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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2017,  2:146

Safety and efficacy of three-dimensional shaping of titanium plate in subtemporal repair of skull defects: study protocol for a data analysis of 38 patients


Department of Neurosurgery, Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, Suzhou, Jiangsu Province, China

Date of Web Publication8-Nov-2017

Correspondence Address:
Wei Qian
Department of Neurosurgery, Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, Suzhou, Jiangsu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.217493

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  Abstract 

Background and objectives: Repair of the damaged skull is necessary after decompressive craniectomy. Previously used autologous bone, allogeneic bone, and organic material are associated with the risk of an unsatisfactory cosmetic outcome and infection. Titanium mesh is an ideal material for cranioplasty. Digital three-dimensional shaping of titanium mesh allows it to perfectly match the skull defect and can restore the anatomic appearance of the defective area.
Design: Retrospective case analysis.
Methods: We analyzed the surgical and follow-up data of 38 patients with skull defects who underwent subtemporal repair using three-dimensional shaping of a titanium plate at the Department of Neurosurgery, Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, China, from January 2015 to December 2016.
Outcome measures: The primary outcome measure was the incidence of complications within 12 months after surgery. The secondary outcome measures were the Glasgow outcome scale score, Karnofsky performance scale score, National Institutes of Health stroke scale score, and skull computed tomography scan results at 1, 6, 12, 18, and 24 months after repair. Partial results have been obtained for 38 patients who have been followed up for 6 to 24 months. No complications or adverse reactions occurred. Skull computed tomography scan results revealed that the titanium mesh and nail were well fixed, the skull shape was symmetrical, and no subcutaneous effusion or intracranial hemorrhage occurred.
Discussion: Complications, neurological function, and imaging findings in patients with frontotemporal skull defects provide an experimental basis for three-dimensional shaping of titanium plates in subtemporal repair of frontotemporal defects.
Ethics and dissemination: The study design was completed in May 2017. The protocols had been approved by the Ethics Committee of The First People's Hospital of Wujiang District in June 2017. This trial was registered in October 2017. Data of patients, who were treated from January 2015 to December 2016, were analyzed in June 2017. Data analysis will be finished in December 2017. The results of the trial will be published in a peer-reviewed journal and will be disseminated via various forms of media.
Trial registration: This trial has been registered in the Chinese Clinical Trial Registry (identifier: ChiCTR-IOC-17012947). All data collection and analysis are currently ongoing.

Keywords: clinical trial; three-dimensional shaping of titanium plate; temporal muscle; skull defects; safety; efficacy; retrospective case analysis


How to cite this article:
Qian W, Zhang W, Jin H, Zhu Yq, Zou Y. Safety and efficacy of three-dimensional shaping of titanium plate in subtemporal repair of skull defects: study protocol for a data analysis of 38 patients. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:146-52

How to cite this URL:
Qian W, Zhang W, Jin H, Zhu Yq, Zou Y. Safety and efficacy of three-dimensional shaping of titanium plate in subtemporal repair of skull defects: study protocol for a data analysis of 38 patients. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2018 Aug 21];2:146-52. Available from: http://www.actnjournal.com/text.asp?2017/2/4/146/217493


  Introduction Top


Background

Decompressive craniectomy is one of the main means of relieving intracranial hypertension (Skoglund et al., 2006). The skull is a membranous bone with poor bone regeneration ability. The new bone mainly originates from the inner periosteum. In general, only defects with a diameter of < 1 cm can self-heal; those with a diameter of 3 cm undergo self-repair with difficulty (Coelho et al., 2014). After decompressive craniectomy, the physiological integrity of the cranial cavity is destroyed. The flap at the site of the skull defect loses its support. Atmospheric pressure is transmitted directly to the brain through the scalp. The subarachnoid space is thus oppressed and blocked, which causes circulation dysfunction of the cerebrospinal fluid and disturbance of the cortical hemodynamics in the brain, leading to the appearance of cranial defect syndrome and affecting the recovery of neurological function (Lee et al., 2011; Kolias et al., 2013; Annan et al., 2015; Chen et al., 2017; Jehan et al., 2017; Smith, 2017). Therefore, skull defects can be repaired 3 to 6 months after decompressive craniectomy (Bostrom et al., 2005).

