Osteointegration in cranial bone reconstruction: a goal to achieve
Abstract
Background
The number of cranioplasty procedures is steadily increasing, mainly due to growing indications for decompressive procedures following trauma, tumor or malformations. Although autologous bone is still considered the gold standard for bone replacement in skull, there is an urgent need for synthetic porous implants able to guide bone regeneration and stable reconstruction of the defect. In this respect, hydroxyapatite scaffolds with highly porous architecture are very promising materials, due to the excellent biocompatibility and intrinsic osteogenic and osteoconductive properties that enable deep bone penetration in the scaffold and excellent osteointegration. Osteointegration is here highlighted as a key aspect for the early recovery of bone-like biomechanical performance, for which custom-made porous hydroxyapatite scaffolds play a major role. There are still very few cases documenting the clinical performance of porous scaffolds following cranioplasty.
Methods
This paper reports 2 clinical cases where large cranial defects were repaired by the aid of porous hydroxyapatite scaffolds with customized shapes and 3D profiles (Fin-Ceramica, Faenza, Italy).
Results
In the long term (i.e., after 2 years), these scaffolds yielded extensive osteointegration through formation and penetration of new organized bone.
Conclusions
These results confirm that porous hydroxyapatite scaffolds, uniquely possessing chemico-physical and morphological/mechanical properties very close to those of bone, can be considered as a tool to provide effective bone regeneration in large cranial bone defects. Moreover, they may potentially prevent most of the postsurgical drawbacks related to the use of metal or plastic implants.
J Appl Biomater Funct Mater 2016; 14(4): e470 - e476
Article Type: ORIGINAL RESEARCH ARTICLE
DOI:10.5301/jabfm.5000293
Authors
Simone Sprio, Marco Fricia, Giuseppe F. Maddalena, Angelo Nataloni, Anna Tampieri
Article History
• Accepted on 30/03/2016
• Available online on 06/06/2016
• Published online on 02/11/2016
Disclosures
Financial support: No grants or funding have been received for this study.
Conflict of interest: Angelo Nataloni is a full-time employee of Fin-Ceramica Faenza S.p.A.
Cranioplasty is a surgical procedure that aims to re-establish the skull integrity following a previous craniotomy due to the occurrence of traumas, tumors and/or congenital malformations. In all cases cranioplasty can be considered as the conclusive action of a surgery initiated by the removal of a bone operculum. In the past decade the number of cranioplasty procedures has been progressively increasing, mainly owing to the growth of indications for decompressive craniotomy procedures (1). The replacement of bone opercula with autologous bone is considered to be the gold standard by surgeons, however this is not a feasible option in the case of large skull parts, due to the limited availability (2). Moreover, a growing concern is related to the ever stricter regulations for the use and storage of autologous bone as well as to the high frequency of cases where the autologous implant is subjected to resorption (3). This may be a serious concern, particularly in the case of cranial bone. The safe and efficient reconstruction of large cranial bone defects is an important clinical need. Ideally, cranioplasty procedures should provide restoration of the protective functions of the skull with maintenance of the original aesthetics and long-term mechanical performance. Today synthetic implants based on metallic (mainly titanium) or acrylic plaques (mainly polymethylmetacrylate or polyetheretherketone) are widely used in cranioplasty procedures. These are bioinert materials with good biocompatibility, resistance to infections, ease of sterilization, ability to be subjected to imaging diagnostics, and the capacity to undergo flexible design for adaptation to different clinical cases (4). Moreover, they exhibit good mechanical strength, which offers adequate brain protection from external shocks (5).
In spite of their features, some drawbacks have also been reported, in terms of enhanced cold/heat conduction or hypersensitivity induced by the contact with metals (6-7-8-9-10). Moreover, inert materials offer limited advantages for the restoration of the original skull functionality. In fact, bone implants with poor osteogenic and osteoconductive ability, such as metals or polymers, do not permit interpenetration of the scaffold with the newly formed bone, thus resulting in a foreign body functioning as a shell expected to provide brain protection, but connected to the surrounding bone only by its perimeter contact surface. Hydroxyapatite (HA) has for decades been widely considered as the gold standard for bone scaffolds, as its composition is very close to that of bone mineral, thus exhibiting excellent biocompatibility, a low inflammatory reaction as well as good osteogenic ability and osteoconductivity (11-12-13). The hydrophilic character of HA favors cell attachment and tight adhesion of bone to the scaffold surface, which is a key target for the stability of the bone/implant interface. Therefore, HA scaffolds presenting wide, open and interconnected multiscale porosity can induce extensive bone ingrowth and penetration throughout the whole scaffold, partly thanks to the possibility of massive fluid perfusion, which triggers and assists neovascularization (14). The progressive interpenetration of bone with the porous implant yields tight physical stabilization of the defect and establishment of bone-like mechanical performance. This is a key target to pursue, particularly in the case of defects affecting load-bearing bones such as the limbs or maxillofacial bones (15-16-17-18).
