Assessments of bone morphogenetic proteins 2 and 7 in treating nonunion / 中国组织工程研究

BACKGROUND: Autologous bone transplantation combined with strong fixation is considered as the gold standard for the treatment of nonunion. At present, there are many cases in which bone nonunion is treated with bone morphogenetic proteins 2 and 7. OBJECTIVE: To describe the osteogenic pathway of bone morphogenetic proteins at the gene level, summarize the clinical cases of nonunion treated with bone morphogenetic protein, and compare the therapeutic effects of bone morphogenetic proteins 2 and 7 on nonunion, followed by evaluation and analysis. METHODS: The first author used a computer to search the full-text database of Chinese journals, WanFang database and PubMed database. The key words were “BMP, nonunion, pathway, external fixator, ORIF, bone graft, infected nonunion, bone defect, osteoblast, osteoporosis " and 59 articles were finally included in the result analysis. RESULTS AND CONCLUSION: Literature review indicates that the gene-level pathway of bone morphogenetic protein can provide therapeutic ideas in clinical practice. In the treatment of bone nonunion, bone morphogenetic proteins 2 and 7 are effective, but there are yet no specifications and standards for the use of bone morphogenetic proteins, such as usage amount and indications. From the overall treatment effect and the treatment effect on infected bone nonunion, we compare the use of bone morphogenetic proteins 2 and 7. The effect of bone morphogenetic protein 2 is better than that of bone morphogenetic protein 7, especially in the treatment of infected nonunion.

Status quo and difficulties in standardized treatment of infected nonunion of tibia / 中华创伤杂志

In recent years,infection and infected nonunion after surgical treatment of tibial fracture have gradually increased,which has brought tremendous psychological and economic burdens to patients.At present,awareness and attention in the field of traumatic bone infections is insufficient,and many experienced orthopedic surgeons lack the basic knowledge and formal training on management of traumatic bone infections.Tibial intramedullary nail infection and infectious bone defect nonunion are difficult to treat and have a high recurrence rate.This article reviews the special principles of bacterial biofilm formation,surface competition,Klemm three factors and bone infection typing in the treatment of bone infection,the reamed debridement of tibial intramedullary nail fixation infection,the application of local antibiotics and the comparison between bone transport and inducing membrane techniques in the treatment of infectious nonunion.This article aims to provide some help for orthopedic surgeons in the systematic treatment of tibial infection.

Application of bone transport with unilateral external fixator combined with locked plate internal fixation in treatment of infected tibial nonunion / 中国修复重建外科杂志

Objective: To summarize the effectiveness of bone transport with unilateral external fixator combined with locked plate internal fixation in treatment of infected tibial nonunion. Methods: Between January 2010 and December 2014, 23 patients with infected tibial nonunion were treated with bone transport with unilateral external fixator combined with locked plate internal fixation. There were 19 males and 4 females with an average age of 37.8 years (range, 19-54 years). The mean length of the bone defect was 6.5 cm (range, 5.2-8.1 cm). The number of previous operations ranged from 2 to 4 times, with an average of 2.5 times. The time from injury to this treatment was 7-23 months, with an average of 11.8 months. The time of bone transport, time of the external fixation, fracture healing time, external fixation index, healing index, and complication were recorded; and the Association for the Study and Application of the Methods of Ilizarov (ASAMI) bone healing and function scores were used to evaluate the effectiveness. Results: All patients were followed up 3-6 years with an average of 4.8 years. Wounds and bone defects healed in all patients. No complication such as infection recurrence, nonunion, re-fracture, malunion, iatrogenic nerve paralysis, or stiffness of knee and ankle joints occurred. Five patients had needle infections which were treated by local care and no deep infection occurred. The time of bone transport was 65-120 days (mean, 75.6 days); the time of the external fixation was 75-145 days (mean, 97.8 days); the fracture healing time was 4-17 months (mean, 8.7 months); the external fixation index was 18-28 days/cm (mean, 22.4 days/cm); and the healing index was 31-52 days/cm (mean, 40.2 days/cm). At last follow-up, according to ASAMI criteria, the result of bone healing was excellent in 15 cases and good in 8 cases, and the result of function was excellent in 18 cases and good in 5 cases, all with the excellent and good rate of 100%. Conclusion: For infected tibial nonunion, bone transport with unilateral external fixator combined with locked plate internal fixation can reduce the time of external fixation and related complications, with a satisfactory effectiveness.

