A novel primary antibiotic cement-coated locking plate as a temporary fixation for the treatment of open tibial fracture.

Complex lower extremity trauma reconstruction remains a challenge. This study used an internal fixation composite structure of antibiotic cement plates as a temporary fixation to treat lower extremity Grade III open fractures; thus, reducing the treatment period and complications of external fixation. We aimed to assess the safety and efficacy of this technique in the initial surgery stage. Between January 2018 and March 2021, 20 patients with Gustilo grade IIIB/C open fractures received an antibiotic cement-coated locking plate as a temporary internal fixator during initial surgery. Thorough debridement and temporary internal fixation were performed with a 3.5-mm system antibiotic cement-coated locking plate. Ten patients required free bone fragment removal, followed by bone cement packing. The final stage involved internal fixation and wound repair with a free anterolateral thigh flap. Clinical and imaging results were retrospectively analysed. The repair time ranged 1-7 days. All flaps survived. Two patients experienced wound infection, and one developed severe bone infection 3 months after three-stage bone graft surgery. Autologous cancellous bone grafting was performed on 10 patients with bone defects 6 weeks after surgery. Bone union was universally achieved after 1 year. This method proved safe and effective, successfully repairing Grade III open fractures of the lower extremity 1-7 days post-treatment.

Estrogen deficiency impedes fracture healing despite eliminating the excessive absorption of the posterior callus in a semi-fixed distal tibial fracture mouse model.

BACKGROUND: Treatment of distal tibial fractures is a challenge due to their specific anatomical location. However, there is no appropriate mouse model to simulate a clinical distal tibial fracture for basic research. The aim of this investigation was to evaluate the feasibility of simulating a clinical fracture of the distal tibia of mice and to investigate the effect of ovariectomy (OVX)-induced osteoporosis on fracture healing in this model. METHODS: Sixty female 8-week-old C57BL/6 mice were randomly divided into two groups, either sham or OVX. A semi-fixation distal tibia fracture was established in the right tibia after 8 weeks of OVX. The right tibias were collected at 7, 14, 21, and 28 days post fracture. RESULTS: In the semi-fixation distal tibia fracture model, the posterior callus in the sham group showed excessive bone resorption and lower bone mass phenotype compared with the anterior site; a similar trend was not found in the OVX group. At 28 days post fracture, the posterior callus was more mineralized than the anterior callus in the OVX group. Although the fracture healing of the sham group showed a special phenotype in this mode, the progress and quality of fracture healing were still better than those of the OVX group. CONCLUSION: A semi-fixed distal tibial closed fracture mouse model was successfully established. In this model, excess bone resorption of the posterior callus impaired normal fracture healing, but not in OVX-induced osteoporotic bone. Although the stress shielding effect was not observed in the OVX group, impaired bone healing caused by OVX was still present. Our results suggest that this fracture model may have potential for studies on distal tibial fractures and stress shielding.

Antibiotic cement-coated rigid locked nails in infected femoral and tibial nonunion. Reoperation rates of commercial versus custom-made nails.

INTRODUCTION: The objective of this study is to assess bone union, infection control, and reoperation rates in a series of patients with infected femoral or tibial nonunion treated with antibiotic-cement-coated rigid nails and to compare the results obtained with custom-made nails versus commercial nails. METHODS: We retrospectively analyzed a series of consecutive patients with infected nonunion of the femur or the tibia treated with antibiotic-cement-coated rigid nails between January 2010 and 2020. We assessed patients' distinctive characteristics, initial injury, type of nail used (custom-made nail with vancomycin or commercial nail with gentamicin), success rate (bone union + infection control), reoperation rate, and failure rate. Comparative analyses were conducted between reoperated and non-reoperated patients regarding the type of nail used. A multivariate regression analysis was performed to assess the risk variables that impacted reoperation rates. RESULTS: We included 54 patients with 22 (40.74%) infected femoral nonunions and 32 (59.25%) tibial nonunions, who were treated with 38 (70.37%) custom-made antibiotic-cement coated nails and 16 (29.62%) commercial nails. Bone union and infection control were achieved in 51 (94.44%) cases. The reoperation rate was 40.74% (n = 22), and the failure rate was 5.55% (n = 3). The use of custom-made nails was associated with a higher risk of reoperation (Odds Ratio 4.71; 95% Confidence Interval 1.10 - 20.17; p = 0.036). CONCLUSION: Antibiotic-cement-coated nails reached a 94.44% success rate. Nails manufactured in the OR coated with vancomycin cement were associated with a higher risk of reoperation than commercial nails loaded with gentamicin cement. LEVEL OF EVIDENCE: III comparative, observational, non-randomized.

