Repairing skull defects in children with nano-hap/collagen composites: A clinical report of thirteen cases

Tuoyu Chen, Yuqi Zhang(?), Huancong Zuo, Yapeng Zhao, Chaoqiang Xue, Bin Luo, Qinglin Zhang, Jin Zhu, Xiumei Wang, Fuzhai Cui

?

Repairing skull defects in children with nano-hap/collagen composites: A clinical report of thirteen cases

Tuoyu Chen1, Yuqi Zhang1(?), Huancong Zuo1, Yapeng Zhao3, Chaoqiang Xue1, Bin Luo1, Qinglin Zhang1, Jin Zhu1, Xiumei Wang2, Fuzhai Cui2

1Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing 100040, China2School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China3The Medical Center, Tsinghua University, Beijing 100084, China

ARTICLE INFO

Received: 5 January 2016

Revised: 2 February 2016

Accepted: 5 February 2016

? The authors 2016. This article is published with open access at www.TNCjournal.com

KEYWORDS

cranioplasty;

children;

biomimetic bone;

3D printing

ABSTRACT

Objective: To evaluate the clinical results of repairing skull defects with biomimetic bone (nano-hap/collagen composites, NHACs) in children.

Methods: Thirteen children with skull defects were treated with NHACs in our hospital. The NHACs molded with the help of a 3D printer were used in the operations.

Results: All 13 operations were successful, and patients recovered without infection. Only one patient suffered from subcutaneous hydrops post-operation. The implanted NHACs remained fixed well after 1 year, and their CT HU values raised gradually. Skull shapes of children developed normally. Recovery of neurological and cognitive function was significant.

Conclusions: NHAC, chosen to repair skull defects in children, can coexist with normal skull and reduce the negative effects on growth and development. NHAC could be a good choice for children with skull defects.

Citation Chen TY, Zhang YQ, Zuo HC, Zhao YP, Xue CQ, Luo B, Zhang QL, Zhu J, Wang XM, Cui FZ. Repairing skull defects in children with nano-hap/collagen composites: A clinical report of thirteen cases. Transl. Neurosci. Clin. 2016, 2(1): 31–37.

? Corresponding author: Yuqi Zhang, E-mail: yuqi9597@sina.com

Supported by the National Natural Science Foundation of China (No. 51572144).

1 Introduction

Skull defects in children result from bone flap decompression during head trauma or brain disease. The traditional artificial skull repairing materials, such as the titanium mesh and some absorbable materials, do not meet the needs of accommodating children’s brain development. Our Department in Tsinghua University Yuquan Hospital chose the biomimetic bone developed by the School of Materials Science and Engineering (Tsinghua University) to repair the skull defects of 13 children from mid-2014. After 1 year, we collected and analyzed the clinical outcomes as described below.

2 Materials and methods

2.1 General information

This study included 13 children who suffered from skull defects; eight were boys and five were girls (Table 1). The age range was from 1 year and 2 months to 14 years. Ten patients needed craniectomy due to brain trauma, including injuries due to traffic accident (4 cases), falling (3 cases), sticks (1 case), slipping (1 case), and crush injury by hitting against the corner of a table (1 case). One patient was treated with craniotomy for hematoma clearing and bone flap decompression after unexplained bleeding in the brain.One patient suffered bone flap decompression during coma with intracranial hypertension after removing tumors in the saddle area. The last one suffered from skull defect because of the unsuccessful frontal ependymoma operation. The average time after craniectomy was 1 year and 5 months, with a range of 3–43 months.

Table 1 Summary of the basic clinical features

2.2 Position and size of the skull defects

Ten cases had unilateral skull defects (6 on the left side, 4 on the right side): three cases were frontal skull defects, and seven cases were frontotemporal skull defects. Three cases had bilateral skull defects: one in the bilateral frontal bone crossing the midline, one remained the bone bridge on the sagital sinus, and the last was due to the removal of the right absorbed bone flap and surgical repair, although the bone bridge in the middle route of the skull was present and the bone flaps were repositioned. The incisions in all patients healed well, and the defect area had low-tension. The size of the defects ranged from 32–116 cm2.