Tratamiento de defectos masivos de tibia: técnica de transporte óseo con fijador AO [Arbeitsgemeinschaft für Osteosynthesefragen] / Treatment of massive defects tibia: bone transport technique with fixator AO / Tratamento de defeitos maciços da tíbia: técnica de transporte ósseo com fixador AO

Introducción: La transportación ósea se refiere al traslado de un fragmento de hueso a través de un defecto óseo, por distracción osteogénica. Objetivo: Describir la técnica quirúrgica con fijador externo AO, y evaluar los resultados de este tratamiento en defectos óseos diafisarios de tibia mayores de 4 cm, secundarios a fracturas expuestas graves o pseudoartrosis infectadas. Material y método: Se realizó un estudio descriptivo de tipo serie de casos, retrospectivo, de los 14 pacientes tratados entre abril del 2011 y abril del 2015, con las lesiones o secuelas mencionadas en diferentes centro de Montevideo. Resultados: Todos los pacientes tenían secuelas a fracturas expuestas graves con defecto segmentario de tibia mayor a 4 cm. El seguimiento promedio fue de 13 meses (entre 6 y 27). La media de edad fue de 32 años (entre 15 y 53), la perdida ósea promedio 6,7 cm (entre 4 y 11), la velocidad de distracción de 0,58 mm/día, el período de distracción promedio fue de 92 días (entre 35 y 172), y el tiempo medio de fijadores externos desde el inicio fue de 194 días. Todos los pacientes requirieron algún procedimiento quirúrgico en el sitio de acoplamiento. Se logró la consolidación en 9 pacientes, hubo 2 pseudoartrosis, 2 pacientes abandonaron el tratamiento y uno decidió la amputación. No hubo ninguna recidiva de infección. Conclusión: La técnica de transportación ósea mediante el uso de fijadores externos AO, es una alternativa válida para el tratamiento de las perdidas óseas diafisarias de tibia con o sin infección.

Introduction: Bone transport is the slow transportation of the bone fragment along a bone defect, providing distraction osteogenesis. Objective: To describe the surgical technique of bone transport using the AO external fixator and to present the result of this procedure in tibial diafisis defects of more than 4 cm long, which were the result of severe open fractures or infected no unions. Material and Methods: This is a retrospective, descriptive study of 14 patients treated in several centers in Montevideo from April 2011 to April 2015. Results: The average age of the patients was 32 years (15-32), the average bone loss 6,7 cm (4-11), the distraction speed 0,58 mm/day, the mean distraction period 92 days (35-172) and the mean time external fixation was 194 days. The mean follow up was 13 months (6-27). All patients needed an additional surgical procedure in the docking site. Bone healing was accomplished in 9 patients and there were 2 no unions. There were 2 further patients who abandoned the treatment and another patient who requested amputation. At the latest follow up there was no recurrence of infection. Conclusion: Bone transport using AO external fixator, is a valid alternative for the treatment of segmental bone loss of the diafisis of the tibia with or without infection.

Introdução: O transporte ósseo é o transporte lento do fragmento ósseo ao longo de um defeito ósseo, que proporciona distração osteogênica. Objetivo: Descrever a técnica cirúrgica de transporte de osso, utilizando o fixador externo AO e apresentar o resultado deste procedimento nos defeitos da diáfise da tíbia de mais de 4 cm de comprimento, que foram um resultado de fracturas expostas graves ou ausência de juntas infectados. Material e métodos: Trata-se de um estudo descritivo e retrospectivo de 14 pacientes atendidos em diversos centros de Montevidéu no período de abril de 2011 a abril de 2015. Resultados: A idade média dos pacientes era de 32 anos (15-32), a 6,7 cm perda óssea média (4-11), a taxa de distracção 0,58 milímetros/dia, período médio de 92 dias distracção (35-172) e o tempo médio de fixação externa foi de 194 dias. O seguimento médio foi de 13 meses (6-27). Todos os pacientes precisaram de um procedimento cirúrgico adicional no local de encaixe. A cicatrização óssea foi realizada em 9 pacientes e não houve 2 articulações. Houve mais 2 pacientes que abandonaram o tratamento e outro paciente que solicitou a amputação. No último seguimento, não houve recidiva da infecção. Conclusão: O transporte ósseo utilizando o fixador externo AO é uma alternativa válida para o tratamento da perda óssea segmentar da diáfise da tíbia com ou sem infecção.