Irisin Modulates Inflammatory, Angiogenic, and Osteogenic Factors during Fracture Healing.

Bone fractures are a widespread clinical event due to accidental falls and trauma or bone fragility; they also occur in association with various diseases and are common with aging. In the search for new therapeutic strategies, a crucial link between irisin and bone fractures has recently emerged. To explore this issue, we subjected 8-week-old C57BL/6 male mice to tibial fracture, and then we treated them with intra-peritoneal injection of r-Irisin (100 µg/kg/weekly) or vehicle as control. At day 10 post fracture, histological analysis showed a significant reduced expression of inflammatory cytokines as tumor necrosis factor-alpha (TNFα) (p = 0.004) and macrophage inflammatory protein-alpha (MIP-1α) (p = 0.015) in the cartilaginous callus of irisin-treated mice compared to controls, supporting irisin's anti-inflammatory role. We also found increased expressions of the pro-angiogenic molecule vascular endothelial growth factor (VEGF) (p = 0.002) and the metalloproteinase MMP-13 (p = 0.0006) in the irisin-treated mice compared to the vehicle ones, suggesting a myokine involvement in angiogenesis and cartilage matrix degradation processes. Moreover, the bone morphogenetic protein (BMP2) expression was also upregulated (p = 0.002). Taken together, our findings suggest that irisin can contribute to fracture repair by reducing inflammation and promoting vessel invasion, matrix degradation, and bone formation, supporting its possible role as a novel molecule for fracture treatment.

Suplementación efectiva de vitamina D en pacientes con fractura tibial / Effective vitamin D supplementation in patients with tibial fracture

OBJETIVOS Determinar la prevalencia de déficit de vitamina D, así como evaluar la seguridad y efectividad de un nuevo método de carga con colecalciferol en pacientes adultos con fractura de tibia. MATERIALES Y MÉTODOS Se reclutaron a 56 pacientes consecutivos con edades entre 18 y 65 años con fractura de tibia ingresados en nuestro hospital durante 1 año. Se determinó el nivel de 25-hidroxivitamina D ([25(OH)-D]) al ingreso y tras suplementación con 100.000 UI semanales de colecalciferol, durante 3 o 5 semanas, en casos de insuficiencia ([25(OH)-D] entre 20 ng/mL y 29,9 ng/mL) o deficiencia ([25(OH)-D] < 20 ng/mL), respectivamente. Se determinó la prevalencia de hipovitaminosis D, el porcentaje de normalización de [25(OH)-D], y los efectos adversos. RESULTADOS Se evaluaron 56 pacientes; 98,2% presentó hipovitaminosis D, y 28 (73,7%) y 10 (26,3%) presentaron déficit e insuficiencia, respectivamente. Tras la suplementación, 92,1% alcanzaron niveles [25(OH)-D] normales. Ningún paciente presentó efectos adversos. DISCUSIÓN La prevalencia de deficiencia de vitamina D en nuestra población fue mayor a la reportada en la literatura. Comprobamos que un esquema de suplementación en altas dosis de vitamina D es seguro, y más efectivo que los previamente recomendados. Este esquema de suplementación puede ser implementado en futuros estudios randomizados. CONCLUSIÓN La prevalencia de hipovitaminosis D en pacientes adultos chilenos con fractura de tibia fue alta (98,2%). El esquema de suplementación con vitamina D propuesto fue efectivo y seguro.

OBJETIVOS Determinar la prevalencia de déficit de vitamina D, así como evaluar la seguridad y efectividad de un nuevo método de carga con colecalciferol en pacientes adultos con fractura de tibia. MATERIALES Y MÉTODOS Se reclutaron a 56 pacientes consecutivos con edades entre 18 y 65 años con fractura de tibia ingresados en nuestro hospital durante 1 año. Se determinó el nivel de 25-hidroxivitamina D ([25(OH)-D]) al ingreso y tras suplementación con 100.000 UI semanales de colecalciferol, durante 3 o 5 semanas, en casos de insuficiencia ([25(OH)-D] entre 20 ng/mL y 29,9 ng/mL) o deficiencia ([25(OH)-D] < 20 ng/mL), respectivamente. Se determinó la prevalencia de hipovitaminosis D, el porcentaje de normalización de [25(OH)-D], y los efectos adversos. RESULTADOS Se evaluaron 56 pacientes; 98,2% presentó hipovitaminosis D, y 28 (73,7%) y 10 (26,3%) presentaron déficit e insuficiencia, respectivamente. Tras la suplementación, 92,1% alcanzaron niveles [25(OH)-D] normales. Ningún paciente presentó efectos adversos. DISCUSIÓN La prevalencia de deficiencia de vitamina D en nuestra población fue mayor a la reportada en la literatura. Comprobamos que un esquema de suplementación en altas dosis de vitamina D es seguro, y más efectivo que los previamente recomendados. Este esquema de suplementación puede ser implementado en futuros estudios randomizados. CONCLUSIÓN La prevalencia de hipovitaminosis D en pacientes adultos chilenos con fractura de tibia fue alta (98,2%). El esquema de suplementación con vitamina D propuesto fue efectivo y seguro.

