To solve the instrument loosening problem, we developed a fibroblast growth factor-2-calcium phosphate composite layer as a novel coating material to improve screw fixation strength. The primary aim of the present study was to demonstrate the safety and feasibility of screws coated with the FGF-2-calcium phosphate composite layer for posterior instrumented surgery of the cervical spine. The trial design was a single-arm, open-label, safety and feasibility study. Patients receiving fusion of the cervical spine from C2 (or C3) to C7 (or T1) were recruited. The primary endpoint to confirm safety was any screw-related adverse events. Seven patients who underwent posterior fusion surgery of the cervical spine were enrolled in the present study. The coated pedicle screws were inserted bilaterally into the lowest instrumented vertebrae. There was only one severe adverse event unrelated with the coated screw”. Three out of the 14 coated screws showed loosening. The present results prove the safety and feasibility of pedicle screws coated with the FGF-2-calcium phosphate composite layer for fusion surgery in the cervical spine. This is the first step to apply this novel surface coating in the field of spine surgery.
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Safety/feasibility study of pedicle screws coated with a fibroblast growth factor-2-calcium phosphate composite layer for posterior cervical fusion surgery
https://doi.org/10.21203/rs.3.rs-1509357/v1
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Recent advances in spinal instrumentation have improved clinical outcomes for various kinds of spinal pathologies. However, the increased usage of spinal instrumentation has led to the emergence of spinal instrumentation-specific surgical complications including increased risk of infection [1][2][3], instrumentation-related neuro-vascular injury [4][5][6][7][8] and loosening of implants [9][10][11]. Extensive efforts have been made to overcome these instrumentation-related surgical complications. Among these complications, implant loosening, which can lead to failure of bony fusion potentially resulting in an unfavorable clinical outcome [12], is one emerging surgical complication, especially for the older population with osteoporosis in Japan [13].
To solve the instrument loosening problem, several countermeasures have been proposed. A combination with hook/wire [14] and penetrating endplate screws [15], both of which increase pull-out strength of the screws, has been used as a technique to prevent loosening. Other approaches include using different screw configurations [16][17][18], cement-augmentation [19] or various kinds of surface coating [20][21].
We developed a fibroblast growth factor-2-calcium phosphate composite layer as a novel coating material to improve screw fixation strength [22]. It is composed of calcium phosphates, which increase initial fixation strength, combined with fibroblast growth factor-2 (FGF-2) incorporated through co-precipitation, which can achieve controlled release of FGF-2 and results in increased wound healing and osteogenesis [23][24]. We previously performed a clinical trial of external fixation pins coated with the FGF-2-calcium phosphate composite layer for distal radius fractures in five patients that resulted in no severe adverse events, demonstrating safety and feasibility [25]. We hypothesize that pedicle screws coated with the FGF-2-calcium phosphate composite layer could prevent pedicle screws from loosening.
The primary aim of the present study was to demonstrate the safety and feasibility of screws coated with the FGF-2-calcium phosphate composite layer for posterior instrumented surgery of the cervical spine.
One patient (No. 2) was excluded because of a significant deviation from the approved process of coating screws (saline for the soaking solution had expired). Therefore, the coated pedicle screws were inserted in seven patients.
One patient (No. 4) died from a rupture of an abdominal aneurism six months after surgery. This was judged by the institutional review board to have “no relationship with the coated screw” (Table 1).
Other adverse events included laboratory data abnormalities, elevation of creatin phospho-kinase (7 cases), liver dysfunction (4 cases) and elevation of serum amylase (1 case), all of which were considered to have "no relationship with the coated screw" (Table 1). As for neurological adverse events, one case of postoperative C5 palsy occurred, which also was considered to have "no relationship with the coated screw" (Table 1). Other types of adverse events included pneumonia (1 case) and urticaria (1 case), both of which were considered to have "no relationship with the coated screw" (Table 31. There were no surgical site infections or malignant diseases during the follow-up period.
Three out of the 14 coated screws showed loosening. One of those was positioned incorrectly, possibly influencing loosening. All loosening was detected with follow-up CT six months after surgery (Figs. 4, 5). Bony union was achieved in all patients one year after surgery. All clinical outcomes were favorable. The average JOA score improved from 10.3 points preoperatively to 15.3 points one year after surgery (p = 0.03). Postoperative VAS arm pain was significantly reduced (71.7 mm to 25.6 mm, p = 0.001) but there was no significant difference between pre- and postoperative neck pain (61 mm to 48 mm, p = 0.65).
This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Number 16K01434. The trial design was a single-arm, open-label, safety and feasibility study. All procedures used in this research were approved by Tsukuba University Clinical Research Review Board (approve number: CRB3180028) and performed in accordance with Declaration of Helsinki and Ethical Guidelines for Medical and Health Research involving Human Subjects issued by Japanese Ministry of Health, Labor and Welfare. The registration number was jRCTs031180078 (https://jrct.niph.go.jp/latest-detail/jRCTs031180078; date of registration: 11/01/2019). Written informed consents were obtained from all patients to participate in this study and for publication. The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Inclusion and exclusion criteria are shown in Table 2. Patients receiving long fusion of the cervical spine from C2 (or C3) to C7 (or T1) were recruited. The primary endpoint to confirm safety was any screw-related adverse events. Secondary endpoints to assess efficacy were the rate of loosening/breakage of the coated pedicle screws and duration until bony fusion. The Japanese Orthopedic Association (JOA) score and visual analogue scale (VAS) for neck/arm pain were used to assess clinical outcomes.