2.3 Clinical symptoms and examinations

The symptoms of contralateral hemiplegia and cerebral palsy were seen in 11 cases: declined limb myodynamia, increased or reduced muscle tension, and poor coordinate dynamic function. Obvious crying and bad affective interaction appeared in three children with defects in the frontal bone, even 1 with serious psychiatric symptoms. Preoperative symptoms of loss of consciousness were found in three patients, with long-term use of antiepileptic drugs. We conducted a cognitive assessment in nine patients older than 4 years old using Wechsler Intelligence Scale for Children (WISC). The other four children were unable to cooperate with the cognitive assessment. The brain damage in all cases was detected by MRI before the surgery.

2.4 Preparation of material

Biomimetic bone materials (nano-hap/collagen composites, NHAC) for cranioplasty have been approved by the Chinese (FDA Certification No: 20143462075) and US governments (FDA Certification No: K141725). The bone materials had been described well previously[1, 2]. They are biodegradable and have primany intensity close to that of the humen compact bone. Patients and their families signed the informed consent, and we obtained the approval of our clinical ethics committee before the surgery.

Next, 3D computed tomography (CT) scans were used to formulate the operation plan. 3D printing wasused for the reconstruction of the skull model. Doctors and technologists decided on the arc and thickness in the process of making the biomimetic bone on the basis of their experience. The thickness of the biomimetic bone depends on the average skull thickness, usually 2 mm thicker than the skull. The size of the biomimetic bone was a little larger than the actual defect for the reconstruction operation (Figure 1a).

2.5 Treatment of preoperative complications

Four patients with severe symptoms of hydrocephalus underwent ventriculo-peritoneal shunt (V-P shunt) with adjustable voltage shunt ventricle. The pressure of the shunt tube was adjusted discontinuously until acceptable balance was achieved.

Figure 1a The preoperative computer reconstruction. Figure 1b Biomimetic bone is suitably fixed by a 10/0 thread, with space for temporal muscle roots reserved. Figure 1(c–d) Postoperative cranial volume rendering technique (VRT) reconstruction reveals suitable head shape, good radian, and moderate thickness. Figure 1e Postoperative computed tomography (CT) of the skull bone window reveals density of the biomimetic bone between the cancellous bone and compact bone

2.6 Operation procedure

All patients underwent general anesthesia with intubation and 0.2% lidocaine with 0.1% adrenalin was injected subcutaneously to reduce bleeding and postoperative pain. Incision was made along the previous scar to cut the skin and subcutaneous fat to free the skin flap under the cap shape tendinous film, and reveal the bone flap completely. The bone fragments wereremoved from the bone window using a rongeur, and holes were drilled both on the edges of the bone window and biomimetic bone. The dura was suspended and the skull bone was fixed with the NHAC using sutures through the holes, using silk thread. If necessary, we could closely remold the edge of the biomimetic bone by rongeur before fixing. The most important step was keeping the temporal muscle free from the bony “window” such that no muscle incarceration and ischemia occurred. Absence or presence of external drainage depended on subcutaneous hydrops (Figure 1b).

3 Results

Only one child had subcutaneous hydrops after operation, caused by the defect of the epidural. He recovered after using pressure dressing and external drainage. The incision in the other 12 children healed well. CT scan was taken 1 week after the operation, and the average CT HU values of 6 points in the biomimetic bone, bone cortex, and bone marrow were measured. The initial CT value of the biomimetic bone was 750 ± 50 HU as the average outgoing intensity (Figures 1c and 1d). Sutures were removed 2 weeks after operation as scheduled. The bone window CT scans showed a similar bone density between the biomimetic bone and the normal bone (Figure 1e).

