[Retracted] Clinical Outcomes of Treatment Strategies for Postoperative Plate Fracture and In Situ Fracture of the Femoral Shaft

Tu, Junbo; Jiang, Haixiang; Li, Cuihe; Huang, Xiaowu; Li, Xingwang

doi:https://doi.org/10.1155/2022/8145438

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Volume 2022 | Article ID 8145438 | https://doi.org/10.1155/2022/8145438

[Retracted] Clinical Outcomes of Treatment Strategies for Postoperative Plate Fracture and In Situ Fracture of the Femoral Shaft

Junbo Tu,¹Haixiang Jiang,¹Cuihe Li,¹Xiaowu Huang,¹and Xingwang Li¹

Academic Editor: Sandip K Mishra

Received01 Jun 2022

Revised18 Jul 2022

Accepted28 Jul 2022

Published26 Aug 2022

Abstract

Objective. To investigate the treatment and clinical efficacy of postoperative plate fracture and in situ fracture of the femoral stem. Methods. We have retrospectively analyzed the clinical data, revised surgery information, and clinical efficacy of patients with postoperative plate fracture of the femoral stem in our hospital. A total of 33 cases were included whose original fractures were located in the upper and cadaveric femur and treated with paralleling intramedullary pins for revision surgery, as well as patients whose original fractures were located in the lower femur which were fixed with retrograde intramedullary nailing or anatomical locking and compression splints in the distal femur. For the selection of bone grafting, the original fracture site with Fernadez-Esteve scab grades I and II was treated with an autologous iliac bone graft. Postoperatively, patients were evaluated for fracture healing time, the clinical outcome of the affected limb, and complications in the iliac bone donor area. Results. All patients were followed up until fracture healing, and all patients achieved clinical healing with a healing rate of 100% and a mean healing time of 6.3 months. No internal fixation failure such as rebreakage or loosening of the internal fixation occurred in all patients during the follow-up period. According to the Tohner-Wrnch criteria, 23 cases were excellent, 10 cases were good, and 0 cases were poor, with an excellent rate of 100%. Complications in the autologous iliac bone donor area amounted to 36.7%. Conclusion. For patients with original fractures located in the upper femoral segment or cadre, it is recommended to perform revision surgery with a paralleling intramedullary pin, while patients with original fractures located in the lower femoral segment are fixed with the retrograde intramedullary nailing or an anatomical type of distal femoral locking and compression splint. Patients with postoperative plate fractures of the femoral stem do not require routine autologous bone grafting for revision surgery.

1. Introduction

Femoral stem fractures are one of the most common lower limb fractures in clinical practice, and internal fixation with an incisional plate and screw is one of the most common methods of treating femoral stem fractures. In clinical practice, it is not uncommon for internal fixation of the femur to fail, with a reported incidence of 3%–10% in the literature [1–3]. In the majority of patients, the plate fracture occurs 3–4 months after surgery. When internal fixation breaks occur, they can cause serious socioeconomic problems for the patient, including prolonged treatment time, abnormal gait, inability to return to work, increased medical costs, physical and psychological damage, and financial burden, affecting the trust between the doctor and patient and exacerbating the conflict between the doctor and patient. The vast majority of patients with broken internal fixation require revision surgery to achieve a satisfactory outcome, making it a challenge for orthopaedic surgeons to perform revision surgery with fewer complications and less secondary trauma while achieving healing. In this study, we collected data on patients with postoperative plate fracture and in situ fracture who underwent revision surgery for femoral stem fracture in our orthopaedic department from March 2013 to January 2021 and the overall satisfactory results were obtained.

2. Information and Methods

2.1. General Information

The inclusion criteria are as follows: all patients had radiographs, were diagnosed with a broken femoral plate and fracture in situ, had a poor alignment, did not achieve functional repositioning, and had a strong desire for early functional exercise. All patients had good compliance, no psychiatric disorders, and no contraindications to reoperation. Exclusion criteria are as follows: (1) deep postoperative infection of the fracture after the first operation, (2) cases of osseous nonunion including infected osseous nonunion, atrophic osseous nonunion, and hypertrophic osseous nonunion, and (3) pathological fractures.

