Evaluation of titanium mesh cranioplasty and ...

Evaluation of titanium mesh cranioplasty and ...

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Strengths and Limitations of This Study

• This will be the first multicenter, randomized controlled study that evaluates the long-term outcome of titanium mesh cranioplasty and polyetheretherketone cranioplasty.

• This study will help neurosurgeons choose alloplastic material, especially for patients who suffer bone resorption with autologous bone cranioplasty and may require reoperation.

• Complications following cranioplasty and the relationship to timing will be detected in the study.

• Subgaleal effusion, less studied in similar research, will also be investigated.

• Different medical conditions and surgeons' experiences are limitations of this study. However, personnel will be trained centrally in advance to reach a uniform standard.

Introduction

Cranioplasty, dating back to 7000 BC, offers protective barrier and cosmetic benefits for patients with cranial defects following cranial surgery, along with neurological and cognitive improvements. Over the past half-century, neurosurgical and emergency care have increasingly improved, making this procedure routine in neurosurgery departments. However, reconstructing cranial defects presents many challenges to surgeons, and the search for ideal materials has been ongoing throughout the development of reconstructive procedures.

Ideally, the implant material should be durable, biocompatible, widely available, and have a low incidence of infection. Several options, ranging from autologous bone, metals, acrylics, and plastics, have been used in reconstruction, with varying success rates. Given the low costs and biocompatibility, autologous bone grafts are traditionally regarded as the gold standard. However, the most common complication following autologous bone transplant is bone flap resorption, often necessitating reoperation and replacement with alloplastic materials. Therefore, exploring optimal alloplastic materials for cranial reconstruction has become crucial.

Nowadays, various synthetic materials have been used in cranioplasty. Polymethylmethacrylate was one of the early materials chosen for cranioplasty. It is strong, heat resistant, radiolucent, and inert, but its exothermic reaction can lead to injuries to soft tissues around it. Other common materials include hydroxyapatite and calcium phosphate, each having its positive and negative characteristics.

Recently, titanium mesh has become a popular material for cranial reconstruction due to its good biocompatibility, low infection rate, good mechanical strength, and low cost. Computer-assisted three-dimensional (3D) modeling in titanium mesh design leads to excellent cosmetic results. However, titanium mesh implants can cause allergic reactions, erosion of overlying soft tissue, and temperature conduction leading to scalp paresthesia.

Newer materials such as polyetheretherketone (PEEK) implants are gaining popularity for craniofacial reconstruction due to their radiolucency, chemical inertness, stiffness, and sterilization capabilities. Additionally, PEEK implants can be designed specific to a patient's cranial defect using computer-assisted 3D printing technology and can also be used in complex craniofacial reconstruction. However, the high cost of PEEK implants may place an excessive economic burden on patients, and many surgeons are troubled by epidural effusion after cranioplasty, speculated to be caused by allergic reactions.

Despite the increasing use of PEEK, there is a lack of research comparing the outcomes of titanium mesh and PEEK cranioplasties. Therefore, this study aims to compare the long-term implant failure rate, aesthetic outcomes, neurological outcomes, and postoperative complication rates of primary PEEK cranioplasty versus primary titanium mesh cranioplasty.

Objective

The primary objective is to compare implant failure rates (defined as implant exposure or infection requiring removal of the synthetic material) at any time within 6 months in patients with cranioplasty. Secondary outcome evaluations include complication rates and their relationship to timing, neurological and cognitive outcomes, motor function, cerebral hemodynamics changes, and cosmetic outcomes.

Design

The PEEK cranioplasty and titanium mesh cranioplasty (PTCP) is a multicenter, prospective, assessor-blinded, randomized controlled clinical trial conducted from December 2019 through June 2021. The treatment schedule and flow chart of this study are shown in figure 1. A total of 15 centers from around China are included in this trial. Personnel from other centers are experienced neurosurgeons skilled in both neurosurgery and cranioplasty, with previous trial experience and high follow-up rates. Additionally, personnel involved in this study will be centrally trained in study requirements, surgical strategies, and standardized measurement of neurological, motor, cognitive function, and assessment of brain hemodynamics, ensuring uniform information from study participants. All participating hospital sites must receive local ethics committee approval or adhere to our ethics committee review decision.