Deer antler extract promotes tibia fracture healing in mice by activating BMP-2/SMAD4 signaling pathway.

BACKGROUND: Deer antler is a traditional Chinese medicine with the function of tonifying kidney and strengthening bone, which is often used to treat orthopedic diseases. METHODS: Eight-week-old C57BL/6 mice were used as the fixation model of open tibial fracture with intramedullary nail. The mice were treated with deer antler extract (DAE) or PBS by oral gavage once daily. The tibial fracture samples were collected and performed to the tissue analysis, including X-ray, micro-CT, histology, qRT-PCR, immunohistochemistry. MC3T3-E1 cells were used to detect the effect of deer antler extract on ability of cell proliferation and migration by CCK-8 assay and cell scratch test. RESULTS: Imaging and micro-CT showed that DAE could promote the healing of tibial fracture in mice, and histological analysis showed that DAE could promote the transformation of cartilage callus to bone callus in fracture area. The results of qRT-PCR and immunohistochemistry showed that DAE could promote intrachondral ossification in fracture zone and the mechanism of promoting fracture healing may be related to the activation of BMP-2/SMAD4 signaling pathway. In the cytological experiment of DAE, it can be found that DAE promoted the proliferation of MC3T3-E1 cells and the migration of MC3T3-E1 cells at a certain concentration, which is also related to the promotion of fracture healing by DAE. CONCLUSION: DAE can promote fracture healing by activating BMP-2/SMAD4 signaling pathway. DAE has the potential to be used in clinic as an important means of promoting fracture healing.

Acute shortening and re-lengthening versus antibiotic calcium sulfate-loaded bone transport for the management of large segmental tibial defects after trauma.

BACKGROUND: The purpose of this paper was to compare the clinical effects of acute shortening and re-lengthening (ASR) technique with antibiotic calcium sulfate-loaded bone transport (ACSBT) technique for the management of large segmental tibial defects after trauma. METHODS: In this retrospective study, 68 patients with large segmental tibial defects were included and completely followed. The bone loss was 3-10 cm. ASR group included 32 patients, while ACSBT group contained 36. There was no significant difference in demographic information between the two groups. The external fixation time (EFT) and external fixation index (EFI) were compared. Bone defect healing and limb functions were evaluated according to the Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria. Complications were compared by Paley classification. RESULTS: The mean EFT was 9.2 ± 1.8 months in ASR group and 10.1 ± 2.0 months in ACSBT group, respectively. The mean EFI was 1.5 ± 0.2 month/cm and 1.4 ± 0.3 month/cm. According to the ASAMI criteria, in ASR group bone defect healing was excellent in 22 cases, good in 7 cases and fair in 3 cases. In ACSBT group, it was excellent in 23 cases, good in 11 cases and fair in 2 cases. In ASR group, the limb function was excellent in 15 cases, good in 7 cases and fair in 10 cases, while it was excellent in 14 cases, good in 9 cases and fair in 13 cases with ACSBT group. There was no significant difference in EFI, bone defect healing and limb functions between the two groups (p > 0.05). The mean number of complications per patient in ACSBT group was significantly lower than that in ASR group (p < 0.05). CONCLUSION: Both techniques can be successfully used for the management of large segmental tibial defects after trauma. There was no significant difference in EFI, limb functions and bone defect healing between the two groups. Compared with ASR group, the complication incidence in ACSBT group was lower, especially the infection-related complications. Therefore, for patients with large segmental bone defects caused by infection or osteomyelitis, ACSBT technique could be the first choice.

Proteasome inhibition-enhanced fracture repair is associated with increased mesenchymal progenitor cells in mice.

