An engineered periosteum for efficient delivery of rhBMP-2 and mesenchymal progenitor cells during bone regeneration.

During bone regeneration, the periosteum acts as a carrier for key regenerative cues, delivering osteochondroprogenitor cells and crucial growth factors to the injured bone. We developed a biocompatible, 3D polycaprolactone (PCL) melt electro-written membrane to act as a mimetic periosteum. Poly (ethyl acrylate) coating of the PCL membrane allowed functionalization, mediated by fibronectin and low dose recombinant human BMP-2 (rhBMP-2) (10-25 µg/ml), resulting in efficient, sustained osteoinduction in vitro. In vivo, rhBMP-2 functionalized mimetic periosteum demonstrated regenerative potential in the treatment of rat critical-size femoral defects with highly efficient healing and functional recovery (80%-93%). Mimetic periosteum has also proven to be efficient for cell delivery, as observed through the migration of transplanted periosteum-derived mesenchymal cells to the bone defect and their survival. Ultimately, mimetic periosteum demonstrated its ability to deliver key stem cells and morphogens to an injured site, exposing a therapeutic and translational potential in vivo when combined with unprecedentedly low rhBMP-2 doses.

Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice.

The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Uniportal video-assisted thoracoscopic lobectomy versus other video-assisted thoracoscopic lobectomy techniques: a randomized study.

OBJECTIVES: A prospective, randomized study was carried out on patients undergoing lung cancer surgery, with the aim of determining if uniportal video-assisted lobectomy has more favourable postoperative outcomes than other video-assisted thoracoscopic lobectomy techniques (Duke approach and Copenhagen approach). METHODS: Patients were randomly assigned to two groups; uniportal video-assisted lobectomy (Group A; n = 51) and other video-assisted thoracoscopic lobectomy techniques (Group B; n = 55). The primary outcome measures were: postoperative pain (analogue visual scale) and supplementary doses of analgesics (morphine, milligrams); the secondary outcome measures were: the delay in removing the paravertebral catheter and the chest drain, the duration of the postoperative hospital stay, postoperative complications and the operative or 30-day mortality. We assessed postoperative pain during the first 3 days to identify possible differences coinciding with paravertebral catheter removal and with the start of mobilization, and we evaluated the type of resection, R0/R1 (a very important factor in assessing postoperative pain). All continuous data were evaluated for normality, and analysed with the Mann-Whitney U-tests or t-tests. Categorical data were analysed by Fisher's exact test. RESULTS: One hundred and six lobectomies were completed. Both groups were comparable with respect to different clinical parameters (age, clinical stage and comorbidity), preoperative and pathological variables. The median visual analogue pain score in the first 3 days did not show statistically significant differences (respectively, P = 0.58, P = 0.64, P = 0.85). Likewise, the median morphine use in the first 3 days did not show statistically significant differences (respectively, P = 0.72, P = 0.81, P = 0.64). There was no difference in timing to remove the paravertebral catheter (P = 0.82) and the chest drain (P = 0.65) and the duration of the postoperative hospital stay (P = 0.62). There was no difference in postoperative complications (one reoperation for bleeding in Group B, P = 0.24). There was no operative or 30-day mortality in either group. CONCLUSIONS: Uniportal video-assisted thoracoscopic lobectomy does not present better postoperative outcomes than other video-assisted thoracoscopic lobectomy techniques.

Risk of postoperative complications in chronic obstructive lung diseases patients considered fit for lung cancer surgery: beyond oxygen consumption.

OBJECTIVES: Patients with poor lung function usually undergo cardiopulmonary exercise testing (CPET) and those with a predicted postoperative maximal oxygen consumption (VO2 max) of >10 ml/kg/min undergo lung resection surgery and still some complications are observed. We aimed to determine other parameters beyond VO2 able to predict postoperative complications in patients undergoing lung resection surgery. METHODS: This is an observational study with longitudinal follow-up. Patients with forced expiratory volume in 1 second (FEV1) or diffusing capacity for carbon monoxide of <40% underwent CPET and those with VO2 max of >10 ml/kg/min were considered fit for surgery. Patients were followed up prospectively for 12 months and postoperative complications and survival were recorded. Physiological parameters obtained during CPET and pulmonary function tests were analysed. RESULTS: Eighty-three chronic obstructive pulmonary disease (COPD) patients were evaluated for surgery between 2010 and 2015. Twenty-four patients were considered unfit for surgery and received an alternative therapy. Fifty-five patients had a VO2 max of >10 ml/kg/min and underwent lung surgery. Among them, 4% died and 41% developed complications postoperatively. Baseline minute ventilation to carbon dioxide output (VE/VCO2) slope was significantly higher among those who developed postoperative complications or died (P = 0.047). Furthermore, VE/VCO2 slope of >35 (at maximal exercise) was the single parameter most strongly associated with the probability of mortality and postoperative complications (hazard ratio 5.14) with a survival probability of 40% after 1 year of follow-up. In a multivariable model, VO2, VE/VCO2 slope of >35 and work load were independently associated with the probability of having an event. CONCLUSIONS: VO2 is not the unique parameter to consider when CPET is performed to evaluate the postoperative risk of lung cancer surgery in COPD patients. The signs of ventilatory inefficiency such as VE/VCO2 slope predict complications better than VO2 does.