Management of Infected Non-Union by Implant Retainment and Papineau Open Bone Grafting – Report of Two Cases.

Introduction : Infection following implant surgery in orthopaedics is a disaster both for surgeon and patient. Management of infected non-union is a most challenging task an orthopaedic surgeon can ever face. Infection following implant surgery not only leads to repeated surgeries, long term antibiotic use, stiffness of neighbouring joints and long term hospital stay but also effects patients economic, social, psychological status. Cases : Here we present report of 2 cases infected non-union ulna which was managed by stabilisation of non-union site by altering position of existing plate followed by period of open dressing till healthy granulation tissue appears. Later open bone grafting procedure done. Both patients were followed up for 15 months. Results : At the end of 4 months both patients achieved bony union without recurrence of infection. So, we conclude management of infected nonunions by altering plate position and by following papineau method of open bone grafting leads to satisfactory results. Conclusion : This technique is simple, effective and done with minimal expenditure and could be best procedure of choice in patients where cost benefit analysis appears critical.

Infected Nonunion of Clavicle Shaft after Operation: A Case Report

The infected nonunion of clavicle with bone defect is an uncommon complication following clavicle shaft fracture. There were a few reports regarding treatment of the infected nonunion after clavicle fracture. We report on a case of infected clavicle nonunion successfully treated with autologous bone graft and dual plate fixation.

The Efficacy of Preserved Posterior Cortex in the Treatment of Infected Nonunion of the Tibia

PURPOSE: We studied the efficacy of preserved posterior cortex connecting to adjacent muscle or periosteum during wide debridement in the treatment of infected nonunion of the tibia. MATERIALS AND METHODS: From January 2001 to May 2011, 12 cases of infected nonunion of the tibia with segmental defect larger than 4 cm after wide debridement were selected. The selected cases were categorized according to two groups; group 1 with preserved posterior cortex in the segmental defect site - six cases, group 2 without posterior cortex - six cases. The results were compared by assessing the size of bone defect, the interval between wide debridement and bone reconstruction, bony union time, complications, and clinical results. RESULTS: The mean length of bone defect of group 1 was 7.6 cm (range 4.3-11.0 cm) and that of group 2 was 6.4 cm (range 4.0-12.0 cm). The interval between wide debridement and bone reconstruction was 10.0 weeks (range 5-18 weeks) for group 1, and 12.1 weeks (range 0-24 weeks) for group 2. The time for bony union of group 1 was 6.2 months (range 5-7 months), and that of group 2 was 10.8 months (range 7-18 months). In group 2, there were two cases of fatigue fracture and two cases of docking site nonunion after distraction osteogenesis. CONCLUSION: The preserved posterior cortex after wide debridement of infected nonunion of the tibia helps bony union and reduces the treatment period.

Comparison of Treatment Outcomes of Infected Nonunion of the Tibia by Ilizarov Fixator according to Location of Nonunion and Reconstruction of Soft Tissue Defect

PURPOSE: To study clinical results and complications in the treatment of infected nonunion of the tibia according to location of nonunion and reconstruction for soft tissue defect. MATERIALS AND METHODS: 36 cases of tibia infected nonunion which were treated with the llizarov included in this study. There were proximal 1/3 in 14, middle 1/3 in 10, and distal 1/3 in 11 cases. Coverage of the soft tissue were treated with the free flap in 8 cases as classified group A and non-free flap in 17 cases classified group B. We evaluated the healing index, complications and comparing the results of each treatment by the Paley method. RESULTS: Bone union was achieved in all cases. The proximal nonunion showed better results than those in the middle and distal area; average healing index: 35.6 days/cm (p=0.038), bone results: 92.9% (p=0.025), functional result: 90.5% (p=0.03). Group B showed significantly better results as it showed average healing index: 30.3 days/cm (p=0.015), bone results: 85.7% (p=0.025), functional results: 90.5% (p=0.015). CONCLUSION: The nonunion of proximal 1/3 showed better results than other sites. Soft tissue reconstruction with free flap that control infection more effectively, could be improved the treatment outcomes.