The ubiquitin/proteasome system controls the stability of Runx2 and JunB, proteins essential for differentiation of mesenchymal progenitor/stem cells (MPCs) to osteoblasts. Local administration of proteasome inhibitor enhances bone fracture healing by accelerating endochondral ossification. However, if a short-term administration of proteasome inhibitor enhances fracture repair and potential mechanisms involved have yet to be exploited. We hypothesize that injury activates the ubiquitin/proteasome system in callus, leading to elevated protein ubiquitination and degradation, decreased MPCs, and impaired fracture healing, which can be prevented by a short-term of proteasome inhibition. We used a tibial fracture model in Nestin-GFP reporter mice, in which a subgroup of MPCs are labeled by Nestin-GFP, to test our hypothesis. We found increased expression of ubiquitin E3 ligases and ubiquitinated proteins in callus tissues at the early phase of fracture repair. Proteasome inhibitor Bortezomib, given soon after fracture, enhanced fracture repair, which is accompanied by increased callus Nestin-GFP+ cells and their proliferation, and the expression of osteoblast-associated genes and Runx2 and JunB proteins. Thus, early treatment of fractures with Bortezomib could enhance the fracture repair by increasing the number and proliferation of MPCs.

Analgesic effects of a 5-HT3 receptor antagonist in an animal model of complex regional pain syndrome.

OBJECTIVE: Complex regional pain syndrome (CRPS) is caused by injuries from fracture after trauma and orthopaedic surgical procedures in the hind limbs. The symptoms of CRPS include warmth, pain, allodynia, and hyperalgesia. It is known that 5-hydroxytryptamine 3 (5-HT3) receptors contribute to hyperalgesia, but their role has not yet been fully elucidated. This study investigated the mechanism of pain relief when a 5-HT3 receptor antagonist was administered in a CRPS animal model. MATERIALS AND METHODS: To establish a CRPS animal model, 10-week-old Sprague-Dawley rats were used in the experiment. On the fourth week post tibial fracture surgery, we performed the von Frey test to measure mechanical allodynia. After performing behavioural tests, we collected blood and tissue samples after sacrificing the animals. Enzyme-linked immunosorbent assay and western blot were also performed. RESULTS: The experimental tibia fracture model-induced CRPS animals elicited increased 5-HT3 receptor expression, and the 5-HT transporter was decreased in the brain stem after 4 weeks of surgical intervention. Additionally, in CRPS-induced animals, both the concentration of substance P and the level of interleukin 6 were increased peripherally and centrally. Treatment with the 5-HT3 receptor antagonist, ramosetron, exerted an analgesic effect in the paw withdrawal test and was dependent on the attenuation of the 5-HT3 receptor population with inflammatory pain mediators. CONCLUSIONS: These data suggest that treatment with the 5-HT3 receptor antagonist, ramosetron, in experimental CRPS animal models alleviated pain-related behaviours and may be a new therapeutic option or potential therapeutic agent for patients with CRPS.

Intra-medullary antibiotics perfusion (iMAP) for the control of fracture-related infection early after osteosynthesis.

PURPOSE: In our hospital, cases of bone and soft tissue infections have been treated with continuous local antibiotics perfusion that allows for continuous circulation of antibiotics throughout the infected lesion. We termed this treatment "intramedullary antibiotics perfusion (iMAP)" for bone infection such as fracture-related infection (FRI) and "intrasoft tissue antibiotics perfusion" for soft tissue infection. Many cases are treated with both modalities. To introduce iMAP, this study focused on the patients with FRI treated with iMAP and reviewed their treatment outcomes. METHODS: We included 10 patients with FRI treated with iMAP between 2004 and 2017. The iMAP needles were inserted near the infected lesion, and an aminoglycoside antimicrobial was continuously administered. Patient characteristics, pathogenic bacteria, administered antibiotics, duration of administration, concentrations of antibiotics in blood and leachate fluid, fracture union rate, implant retention rate, and complications were studied. RESULTS: The mean age of patients was 59.9 years, and the mean follow-up period was 2.5 years. Affected bones were the tibia (n = 8), humerus (n = 1), and fibula (n = 1). Deep infections developed on average 29.9 days after osteosynthesis. Pathogenic bacteria were methicillin-susceptible Staphylococcus aureus (n = 6), methicillin-resistant S. aureus (n = 2), and unknown (n = 2). Average iMAP duration was 17.1 days. In all patients, infection was eradicated while preserving the implants, and fracture union was achieved without complications. CONCLUSION: iMAP is a novel local drug delivery system allowing high concentrations of antibiotics to be administered without complications and is useful in the treatment of FRI.

Effects of icariin on the fracture healing in young and old rats and its mechanism.