A total of 41 patients with postoperative plate fracture and in situ fracture of femoral stem fracture and who underwent revision surgery in our orthopaedic department from March 2013 to January 2021 were collected, of which 8 patients with a postoperative refracture time of fewer than 12 weeks were excluded from this study and a total of 33 cases were included in this study.

X-ray Fernadez-Esteve fracture callus tissue grading status [4] grade I (no blurring of the joint margins for radiological detection) has 7 cases, grade II (cloudy blurring of the joint margins for radiological detection) 8 cases, grade III (crust formation on one side of the fracture end in the frontal and lateral positions) 12 cases, grade IV (crust formation on both sides of the fracture end in the frontal and lateral position) 5 cases, and grade V (structural crust formation) 1 case; 10 cases of femoral antegrade intramedullary nail and 12 cases of femoral retrograde medullary internal fixation. All patients signed an informed consent form. All patients signed the informed consent form for surgery and gave informed consent for this retrospective study, in accordance with the regulations of the state council for medical institutions [5]. All patients signed informed consent forms and gave informed consent to this review study, approved by the regulations of the state council on medical institutions (ethical number: YT152648).

2.2. Surgical Methods

Under continuous epidural anaesthesia or general anaesthesia, the patient is placed in a flat position, the skin and subcutaneous tissue are incised layer by layer in the original incision, the original plate and fracture ends are exposed, the traction frame is always kept in longitudinal traction on the lower limb, the fracture end is protected by gentle manipulation, the original internal fixation device is removed, the scar and fibrous tissue at the fracture ends are flushed and cleared, the fracture end is repositioned, and the fracture end is confirmed to be well aligned by C-type X-ray fluoroscopy. Select the appropriate size and length of internal fixation. For the choice of the revision internal fixation device, replace the distal femur fracture with a longer anatomical locking compression plate or retrograde intramedullary nail for internal fixation and choose an intramedullary interlocking nail for patients with mid-upper femur fractures and ischial fractures. The choice of iliac bone grafting is as follows: grade I and II Fernadez-Esteve scabs are treated with autologous iliac bone grafting, and grade III, IV, and V Fernadez-Esteve scabs are not treated with bone grafting. The intramedullary nailing procedure was performed as follows: preoperative measurements were taken on both lower limbs to compare the measurements, and the diameter of the femoral medullary cavity was also measured to make a preliminary comprehensive assessment of the length and size of the intramedullary nail.

To insert the intramedullary nail in a cascade, make a 5 cm incision above the greater trochanter, separate the trochanter layer by layer, probe the greater trochanter, insert a guide needle using the medial aspect of the apex of the greater trochanter as the entry point, open the opening with a rigid medullary expander, then gradually expand the medullary cavity from a small diameter, expand the medullary cavity until there is a clear sense of resistance to the medullary drill or the diameter of the expanded medullary nail is 1 mm greater than the expected diameter of the implanted intramedullary nail, collect and preserve the cancellous bone mud after expansion, and leave it at the original fracture end. After reaming, the intramedullary nail of the appropriate length and diameter is inserted in a prograde fashion. Two static locking screws are given proximally, and three static locking nails are given distally.

A small incision is made between the inferior pole of the patella and the tibial tuberosity, the patellar ligament and the joint capsule are incised, the intercondylar femur is exposed, the posterior cruciate ligament is opened 0.5 cm before the stop, the medulla is expanded, an intramedullary nail of appropriate length and diameter is placed, three distal nails are locked, then two proximal nails are locked, and the main nail ends 0.5 cm below the intercondylar cartilage. In patients with Fernadez-Esteve scab grades I and II, the distal screws are locked first, and then, the proximal end is locked after appropriate pressure has been applied to the fracture end. In patients with Fernadez-Esteve scab grades II, III, IV, and V, the assistant has to continuously immobilise the affected thigh with the aid of a retractor to avoid intraoperative damage to the fracture scab, especially during the medullary expansion phase.

For anatomical internal fixation of the femur with a locking compression plate, the original surgical incision is used to minimise the destruction of the bone fragments around the original fracture end and to expose the plate. After removal of the original internal fixation device, the fibrous tissue and granulation tissue at the fracture ends are thoroughly removed, the fracture end is repositioned, and the fracture alignment is confirmed under C-arm fluoroscopy. In patients with Fernadez-Esteve scab grades I and II, the fracture end is drilled and freshly debrided to the point where blood is visible on the fracture surface and as much of the freshly debrided bone is retained at the fracture end as possible. In patients with grade II, III, IV, and V fracture callus tissues, the assistant should keep the affected thigh immobilised to avoid intraoperative destruction of the fracture end scabs and any scabs protruding from the lateral femur should be trimmed to facilitate plate placement.