All 13 patients were followed up for 1 year, and CT scan or radiographic imaging was taken every 3 months. Postoperative radiography taken at 1 year showed cracks on the biomimetic bone in one case (Figure 2), while no instability occurred. The imaging results of the other cases showed symmetric skull shapes and smaller bone gaps. Different cases of cranioplasty show well appearances in postoperative cranial VRT reconstruction (Figures 3a–3f). The temporal muscle had free movement (Figures 3c–3f). The value of the CT scan changed from 750 ± 50 HU to 875 ± 50 HU (Max 925) in 1 year. The cancellous bone/compact bone differentiation appeared in two cases (Figures 4a and 4b).

The symptoms of contralateral hemiplegia and cerebral palsy in 10 cases improved 1 year later, especially in the muscle power of the paralytic limbs. Preoperative symptoms of epilepsy in three patients disappeared although antiepileptic drugs were stopped 1 month after operation. Three children with obvious preoperative crying and bad affective interaction became emotional rehabilitation. The improvement of cognitive function in one child with serious psychiatric symptoms was significant.

Figure 2a Postoperative head X-ray image of 1 case reveals satisfactory fixation of the biomimetic bone, good radian, connected to the coronal suture without crack. Figure 2b Postoperative head X-ray image of the same case 1 year later shows density of the biomimetic bone close to the normal bone, but visible cracks can be observed, consistent with child’s normal skull development.

4 Discussion

Due to the restriction of the traditional concepts and repair materials, researchers previously thought that development of the brain and skull in a child would be affected by early repair of the skull defect. With the advent of new materials and technology, early cranioplasty is advised[1].

4.1 The advantages of early cranioplasty in children

The advantages of early cranioplasty in children[2]are: (1) Skull defect larger than 3 cm2 cannot heal itself, although children are in a rapid growth period. It will increase huge psychological burden on the children and parents. Syndrome of the trephined may lead to symptoms such as headache, giddy, irritability, and epilepsy. (2) Compared to the physical trauma, psychological effects of skull defect are more serious and include autism and inferiority complex. (3) Skull provides protection to the brain. Children love to play and fight. They may be in a dangerous situation when hurt in the defect area. (4) The osteogenesis of children’s skull is affected by both the dura and periosteum. When skull defect occurs, the newly formed bone induced by the dura will not be sufficiently hard. This will restrict the development of the brainand cause serious epilepsy sometimes. (5) Without the protection of the skull, the activity of the brain becomes larger. Encephalocele or local excavation will appear when patients bow or raise their heads. The midline of the brain will move when they shake their heads. Intracranial pressure change will affect the brain’s blood supply. Accordingly, the symptoms of intracranial hypertension or low pressure will occur.

Figures 3(a–f) Different cases of cranioplasty show well appearances in postoperative cranial VRT reconstruction. Figures 3c–3f show the movement of temporal muscle was free.

Figure 4(a–b) Cancellous bone/compact bone differentiation appeared in two cases 1 year postsurgery, although some absorption appears on the edge of the biomimetic bone.

4.2 The choice of the operation time

The right time for cranioplasty in children is debatable[3]. Recently, most doctors are inclined towards early cranioplasty. Patients needing cranioplasty must meet the following requirements: (1) no intracranial infection, incision infection, subcutaneous effusion, and foreign body rejection; (2) normal intracranial pressure, no encephalocele; (3) no intracerebral hemorrhage or infarction, and no brain hernia.

4.3 The choice of materials

The current allograft bone repair materials used are mainly as follows: metallic, polymer, and medical tissue engineering materials. Inactivated autologous bonepreserved in liquid nitrogen or subcutaneous/subgaleal tissue has been used from the past to present. However, it is rarely used now because of absorption. Umbilication and epilepsy occurred in one child with unexplained intracranial hemorrhage 6 months after an autologous bone repair[4].