The Treatment of Infected Nonunions of Femur using Sequestrectomy and Distraction Osteogenesis / 대한정형외과학회잡지

PURPOSE: From this study we are to know the result of distraction osteogenesis for infected nonunions of femur using sequestrectomy and Ilizarov external fixator. MATERIALS AND METHODS: 17 patients who had distraction osteogenesis using external fixator and also had more than 2.5 cm bone loss after sequestrectomy for having infected nonunions of femur from 1991 to 2005. Their average age was 32.4 (range, 10-60) years and mean follow up period was 22 (range, 14-36) months. We used Healing index as an index for bone formation. The results were divided into bone results and functional results and analyzed by grading. Also we estimated the complication according to the Paley's classification. RESULTS: After seqestrectomy, bone defect was ranged from 5cm to 13 cm (average, 7.3 cm) and The average of transportation was 5.8 cm (range, 3-10 cm). HI was 47.4 (27.17-65.80) days/cm. Solid bony union occurred in the all cases after surgery but, 4 cases needed bone graft at docking site. According to the final examination there were 2 cases with leg-length discrepancy that is bigger than 2.5 cm and the average size of was 1.0 cm. CONCLUSION: We consider distraction osteogenesis using Ilizarov external fixator as useful method to restore bone loss caused after sequestrectomy for infected nonunions of femur.

Vascularized Fibular Graft in the Treatment of Intractable Infected Nonunion of Femur: 3 Cases

PURPOSE: To report the clinical results of the vascularized fibular graft in the treatment of intractable infected nonunion of femur. MATERIALS AND METHODS: We reviewed 3 patients who were performed vascularized fibular graft in treated for intractable infected nonunion of femur. They had received an average of 5.6 times(4~8 times) surgical treatment at different hospitals. 1 case was of a infected nonunion in a fracture treated with internal fixation, the fracture having occurred after resection of a malignant tumor and transplantation of pasteurized autologous bone. 2 cases occurred after internal fixation in closed fractures. Surgical treatment was performed an average of 4 times(3~5 times) at our hospital and in all of the cases debridement of necrotic tissue and sequestrectomy. And vascularized fibular graft was performed. In all cases unilateral external fixation devices were used, of these, 1 case was changed into internal fixation. The final conclusion was made by assessment of functional outcomes and complications according to the standards of Paley. RESULTS: As a result, in all of the cases bone union was achieved, and in the last follow up the functional results were excellent in 2 cases and good in 1 case. There were not presented leg length discrepancy of more than 2 cm, and further loss of knee joint motion. After previous treatment, average 23.3 months(16~30 months) was taken to eliminate infection and achieve complete bone union via vascularized fibular graft in our hospital. CONCLUSION: In treatment of intractable infected nonunion of femur, fairly good results can be expected after firm fixation, through debridement and vascularized fibular graft.

The Treatment of Infected Non-union of Long Bones with Plate and Screws

PURPOSE: To evaluate the usefulness of internal fixation with plate in treating infected nonunion of long bone. MATERIALS AND METHODS: From March 1993 to February 2004, ten patients who underwent internal fixation with plate and cancellous bone graft on account of infected nonunion of long bone were retrospectively examined. The medical treatment were composed of thorough and adequate debridement of necrotic tissue, irrigation and plate fixation. Two patients were operated on with bridging plate method. Autologous cancellous bone graft was performed in 6 patients. In 2 cases, it was performed 4 weeks after internal fixation. RESULTS: In 9 patients, radiographic union appeared on the average of 6.8months and infections were cured before union occurred. CONCLUSION: Internal fixation with plate is a useful method for the solid fixation in the treatment of infected nonunion. The general concern was that the inserted hardware worsened the infection, which was overcomed with the operative techniques as bridging plate, debridement and cancellous bone graft.