Autologous bone, allogeneic bone, organic material, and metal are the most common materials used to repair skull defects. Autologous bone must be surgically collected from the ribs or ilium, which increases the patient's pain and does not have an ideal shaping effect. In addition, it is associated with bone resorption defects and is difficult to preserve (Sultan et al., 2011). Allogeneic bone has a long preservation time and high risk of infection and foreign body reaction (Liu et al., 2000). Some organic materials readily age, have low strength, and exhibit problems such as self-coagulation, heat production, and toxicity (Wang et al., 2010). Titanium alloys have good biocompatibility, a low rate of tissue rejection, stable chemical properties, and low corrosion resistance and absorption and can be examined by computed tomography (CT) and magnetic resonance imaging through radiation. After implantation, fibroblasts grow in the pores of titanium mesh and integrate with tissues. Therefore, such mesh is widely used both inside and outside of China (Hill et al., 2012; Kung et al., 2012; Jin et al., 2016). Titanium mesh is made by hand-molding and digital three-dimensional shaping. Hand-molding involves the manual cutting and shaping of the titanium mesh according to the size, shape, and curvature of the skull defect; the error is large; and it needs to be fixed with a large number of titanium nails. Digital three-dimensional shaping of titanium mesh allows for the creation of a custom-made material with an individual design that can perfectly match the patient's skull defect. Thus, there is no need for reprocessing, the shape of the skull can be restored, and the number of titanium nails is less than that required for hand-molding.



Frontotemporal skull repair is classified into subtemporal repair and external temporal repair according to whether the temporal muscle is separated. External temporal repair involves direct fixation of the titanium plate outside the temporal muscle without separation of the temporal muscle, and the operation is relatively simple. Some patients have a thin skin flap and poor blood supply, which can lead to scalp damage and exposure of the titanium plate. Because of lower temporal muscle occlusion, the bone window edge cannot be fully revealed. Titanium nail fixation is relatively difficult, readily leading to titanium mesh loosening after surgery. Because the titanium plate presses the temporal muscle directly, leading to dysfunction of the temporal muscle, patients may develop masticatory pain after the operation (Wang et al., 2009). Placing the repair material between the temporal muscle and dura mater or sham dura mater will reduce the occurrence of these problems.

Characteristics of the Trial

Previously reported methods of skull defect repair required hand-molding during surgery, which prolongs the duration of surgery and increases the possibility of postoperative infection. Moreover, titanium mesh itself has a certain degree of flexibility and plasticity, and it is difficult to achieve the ideal stable shape within a short time. Fixation of the titanium mesh is difficult after it has been inserted, and its edge is rough and sharp. Thus, cutting injury of the subcutaneous tissue and muscle may readily occur. The temporal lobe and its surrounding tissues are very sensitive to ischemia, hypoxia, and injury, which can induce epilepsy (Xiong, 2015). Three-dimensional shaping of titanium mesh is based on the three-dimensional data of the skull on the uninjured side in patients with brain defects. The flat titanium mesh is molded into a prosthesis, which is larger than the bone margin by 0.5 to 1.0 cm, and the shape is completely symmetrical with the skull on the uninjured side; it can effectively eliminate the rebound and residual stress caused by hand-molding and achieve the precise combination of the prosthesis and defect zone (Feng et al., 2014). Three-dimensional shaping of titanium mesh has been extensively used to repair skull defects, can restore the anatomical features of the defect site, and can be retained for the patient's lifetime after implantation.

Main Objective

This retrospective analysis was performed to identify the safety and efficacy of three-dimensional shaping of titanium plates in the subtemporal repair of frontotemporal skull defects at the Department of Neurosurgery, Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, China.


  Methods/Design Top


Study design

This is a retrospective case analysis involving the data of 38 patients with skull defects undergoing subtemporal repair using three-dimensional shaping of titanium plates at the Department of Neurosurgery, Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, China from January 2015 to December 2016. The study design is compliant with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Additional file 1 [Additional file 1]). The primary outcome measure was the incidence of complications within 12 months after surgery. The secondary outcome measures were the Glasgow outcome scale score, Karnofsky performance scale score, National Institutes of Health stroke scale score, and skull CT scan results at 1, 6, 12, 18, and 24 months after repair.

Study participants

Thirty-eight patients with skull defects who underwent subtemporal repair using three-dimensional shaping of titanium plates at the Department of Neurosurgery, Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, China, were recruited in this study.

Inclusion criteria

Patients presenting with all of the following criteria were considered for study inclusion:

  • Unilateral frontotemporal skull defects
  • Skull defect diameter of > 3 cm
  • Skull repair 3 months after decompressive craniectomy
  • No obvious edema, no obvious shift in the midline structure, and no obvious ventricular dilatation as revealed by skull CT scan
  • Consciousness and Glasgow coma scale scores (Green et al., 2017) of > 13 points
  • Stable heart, lung, liver, and kidney indicators
  • Age of 20 to 70 years


Exclusion criteria

Patients with one or more of the following conditions were excluded from this study:

  • Skin infection at the surgical area
  • Intracranial hypertension after decompressive craniectomy
  • Thin scalp at the defect site
  • Asymmetrical bilateral skull halves before the first craniotomy
  • Severe heart, liver, or kidney dysfunction
  • Poor general condition
  • Severe neurological deficits
  • Possibly sensitive to titanium mesh materials
  • Participation in other material clinical trials within 3 months
  • Pregnant, possibly pregnant, and breastfeeding women


Withdrawal criteria

Patients who met one or more of the following criteria during the trial were withdrawn from this study:

  • Incomplete information affecting the efficacy or safety of participation
  • Complications affecting efficacy and safety judgments or onset of diseases affecting the outcome


Study Schedule

The study design was completed in May 2017. The data of patients who were treated from January 2015 to December 2016 were analyzed in June 2017. Data analysis will be finished in December 2017.