Figure 1

Flow chart of the participants (procedure) through the trial. EEG, electroencephalography; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale; MMSE, Mini-Mental State Examination; PEEK, polyetheretherketone; TCD, transcranial Doppler sonography, DC, decompressive craniectomy; CP, cranioplasty; CSF, cerebrospinal fluid

Recruitment and Eligibility

Two recruitment strategies are included in this trial. First, participants are recruited through the outpatient department. Second, after reviewing patient databases, those who have undergone craniectomy will be informed for subsequent visits. Recruitment began in December 2019. Each subject will receive financial compensation.

Inclusion Criteria

1. Patients aged over 18 years, of either sex.

2. Diagnosed with a cranial defect (due to severe traumatic brain injury, ischemic stroke, hemorrhagic stroke, infiltrative tumor, etc.).

3. The defect size is over 25 cm².

4. Agree to participate in this clinical trial, with informed consent signed by patients or their next of kin on behalf of the patient.

Exclusion Criteria

1. Bilateral cranial defect.

2. Active smoking.

3. Diagnosed with diabetes or coronary heart disease.

4. History of radiation therapy.

5. Hydrocephalus or previous bypass surgery.

6. Previous scalp free tissue transfer.

7. Documented allergy to titanium.

8. Non-initial cranioplasty surgery.

9. Uncontrolled intracranial infection.

10. Intracranial hematoma.

11. Unhealed scalp.

12. Operative contraindications and not suitable for surgery (e.g., pulmonary infection, poor general condition).

13. Dural defect or dural tearing during the cranioplasty procedure.

Sample Size

Previous studies reported that over 25% of patients experienced implant failure following titanium cranioplasty, compared with a less than 10% implant failure rate using PEEK cranioplasty. We calculated that a sample size of 120 will be required in this clinical trial with a significance level of 5% (two-sided) and a power of 80% to demonstrate a 20% difference in satisfactory outcome rates due to implant failure. To ensure the study's quality, the sample size is enlarged to 140.

Randomisation and Blinding

After obtaining consent from eligible patients, they will be randomly allocated to PEEK cranioplasty or titanium mesh cranioplasty using randomization software. Blinding the participants and surgeons is impossible as the implanted materials are identifiable. Therefore, participants will be informed about their allocated material. Blinding will be ensured for assessors who will not contact the researcher conducting the randomization process.

Intervention

After patient recruitment, investigators will collect basic information and obtain informed consent. Patients will undergo surgery based on randomization results. Our previous study outlined the surgical strategies, and personnel involved in this trial will be centrally trained to achieve uniform procedures.

Manufacture of Custom-Made Titanium and PEEK Cranioplasties

Using high-resolution CT scans of patients' heads and computer-assisted techniques, virtual 3D models of the skull are generated. The titanium mesh and PEEK cranioplasties are designed individually for each patient to restore structural integrity and achieve bone symmetry. Titanium meshes are generated by compression into a mold, cutting to shape with a thickness from 0.6 to 1.0 mm. PEEK implants are fabricated using 3D print technology according to the model. Thus, the titanium mesh range is usually slightly larger than the cranial defect size, while the PEEK implant perfectly matches the cranial defect.

Surgical Procedure

This multicenter study ensures personnel are centrally trained to reach a standard surgical uniform. If a patient shows cerebral swelling, lumbar cistern drainage is performed until the swelling subsides and the patient stabilizes. The patient's hair is completely shaved, taking care not to damage the scalp. Following anesthesia, the scalp is vigorously washed, and skin preparation is applied to avoid contamination. After preparation, the scalp is dissected and reflected using scissors, avoiding dural tearing to prevent postoperative CSF leakage. Bleeding on the scalp or dura is controlled by a bipolar coagulator. Hydrogen peroxide is used to wash the scalp and the dura to minimize bleeding and contamination. The skull defect margin is debrided, considering the shape of the titanium mesh implant. The exposed area is 0.5–1.0 cm larger than the cranial defect to accommodate the required implant. The temporalis muscle is cautiously dissected and managed according to experience.

The custom-made implant is then placed and adjusted to ensure precise positioning intraoperatively. After dural suspension, the titanium or PEEK material is anchored using screws. A wound drain is positioned to drain blood above the implant material. The galeal layer and the skin are closed with sutures. The drain is left for about 3 days after cranioplasty and removed when the drainage is low.

Outcomes

Primary Outcome

The primary outcome of this clinical study is the implant failure rate within 6 months, defined as infection or implant exposure requiring removal of the implant.