CONTEXT: Icariin has attracted increasing attention because of its wide variety of pharmacological effects. OBJECTIVE: This study investigates whether icariin could promote fracture healing in young and old rats and its mechanisms. MATERIALS AND METHODS: A Wistar rat model for the tibia fracture in relatively young and old rats, respectively, was established. The rats were divided into four groups: model group, L-icariin (50 mg/kg icariin), M-icariin (100 mg/kg icariin) and H-icariin (200 mg/kg icariin), and intragastric administration of icariin was performed for 10 days or 20 days. In addition, isolated and cultured rat bone mesenchymal stem cells (rBMSCs) from young and old rats were cultured with 5% and 20% of icariin-containing serum, respectively, then cell viability and alkaline phosphatase (ALP) activity were measured. RESULTS: Icariin administration induced the expression of Runx2, Osterix, BMP-2, p-Smad5 and osteocalcin secretion (young rats: model: 2.50 ± 0.71; L-icariin: 10.10 ± 1.55; M-icariin: 24.95 ± 2.19; H-icariin: 36.80 ± 2.26; old rats: model: 1.55 ± 0.49; L-icariin:6.55 ± 0.50; M-icariin: 15.00 ± 0.85; H-icariin:20.50 ± 2.27) at the fracture site, and increased the levels of bone formation markers (OC, BAP, NTX-1 and CTX-1) in a dose-dependent manner. In vitro, icariin treatment promoted rBMSC viability, increased ALP activity and the expression of BMP-2/Smad5/Runx2 pathway proteins. DISCUSSION AND CONCLUSIONS: Icariin may accelerate fracture healing by activating the BMP-2/Smad5/Runx2 pathway in relatively young and old rats. The research on the mechanism of icariin to promote fracture healing can provide a theoretical basis for the clinical application and promotion of icariin.

Antibiotic calcium sulfate-loaded hybrid transport versus traditional Ilizarov bone transport in the treatment of large tibial defects after trauma.

BACKGROUND: The purpose of this study was to compare the clinical effects of antibiotic calcium sulfate-loaded hybrid transport (ACSLHT) and traditional Ilizarov bone transport (TIBT) in the treatment of large tibial defects after trauma. METHODS: Eighty-five patients with large tibial defects after trauma were selected for retrospective study. The range of tibial defects was 6-22 cm. After thorough debridement and infection controlled, bone transport technique was used to reconstruct tibial defects. Forty-four patients were treated with ACSLHT technique (the ACSLHT group), while the other 41 were treated with TIBT technique (the TIBT group). Time in external fixator was evaluated by EFI score. Enneking score was used to evaluate limb functions. SAS score was used to evaluate postoperative anxiety status. In addition, complication incidence was compared, including axis deviation, docking site nonunion, infection recurrence and so on. RESULTS: There was no significant difference in preoperative general data between ACSLHT and TIBT group. EFI score in ACSLHT and TIBT group was 0.6 ± 0.1 cm/month and 1.7 ± 0.3 cm/month, respectively (P < 0.05). Enneking score of ACSLHT and TIBT group was 86.5% and 75.1% (P < 0.05). SAS score of ACSLHT group was significantly lower than that of TIBT group (P < 0.05). Complication incidence in ACSLHT group was significantly lower than that in TIBT group (P < 0.05). CONCLUSIONS: Compared with TIBT group, ACSLHT group had shorter time in external fixator, better limb functions, lower postoperative anxiety score and lower complication incidence which is worth of clinical promotion.

Type II collagen from squid cartilage mediated myogenic IGF-I and irisin to activate the Ihh/PThrp and Wnt/ß-catenin pathways to promote fracture healing in mice.

Fractures are the most common large-organ, traumatic injury in humans. The fracture healing stage includes the inflammatory stage (0-5d), cartilage callus stage (5-14d) and hard callus stage (14-21d). All mice underwent open tibial fracture surgery and were treated with saline, Glu or SCII for 21d. Calluses were harvested 5d, 10d and 21d after fracture. Compared with the model group, SCII significantly decreased TNF-α and increased aggrecan serum levels by 5d. H&E results showed that fibrous calluses were already formed in the SCII group and that chondrocytes had begun to proliferate. By 10d, the chondrocytes in the SCII group became hypertrophic and mineralized, and the serum TGF-ß and Col-Iα levels were significantly increased, which indicated that the mice with SCII treatment rapidly passed the cartilage repair period and new bone formation was accelerated. Skeletal muscle repaired bones through muscle paracrine factors. IGF-1 and irisin are the two major secretory cytokines. The results showed that the content of muscle homogenate IGF-1 in the SCII group reached the peak at 10d, followed by the up-regulation of Ihh, Patched, Gli1 and Col10α in the callus through the bone surface receptor IGF-1R. Besides, SCII also significantly elevated the muscle irisin level (10 and 21d), and then increased Wnt10b, LRP5, ß-catenin and Runx2 expression in the callus by receptor αVß5. These results suggest that SCII can accelerate the process of endochondral osteogenesis and promote fracture healing through activating the Ihh/PThrp and Wnt/ß-catenin pathways by regulating muscle paracrine factors. To our knowledge, this is the first study to investigate the effect of marine-derived collagen on fracture healing. This study may provide a theoretical basis for the high-value application of the laryngeal cartilage of squid in the future.

