Bone morphogenetic protein-2 (BMP-2) is a novel differentiation factor that is capable of inducing osteoblast differentiation and bone formation, making it an attractive option in treatment of bone defects, fractures, and spine fusions. Inflammation, which was a common situation during bone healing, is recognized to inhibit osteogenic differentiation and bone formation. However, the effect of inflammation on BMP-2-induced osteoblastic differentiation remains ambiguous. In this study, we showed that an inflammatory environment triggered by lipopolysaccharide (LPS) in vitro would suppress BMP-2-induced osteogenic differentiation of bone marrow mesenchymal stem cells, which represented by decreased alkaline phosphatase (ALPase) activity and down-regulated osteogenic genes. In addition, LPS activated nuclear factor-κB (NF-κB) via a TLR4/MyD88-dependent manner and inhibited BMP-2-induced phosphorylation and nuclear translocation of Smad1/5/8. The blocking of NF-κB signaling by pretreatment with specific inhibitors such as BAY-11-7082, TPCK and PDTC, or by transfection with plasmids encoding p65 siRNA or IκBα siRNA could significantly reverse the inhibitory effect of LPS on BMP-2-induced BMP/Smad signaling and osteogenic differentiation. By contrast, even without stimulation of LPS, overexpression of p65 gene showed obvious inhibitory effects on BMP-2-induced BMP/Smad signaling and ALPase activity. These data indicate that the LPS-mediated inflammatory environment inhibits BMP-2-induced osteogenic differentiation, and that the crosstalk between TLR4/MyD88/NF-κB and BMP/Smad signaling negatively modulates the osteoinductive capacity of BMP-2.

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Large bone defect treatment represents a great challenge due to the difficulty of functional and esthetic reconstruction. Tissue-engineered bone grafts created by in vitro manipulation of bioscaffolds, seed cells, and growth factors have been considered potential treatments for bone defect reconstruction. However, a significant gap remains between experimental successes and clinical translation. An emerging strategy for bridging this gap is using the in vivo bioreactor principle and flap prefabrication techniques. This principle focuses on using the body as a bioreactor to cultivate the traditional triad (bioscaffolds, seed cells, and growth factors) and leveraging the body's self-regenerative capacity to regenerate new tissue. Additionally, flap prefabrication techniques allow the regenerated bone grafts to be transferred as prefabricated bone flaps for bone defect reconstruction. Such a strategy has been used successfully for reconstructing critical-sized bone defects in animal models and humans. Here, we highlight this concept and provide some perspective on how to translate current knowledge into clinical practice.

Background: Postoperative hypertrophic scarring of the medial canthal area is a common phenomenon and deterrent for patients considering epicanthoplasty. Botulinum toxin type A has been reported for hypertrophic scar and keloid treatment. However, there is a lack of high-level evidence regarding the effects of botulinum toxin type A in the medial canthal area. Methods: In this split-face, double-blind, randomized trial, 43 consecutive consenting patients undergoing Park Z-epicanthoplasty were randomized to receive 5 U of botulinum toxin type A or the same volume of saline injections at days 6 to 7 postoperatively. Scars were assessed independently using the Vancouver Scar Scale, the visual analogue scale, and patient satisfaction rating at the 1-, 3-, and 6-month follow-ups. Results: Overall, 30 patients completed this trial. The botulinum toxin type A–treated side achieved significantly improved Vancouver Scar Scale scores. The most obvious improvements were observed at the 3-month follow-up visit. Among the four subscores of the Vancouver Scar Scale, the most significantly improved subscores were the height and pliability. The visual analogue scale scores also decreased significantly on the botulinum toxin type A–treated side at all three follow-up visits. Approximately 86.7 percent of the patients were satisfied with the scar and epicanthoplasty outcomes. No severe complications were reported. Conclusions: Early postoperative botulinum toxin type A injection in the medial canthal region efficiently reduces hypertrophic scarring and improves the outcome of epicanthoplasty. Therefore, botulinum toxin type A injection can be used as a routine method to prevent hypertrophic scarring and improve the outcome of epicanthoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used in the clinic for bone defect reconstruction because of its powerful osteoinductive capacity. However, commercially available rhBMP-2 requires a high concentration in the clinical setting for consistent bone formation. A high dose of rhBMP-2 induces a promising bone formation yield but also leads to inflammation-related events, deteriorated bone quality, and fatty tissue formation. We hypothesize that the seemingly contradictory phenomenon of coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids may be associated with interleukin-6 (IL-6), which is significantly elevated after application of rhBMP-2/absorbable collagen sponge (rhBMP-2/ACS). Here, we show that IL-6 injection enhances new bone regeneration and induces excessive adipose tissue formation in an rhBMP-2/ACS-induced ectopic bone formation model in rats. In vitro data further show that IL-6 and its soluble receptor sIL-6R synergistically augment rhBMP-2-induced osteogenic and adipogenic differentiation of human BMSCs (hBMSCs) by promoting cell surface translocation of BMPR1A and then amplifying BMPR1A-mediated BMP/Smad and p38 MAPK pathways, respectively. Our study suggests elevated IL-6 may be responsible for coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids.