Hence, cranial reconstruction using synthetic porous HA has recently become the subject of intense debate among surgeons, and it now represents a new concept in cranioplasty procedures (19-20-21). Indeed, osteoconductive porous HA scaffolds, promising excellent safety and extensive colonization with new mature bone, can be excellent candidates for the reconstruction of large cranial bone defects with restoration of the physiological bone biomechanics. Indeed, the early colonization of the scaffold can progressively enhance the strength and the elastic properties of the bone/biomaterial construct up to the levels of healthy bone. Thus, in the case of secondary traumas potentially occurring in the scaffold area, well-integrated scaffolds having bone-like mechanical behavior can oppose a higher resistance to fracture and resilience to movement, leading to implant dislocation that potentially causes damages to the underlying soft tissues and the brain.
Porous HA scaffolds implanted in cranial or maxillofacial defects have been evaluated in several animal models (15, 21) and clinical cases in which patients treated with custom-made HA implants have been reported on (22-23-24-25-26-27). Histology is the most adequate method to assess the performance of a bone scaffold, however it cannot be performed on a statistically relevant basis on humans. Nevertheless, in 1 reported case (24), the osteointegration of the implant with the surrounding bone was evidenced, particularly along the epidural and subgaleal surfaces. Extensive ossification at the bone/implant interface was confirmed in another clinical case in which a female affected by atypical meningioma underwent revision surgery (26). However, upon removal of the implant after 4 years it was observed that bone neoformation was not uniform but rather limited to the areas in contact with healthy dura mater, whereas bone formation did not occur in the presence of synthetic dura mater. This study draws attention to some possible aspects relevant for osteointegration, such as the size of bone defect, the presence of a healthy dura, cutaneous trophism, previous infections, scars, as well as features related to the individual, such as age, metabolic diseases, and etiology of the cranial defect. Of note, this result suggested that dura is more relevant than periosteum in inducing new bone formation, thus representing a relevant indication for the use of bioactive scaffolds rather than bioinert plaques in cranial reconstruction.
In another study, 2 patients underwent surgical explant of cranial implants after postoperative complications (28). In one case, a 42-year-old female was firstly implanted with a titanium mesh and then, due to wound dehiscence, the implant was removed and replaced with custom-made porous HA (defect size = 120 cm2). Due to recurrence of the wound dehiscence, the patient again underwent scaffold removal after 2 years. The implant was tightly integrated with surrounding bone, so that the use of a craniotome was needed for the scaffold removal. Thorough investigation by radiological, microtomographical, and histological analyses confirmed the presence of areas of newly formed bone on the external and lateral surface of the implant. The new bone exhibited tight contact with the scaffold and penetration into its pores. The prostheses showed focal zones of scaffold resorption in correspondence of the newly formed bone, and no signs of inflammation or cytotoxicity were observed.
In a second case, a 12-year-old patient underwent decompressive craniotomy following a serious trauma, and was treated with custom-made porous HA (defect size = 140 cm2). After 21 months the scaffold was removed due to skin dehiscence. Histological and 3D microtomographical evaluation of the explanted scaffold highlighted the presence of newly formed bone surfaces with trabeculae of lamellar bone filling the macropores of the prosthesis, with no connective tissue interface between the host bone and implant material. Implant resorption in correspondence of the newly formed bone was also observed.
In another study, a long-term follow up (8 years) of an adolescent boy treated with custom-made porous HA was reported. CT scan performed at different timepoints revealed extensive osteointegration and healthy bone filling all the scaffold pores with no formation of fibrous tissue and resorption of the implant (29).
In our clinical experience, after years of implanation, osteointegration has also been detected in areas far from the interface with the implant (25). Indeed, in a patient who underwent revision surgery due to atypical meningioma, the tumor was found to have colonized the scaffold and its cells were found in the inner part of the scaffold (over 15 cm wide). This proves that in the presence of porous HA scaffolds, under adequate conditions bone colonization can be driven throughout the whole implant.
