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This work aimed at investigating the possibility and effectiveness of osteoinductive calcium phos- phate (CaP) ceramics to close the drilled skull holes and prevent the postoperative cerebrospinal ﬂuid (CSF) leaking in children’s endoscopic neurosurgery. Five children patients (four boys and one girl, 3- to 8-years old) underwent the surgery, in which the endoscopic third ventriculostomy (ETV) was operated in four cases of hydrocephalus, and biopsy and ETV were both performed in one case of pineal tumor. The drilled skull holes were ﬁlled with the commercial osteoinductive CaP ceramics. The patients were followed up by CT scan at 1, 7 days, 3 and 6 months postopera- tively. All the ﬁve cases were successful, and the holes were closed well after ﬁlled with the ceramics. The follow-up survey showed that no CSF leaking or rejection reaction was found. The CT scan indicated that the drilled holes began healing at 7 days postoperatively, and a relatively complete healing happened at 6 months postoperatively. The excellent ability of the CaP ceramics to induce bone regeneration was also conﬁrmed by repairing the skull defects in a monkey model. The results of l-CT and histological analysis showed that a bony structure with irregular array oc- curred at the defect area, and the newly formed bone volume density reached 65.7%. In conclusion, the osteoinductive CaP ceramics could be an ideal material to treat the drilled skull holes in child- ren’s endoscopic neurosurgery and prevent CSF leaking afterwards. However, further investigation with more cases and longer follow-up was required to evaluate the clinical effect. Keywords: neuroendoscopy; skull holes; CSF leaking; osteoinductive CaP ceramics; bone healing Introduction track communicating with ventricle, as well as the limited size of the drilled skull hole, the hard mask is hard to be sutured, leading to the Neuroendoscopy is one of the most important surgical managements permanent existence of the CSF leaking. In that case, it is imperative in minimally invasive neurosurgery [1, 2]. With technological ad- to repair the hard mask again by second operation. Otherwise the vance, this surgical technique has been adapted to children [3–7]. persistent CSF leaking could induce the incision or even the intracra- However, it is undefined how to deal with the drilled skull holes due nial infection. to the endoscopic surgery, and inappropriate treatment may lead to In order to prevent the CSF leaking, some surgeons adjusted the cerebrospinal fluid (CSF) leaking, especially in infants and young position of the drilled skull holes to avoid the holes directly facing the children [8–10]. So, the management of CSF leaking is very difficult incision. Besides the special surgical method, a bio-inert sealing agent, after the neuroendoscopic surgery. Due to the existence of the cortex V C The Author(s) 2018. Published by Oxford University Press. 221 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/rb/article-abstract/5/4/221/5004400 by Ed 'DeepDyve' Gillespie user on 07 August 2018 222 Wei et al. Figure 1. The Surgical procedure in children’s endoscopic neurosurgery Table 1. The Criteria for evaluating the operative effect Materials and methods Operative effect Description Materials Commercial osteoinductive CaP ceramics (Trade name: Osteoinductive Class I Good wound healing, no any complications artificial bone) were supplied by Engineering Research Center in Class II Good wound healing, slight subcutaneous hydrops Biomaterials, Sichuan University, China. This ceramic was composed of Class III Wound dehiscence, CSF leaking, need the second hydroxyapatite (HA) and b-tricalcium phosphate (b-TCP), and the ratio operation Class IV Wound breakdown, severe CSF leaking and infection, of HA to b-TCP was about 20/80. The sterilized samples (c-ray irradia- possible threat to life tion) with the size of U 10 5mm were used in this study. The mor- phology, porous structure and permeability were analyzed by field emission scanning microscopy (S4800, Hitachi, Japan) and automatic mercury porosimeter (AutoPore IV 9500, Micromeritics, America), i.e. bone wax, was used to close the skull holes after the operation respectively. . However, the foreign body reaction resulted from the bone wax could lead to the delayed healing of the scalp wound in the children Animal experimental study patients. Moreover, the weak biocompatibility of bone wax lead to To evaluate the effect of the CaP ceramics on the skull defect repair, difficulty in integrating with the host bone, the frequently occurred a preliminary animal experiment was performed in WestChina- drifting of the material would result in the failure of the sealing. Frontier PharmaTech Co., Ltd. (WCFP)/National