Preparation of screws coated with the FGF-2-calcium phosphate composite layer
An outline showing steps in formation of the FGF-2-calcium phosphate composite layer is shown in Fig. 1. The coating procedure was performed under the air cleanliness condition class 6 (ISO 14644-1) on a clean bench that is installed in a clean room (class 5) of the Cell Processing Factory at our institute. Three screws were coated with the FGF-2-calcium phosphate composite layer at one time, one for a quality check and two for surgery. The diameter and length of the pedicle screws were determined based on a preoperative CT measurement. Titanium alloy pedicle screws were used in the present study (Mounteneer®, DePuy Synthes spine, Bethesda, MA). The coating procedure is described elsewhere [25]. Briefly, FGF-2 (Fiblast®, Kaken Pharmaceutical, Tokyo, Japan; 4µg/mL) was dissolved in a supersaturated calcium phosphate solution prepared by using clinically available infusions, and injection fluids. The screws were soaked for 48 hours at 37o C in the supersaturated calcium phosphate solution. A specific jig was made to hold the screws within the solution (Fig. 2A). After 48 hours of soaking, precipitate on the bottom of the cup and coating on the surface of the screws were confirmed (Fig. 2B, C).
One out of the three coated screws was used to check quality. The coated layer was dissolved in citrate solution and a protein assay (Bradford method), chemical analysis for the Ca/P molar ratio, and FGF-2 bioassay (NIH 3T3 cell proliferation) were performed. The supersaturated calcium phosphate solution was collected and subjected to bacteriological and endotoxin examinations.
Eight patients who underwent posterior fusion surgery of the cervical spine were enrolled in the present study (Fig. 3 and Table 3). Indications for surgery included ossification of the posterior longitudinal ligament (6 cases) and cervical spondylotic myelopathy (2 cases). The average age at surgery was 59.6 years old (48–64 yo).
The coated pedicle screws were inserted bilaterally into the lowest instrumented vertebrae (C7 or T1). All the patients were followed by assessment of clinical outcomes, X-rays, CT and laboratory investigation for one year after surgery. The definition of screw loosening was observation of a 1 mm or more lucent zone on the CT images. Bony union was evaluated by continuity between facet joints on a sagittal reconstruction CT multiplanar image.
Adverse events were defined as any symptom or disease in patients after informed consent with or without causal relationship to the coated screw. All adverse event-related terminology was coded by the investigators according to the ICH International Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J).
This clinical trial showed no adverse events related to the coated screws. The only severe adverse event (SAE) was death due to the rupture of an abdominal aortic aneurism. This SAE was considered to have "no relationship with the coated screw" because the patient died six months after surgery and a retrospective check of the preoperative CT revealed the aneurism.
Abnormalities detected by laboratory analyses were possibly influenced by surgical invasiveness and/or drugs used in the perioperative period, including anesthetics, analgesics, and antibiotics. The number and degree of abnormalities were comparable to those of a standard postoperative course, and all the abnormalities were rapidly resolved without any specific treatment. Therefore, they were considered to have "no relationship with the coated screw". Previous reports revealed that FGF-2 is safe for the central nervous system because it had been used safely in laboratory investigations and clinical trials for spinal cord injury and brain infarction [26][27]. As for neurological adverse events, one case of postoperative C5 palsy occurred, which was considered to have "no relationship with the coated screw" (Table 3) because previous reports revealed that the incidence of C5 palsy after cervical spine fusion surgery is approximately 10%, similar to that in the present study [8].
Our previous report showed screw loosening occurred up to 40% of the time at the caudal end of the long cervical fusion construct, possibly because long fusion leads to a longer lever arm [28]. Countermeasures for screw loosening at the end of the constructs are mandatory because mechanical stress concentrations can occur there. In the present study, 3 of 14 coated pedicle screws loosened at the caudal end of the long fusion. The rate of screw loosening was comparable to our previous series. However, we cannot draw a definitive conclusion because the present study was designed as a single arm study without any control group. Further exploration using a randomized controlled design is mandatory to reveal the true efficacy of the coated layer on the pedicle screw to counteract screw loosening.
The present results prove the safety and feasibility of pedicle screws coated with the FGF-2-calcium phosphate composite layer for fusion surgery in the cervical spine. This is the first step to apply this novel surface coating in the field of spine surgery.
Availability of data and materials
The datasets used and/or analyzed during the current study available from the corresponding author on request
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Table 1: List of all the adverse events (AE).
The only severe adverse event was death due to the rupture of an abdominal aortic aneurism. This severe adverse event was considered to have "no relationship with the coated screw" because the patient died six months after surgery and a retrospective check of the preoperative CT revealed the abdominal aortic aneurism.
Table 2: Inclusion / Exclusion criteria.
Inclusion and exclusion criteria are shown. Patients receiving long fusion of the cervical spine from C2 (or C3) to C7 (or T1) and aged from 20 to 90 were recruited. Exclusion criteria were set mainly for safety.
Table 3: List of participants.
Eight patients who underwent posterior fusion surgery of the cervical spine were enrolled in the present study. One patient (No. 2) was excluded because of a significant deviation from the approved process of coating screws (saline for the soaking solution had expired). Therefore, the coated pedicle screws were inserted in remaining seven patients.
No competing interests reported.