No abstract

The utilization of growth factors for bone regeneration is a widely studied field. Since the approval of bone morphogenetic protein-2 (BMP-2) for therapeutic use in humans, the concept of utilizing growth factors for bone regeneration in translational medicine has become even more attractive. Despite many studies published on individual growth factors in various bone models, comparative analysis is largely lacking. The aim of our study was to compare three different proosteogenic factors under identical in vivo conditions. Thus, we tested the bone regeneration capacity of the three different growth factors BMP-2, fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor A (VEGFA) in a calvarial defect model. We demonstrated that BMP-2 and VEGFA had similar bone healing capacities, resulting in complete calvarial healing as early as week 3. FGF-2 also showed a significantly higher bone regeneration capacity; however, the healing rate was lower than with BMP-2 and VEGFA. Interestingly, these findings were paralleled by an increased angiogenic response upon healing in BMP-2-and VEGFA-treated calvarial defects as compared with FGF-2. Immunohistochemistry for proliferating and osteoprogenitor cells revealed activity at different points after surgery among the groups. In conclusion, we demonstrated an efficient bone regeneration capacity of both BMP-2 and VEGFA, which was superior to FGF-2. Moreover, this study highlights the efficient bone regeneration of VEGFA, which was comparable with BMP-2. These data provide a valuable comparative analysis, which can be used to further optimize growth factor-based strategies in skeletal tissue engineering.

The aim of the study was to compare the early results in 52 patients randomly allocated to undergo either stapled or open hemorrhoidectomy. Seventy‐four patients with grade III and IV hemorrhoids were randomly allocated to undergo either stapled (37 patients) or open (37 patients) hemorrhoidectomy. Stapled hemorrhoidectomy was performed with the use of a circular stapling device. Open hemorrhoidectomy was accomplished according to the Milligan‐Morgan technique. Postoperative pain was assessed by means of a visual analogue scale (V.A.S.). Recovery evaluation included return to pain‐free defecation and normal activities. A 6‐month clinical follow‐up and a 17.5 (10 to 27)‐month median telephone follow‐up was obtained in all patients. Operation time for stapled hemorrhoidectomy was shorter (median 25 [range 15 to 49] minutes versus 30 [range 20 to 44] minutes, p = 0.041). Median (range) V.A.S. scores in the stapled group were significantly lower (V.A.S. score after 4 hours: 4 [2 to 6] versus 5 [2 to 8], p = 0.001; V.A.S. score after 24 hours: 3 [1 to 6] versus 5 [3 to 7], p = 0.000; V.A.S. score after first defecation: 5 [3 to 8] versus 7 [3 to 9], p = 0.000). Resumption of pain‐free defecation was significantly faster in the stapled group (10 [6 to 14] days vs 12 [9 to 19] days, p = 0.001). At follow‐up 4 weeks and 6 months postoperatively the median (range) symptom severity score was similar in both groups (1 [0 to 2] versus 0 [0 to 3], p = 0.150 and 0 [0 to 2] versus 0 [0 to 2], p = 0.731). At long‐term follow‐up occasional pain was present in 6/37 (16.2) patients in the stapled group and 7/37 (18.9%) in the Milligan‐Morgan group (p = 1.000); episodes of bleeding were reported by 8/37 (21.6%) patients in the stapled group and 5/37 (13.5%) patients in the Milligan‐Morgan group (p = 0.542). No problems related to continence and defecation were reported in either group. Patients were satisfied with the operation in 33/37 (89.2%) cases in the stapled group and 31/37 (83.8%) cases in the Milligan‐Morgan group (p = 0.735). Hemorrhoidectomy with a circular staple device is easy to perform and achieves better results than the Milligan‐Morgan technique in terms of postoperative pain and recovery. Comparable results are obtained at long‐term follow‐up.

The expertise of dedicated centers had a positive impact on the outcome of patients with ACC, resulting in a lower recurrence rate and improved mean time to recurrence. The improved patient outcome could be related not only to the appropriateness of the surgical procedure, but also to a more adequate multidisciplinary approach.

Mesenchymal stem cells (MSCs) show promise for cellular therapy and regenerative medicine. Human adipose tissue-derived stem cells (hASCs) represent an attractive source of seed cells in bone regeneration. How to effectively improve osteogenic differentiation of hASCs in the bone tissue engineering has become a very important question with profound translational implications. Numerous regulatory pathways dominate osteogenic differentiation of hASCs involving transcriptional factors and signaling molecules. However, how these factors combine with each other to regulate hASCs osteogenic differentiation still remains to be illustrated. The highly conserved developmental proteins TWIST play key roles for transcriptional regulation in mesenchymal cell lineages. This study investigates TWIST1 function in hASCs osteogenesis. Our results show that TWIST1 shRNA silencing increased the osteogenic potential of hASCs in vitro and their skeletal regenerative ability when applied in vivo. We demonstrate that the increased osteogenic capacity observed with TWIST1 knockdown in hASCs is mediated through endogenous activation of BMP and ERK/FGF signaling leading, in turn, to upregulation of TAZ, a transcriptional modulator of MSCs differentiation along the osteoblast lineage. Inhibition either of BMP or ERK/FGF signaling suppressed TAZ upregulation and the enhanced osteogenesis in shTWIST1 hASCs. Cosilencing of both TWIST1 and TAZ abrogated the effect elicited by TWIST1 knockdown thus, identifying TAZ as a downstream mediator through which TWIST1 knockdown enhanced osteogenic differentiation in hASCs. Our functional study contributes to a better knowledge of molecular mechanisms governing the osteogenic ability of hASCs, and highlights TWIST1 as a potential target to facilitate in vivo bone healing.