Chengdu Center Calcium phosphate (CaP) ceramics have the similar inorganic for Safety Evaluation of Drugs (NCCSED). The experimental components of the natural bone and have exhibited excellent bio- scheme was checked and approved by Institutional Animal Care and compatibility, osteoconductivity and osteoinductivity when used Use Committee (IACUC). as artificial bone substitutes [12, 13]. Generally, the highly inter- An adult rhesus monkey (male, 5.4 Kg) was used in this study. connected porous structure is essential for the osteoinductivity of After tracheal intubation anesthesia, the head hair of the animal was CaP ceramics [14–16]. It is known that the highly porous scaffolds shaved by an electric razor, and the head was sterilized by iodine. should have good air permeability. Therefore, when used for A 3-cm incision parallel to the mid-line was made in the right of the repairing skull defects, the porous CaP ceramic could decrease the head, and then a skull hole of 1.0 cm in diameter was drilled by a intracranial pressure. However, the water permeability of the po- hand trephine. The CaP ceramic sample was reshaped appropriately rous ceramic is dependent on its permeability and the inner and and fitted to the skull hole, followed by spraying a certain amount outer pressure difference. With better bone repair ability, the po- of normal saline to wet the material and make it adhere to the sur- rous CaP ceramic with excellent osteoinductivity could have the rounding bone. Finally, each layer of the scalp was tightly sutured. potential to inhibit the CSK leaking after neuroendoscopic surgery. The monkey was sacrificed at 6 months postoperatively. The bone To verify this assumption, a commercial osteoinductive CaP ce- specimen containing the implant was retrieved and then fixed in 4% ramic was used in this study to seal the drilled holes during the en- paraformaldehyde solution for 7 days for the subsequent analysis. doscopic surgery, and its sealing effect was remarkable in the High-resolution micro-computed tomography imaging (m-CT, short-term follow-up. SCANCO VivaCT80, Switzerland) was used to assess new bone Downloaded from https://academic.oup.com/rb/article-abstract/5/4/221/5004400 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Application of osteoinductive CaP ceramics in children’s endoscopic neurosurgery 223 Figure 2. The macroscopic and microscopic morphologies of the osteoinductive CaP ceramics Table 2. The porosity and permeability of the osteoinductive CaP and 3.0 cm next to the mid-line, and then a frontal skull hole of ceramics about 1.0 cm in diameter was drilled (Fig. 1a). All the five cases were treated with endoscopic third ventriculos- Material Porosity, % Permeability, Darcy tomy (ETV). Endoscope was firstly punctured into the lateral ventri- Osteoinductive CaP ceramic 76.0 12.1 cle and entered into the third ventricle through the interventricular foramen (Fig. 1b), and then, a small hole was formed at the weakest part of the trigonum in front of both mammillary bodies by bipolar electrocoagulation burning (Fig. 1c). After that, a balloon catheter formation within the implant. Scanning was performed at 70 kV for dilation was inserted into the hole to expand the fistula to about and 114 mA in high-resolution mode, 2048 rescontruction pixels 0.5 cm in diameter. The fistula was flushed with the 37 C balance and 200 ms integration time. Differences in voxel size (e.g. 10–20 liquid, and the endoscope was put in the fistula to check the arach- lm) have little influence on the evaluation of trabeculae structures noid at the bottom, i.e. liliequist membrane. A pair of forceps or bal- in large animal models with relatively high thickness (i.e. 100–200 loon was used to penetrate the membrane to confirm the fistula was lm) . Therefore, the 2D gray-scale images of the skull of an adult unobstructed (Fig. 1d). monkey were scanned at an isotropic voxel size of 15 lm. The A child patient with pinealoma was observed endoscopically that obtained radiographic images were then stored in DICOM format the tumor tissue had penetrated into the third ventricle. After burn- and reconstructed using MIMICS 17.0 (Materialise, Leuven, ing the tumor surface with bipolar electrocoagulation, the tumor tis- Belgium). A threshold (value ¼ 1885) was used to exclude the sue was grasped by the grasping forceps and sent to the pathologic interference of non-mineralized tissue and a higher threshold (value examination. The wound was flushed with the 37 C balance liquid, ¼ 6509) was used to distinguish the material from the mineralized and the bipolar electrocoagulation was used to stop bleeding. The bone tissue. After thresholding, the ratio of the calculated new bone postoperative pathologic examination indicated that