Secondary Outcome

The secondary outcomes include:

1. Complication events occurring within 6 months after cranioplasty, including postoperative new seizures, postoperative hematomas, postoperative hydrocephalus, cerebrospinal fluid rhinorrhea, subgaleal effusion, and superficial surgical site infections treatable conservatively.

2. Neurological outcomes assessed using Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) scores, with cognitive evaluation using the Mini-Mental State Examination (MMSE) prior to surgery and at 3 and 6 months after surgery.

3. Motor function evaluated using the Oxford grading system, comprising 6 grades from 0 (no contraction) to 5 (full resistance), assessed before admission and at 3 and 6 months follow-up visits.

4. Cerebral hemodynamics measured by transcranial Doppler sonography (TCDS) prior to and at 3 and 6 months after cranioplasty. Variability in TCDS assessment is minimized by centrally training clinicians and providing uniform assessment standards.

5. Cosmetic outcomes assessed by patients and neurosurgeons, focusing on the degree of temporal hollowing.

6. Total costs including surgery expenses over a 6-month period.

Data Collection

After enrolling in the study, experienced staff at each participating center will collect baseline data, including neurological function evaluations, cognitive assessments, cerebral hemodynamics, and imaging. Follow-up data will be collected and recorded at 3 and 6 months post-cranioplasty. Data collection plans are shown in table 1.

Table 1

Study schedule

Family members will assist patients in completing evaluations if needed. Data will be paper-based and anonymized by each center before being transferred to assessors and entered into an electronic database. Adverse events occurring during the study are documented. All data will be recorded in the data collection form promptly.

Data and Safety Monitoring

An independent data monitoring committee (DMC) will periodically monitor this trial's safety and efficacy, identifying if adjustments are needed. The DMC consists of neurosurgeons, neurologists, statisticians, and data analysts, who will assess the trial annually to review study data.

Statistical Analysis

Statistical analyses will be performed using SPSS V.22, with p-values < 0.05 considered statistically significant. Continuous variables will be described as arithmetic means ± SD and medians (range) for normal and non-normal distributions, respectively. Implant failure rates and complication rates will be analyzed using the χ² test, while continuous parameters will be analyzed using t-tests or Mann-Whitney U tests for non-parametric cases. Subgroup analysis, stratified by age, subgaleal effusion status, cranioplasty location, cerebral hemodynamics, and neurological function, is pre-planned, and regression methods will be used.

Patient and Public Involvement Statement

No patients or public were involved in the design, recruitment, or conduct of this research. Participants will be informed that they can contact the researchers for emotional support if needed. A journal manuscript will be prepared to provide feedback on the research results following the trial's completion.

Ethics and Dissemination

All patients will be fully informed about the implant materials, potential complications after surgery, and their responsibilities during the trial before signing the informed consent. If a patient's cognitive function is impaired, their next of kin will be carefully informed. Possible adverse events include infection, implant exposure, postoperative seizures, postoperative hydrocephalus, intracranial hematoma, and subgaleal effusion, which are common cranioplasty complications. All reported complications will be documented.

The results will be disseminated through academic conferences, student theses, and publication in a peer-reviewed journal.

Discussion

Cranioplasty is a common surgical procedure performed using either autologous bone or implanted materials. Titanium mesh has been the most commonly used alloplastic material for reconstruction, though it is associated with high complication rates. The increasingly popular PEEK material has demonstrated advantages over titanium mesh. This study seeks to fill the data gap due to a lack of high-quality studies by providing robust evidence comparing implant failure rates, complication rates, and neurological improvement between different cranioplasty materials. The primary outcome is the implant failure rate within 6 months, and secondary outcomes include complication rates and neurological improvements. This study aims to help neurosurgeons choose the best cranioplasty materials, especially for patients needing reoperation due to bone resorption with autologous bone cranioplasty. It will also detect a wide range of cranioplasty complications and their relationship to timing, with a focus on investigating subgaleal effusion, a common yet understudied complication. Despite variations in medical conditions and surgeon experience across centers, personnel will be centrally trained to ensure uniform standards.

Minimizing Risk of Customized Titanium Mesh Exposures

This study shows that treatment with customized titanium meshes offers the opportunity to provide high-quality work in large three-dimensional bony defects. The benefits like precise fit, shorter time of surgery, predictable outcome and good acceptance