2.3. Postoperative Management

The patient was instructed to start contraction training of the quadriceps muscle on the second day after surgery. 1 to 2 weeks after surgery, the patient was instructed to strengthen the hip and knee flexion and extension training. 4 to 6 weeks after surgery, the patient was instructed to walk from partial weight bearing to abandoning the crutches according to the healing of the fracture callus tissues.

2.4. Postoperative Follow-Up Observation Indicators and Evaluation Criteria

All patients were followed up for 12–24 months until clinical healing of the fracture, with some observations being made and recorded during the patient’s hospitalisation. After discharge, the patients are followed up regularly through outpatient clinics, during which all patients routinely undergo front and side views of the affected limb. The recovery of the affected limb is assessed both subjectively and objectively. Adverse events including incision healing, loosening, and fracture of the internal fixation and fracture healing time are recorded.

2.5. Clinical Criteria for Fracture Healing

No significant swelling of the affected limb, no percussion pain at the fracture site, no longitudinal percussion pain, no abnormal activity, no pain on weight for more than 3 minutes, radiographs showing at least three cortical fracture lines blurred and continuous presenting fracture callus tissues passing through [6, 7]. The fracture line is blurred on at least three sides of the cortical fracture, and there is continuous existing bone fragmentation.

2.6. Evaluation of the Clinical Outcome of the Affected Limb

Tohner-Wrnch criteria are as follows: excellent—no local pressure pain and abnormal activity, the fusion of the fracture callus tissue with the cortical bone, disappearance of the fracture line, and normal weight-bearing activity; good—no local pressure pain and abnormal activity, fracture callus tissue across the fracture end, fracture line still visible, and partial weight-bearing activity; and poor—mild local pressure pain, no abnormal activity, a small amount of fracture callus tissue across the fracture end, clear fracture line, and no weight-bearing activity [8].

3. Results

3.1. Patient Characteristics

Of all included patients, 20 were male and 13 were female. The age ranged from 20 to 74 years, with a mean of 47.2 years. For the site of original femoral fracture, there 9 cases of the upper-middle segment, 10 cases of external-internal fixation failure, and 14 cases of lower-middle segment; for the time to fracture, there are 12 weeks to 8 months after surgery, with a mean of 4.7 months; there 13 cases of internal fixation failure in our hospital and 20 cases of external-internal fixation failure. All patients were followed up until fracture healing after surgery. All patients were successfully discharged from the hospital, and there were no deaths. All patients met the clinical healing criteria for fracture and obtained clinical healing, with a healing rate of 100% and a healing time of 4.0 to 11 months, with a mean healing time of 6.3 months. No internal fixation failure such as rebreaking or loosening of the internal fixation occurred in any of the patients during the follow-up period. According to the Tohner-Wrnch criteria, 23 cases were excellent, 10 cases were good, and 0 cases were poor, with an excellent rate of 100%.

3.2. Adverse Events

Two patients developed superficial surgical incision infections, which were treated with dressing changes and anti-infection, and the wounds healed.

3.3. Donor Area Complications

One obese patient presented with a deep infection secondary to fat liquefaction in the iliac donor area incision forming a large subcutaneous cavity (Figures 1(e) and 1(f)), and the wound healed after second-stage debridement. The other patient had a wound healing scar and contact allergic dermatitis (Figure 2); the other patient presented with intractable pain in the donor area, which improved slightly with local medication (Figure 3).

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(b)

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(d)

(e)

(f)

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(b)

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(d)

(e)

(f)

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4. Typical Cases

4.1. Baseline Information on Patients Is as Follows (See Table 1)

5. Discussion

5.1. Analysis of the Etiology of Internal Fixation Fracture

The most direct cause of fracture of internal fixings lies in metal fatigue. Steel plates under cyclic stress-strain produce irreversible cumulative damage locally and crack or fracture suddenly after a certain number of cycles. The literature reports a variety of causes for fatigue fracture of steel plates. Based on our clinical practice observations, the following non-negligible medical factors need to be repeatedly mentioned and reasonably disposed of in clinical work to prevent failure of internal fixation.