the tumor was volume (BV) to the total volume (TV) at the defect site was deter- a germinoma, and the patient was transferred into the radiotherapy mined as the bone volume fraction (BV/TV). department for further radiotherapy. After l-CT analysis, the fixed specimen by 4% paraformalde- After the endoscopic operation, the cerebral cortex track was hyde solution was decalcified in 10% ethylene diamine tetraacetic filled with gelatin sponge, and the CaP ceramic samples were shaped acid (EDTA) solution, dehydrated in ascending concentrations of and fitted to the skull holes (Fig. 1e), with each layer of the scalp alcohols from 75 to 100%, and embedded in paraffin. The sections tightly sutured. The local wound was pressure dressing for 3 days af- were cut, ground and polished to a final thickness of 5 lm, and ter the operation. then transferred onto 3-aminopropyltriethoxysilane-coated glass At 1, 7 days, 3 and 6 months postoperatively, the leaking of CSF slides. Finally, the sections were subjected to the hematoxylin and in the patients was checked carefully. The skull CT scan was applied eosin (H&E) staining for histological observation. to determine the closure and healing of the bone. The operative ef- fect was evaluated according to the criteria shown in Table 1. Clinical study The clinical research was conducted in the Shanghai Children’s Hospital affiliated to Shanghai Jiao Tong University, China. Results There were five children in this group, four boys and one girl, aged Materials characterization from 3- to 8-years old, four cases of hydrocephalus (including ob- Figure 2 shows the macroscopic and microscopic morphologies of structive and communicating hydrocephalus), and one case of pineal the osteoinductive CaP ceramics. They had interconnected macro- tumor with obstructive hydrocephalus. pores (100–500 lm) and abundant micropores (<10 lm) occurred All patients were operated with tracheal intubation anesthesia in a supine position and Mayfield head holder. A 3.0-cm longitudinal on the rough wall of those macropores. Table 2 indicates the testing incision was made about 1.0 cm in front of the right coronal suture result of mercury porosimetry. The porosity of this ceramic was Downloaded from https://academic.oup.com/rb/article-abstract/5/4/221/5004400 by Ed 'DeepDyve' Gillespie user on 07 August 2018 224 Wei et al. Figure 3. The 3D (a) and 2D (b) reconstructed images by l-CT analysis Figure 4. The light microscopic images of the decalciﬁed histological sections with H&E staining (b is the partial enlarged drawing of a). Arrow, bone-implant in- terface; HB, host bone; NB, new bone; M, residual material; *, blood vessel; #, marrow cavity) 76.0%, and its permeability was 12.1 Darcy, showing that this ce- (Table 1). The usage of the CaP ceramics was convenient in the op- ramic could allow the penetration of body fluid under certain differ- eration. The ceramics could be remodeled again according to the ential pressure. size and shape of the drilled holes and the thickness of bone flap. The ceramics were closely connected to the surrounding bone to seal the drilled holes in an effective way without CSF leaking. Figure 5 Animal experimental evaluation shows the results of the skull CT scan before and after operation. At The postoperative gross observation indicated that the incision 1 day postoperatively, the follow-up CT found that the artificial healed well and no macroscopic wound infection. At 6 months post- bone and the surrounding bone was tightly bonded and sealed well. operatively, the animal was sacrificed and the retrieved implant with The density of the artificial bone was in high accordance with that the surrounding skull bone was subjected to the l-CT and histologi- of the surrounding bone on CT. No subcutaneous effusion and in- cal analysis. Figure 3 shows the 3D and 2D reconstructed images. The newly formed bone at the defect site could be well distinguished fection were found based on the observation at 7 days postopera- from the remained material (white) by the set global grayscale tively, indicating that the wound healed well. At 3 months threshold. The degradation of the ceramic and the bone substitution postoperatively, the follow-up CT demonstrated that new bone can be seen clearly. The quantitative analysis demonstrated that the could have formed in the drilled holes and the bone healing was ba- newly formed bone volume density was BV/TV¼65.7%. Figure 4 sically completed. At 6 month postoperatively, the follow-up CT in- dicated the perfect bone healing happened at the defect site, and shows the light microscopic images of the decalcified histological sections with H&E staining. Besides some residual materials, the de- only the trace of the ETV operation could be seen on the skull. fect area