Edwards had put forward specific requirements regarding ideal materials for skull defects in children as follows[5]: (a) non-toxic, no biological activities, no antigenicity and rejection; (b) light, strong, and durable, similar intensity as the normal skull bone; (c) stable physicochemical properties, non-carcinogenic, nonabsorbent, not affected by electromagnetism, nonconductive, and athermic; (d) compatible with various methods of sterilization; (e) good plasticity during operation and little postoperative complications; (f) nice exterior, synchronous with the growth of the children’s skull.

Nowadays, in China, the most widespread metallic material is the titanium mesh for its advantage of good histocompatibility, easy manufacturing technology, and ease of sterilization. However, pediatric neurosurgeons use autogenous bone graft in countries outside China.

With the development of medical bionic materials and 3D printing, we have made great progress in cranioplasty.

4.4 The characteristics of the biomimetic bone

The microscopic structure of the biomimetic bone mimics the natural bone. The inorganic phase in the composite is carbonate-substituted hydroxyapatite with low crystallinity.

The mineral precipitates, with a crystal size on a nanometer scale, are uniformly distributed on the collagen matrix. Its biggest advantage is that the nutritional and metabolic waste exchange and transfer occurs through the bone tissue network channel composed of newly formed blood vessels and bone tubular structure, in order to participate in the metabolic processes of the human body[6, 7]. Scientists have found that hydroxyapatite components used for treating the bone defect can fuse with the surrounding bone in 3 years. This is particularly important for the proper development of children[8].

The surface of the biomimetic bone can provide a comfortable platform to induce adhesion of collagen/ mineral deposits and osteoblasts[9]. Studies have shown that once the osteoblasts induced by the blood supply attach on the skull surface, their migration process similar to fracture healing begins[10]. The outside-in approach of bone regeneration is called bonding osteogenesis, which is a typical process in osteogenesis of bioactive bone repair materials[11].

At the same time, the surface between the autologous tissue and repair material is in an alternating process of dissolution and calcinosis. It is similar to the physiological bone regeneration process. The biomimetic bone can participate in the bone metabolic cycle through the above pathway. Finally, it will be replaced by the newly formed bone tissue[12].

4.5 Surgical skills and difficulties

(1) Fixation of biomimetic bone is difficult. The materials such as titanium nail, titanium sheet, metal skull lock, and absorbable skull lock have been considered before. We chose 10/0 stainless threads. Its intensity is between absorbable skull lock and metal skull lock. However, the suture knot can be felt in some patients with thin scalp, and even rejection appeared in one case. More time is needed in the process of drilling holes. In addition, heterotopic ossification caused by bone dreg will be harmful.

(2) Moderate plasticity is necessary in the operation for the following reasons: 1. Growth of the bone window edge may continue during the 3 weeks required for biomimetic bone preparation. 2. Sufficient space for temporal muscle roots is essential to prevent muscle incarceration. 3. Ossification in parts of the dura persists to form a “hard armor” that will influence the installation of the biomimetic bone and dura suspension.

(3) Bleeding of the skull cannot be stopped by bone wax except from the emissary vein. This can increase the blood supply as much as possible to induce bonding osteogenesis.

4.6 Postoperative assessment

The time of new bone formation may vary from one another according to the area size, location, blood supply, and integrity of the dura. In our research, the CT value of the compact bone in all children was 1 500 ± 100 HU, and the CT mean value of the spongy bone was 561 HU (345–733 HU). One year later, theCT values of most children were still between 700–800 HU, which is more than the initial data. The CT values of two children had increased to 900 HU. The CT scan showed obvious bone differentiation phenomenon in two other children.

The influencing factors for the above results could be as follows: smaller defect size, rich blood supply, more dura matter, less scope of epidural calcification, and children in the peak of growth and development. Bonding osteogenesis is easier when calcium deposition occurs well on the bionic bone material.