The effect of aqueous extract of Prunus dulcis on tibial bone healing in the rabbit.

BACKGROUND: Bone fractures are medical emergencies that require prompt intervention to help return bone to its normal function. Various methods and treatments have been utilized to increase the speed and efficiency of bone repair. This study aimed to investigate the treatment effects of Prunus dulcis aqueous extract on tibial bone healing in rabbits. METHODS: All animals were distributed in five groups with six rats in each group, including the sham group, the control group in which tibial lesion was made and received distilled water, treatment groups with 150 mg kg-1, 300 mg kg-1 doses of Prunus dulcis extract, and osteocare treated group. Biochemical blood factors including calcium, phosphorus, and alkaline phosphatase (on days 0, 10, 30, and 50), biomarkers of oxidative stress such as GPx, CAT, and MDA (on days 10 and 30), radiological evaluation, histopathological parameters, and osteocalcin immunohistochemical expression were assessed. RESULTS: The data showed calcium levels in the treatment groups increased significantly from day 10 to day 50, respectively, and blood phosphorus levels decreased from day 10 to day 50 in the treatment groups. Alkaline phosphatase initially increased and then decreased in treatment groups. In the treatment groups, GPx and CAT levels significantly increased, and the serum amount of MDA reduced. The best antioxidant results were related to the extract-treated group with a higher dose. Radiographic score was significantly higher in the treatment groups than the control group on day 30. Based on the pathological findings, the healing occurred faster in the extract-treated group with a higher dose. Osteocalcin expression was significantly higher in the control group than that in the treatment groups. CONCLUSIONS: Treatment with Prunus dulcis extract with a dosage of 300 mg/kg accelerated tibial bone healing in rabbits.

Comparison of the effectiveness and safety of intravenous and topical regimens of tranexamic acid in complex tibial plateau fracture: a retrospective study.

BACKGROUND: Previous studies have demonstrated the effectiveness and safety of tranexamic acid (TXA) in orthopedic surgery. However, no study has investigated TXA in complex tibial plateau fracture surgery. Therefore, the purpose of this study was to confirm the safety and effectiveness of i.v. (intravenous) TXA and topical TXA. MATERIAL AND METHODS: This was a retrospective analysis of prospectively collected data. The control group received an equal amount of placebo (physiological saline solution); the i.v. group received 1.0 g TXA by intravenous injection before the tourniquet was inflated and before the surgical incision was closed, and the topical group received 3.0 g TXA in 75 mL of physiological saline solution 5 min prior to the final tourniquet release. Perioperative blood loss, vascular events, wound complications, and adverse reactions were compared among the three groups. The pain, knee function, and quality of life (QoL) assessments were based on their corresponding scoring systems. RESULTS: Baseline data were comparable for all groups. The i.v. group showed the best results for total blood loss (TBL) and hidden blood loss (HBL) (424.5 ± 49.4 mL and 219.3 ± 33.4 mL, respectively, all P values < 0.001). Patients in the i.v. group had lesser real Hb decrease than those in the control group (0.9 vs 1.5, P<0.001) and topical group (0.9 vs 1.2, P = 0.026). The blood coagulation level as measured using fibrinolysis (D-dimer) was lower in the i.v. group than in the control and topical groups on POD1 and POD3; however, this difference was not significant; the fibrin-degradation products also showed a similar trend. Patients in the topical group experienced less pain than those in the control group on POD2, POD4, and PO6W. The VAS pain score was 3.6 vs. 4.4 (POD2, P<0.05), 2.8 vs 3.3 (POD4, P<0.05), and 2.1 vs. 2.6 (PO6W, P<0.001) in the topical group vs control group, respectively. No significant differences were identified in vascular events, wound complications, adverse reactions, knee function, and QoL among the three groups. CONCLUSION: To our knowledge, this is the first study that showed both i.v. TXA and topical TXA are safe and effective for complex tibial plateau fractures. The i.v. regimen effectively reduced blood loss during the perioperative period, whereas patients under the topical regimen had less vascular events, wound complications, and a lower incidence of adverse reactions compared to those in the i.v. group. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry ( ChiCTR-TRC-1800017754 , retrospectively registered from 2018 to 01-01).

