[The wrapping induced membrane technique for treating recalcitrant non unions]. / La technique de la membrane induite « engainante ¼ pour le traitement des pseudarthroses rebelles sans perte de substance osseuse et le renforcement des reconstructions osseuses segmentaires fragiles. Rapport préliminaire.

The induced membrane technique is now well accepted for reconstruction of segmental bone defect. On the other hand, some cases of aseptic non-union are unsuccessfully treated by several surgical attempts for obtaining bone healing. The two stages wrapping induced membrane technique was developed initially for treating atrophic and recalcitrant aseptic non union without bone loss. At the first stage, the site of non-union was firmly fixed and tiles of cement were placed close to the bone on two or three aspects of the bone. At the second stage, after removing the spacers, the induced cavities were filled with cancellous bone autograft. In the two reported cases bone healing was acquired in 4 months. One case was a recalcitrant atrophic non-union of the humeral shaft, the other case concerned the enhancement of an insufficient segmental reconstruction of the femur. The follow up were respectively 3 years and 2 years without complication. The membrane induced by the cement tiles prevents the bone graft resorption and improves the osteogenicity through its biological properties.

Inflammatory processes and elevated osteoclast activity chaperon atrophic non-union establishment in a murine model.

BACKGROUND: Delayed bone healing, especially in long bones poses one of the biggest problems in orthopeadic and reconstructive surgery and causes tremendous costs every year. There is a need for exploring the causes in order to find an adequate therapy. Earlier investigations of human scaphoid non-union revealed an elevated osteoclast activity, accompanied by upregulated levels of TGF-beta and RANKL. Interestingly, scaphoid non-union seemed to be well vascularized. METHODS: In the current study, we used a murine femur-defect model to study atrophic non unions over a time-course of 10 weeks. Different time points were chosen, to gather insights into the dynamic processes of non-union establishment. RESULTS: Histological analyses as well as western blots and qRT-PCR indicated enhanced osteoclast activity throughout the observation period, paralleled by elevated levels of TGF-beta, TNF-alpha, MMP9, MMP13 and RANKL, especially during the early phases of non-union establishment. Interestingly, elevated levels of these mediators decreased markedly over a period of 10 weeks, as inflammatory reaction during non-union establishment seemed to wear out. To our surprise, osteoblastogenesis seemed to be unaffected during early stages of non-union establishment. CONCLUSION: Taken together, we gained first insights into the establishment process of atrophic non unions, in which inflammatory processes accompanied by highly elevated osteoclast activity seem to play a leading role.

Percutaneous injection of platelet-rich plasma to treat atrophic nonunion after internal fixation of ulnar fracture: a case report.

Non-union is a serious postoperative complication of fracture. Early detection and intervention can avoid revision surgery. Platelet-rich plasma releases many active tissue factors and has potential to promote fracture healing. Percutaneous injection of platelet-rich plasma at the fracture site may avoid surgical treatment when non-union occurs. We present a case of atrophic non-union of an ulna fracture treated conservatively with percutaneous injection of platelet-rich plasma.

Development of a novel atrophic non-union model in rabbits: A preliminary study.

BACKGROUND AND AIM: The currently available atrophic non-union models rely on wide segmental excision of bone diaphysis to impede the process of healing but lack resemblance to the clinical scenario. The present study focused on developing an in vivo model of atrophic non-union fracture in rabbit radius that can replicate the clinical scenario. MATERIALS AND METHODS: The atrophic non-union fracture model was developed by creating a 10 mm segmental bone defect in the radial diaphysis of five adult New Zealand White rabbits. The periosteum (2 mm) of the cut bone ends was cauterized using electrocautery to induce atrophy. Atrophic non-union was confirmed using radiographic and histologic evaluations on 30th postoperative day. RESULTS: The radiographic signs of healing were completely absent in all the rabbits on 30th postoperative day, indicating inert bone ends. Histological findings further confirmed the presence of inert bone ends, indicating the development of atrophic non-union. CONCLUSION: The combination of the segmental bone defect, electrocautery induced thermal damage of bone end periosteum, and delayed treatment can induce the development of atrophic non-union fracture model in rabbits that can replicate the clinical scenario.

miR-1323 suppresses bone mesenchymal stromal cell osteogenesis and fracture healing via inhibiting BMP4/SMAD4 signaling.