BackgroundLow satisfaction rates and severe complications are two major limitations for temporal hollowing augmentation using autologous fat grafting. Despite fat compartments in temporal region have been reported, its clinical applied anatomy for fat grafting have not been the subject of studies that show its benefits objectively and statistically.ObjectivesTo investigate temporal fat compartments and relative neurovascular structures in cadavers, developing a safe and effective fat grafting technique for temporal hollowing augmentation.MethodsThe study was conducted on 8 cadavers (16 temples). The tissue layers, fat compartments, ligaments, and neurovascular structures in the temporal region were analysed. The variables were the number and location of sentinel veins, perforator vessels of the middle temporal vein. Measurements were taken with a digital calliper.ResultsTwo separate fat compartments, the lateral temporal-cheek fat compartment and lateral orbital fat compartment, were found in the subcutaneous layer, and two separate septum compartments, the upper and lower temporal compartment, were found in the loose areolar tissue layer. One sentinel vein and 1 to 6 perforator vessels were found to travel through the subcutaneous tissue layer, traverse the overlapping tissue layers in the lower temporal septum region, and finally join in the middle temporal vein.ConclusionsThe four fat compartments in the temporal region are ideal receipt sites for fat grafting. The medial border of the junction of the hairline and temporal line is a safe and effective cannula entry site for temporal fat grafting. The anterior half of the lower temporal compartment is a “zone of caution” for temporal fat grafting.

Traditional bone tissue engineering (BTE) strategies induce direct bone-like matrix formation by mimicking the embryological process of intramembranous ossification. However, the clinical translation of these clinical strategies for bone repair is hampered by limited vascularization and poor bone regeneration after implantation in vivo. An alternative strategy for overcoming these drawbacks is engineering cartilaginous constructs by recapitulating the embryonic processes of endochondral ossification (ECO); these constructs have shown a unique ability to survive under hypoxic conditions as well as induce neovascularization and ossification. Such developmentally engineered constructs can act as transient biomimetic templates to facilitate bone regeneration in critical-sized defects. This review introduces the concept and mechanism of developmental BTE, explores the routes of endochondral bone graft engineering, highlights the current state of the art in large bone defect reconstruction via ECO-based strategies, and offers perspectives on the challenges and future directions of translating current knowledge from the bench to the bedside.

These data indicate that an exaggerated inflammatory environment may decrease BMP-2/ACS-induced bone mass in vivo by suppressing BMP-2-induced osteoblastic differentiation and by increasing the number or activity of osteoclasts. The negative role of exaggerated inflammation deserves consideration for future clinical use of BMP-2 in inducing bone regeneration.