6 months follow-ups) raised grip strength in ESWT group and the scores for subjective evaluation of efficacy indicated that ESWT offers more effective therapy for lateral epicondylitis than US therapy.