BACKGROUND: Atrophic non-union fractures show no radiological evidence of callus formation within 3 months of fracture. microRNA dysregulation may underlie the dysfunctional osteogenesis in atrophic non-union fractures. Here, we aimed to analyze miR-1323 expression in human atrophic non-union fractures and examine miR-1323's underlying mechanism of action in human mesenchymal stromal cells. METHODS: Human atrophic non-union and standard healing fracture specimens were examined using H&E and Alcian Blue staining, immunohistochemistry, qRT-PCR, immunoblotting, and ALP activity assays. The effects of miR-1323 mimics or inhibition on BMP4, SMAD4, osteogenesis-related proteins, ALP activity, and bone mineralization were analyzed in human mesenchymal stromal cells. Luciferase reporter assays were utilized to assay miR-1323's binding to the 3'UTRs of BMP4 and SMAD4. The effects of miR-1323, BMP4, and SMAD4 were analyzed by siRNA and overexpression vectors. A rat femur fracture model was established to analyze the in vivo effects of antagomiR-1323 treatment. RESULTS: miR-1323 was upregulated in human atrophic non-union fractures. Atrophic non-union was associated with downregulation of BMP4 and SMAD4 as well as the osteogenic markers ALP, collagen I, and RUNX2. In vitro, miR-1323 suppressed BMP4 and SMAD4 expression by binding to the 3'UTRs of BMP4 and SMAD4. Moreover, miR-1323's inhibition of BMP4 and SMAD4 inhibited mesenchymal stromal cell osteogenic differentiation via modulating the nuclear translocation of the transcriptional co-activator TAZ. In vivo, antagomiR-1323 therapy facilitated the healing of fractures in a rat model of femoral fracture. CONCLUSIONS: This evidence supports the miR-1323/BMP4 and miR-1323/SMAD4 axes as novel therapeutic targets for atrophic non-union fractures.

TNF-α modulation via Etanercept restores bone regeneration of atrophic non-unions.

Treatment of atrophic non-unions, especially in long bones is a challenging problem in orthopedic surgery due to the high revision and failure rate after surgical intervention. Subsequently, there is a certain need for a supportive treatment option besides surgical treatment. In our previous study we gained first insights into the dynamic processes of atrophic non-union formation and observed a prolonged inflammatory reaction with upregulated TNF-α levels and bone resorption. In this study we aimed to improve bone regeneration of atrophic non-unions via TNF-α modulation in a previously established murine femoral segmental defect model. Animals that developed atrophic non-unions of the femur after 5 and 10 weeks were treated systemically for 10 and 5 weeks with Etanercept, a soluble TNF-α antibody. µCT scans and histology revealed bony bridging of the fracture gap in the treatment group, while bone formation in control animals without treatment was not evident. Moreover, osteoclasts were markedly decreased via modulation of the RANKL/OPG axis due to Etanercept treatment. Additionally, immunomodulatory effects via Etanercept could be observed as further inflammatory agents, such as TGF-ß, IL6, MMP9 and 13 were decreased in both treatment groups. This study is the first showing beneficial effects of Etanercept treatment on bone regeneration of atrophic non-union formation. Moreover, the results of this study provide a new and promising therapeutic option which might reduce the failure rate of revision surgeries of atrophic non-unions.

Accordion technique combined with minimally invasive percutaneous decortication for the treatment of bone non-union.

BACKGROUND: A variety of approaches have been used to treat oligotrophic or atrophic non-union. Conventional methods are often associated with great operative trauma, increased blood loss, a risk of re-infection, higher medical costs, and complications at the donor site. This study aimed to assess the clinical efficacy of the accordion technique combined with Minimally Invasive Percutaneous Decortication (MIPD) for these types of bone non-union. METHODS: From January 2010 to December 2015, 20 patients with long bone aseptic non-unions of the lower extremities without bone defects who were treated with the accordion technique combined with MIPD. The limb-length discrepancy (LLD) was less than 2cm in all patients. None of the patients received autogenous bone grafts during follow-up. All surgeries were performed by the same surgeon, and the modified Application of methods of Ilizarov (ASAMI) criteria were used to evaluate the operative effectiveness. RESULTS: A total of 20 patients were included in this study, and 1 patient was lost during follow-up. Fifteen of these patients presented with oligotrophic non-unions, and 5 patients presented with atrophic non-unions. The average follow-up period in these patients was 12.1 months (range: 8-42 months). The alternative compression and distraction procedure was repeated 1-3 times. Blood loss was 30 to 250ml during surgery. Ultimately, bone union was achieved in 19 patients and failed in 1 patient. The fractures healed within 4-8 months (average time: 5.9 months), and fracture healing was considered excellent in 19 patients and poor in 1 patient. Postoperative function was evaluated as excellent in 9 patients, good in 6 patients, fair in 4 patients, and poor in 1 patient. CONCLUSION: The accordion technique combined with MIPD, which is a simple, minimally invasive procedure that does not require autologous bone grafting, resulted in a high bone union rate and good postoperative function.

Autologous bone grafts with MSCs or FGF-2 accelerate bone union in large bone defects.