5.1.1. Separation of Fracture Ends and Bone Defects

Separation of the fracture end or bone defect increases the difficulty of crust crawling and affects the stress transmission at the fracture ends after internal fixation, making the stress concentrated in the intramedullary nail or plate, and the tension on the internal fixation device becomes a cyclic reciprocal bending stress; when a certain limit is reached, the plate or screw breaks or loosens [9, 10]. When a certain limit is reached, the plate or screw fractures or loosens. The literature reports that there is a correlation between the presence of a bone defect greater than 5 mm on the contralateral side of the plate and the failure of internal fixation [1]. The literature reports a correlation between the presence of a bone defect greater than 5 mm on the contralateral side of the plate and internal fixation failure. Therefore, it is important to achieve good fracture repositioning, avoid bone loss or separation on the contralateral side of the plate, and perform a bone grafting or double-plate internal fixation in one stage if necessary. In the present case study, six patients had a tragic plate fracture due to medial cortical separation or poor repositioning and lack of medial support, despite the postoperative growth of fracture callus tissues.

5.1.2. Emphasis on the Principle of Biological Fixation of the Fracture

The principle of biological fixation is the protection of the fracture blood flow, which in long tubular bones is mainly to restore its length and mechanical axis while correcting rotation. For comminuted fractures that do not involve the articular surface, anatomical repositioning should not be pursued in such a way as to severely disrupt the blood flow at the fracture end, as this will result in delayed healing and even bone discontinuity, leading to failure of internal fixation. In the present study, five patients had anatomical fracture repositioning and no other defects were found but the patients had only a small amount of fracture callus tissue growth after 6 months, which was considered delayed healing, and the patients had plate fractures on weight bearing.

5.1.3. Improper Application and Manipulation of Locking Compression Splints

Concerning the indications for the plate for femoral stem fractures, the plate is suitable for children or for patients who are not suitable for intramedullary pinning and intramedullary pinning of femoral stem fractures should be the preferred option [2, 11, 12]. Intramedullary fixation should be the preferred option. The following principles need to be followed when choosing a plate fixation style: (1) “The longer the plate, the less likely it is to fracture.” The length of the plate should be 4–5 times the diameter of the fracture site and the length of the screw should be through the contralateral cortex to ensure the holding power of the screw, especially in elderly patients with osteoporosis. For femoral fractures, a plate with 8–10 holes is usually chosen and four screws at each end of the fracture should be secured. (2) Locking compression plates are used for a wide range of indications, with different principles of application. The compression principle is used for simple fractures, and the bridging principle is used for comminuted fractures. For simple fractures, the compression screws should be placed first followed by the locking screws. For comminuted fractures, the fracture site should be left without screws in at least 3–4 holes in the plate, leaving a longer area to act as a stress distraction. In our experience, for comminuted fractures or fractures with a butterfly block at the end of the fracture requiring tension screw fixation, the screw should be placed outside the plate as far as possible to avoid stress concentration and to enhance the rotational resistance of the plate and reduce plate fracture; in addition, the use of titanium cable around the plate to fix the butterfly block needs to be used with caution intraoperatively, as reported in the literature [13–16]. In addition, the use of titanium cable around plate fixation has been reported in the literature to cause local stress concentration in the plate, resulting in fatigue fracture of the plate, with a failure rate of 43%. In three of the patients in this group, the reason for plate fracture was considered to be an improper application of the cable. (3) The angle of locking plate screw placement should be in line with the angle of the plate; some literature [17] has shown that deviations of more than 5° can easily lead to screw fracture and internal fixation failure. The application of locking compression plates should be strictly controlled for its indications and the technical principles of its operation to reduce the risk of internal fixation failure due to mechanical defects.