Maresin 1 resolves aged-associated macrophage inflammation to improve bone regeneration.

Inflammaging is associated with poor tissue regeneration observed in advanced age. Specifically, protracted inflammation after acute injury has been associated with decreased bone fracture healing and increased rates of nonunion in elderly patients. Here, we investigated the efficacy of using Maresin 1 (MaR1), an omega-3 fatty acid-derived pro-resolving agent, to resolve inflammation after tibial fracture injury and subsequently improving aged bone healing. Aged (24-month-old mice) underwent tibial fracture surgery and were either treated with vehicle or MaR1 3 days after injury. Fracture calluses were harvested 7 days, 14 days, 21 days, and 28 days after injury to investigate inflammatory response, cartilage development, bone deposition, and mechanical integrity, respectively. Healing bones from MaR1-treated mice displayed decreased cartilage formation and increased bone deposition which resulted in increased structural stiffness and increased force to fracture in the later stages of repair. In the early stages, MaR1 treatment decreased the number of pro-inflammatory macrophages within the fracture callus and decreased the level of inflammatory biomarkers in circulation. In tissue culture models, MaR1 treatment of bone marrow-derived macrophages from aged mice protected cells form a pro-inflammatory phenotype and induced an anti-inflammatory fate. Furthermore, the secretome of MaR1-treated bone marrow-derived macrophages was identified as osteoinductive, enhancing osteoblast differentiation of bone marrow stromal cells. Our findings here identify resolution of inflammation, and MaR1 itself, to be a point of intervention to improve aged bone healing.

Retrospective analysis of risk factors for deep infection in lower limb Gustilo-Anderson type III fractures.

BACKGROUND: Open fractures are among the most severe injuries observed in orthopedic patients. Treating open fractures is difficult because such patients with infections may require multiple operations and amputations. Furthermore, only a few studies have focused on antibiotic prophylaxis in open fractures and evaluated how to cover lost soft tissue to increase the success rate of reconstruction. We evaluated the risk factors for deep infection in lower limb Gustilo-Anderson (G-A) type III fractures. MATERIALS AND METHODS: This retrospective study investigated patients who underwent surgical procedures for lower limb G-A type III fractures between January 2007 and January 2017 at our institution. We enrolled 110 patients with 114 lower limb G-A type III fractures (77 G-A type IIIA fractures and 37 G-A type IIIB fractures) who were followed up for at least 2 years. We compared patients presenting infections with those without infections by assessing the following factors: severe contamination, diabetes, smoking, Injury Severity Scale, segmental fracture, location of fracture, G-A classification, damage control surgery, methods of surgery, timing of fixation, combination of antibiotics used, duration of antibiotic prophylaxis, timing of wound closure, and soft-tissue reconstruction failure. RESULTS: Eighteen fractures presented deep infections. Compared with patients without infections, patients developing infections differed significantly in terms of severe contamination (P < 0.01), G-A classification (P < 0.01), duration of antibiotic prophylaxis (P < 0.01), timing of wound closure (P < 0.01), and incidence of soft-tissue reconstruction failure (P < 0.01). Skin grafting was associated with significantly higher failure rates than muscle and free flap reconstructions (P = 0.04). Treatment with antibiotics was significantly longer in patients with drug-resistant bacterial infections than in those without infections (P < 0.01). CONCLUSION: Early flaps rather than skin grafting should be used to cover G-A type IIIB fractures, because skin grafting resulted in the highest failure rate among soft-tissue reconstructions in open fractures. Longer duration of antibiotic use had a significant impact not only on deep infection rates but also on the presence of drug-resistant bacteria. These findings suggest that prolonged use of antibiotics should be avoided in cases of open fractures. LEVEL OF EVIDENCE: Level IV retrospective observational study.

The Adenosine A2A Receptor Agonist Accelerates Bone Healing and Adjusts Treg/Th17 Cell Balance through Interleukin 6.