BACGROUND: Although the contribution of fibroblast growth factor (FGF)-2 and mesenchymal stromal cells (MSCs) to bone formation is well known, few studies have investigated the combination of an autologous bone graft with FGF-2 or MSCs for large bone defects. METHODS: We studied an atrophic non-union model with a large bone defect, created by resecting a 10-mm section from the center of each femoral shaft of 12-week-old Sprague-Dawley rats. The periosteum of the proximal and distal ends of the femur was cauterized circumferentially, and excised portions were used in the contralateral femur as autologous bone grafts. The rats were randomized to three groups and given no further treatment (group A), administered FGF-2 at 20 µg/20 µL (group B), or 1.0 × 106 MSCs (group C). Radiographs were taken every 2 weeks up to 12 weeks, with CT performed at 12 weeks. Harvested femurs were stained with toluidine blue and evaluated using radiographic and histology scores. RESULTS: Radiographic and histological evaluation showed that bone union had been achieved at 12 weeks in group C, while group B showed callus formation and bridging callus but non-union, and in group A, callus formation alone was evident. Both radiographic and histological scores were significantly higher at 2, 4, 6, 8, 10, and 12 weeks in groups B and C than group A and also significantly higher in group C than group B at 12 weeks. CONCLUSIONS: These data suggest that autologous bone grafts in combination with MSCs benefit difficult cases which cannot be treated with autologous bone grafts alone.

Extracorporeal shockwave therapy (ESWT) in the treatment of atrophic non-unions of femoral shaft fractures.

INTRODUCTION: As of now, the role of extracorporeal shockwave therapy (ESWT) in the treatment of atrophic non-unions is inconclusive. The purpose of the study was to investigate the effectiveness of ESWT and the role of this technology in the treatment of atrophic non-union of femurs. METHODS: We retrospectively analyzed 22 patients treated between July 1999 and September 2007 in our hospital with ESWT for atrophic non-unions of isthmic femoral shaft fractures that were initially treated surgically using closed reamed nailing procedure. Patients with open fractures, skeletal immaturity, on anti-osteoporotic medications, with infections, pathological fractures, smokers, with systemic disease compromising bone healing, and excessive deformity were excluded from this study. Due to incomplete follow-up one (1) patient who moved abroad after ESTW treatment was not included in this study and as part of the 22-patients cohort. Radiographs were obtained before treatment and once a month after treatment for 12 months. RESULTS: Using ESWT we showed that 14 fractures out of 22 (63.6%) achieved bony union with an average union time of 9.2 months (range 6-13 months). The union rate was 100% (8 of 8 cases) when ESWT was performed within 12 months from closed reamed nailing surgery versus 42.9% (6 of 14 cases) when ESWT was performed after 12 months from initial surgery. The eight (8) patients out of the total 22 patients cohort, who did not achieve bony union after ESWT, received subsequent treatment with bone grafting with augmentative plating surgery and all achieved bony union within 5 months after intervention. CONCLUSION: For patients with atrophic non-unions of femoral shaft fractures, ESWT can be used as an alternative and effective non-invasive method of treatment. ESWT treatment does not negatively influence/compromise previous surgeries and if needed it can be followed by additional surgeries without any complications.

Volkmann's Ischemic Contracture with Atrophic Non-union of Ulna Managed by Bone Shortening and Transposition of Radial Autograft.

INTRODUCTION: Volkmann's ischemic contracture (VIC) is a complex and variable flexion deformity of wrist and fingers resulting from fibrosis and contracture of flexor muscles of forearm. It is caused by ischemic injury to the deep tissues enclosed in the tight unyielding osteo-facial compartments secondary to neglected acute compartment syndrome. VIC may be associated with malunion or non-union of forearm fractures. To the best of our knowledge, this article is the first case report of VIC associated with atrophic non-union of ulna managed by shortening of forearm bones combined with transposition of intercalary auto graft from the fellow bone. CASE REPORT: A seven year old boy presented with flexion deformity of wrist and hand with inability to use his left hand since three and half months subsequent to an injury to his left forearm due to fall from a tree of six feet height. The patient was diagnosed and treated by a native traditional bone setter for his Radius and Ulna fracture of left forearm with massaging and tight bandaging. On examination there was wasting of left forearm with positive Volkmann's sign, flexion contracture of wrist with loss of grip strength and tenderness over the upper and middle third junction of left ulna with a palpable gap. The radiograph of forearm revealed atrophic non-union of left ulna. In order to tackle both the issues, shortening osteotomy of radius with transposition of tubular radius intercalary graft onto ulna was done. Radius was fixed with a dynamic compression plate and Ulna was fixed with a rush nail effecting overall two and half centimetres shortening of both bones of forearm. This approach has addressed both atrophic non-union of ulna and VIC in a single stage and gave excellent functional outcome till the last follow-up of three years from the date of surgery. CONCLUSION: Bone shortening and transposition of auto-graft from the fellow bone may prove to be an excellent treatment modality for VIC with associated non-union of involved compartmental bones in properly selected and executed cases.