5.1.4. Incorrect Functional Exercise and Premature Weight Bearing

The literature reports that [1, 18] this is consistent with our statistics, with 78.8% of patients suffering from internal fixation failure between 3 and 6 months postoperatively. At 3 months postoperatively, there is abundant fracture callus tissue growth and the patient feels no significant discomfort in the affected limb but the fracture is not strong enough to heal and most patients begin to move around on their own, leading to fracture of the internal fixation. Some patients at this stage are also psychologically lax and develop a fracture in situ and fail the internal fixation with another minor trauma. In this study, the causes of internal fixation fracture were prematurely weight bearing in 5 cases, retrauma in 3 cases, and irregular functional exercise in 2 cases. This was associated with untimely interventions for postoperative follow-up. Because the rate of fracture healing varies from person to person and is influenced by many factors, there is no definitive time that is universally applicable. This requires us to strengthen the follow-up and properly guide the patient in postoperative rehabilitation and not to take any chances. We need to strengthen the communication between the patient and the doctor so that the patient understands that discharge from hospital is not the same as healing and that the patient understands the importance of regular postoperative follow-up and guidance on rehabilitation according to the healing of the fracture. The author believes that a comprehensive follow-up system can, to a certain extent, even compensate for surgical flaws, detect hidden problems at an early stage, and prevent such adverse events from occurring.

5.2. Treatment Strategies for Fractured Internal Fixation

Revision surgery is often required to restore alignment and mechanical stability of the fracture and to promote healing after internal fixation failure. The most common fixation methods used in revision surgery include external fixation frames, intramedullary pins, plate screws, and bridging combination internal fixation systems [19, 20]. The external fixation brace is used to facilitate healing. Given the inconvenience of postoperative rehabilitation and care with external fixation braces, patients undergoing revision surgery at our hospital receive either intramedullary pinning or plate internal fixation. Intramedullary nailing is the central fixation and has obvious biomechanical advantages, so it is preferred by many scholars for revision surgery of failed internal fixation [19, 21]. It is the preferred choice for revision surgery for failed internal fixation. In addition, the debris generated during the expansion of the intramedullary nail is carried to the fracture end, allowing for “autogenous bone grafting,” osteoinductive capacity, and increased extraperiosteal blood supply to facilitate fracture healing [21, 22]. It also increases extraperiosteal blood supply and promotes fracture healing. Jian et al. [19, 23–25] reported good clinical results with the use of intramedullary pins for the treatment of internal femoral fixation fractures. However, it has been suggested that replacing the intramedullary pin with a larger diameter during revision surgery may not match the size of the patient’s femoral medullary cavity, which may disrupt the endosteal blood supply, leading to osteolysis of the fracture end and widening of the fracture end gap [26, 27]. This may lead to delayed fracture healing or even nonhealing. Some scholars also believe that the clinical efficacy of intramedullary pin fixation is not superior to that of plate fixation, which has its own unique advantages and irreplaceable effects [28–30]. The plate has its own unique advantages and irreplaceable functions, including the following: the full exposure of the fracture end during surgery, the cleaning and trimming of the fracture end, the bone grafting, the improvement of the contact area of the fracture end, and the effective compression; the plate has obvious advantages over the intramedullary pin in terms of rotation resistance, especially in non-isthmus fractures of the femur; the plate does not need to disrupt the blood flow in the medullary cavity during the surgery; in addition, for patients with fractured plates, the internal fixation device needs to be removed by incision during surgery and a longer plate can be implanted in the original surgical approach without another. The plate can be implanted in the original surgical approach without an additional incision, which reduces secondary trauma and is more acceptable to the patient [20]. In addition, for patients with plate fractures, a longer plate can be implanted intraoperatively without a second incision. Some scholars have concluded through comparative studies that [23, 31, 32] in the present study, the results were satisfactory for patients with failed internal fixation of the femur, regardless of whether the revision was performed with an intramedullary pin or a plate, with no significant differences in fracture healing rates or healing times. In our data, patients with original fractures in the upper and cadaveric femur were revised using paralleling intramedullary pins, while patients with original fractures in the lower femur were fixed using retrograde intramedullary nailing or anatomical locking and compression plates in the distal femur. We believe that the use of intramedullary pins or plates for revision surgery can be used to achieve satisfactory clinical results by adhering to the principles of operation of various internal fixation devices.