Free Vascularized Fibular Grafts for Treatment of Infected Nonunion of the Tibia

PURPOSE: To analyze the result of free vascularized fibular grafting for treatment of infected nonunion of the tibia with radical bone and soft tissue defect. MATERIALS AND METHODS: 17 patients with infected nonunion of the tibia who underwent a reconstruction using free vascularized fibular grafting were reviewed retrospectively. The mean follow-up period was 70.3 months. We analyzed the results radiographically which included the time of bone union, the amount of hypertrophy of grafted bone and complications. RESULTS: The average length of bone defect was 8.8 cm (5~15 cm), and the average length of fibular graft was 14.1 cm (10~17.5 cm). Bony union was achieved in 11 of 17 cases and the average time of bone union was 5.2 months (4~6 months). There were 6 cases of nonunion. All nonunions developed at the proximal end of graft in patients who underwent fixation using pin and external fixator. Union was eventually achieved in all cases in 6.0 months (5~8 months) after the cancellous bone graft and plate internal fixation. Hypertrophy of grafted bones with more than 20% developed only in 4 cases out of 17. There were 3 cases of stress fracture, however there was no recurrence of infection or serious donor site morbidity. CONCLUSION: Free vascularized fibula grafting is one of the most effective reconstruction options for the infected nonunion of the tibia with radical bone and soft tissue defect. Strong internal fixation using plate and screws is required to reduce the rate of nonunion and stress fracture of grafted fibulas.

Radical Necrotic Bone Resection and Ilizarov Technique for Infected Nonunion of the Tibia

PURPOSE: To evaluate the clinical results of radical necrotic bone resection and distraction osteogenesis for the treatment of infected nonunion of tibia using the Ilizarov technique. MATERIALS AND METHODS: 32 patients who were followed up at least 1 year after the treatment of infected nonunion of tibia from March 1995 to March 2001 were evaluated. Their mean age was 43 years and mean duration of follow-up was 37 months. The results were divided into bone results and functional results and analyzed by grading to excellent, good, fair, and poor. RESULTS: The average amount of bone lengthening was 5.3 cm (range, 2~10 cm) and the average healing index was 61.5 days/cm (range, 52.7~70.4 days/cm). Bony union was obtained at average 10.3 months in all cases. The bone result was excellent in 9 cases, good 18, and fair 5. The functional result was excellent in 8 cases, good 16, fair 7, and poor 1 case. CONCLUSION: Ilizarov technique is an effective method in the treatment of infected nonunion of tibia for early range of motion exercise, weight bearing and correction of limb shortening.

Treatment for Intractable Infected Nonunion of Lower Extremity in Elderly People using External Fixator

PURPOSE: To introduce and report the results of treatment of old patients' infected nonunion using external fixator. MATERIALS AND METHODS: Nine patients more than 60 years old were included in the study. Four cases had combined medical problems of diabetes, hypertension, and vascular disorder. We used Ilizarov fixator in eight cases and uni-lateral external fixator in one. All patients were treated with debridement, broad sequestrectomy, segmental resection, bone graft and compression of fracture site about 1~1.5 cm. We evaluated the final results by functional result and complication according to the criteria of Paley. RESULTS: Average length discrepancy was 1.7 cm before operation by initial bone loss and final follow-up shortening was average 2.6 cm. Mean duration of fixtor removal was 5.2 months. We acquired bony union lastly in 8 cases. Final functional result was 3 excellent, 2 good, 2 fair and 2 poor. Among them, 2 good, 1 fair and 1 poor cases had medical problem. CONCLUSION: In old patients, compression of nonunion site and early joint motion using external fixator seemed to be very useful in the treatment of intractable infected nonunion of lower extremity and in minimizing duration of treatment.

Two-Stage Reconstruction of Infected Nonunion of Long Bones using Antibiotics-Impregnated Cement Beads

PURPOSE: To evaluate treatment results between internal and external fixation groups in two-stage reconstruction of infected nonunion of long bones using antibiotics-impregnated cement beads. MATERIALS AND METHODS: In the first stage, preexisting hardwares were removed and radical debridement was done. The dead space was filled with antibiotics -impregnated cement beads and the nonunion site was immobilized by external fixation, cast or skeletal traction. In the second stage, all cases were divided into two groups; the nonunion was fixed by internal fixation in group I versus external fixation in group II. The intervening period between the first and second stage was average 8.7 weeks (range, 3~23 weeks). RESULTS: The follow-up period was average 45 months (range, 16~71 months). Infection control and bone union were achieved in all 13 cases of group I. Infection recurred in two of 28 cases in group II, one underwent above-knee amputation and the other case was lost in follow-up. The mean number of supportive operations including repeated curettage, augmentation and change of infected pins, angular correction, and soft tissue flap was average 2 and 6.2 times respectively in group I and group II. Bony union period was average 19.3 and 23.1 weeks in each group. According to Paley's classification, group I was similar to group II in bony and functional result (p>0.05). CONCLUSION: Antibiotics-impregnated cement beads provided positive effect on infection control. Internal fixation group showed less number of additional operations and earlier bony union than external fixation group.

