Rationale: Chronic nonhealing diabetic wound therapy and complete skin regeneration remains a critical clinical challenge. The controlled release of bioactive factors from a multifunctional hydrogel was a promising strategy to repair chronic wounds. Methods: Herein, for the first time, we developed an injectable, self-healing and antibacterial polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived mesenchymal stem cells exosomes (AMSCs-exo) release for synergistically enhancing chronic wound healing and complete skin regeneration. The materials characterization, antibacterial activity, stimulated cellular behavior and in vivo full-thickness diabetic wound healing ability of the hydrogels were performed and analyzed. Results: The FHE hydrogel possessed multifunctional properties including fast self-healing process, shear-thinning injectable ability, efficient antibacterial activity, and long term pH-responsive bioactive exosomes release behavior. In vitro , the FHE@exosomes (FHE@exo) hydrogel significantly promoted the proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs). In vivo , the FHE@exo hydrogel significantly enhanced the healing efficiency of diabetic full-thickness cutaneous wounds, characterized with enhanced wound closure rates, fast angiogenesis, re-epithelization and collagen deposition within the wound site. Moreover, the FHE@exo hydrogel displayed better healing outcomes than those of exosomes or FHE hydrogel alone, suggesting that the sustained release of exosomes and FHE hydrogel can synergistically facilitate diabetic wound healing. Skin appendages and less scar tissue also appeared in FHE@exo hydrogel treated wounds, indicating its potent ability to achieve complete skin regeneration. Conclusion: This work offers a new approach for repairing chronic wounds completely through a multifunctional hydrogel with controlled exosomes release.

Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD.

Studies revealed that navigation systems that provided intraoperative assistance might improve pedicle screw insertion accuracy, and also implied that different systems provided different pedicle screw insertion accuracy. A systematic review and meta-analysis was conducted to focus on the pedicle screw insertion accuracy with or without the assistance of image-guided system, and the variance among the different navigation systems. Comparative studies were searched on pedicle screw insertion accuracy between conventional and navigated method, and among different navigation systems. A total of 43 papers, including 28 clinical, 14 cadaveric and 1 model studies, were included in the current study. For clinical articles, there were 3 randomized clinical trials, 4 prospective comparative studies and 21 retrospective comparative studies. The incidence of pedicle violation among computer tomography-based navigation method group was statistically significantly less than that observed among the conventional group (OR 95% CI, in vivo: 0.32-0.60; in vitro: 0.24-0.75 P \ 0.01). Two-dimensional fluoroscopybased navigation system (OR 95% CI, in vivo: 0.27-0.48; in vitro: 0.43-0.88 P \ 0.01) and three-dimension fluoroscopy-based navigation system (OR 95% CI, in vivo: 0.09-0.38; in vitro: 0.09-0.36 P \ 0.01) also obtained significant reduced screw deviation rate over traditional methods. Between navigated approaches, statistically insignificant individual and pooled RR values were observed for all in vivo subgroups. Pooled estimate of in vitro studies show that computer tomography-based and three-dimension fluoroscopy-based navigation system provided more accurate pedicle screw insertion over two-dimension fluoroscopy-based navigation system. Our review showed that navigation provided a higher accuracy in the placement of pedicle screws compared with conventional methods. The superiority of navigation systems was obvious when they were applied to abnormal spinal structure. Although no strong in vivo evidence has detected significantly different pedicle screw placement accuracy among the three major navigation systems, meta-analysis revealed the variance in pedicle screw insertion accuracy with different navigation methods.

This research was aimed to study the mechanisms by which diabetes aggravates intervertebral disc degeneration (IDD) and to discuss the relationship between autophagy and IDD in nucleus pulposus (NP) cells. Sixteen weeks after injecting streptozotocin (STZ), the intervertebral discs (IVDs) were studied by histology, Alcian blue, 1,9-dimethylmethylene blue (DMMB), immunohistochemistry, and RT-PCR to explore the IDD. The apoptosis and senescence of NP cells was investigated by terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot for caspase3, caspase8, caspase9, and p16lnk4A (increased in cellular senescence). The level of autophagy in NP cells was detected by Western blot, immunohistochemistry, and transmission electron microscopy (TEM). The proteoglycan and collagen II in the extracellular matrix and the aggrecan and collagen II mRNA expression in NP cells of diabetic rats were decreased compared with the control group. Diabetes increased apoptosis of NP cells and led to activations of initiators of intrinsic (caspases-9) and extrinsic (caspase-8) pathways as well as their common executioner (caspase-3). Cellular senescence was increased about twofold in NP of diabetic rats. In addition, the Western blot, immunohistochemistry, and TEM demonstrated higher level of autophagy in NP cells of diabetic rats than control rats to a statistically significant extent. These findings support that diabetes induced by STZ can cause IDD by accelerating the apoptosis and senescence of NP cells excluding the overweight influence. And the results suggest that the autophagy may be a response mechanism to the change of NP cells in diabetic rats. ß

Improved pedicle screw insertion accuracy has been reported with the assistance of computer tomography-based navigation. Studies also indicated that fluoroscopy-based navigation offers high accuracy and is comparable to CT-based assistance. However, different population characteristics and assessment methods resulted in inconsistent conclusions. We searched OVID, Springer, and MEDLINE databases to conduct a meta-analysis of the published literature specifically looking at accuracy of pedicle screw placement with different navigation methods. Subgroups and descriptive statistics were determined based on the subject type (in vivo or cadaveric), navigational method, and spinal level. A total number of 7,533 pedicle screws were summarised in our database with 6,721 screws accurately inserted into the pedicles (89.22%). Overall, the median placement accuracy for the in vivo CT-based navigation subgroup (90.76%) was higher than that with the use of two-dimensional (2D) fluoroscopy-based navigation (85.48%). We concluded that CT-based navigation could provide a higher accuracy in the placement of pedicle screws for all subgroups presented. In the lumbar level, 2D fluoroscopy-based navigation was comparable with CT-based navigation. Discrepancy between the two navigation types increased in the thoracic level for the in vivo populations, where there was less potential in the use of 2D fluoroscopy-based navigation than CT-based navigation.