Recruitment

Thirty-eight patients listed in the medical record library of Wujiang Hospital (The First People's Hospital of Wujiang District) of Nantong University who met the inclusion criteria of this study were informed of our study by telephone. After providing informed consent, the data of these patients were collected for our study.

Baseline Analysis

The patients' baseline information, including demographic data and general disease history, are shown in [Table 1].
Table 1: Baseline data and general disease history of the included patients

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Interventions

The titanium mesh used in this trial was made with TA3 pure titanium meeting GB/T13810 standards (Jiangsu Aidier, Zhangjiagang, Jiangsu Province, China) (General Administration of Quality Supervision, Inspection and Quarantine of the People's Republic of China and Standardization Administration of the People's Republic of China, 2007).

Before surgery, all patients underwent a 64-slice spiral CT scan (slice thickness: 0.625 mm). Three-dimensional reconstruction was conducted using these CT scan data by Shanghai Tuchuang Biological Technology of China. The individual titanium mesh repair material was formed after strict examination and confirmation of the patient information and defect location.

Skull defects were repaired 3 months after decompressive craniectomy. Antibiotics were used for prevention in all patients 30 minutes before surgery. After administration of general anesthesia, an incision was made at the site of the original incision. The flap was first separated from the temporal muscle under the capsular aponeurosis. The temporal muscle was isolated from the temporal and sham dura spaces. During separation, if the sham dura was broken, a gelatin sponge was used to fill the defect and size 0 suture was used to close the wound. After exposure of an approximately 1-cm bone window margin, the customized three-dimensionally shaped titanium plate was overlaid with the bone window and fixed with a titanium nail. According to the intracranial pressure, the dura mater was suspended on the titanium plate. The isolated temporal muscle was sutured to the titanium plate with proper tension to reconstruct the attachment site of the temporal muscle. A drainage tube was placed under the epicranial aponeurosis. The skin was sutured layer by layer, and aseptic dressing was applied.

Antibiotics were utilized for 3 days postoperatively. The drainage tube was removed on day 2, and the sutures were removed 1 week later.

Outcome measures

Primary outcome measure

The primary outcome measure was the incidence of complications within 12 months after surgery. Complications included a nonhealing or poorly healing wound, pain during chewing, loose or exposed titanium plate, subcutaneous effusion, and intracranial hemorrhage.

Secondary outcome measures

  • The Glasgow outcome scale score, which ranges from 1 to 5, was assessed at 1, 6, 12, 18, and 24 months after repair. A lower score indicates a poorer prognosis (Idris et al., 2014).
  • The Karnofsky performance scale score was assessed at 1, 6, 12, 18, and 24 months after repair. This scale was developed by Karnofsky from the Eastern Cooperative Oncology Group. The patient's status was evaluated according to normal activities, illness, and self-care ability. Each grade comprises 10 points, and the highest possible score is 100 points. Higher scores indicate a better health status (Oken et al., 1982).
  • The National Institutes of Health stroke scale score was assessed at 1, 6, 12, 18, and 24 months after repair. This scale reflects neurological function. The total score is 42. Higher scores indicate more severe nerve damage (Siniscalchi et al., 2017).
  • Skull CT scans were performed at 1, 6, 12, 18, and 24 months after repair to examine the fixation effects of the titanium mesh and titanium nails and symmetry of the bilateral skull halves. The symmetry of the bilateral skull halves was observed using the median layer of the bone window phase of the CT images. The difference in the distance between the bilateral outer table of the skull and median line was compared, and its theoretical value was 0. However, the thickness of the titanium mesh was 0.625 mm; therefore, we set the symmetry standard at < 1 mm.
  • Surgical indicators included the operation time, intraoperative blood loss, number of titanium nails, and postoperative hospital stay.


Trial timeline

The trial flow chart is shown in [Figure 1]. The schedule of outcome measurement assessments is shown in [Table 2].
Figure 1: Trial flow chart.

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Table 2: Timing of outcome assessment

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Monitoring Plan

The inspector conducted an audit every 3 months. In the early stage of the trial, the inspector optimized the research program, evaluated the criteria, and completed the personnel training. In the middle stage of the trial, the inspector focused on monitoring the test schedule, ensuring that informed consent was obtained, checking the initial data, and evaluating the trial implementation. In the late stage of the trial, the inspector compiled the data and guided the researchers in keeping the necessary test documents.