5.3. Bone Grafting or Not

The need for routine bone grafting in revision surgery for failed internal fixation is still a controversial measure. Some surgeons [18, 19, 21, 23, 31, 33, 34] recommend routine one-stage bone grafting during revision surgery for internal fixation failure to promote fracture healing and reduce the incidence of osseointegration. In contrast, Emara et al. [35] concluded that there is no significant difference in fracture healing rates and mean fracture healing times between patients with bone grafting and those without bone grafting in the revision of failed femoral fracture plates using intramedullary pins. In view of this, Emara et al. concluded that revision surgery in patients with failed plate fixation of femoral fractures does not require routine bone grafting to avoid secondary trauma to the patient. However, the authors did not describe and analyze the growth of fracture callus tissues in patients with fractured internal fixation. In our data, patients with Fernadez-Esteve scab grades I and II received autologous iliac bone grafting, whereas patients with Fernadez-Esteve scab grades III, IV, and V did not receive bone grafting during revision surgery, and the mean clinical healing time after surgery was 6.3 months and all fractures healed after surgery. There are various options for bone grafting, including demineralised bone matrix (DBM) allogeneic bone, autologous bone, and autologous bone grafting from the iliac bone which is still the preferred option [19]. Autologous bone grafting from the iliac bone is still the preferred option. In contrast, the literature suggests that [36] donor-area complications, particularly chronic pain, occur in up to 38%–39% of patients [37]. The literature suggests that up to 38–39% of patients experience donor complications, particularly chronic pain. In our data, 15 patients underwent iliac bone grafting and 4 patients developed donor complications, giving a donor complication rate of 36.7%. Considering that it is difficult to determine the potential for fracture growth by the growth of fracture callus tissues in patients with a postoperative plate break within 12 weeks, we excluded cases of fracture nonunion in this group and all cases were those that did not meet the criteria for bone nonunion healing and all had an internal fixation break of more than 12 weeks. After analysis, we concluded that for patients with plate fracture after 3 months postoperatively, revision surgery is not necessary for routine bone grafting, and for patients with Fernadez-Esteve fracture callus tissues of grades I and II, we considered that this part of the fracture healing potential is limited, especially after revision surgery for secondary disruption of blood flow to the fracture end, whereas autologous bone grafting brings abundant and excellent osteoblasts with clear osteogenic potential. The osteogenic induction effect is clear, accelerating the rate of fracture healing and improving the rate of fracture healing. For this group of patients, we recommend the use of autologous iliac bone grafting to ensure fracture healing. For patients with Fernadez-Esteve crusts of grades III, IV, and V, we believe that these patients have a high potential for fracture healing and that revision surgery without conventional bone grafting can reduce secondary trauma and donor area complications and reduce dissatisfaction and disputes between doctors and patients. The other group of patients with medial femoral bone defects, even if they have abundant fracture callus tissue growth, is also recommended for revision with a stage I medial femoral bone graft to restore the continuity of the medial femoral wall as soon as possible and to increase the support of the medial femoral wall. This ensures that in the race between fracture healing and metal fatigue fracture, fracture healing wins.

We believe that the choice of an internal fixation device for revision surgery needs to be individualised according to the patient’s fracture healing status. In our data, one patient had a plate fracture 3 months after femoral stem surgery and a Fernadez-Esteve grade I fracture callus tissue three months after surgery. The cause of the internal fixation fracture was considered to be the following: the medial butterfly bone block of the femoral stem was not fixed, the stress dispersion area of the plate was too short, and the proportion of nail holes was too large, resulting in no medial support, and the plate fracture was caused by minor trauma three months after surgery. The reason for the fracture was that the medial pterygoid bone block was not fixed and the support of the medial pterygoid bone block was not restored; at the same time, no bone graft was given during the first revision surgery and the postoperative fracture callus tissue grew slowly. The Fernadez-ESTEVE grade III fracture was not stabilized after revision, resulting in a refracture of the plate. The patient has referred to our hospital for revision surgery again, considering that the patient’s bone marrow cavity was not closed and that the medial butterfly bone mass had a large amount of fracture callus tissue attached to the bone stem. We used one period of fixation removal and internal fixation with intramedullary pins and no intraoperative bone grafting. Clinical healing of the fracture was achieved 4 months after surgery and the patient resumed daily activities.

6. Conclusion

Revision surgery after failed plate fixation of a femoral fracture should be based on the use of an appropriate internal fixation device, either an allogeneic autologous or allogeneic bone graft or other techniques. Factors include the presence or absence of infection, the cause and type of internal fixation failure, the growth of the fracture callus tissue, the type of bone discontinuity, the presence of bone loss or shortening, and the patient’s factors.

Data Availability

The data used to support this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

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Copyright © 2022 Junbo Tu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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