Usefulness of Ilizarov's Procedure in Infected Non-union of Tibia and Femur

A total of 46 patients with infected diaphyseal non-union of tibia (38) and femur (8) were subjected to Ilizarov's ring fixator. Thirty six cases were of infected nonunion with gap requiring bone transport (Group I) while 10 cases did not require bone tranasport (Group II). In majority of group I cases unifocal corticotomies were done through metaphyses of the bone. In two cases, where the gap was large, bifocal corticotomies were done in tibia to shorten the treatment time. Controlled distraction was begun after 7 day's time. Normotrophic regenerate was observed in all cases except one case of tibia and one femur. Both these cases required cancellous bone grafting. In group II, six cases of infected non-union of tibia and four of infected femur required only radical debridement and acute compression at the fracture site. Failure of union was seen only in two cases. Forty four patients showed union clinically and radiologically with a success rate of 95.4%.Equinus contracture (mild) and toe drop were seen in one case of group I. Average follow up is of 67 months. Average distraction at corticotomy site was 60 mm. Average time for fixator removal was 239 days.

Treatment of the tibia infected nonunion by Ⅰ-stage bone grafting and debriding / 医学研究生学报

Objective:To investigate the treatment of infected nonunion of tibia. Methods:We treated 38 cases with debriding thoroughly and primary bone grafting. Results:There were 35 cases who got infection suppressed and reached bone union. There were three failures, in which two failed with relapsed infection and one with bone nonunion. Conclusion:It is a feasible method to treat infected nonunion of tibia with thorough debridement and primary bone graft.

Fixation of Infected Nonunion of Femur by a Kuntscher Nail Stuffed with Antibiotic Laden Bone Cement: A Case Report / 대한정형외과학회잡지

A case of established infected nonunion of femur after open reduction and internal fixation of proximal femoral fracture with plate and screws in a 20-year-old man has been satisfactorily treated with a conventional Kiintscher nail filled with antibiotic laden bone cement in its hollow cavity. Though the removal of plate and screws, wound debridement, insertion of antibiotic laden bone cement bead at the nonunion site with temporary external skeletal fixation and skeletal traction preceded, a rigid fixation by the nail and vancomycin elution from the cement are believed to have contributed for bony union without troublesome complication of infection in this case.

Treatment of Infected Nonunion of the Femur with Marked Shortening by Compression and Gradual Distraction at the Nonunion Site: A Report of 2 cases / 대한정형외과학회잡지

The authors report two cases of successful reconstruction in infected nonunion of the femur involving marked shortening by compression and gradual distraction at the nonunion site using Ilizarov external fixator. At first, infection was controlled by radical excision & the administration of systemic antibiotics for four weeks and we also started compression at the nonunion site 3 days after operation. Autogenous iliac bone graft was added to strengthen the site of new bone formation lastly. In this report, the role of the compression seems to provide a good environment for distraction osteogenesis by focal necrosis and triggering inflammation. Compression and gradual distraction may be one of the treatment mordalities for nonunion of a long bone with massive bone loss or shortening, even infected.

Infected Nonunion of Long Bones Treated with Dual Plate / 대한정형외과학회잡지

Infected nonunion of the long bone, while less common today than in the past, continues to challenge orthopaedic surgeons. Various treatment methods including current techniques of internal fixation, bone graft, electrical stimulation and external fixation have been tried, but results are not always satisfactory. Authors reported successful treatment of infected nonunion by rigid internal fixation with one plate and autogenous bone graft in previous volumes 1989. Recently we adopted dual plate method, by which we overcame a greater amount of bone defect and obtained more rigid internal fixation. We have treated 14 cases of infected nonunion with this method from Oct. 1992 to Oct. 1994, and the results are as follows; 1. Tibia fractures were 9 cases, and femur fractures were 5 cases. 2. Six cases showed large bone defect. The average bone defect was 4.5cm in length and we could overcome it by Dual plate method and autogenous bone graft. 3. Six cases which showed large bone defect were united in average 5 months. 4. In remaining 8 cases, union was obtained in average 3 months.