Statistical Analysis

The database was established using Epidata3.0 software (Epidata Association, Odense, Denmark). All data were analyzed using SPSS 13.0 software (SPSS, Chicago, IL, USA). Measurement data are expressed as the mean ± standard deviation. Count data are expressed as ratios.

A previous study showed that the incidence of complications was approximately 20% (Wang et al., 2017). Our expected incidence of complications was 10%. Taking β = 0.1 and power = 90% with a significance level of α = 0.05, the final sample size of 112 was calculated using PASS 11.0 software (MCSS, MD, USA). Assuming a patient loss rate of 20%, we required 135 patients per group. Based on our experimental funding and limited time, 38 patients were included in the trial.

Data Management

The lead researcher checked and locked the data. None of the data could be altered after locking. The data were analyzed by professional statisticians. All data were preserved in Wujiang Hospital (The First People's Hospital of Wujiang District), Nantong University, China. The anonymized trial data will be published at www.figshare.com.

Feasibility Analysis of the Present Study

Cranioplasty can be used to repair skull defects, restore the physical protection ability of the skull, and avoid direct damage by atmospheric pressure. Three-dimensional shaping of titanium mesh has been extensively used to repair skull defects and has good biocompatibility. Perfect restoration of the skull on the injured side according to the contralateral skull shape is an individualized treatment for skull defects after traumatic brain injury. The authors' team performed nearly 40 of these surgical procedures in 2015 and 2016.

Quality Control

All test personnel used standard operating procedures to ensure quality control and quality assurance. All data and findings in the clinical trials were verified, and the quality was controlled at all stages of the trial. The data in the clinical trials will be kept and managed as required.

Ethical Requirements and Dissemination

The protocols were approved by the Ethics Committee of The First People's Hospital of Wujiang District. The results of the trial will be published in a peer-reviewed journal and disseminated via various forms of media.

Confidentiality

After providing informed consent, the patients will authorize the inspectors, arbitrators, and ethics committee to directly access their original medical records for verification of test procedures or test data. The trial methods and results will be kept confidential. No release is allowed unless authorized by the party.


  Results Top


Trial status: This trial was registered in the Chinese Clinical Trial Registry (identifier: ChiCTR-IOC-17012947). The partial results are as follows: Thirty-eight patients were followed up for 6 to 24 months. All incisions healed well. No scalp infection or titanium mesh exposure was found. The shape of the defect site was satisfactory, and no obvious symptoms of pain during chewing occurred. Skull CT scans revealed that the titanium mesh and titanium nail were well fixed and that the skull was symmetrical. No subcutaneous effusion or intracranial hemorrhage was visible.


  Discussion Top


Significance of this study

After repair using three-dimensional shaping of titanium mesh, the repaired frontotemporal region is similar to the healthy side, and the appearance is symmetrical according to the two-dimensional CT images as well as the images of the skull and temporal muscle on the uninjured side (Kung et al., 2012). The findings of the present study indicated that few postoperative complications develop after three-dimensional shaping of titanium plates in the repair of skull defects for restoration of the normal anatomic structure of the skull, temporal muscle, and scalp. Thus, this material is more acceptable to the patient than are other materials.

Advantages and limitations of this study

Three-dimensional shaping of titanium plates has high design accuracy, can shorten the operation time, reduces the duration of exposure of the surgical field to air, and reduces the postoperative infection rate. The three-dimensionally shaped titanium plate is highly consistent with the original skull defect site. After the operation, the titanium plate does not readily tilt, which reduces the incidence of common complications such as material exposure, loosening, infection, and poor shaping caused by the poor anastomosis between the repair material and defect site. The shape of the skull can be restored effectively through three-dimensional reconstruction of the defect site according to the anatomic data on the uninjured side. This trial has not been completed; therefore, the long-term effects require further follow-up observation. Because of the retrospective nature of this study, the clinical data were collected with poor integrity and homogeneity, and follow-up studies are needed to further validate the results.

Evidence for contribution to future studies

The findings regarding neurological function, imaging, and complications of these 38 patients with frontotemporal defects can provide objective data for clinically customized three-dimensional shaping of titanium plates in the repair of skull defects.[24]

 
  References Top

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Author contributions
WQ, WZ, HJ, YQZ, YZ conceived the study, designed the study protocol, drafted and revised the manuscript, collected the data. All authors read and approved the final manuscript.
Conflicts of interest
None declared.
Research ethics
The protocols had been approved by the Ethics Committee of The First People's Hospital of Wujiang District in June 2017. This trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-IOC-17012947) on October 11, 2017.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Data sharing statement
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.
Additional file
Additional file 1: SPIRIT checklist.


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