In one baby who was no more than 2 years old, the postoperative head X-ray and volume rendering technique (VRT) imaging after 1 year showed visible cracks. We assume that the brain grew faster than the speed of bonding osteogenesis, causing the biomimetic bone to crack at the place of the coronal suture (Figure 2). However, negligence by parents cannot be ruled out. The following are the limitations of this study: this study sample size is small, follow-up time is short, and clinical curative effect needs further research.

Recently, the technology of quantitative CT (QCT) has been advocated because its value is close to the density of the bone mineral, and it is not affected by the size and composition[13]. Postoperative evaluation criteria are still flawed, with the exception of physical examination, cognitive assessment, and magnetic resonance imaging. In the future research, we will choose transcranial Doppler ultrasound (TCD) and near infrared reflectance spectroscopy (NIRS) to evaluate the changes in the cerebral blood supply before and after cranioplasty in children. In addition, we will consistently follow-up these 13 children, and continue to find out more evidence of osseointegration between biomimetic bone and autogenous bone.

Conflict of interests

The authors have no financial interest to disclose regarding the article.

References

[1] Josan VA, Sgouros S, Walsh AR, Dover MS, Nishikawa H, Hockley AD. Cranioplasty in children. Child’s Nerv Syst 2005, 21(3): 200–204.

[2] Blum KS, Schneider SJ, Rosenthal AD. Methyl methacrylate cranioplasty in children: long-term results. Pediatr Neurosurg 1997, 26(1): 33–35.

[3] Takumi I, Akimoto M. Catcher’s mask cranioplasty for extensive cranial defects in children with an open head trauma: A novel application of partial cranioplasty. Child’s Nerv Syst 2008, 24(8): 927–932.

[4] Shah AM, Jung H, Skirboll S. Materials used in cranioplasty: A history and analysis. Neurosurgical Focus 2014, 36(4): E19.

[5] Edwards MSB, Oustehout DK. Autogeneic skull bone grafts to reconstruct large or complex skull defects in children and adolescents. Neurosurgery 1987, 20(2): 273–280.

[6] Qiu ZY, Zhang YQ, Zhang ZQ, Song TX, Cui FZ. Biodegradable mineralized collagen plug for the reconstruction of craniotomy burr-holes: A report of three cases. Transl Neurosci Clini 2015, 1(1): 3–9.

[7] Song Q, Hu K, Cui FZ, He ZY. Effect of high temperature on morphology and structure of nano-hydroxyapatite/collagen composite. Mater Sci Forum 2009, 610–613: 1360–1363.

[8] Itokawa H, Hiraide T, Moriya M, Fujimoto M, Nagashima G, Suzuki R, Fujimoto T. A 12 month in vivo study on the response of bone to a hydroxyapatite-polymethylmethacrylate cranioplasty composite. Biomaterials 2007, 28(33): 4922–4927.

[9] Du C, Cui FZ, zhang w, Feng QL, Zhu XD, de Groot K. Formation of calcium phosphate/collagen composites through mineralization of collagen matrix. J Biomed Mat Res 2000, 50: 518–527.

[10] Qiu ZY, Cui Y, Tao CS, Zhang ZQ, Tang PF, Mao KY, Wang XM, Cui FZ. Mineralized collagen: Rationale, current status, and clinical applications. Materials 2015, 8: 4733–4750.

[11] Okumura M, Ohgushi H, Tamai S. Bonding osteogenesis in coralline hydroxyapatite combined with bone marrow cells. Biomaterials 1991, 12(4): 411–416.

[12] Lian XJ, Qiu ZY, Wang CM, Guo WG, Zhang XJ, Dong YQ, Cui FZ. Structural and biomedical properties of zirconiahydroxyapatite nano-crystal ceramics. Biomater Tissue Eng 2013, 3(3): 330–334.

[13] Maire E, Withers PJ. Quantitative X-ray tomography. Int Mater Rev 2014, 59(1): 1–43.