The aim of this study was to explore the effect of adenosine A2A receptor agonists on fracture healing and the regulation of the immunity system after bone fracture. We implanted fibrin gel containing adenosine A2A receptor agonist CGS 21680/inhibitor ZM 241385/saline locally in rat tibial fracture models, finding that the adenosine A2A receptor agonist could promote fracture healing. At the same time, the adenosine A2A receptor agonist decreased the level of IL-6 in blood and the fracture area, increased Treg cells, and decreased Th17 cells in blood of bone fracture rats. Further, tibial fracture rats implanted with the adenosine A2A receptor agonist gel were injected with IL-6. We found that IL-6 could reverse the effect of adenosine A2A receptor agonists on fracture healing and Treg/Th17 cells in blood. Through the above results, we believe that the adenosine A2A receptor agonist can promote fracture healing and regulate Treg/Th17 cells in blood of rats with fractures. These effects are related to IL-6.

Efficacy of Momiai in Tibia Fracture Repair: A Randomized Double-Blinded Placebo-Controlled Clinical Trial.

Objectives: Momiai ( shilajit, mummy, mumie, or mineral pitch) has been used traditionally in different medical systems for the treatment of a variety of ailments since hundreds of years ago. It is a natural substance found in different rocky parts of the world, formed by plants, mineral, and animal remains gradually. There is also worthwhile evidence supporting its oral use for bone repair in Persian medicine. The aim of this study was to evaluate the efficacy and safety of momiai in tibia fracture healing. Design: This study is a randomized double-blinded controlled trial. Settings/Location: Three different hospitals in Tehran, Iran. Subjects: Patients with age range of 18-60 years admitted due to new tibia fracture were enrolled after meeting the inclusion criteria. Interventions: The patients were divided into two groups randomly and received two 500 mg capsules of momiai or placebo for 28 days. Outcome measures: The process of bone healing was assessed by frequent X-ray radiographies and adverse effects were recorded. Results: Totally, 160 patients participated in the study either in two equal intervention or placebo groups. There was no significant difference between groups in terms of demographic and descriptive data. At the end of the study, the mean time of tibial bone union was 129 days in the experimental group, while it was 153 days in the placebo group (p < 0.049). There was no significant difference in the reported adverse effects between the two groups (p = 0.839). Conclusions: The current study showed that oral consumption of momiai after tibial shaft fracture surgery could be a promising option to reduce the healing time.

Early Treatment With Metformin in a Mice Model of Complex Regional Pain Syndrome Reduces Pain and Edema.

BACKGROUND: Metformin, an adenosine monophosphate (AMP)-activated protein kinase activator, as well as a common drug for type 2 diabetes, has previously been shown to decrease mechanical allodynia in mice with neuropathic pain. The objective of this study is to determine if treatment with metformin during the first 3 weeks after fracture would produce a long-term decrease in mechanical allodynia and improve a complex behavioral task (burrowing) in a mouse tibia fracture model with signs of complex regional pain syndrome. METHODS: Mice were allocated into distal tibia fracture or nonfracture groups (n = 12 per group). The fracture was stabilized with intramedullary pinning and external casting for 21 days. Animals were then randomized into 4 groups (n = 6 per group): (1) fracture, metformin treated, (2) fracture, saline treated, (3) nonfracture, metformin treated, and (4) nonfracture, saline treated. Mice received daily intraperitoneal injections of metformin 200 mg/kg or saline between days 14 and 21. After cast removal, von Frey force withdrawal (every 3 days) and burrowing (every 7 days) were tested between 25 and 56 days. Paw width was measured for 14 days after cast removal. AMP-activated protein kinase downregulation at 4 weeks after tibia fracture in the dorsal root ganglia was examined by immunohistochemistry for changes in the AMP-activated protein kinase pathway. RESULTS: Metformin injections elevated von Frey thresholds (reduced mechanical allodynia) in complex regional pain syndrome mice versus saline-treated fracture mice between days 25 and 56 (difference of mean area under the curve, 42.5 g·d; 95% CI of the difference, 21.0-63.9; P < .001). Metformin also reversed burrowing deficits compared to saline-treated tibial fracture mice (difference of mean area under the curve, 546 g·d; 95% CI of the difference, 68-1024; P < .022). Paw width (edema) was reduced in metformin-treated fracture mice. After tibia fracture, AMP-activated protein kinase was downregulated in dorsal root ganglia neurons, and mechanistic target of rapamycin, ribosomal S6 protein, and eukaryotic initiation factor 2α were upregulated. CONCLUSIONS: The important finding of this study was that early treatment with metformin reduces mechanical allodynia in a complex regional pain syndrome model in mice. Our findings suggest that AMP-activated protein kinase activators may be a viable therapeutic target for the treatment of pain associated with complex regional pain syndrome.