presented a bony structure with irregular array. There were some vessels and marrow cavities formed at the defect site, in which Discussion the blood cells and myeloid tissue could be seen clearly. No obvious boundary between the implant and host bone could be observed, in- Since Mixter performed the first case of ETV in 1923, neuroendo- dicating the excellent osteointegration and bone regeneration ability scopy was used in the management of hydrocephalus and got a full of the ceramic. This result was in good accordance with the above development later on. For children patients, the reported effective micro-CT analysis. rate of curing hydrocephalus by ETV was above 60% . However, children with severe hydrocephalus are generally young. Many scholars thought that infants below 2-years old, especially Clinical evaluation The operations on all the five cases of children patients were carried those <1-year old, were not suitable for ETV due to the high failure out successfully. After follow-up for 6 months, all the five cases rate [18–20]. The possible reason is that the absorption mechanism obtained the Class I operative effect according to the criterion of CSF in infants is immature, leading to a poor absorption result. Downloaded from https://academic.oup.com/rb/article-abstract/5/4/221/5004400 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Application of osteoinductive CaP ceramics in children’s endoscopic neurosurgery 225 Figure 5. The skull CT scan before and after operation Besides, the postoperative stoma is easy to be closed again, or the Thus far, besides the excellent biocompatibility and osteocon- new membrane could be formed. Moreover, infants with severe ductivity, the osteoinductivity of CaP ceramics with specific porous hydrocephalus are prone to have postoperative CSF leaking from structure and phase composition has been well confirmed by many scalp due to the severe ventricular dilatation, thin cortex and literature reports [12, 14, 25–30]. The CaP ceramics often exhibit head circumference . Generally, the infants patients have increas- excellent bone healing effect when used for large bone defect repair. ing head circumference and thinned scalp, CSF leaking from the ce- Yuan et al.  reported that the osteoinductive b-TCP ceramic had rebral cortex track and drilled skull holes can thus lead to the the similar repairing effect with the autologous bone graft at a poor wound healing, wound infection and even intracranial critical-sized iliac bone defects. Zhu et al.  used a HA whisker infection [19, 21]. strengthened CaP ceramic to treat the segmental femoral bone The common methods dealing with CSF leaking from the scalp defects at a beagle model, and a mass of new bone formation at the includes the tight suture of dura, pressure dressing, subcutaneous defect sites and a high fracture load were acquired after implanta- drainage, lumbar cistern drainage etc. [22–24]. As the size of the tion for 3 months. In this study, the osteoinductive CaP ceramics, drilled holes is only about 1 cm during the endoscopic surgery, the whose angiogenesis and osteogenesis abilities has been well con- dura is hard to be sutured tightly. Moreover, the physiological char- firmed in our previous studies [30, 33–35], were firstly used for the acteristics of children who may be in a restless state after operation repair of skull defects at a monkey model. The excellent bone regen- would influence the positive effect of the methods mentioned above. eration and degradability were well demonstrated by the l-CT Therefore, some other treatments, such as the size and position ad- analysis and histological evaluation (Figs. 3 and 4), indicating the justment of the drilled holes, application of bone wax sealing and so great potential of the CaP ceramics in the repair of cranial defects. forth, were tried [7, 11]. However, in our previous clinical practice, According to the data shown in Fig. 2 and Table 2, the CaP a case of delayed healing of the scalp wound was observed, and it ceramics had good interconnected macropores, abundant micro- could be resulted from the foreign body reaction of bio-inert bone pores on the skeleton and high porosity, endowing it with certain wax. Although the appearance of the patient is not affected by the permeability. This meant that the porous CaP ceramics could have minor skull holes, there are still some potential risks for infants and better air permeability, which was favorable for release of the intra- little children. cranial pressure. However, only under relatively high differential Downloaded from https://academic.oup.com/rb/article-abstract/5/4/221/5004400 by Ed 'DeepDyve' Gillespie user on 07 August 2018 226 Wei et al. 8. Bouras T, Sgouros S. 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