The bone-mimicking features of HA in cranioplasty procedures were also demonstrated in a previous study (28), in which histological changes were observed in a hydroxyapatite plate and granules used to repair a craniotomy defect in a 20-year-old female. The implant was removed after 2 years and 9 months of use, thus revealing complete fusion of the hydroxyapatite plates and granules with the cranium, with new bone formation on the dural side extending in a three-dimensional (3D) matrix along the pores with the Haversian system in the center. The hydroxyapatite plate had fused tightly to the cranium and could be excised only by using a diamond drill. Light microscopy showed that new bone was formed not only in the margin of the hydroxyapatite plate in direct contact with the skull, but also in noncontact areas such as the hydroxyapatite plate vault or inside the pores.
All these findings confirm that hydroxyapatite is fully biocompatible and possesses osteoconductive properties, when implanted in cranial defects as well, thus proving adequate for regenerative cranioplasty. These previous reports highlight that bioactive porous scaffolds can function as 3D templates, thus driving extensive scaffold colonization with new healthy bone. Therefore, in the presence of conditions favoring physiological bone formation and development, patients may expect to experience optimal osteointegration within months from surgery, with recovery of satisfactory mechanical properties. The present paper will examine and illustrate 2 further clinical cases of cranioplasty performed with porous hydroxyapatite in which CT data were associated with morphological assessment.
Materials and methods
Two clinical cases are considered in this work. Both patients underwent cranioplasty by the use of CustomBone® (Fin-Ceramica Faenza), namely custom-made, porous hydroxyapatite scaffolds (HA: Ca10(PO4)6(OH)2; Ca/P = 1.67) with total porosity in the range of 60% to 70% and pore architecture based on macropores (>100 μm) interconnected with micropores (5-10 μm). CustomBone® scaffolds were obtained by reproduction of the patient’s bone defect, as modeled by 3D CT scan. Informed consent was obtained from each patient. The study was performed in conformity to the 1975 Declaration of Helsinki.
Case 1
Two patients (R.I., female and C.F., male) were subjected to cranioplasty with custom-made porous hydroxyapatite in the years 2010-2011. In the case of R.I. the implant was implemented with the use of osteoactivators, such as piastrinic gel added with adipose stem cells; in the case of C.F., only adipose stem cells were used. Adipose stem cells were extracted from autologous abdominal fat and separated by centrifugation at 400 rpm (My Stem; Bi-Medica) to obtain 3 mL of cell-rich matter from 10 mL of fat. Piastrinic gels were obtained from the patient’s venous blood. A total of 10 mL of blood was taken and separated by centrifugation at 1,500 rpm (My Stem, Bi-Medica) to obtain 5 mL of platelet gel. CustomBone® scaffolds were engineered by creating small holes in the bone in contact with the scaffold by drilling and then filling the bone holes with the osteoactivators using a syringe. The osteoactivators were also spread on the bone edge in contact with the scaffold, as well as on the pores of the scaffold itself. Both the patients were treated with Technetium99 Medronate II (Osteocis; IBA Molecular), using a 3-phase technique (perfusion and hyper-concentration of the radiopharmaceutical in the late phase), radioisotope selective for the metabolically active bone areas and for the growth centres. R.I. was analyzed 7 months after surgery.
Case 2
This study regards a 37-year-old female patient, affected by bone deficit at the left frontal-temporoparietal region due to decompressive craniotomy. The surgery was performed to remove an acute hemispheric subdural hematoma formed in the left side of the cranium, after a car accident provoked a polytrauma that put the patient into a coma. After a 2-month period of neurological and physical rehabilitation, the patient underwent cranioplasty by custom-made porous hydroxyapatite for reconstruction of the cranial defect. The patient was monitored by encephalic CT scan at 2 and 12 months after surgery to investigate the degree of bone ingrowth in the scaffold pores. CT scans (GE LightSpeed VCT 64 slice; General Electric) (helicoidal acquisition: 280 mA; 120 kV; pitch 0.9; tube rotation speed 0.8; DLP = dose length product: 800 mGy*cm; section thickness 0.6 mm with multiplanar reconstructions) were performed without contrast media using a 16-detector scanner (General Electric), with postimplant control by Windows Advantage 4-3.
The 3D CT scans were used for qualitative analysis of the degree of ossification, according to the type of calcifications under the prosthesis. The measured quantities were bone defect surface, space height between the prostheses and the newly formed bone, maximal thickness of underprosthetic bone, intraprosthetic region of interest study with maximal, minimal, average calcic density measurement in Hounsfield scale (30). These data were collected following 2 orthogonal axes passing through the center of the implant, at distances of 5, 10 and 20 mm from the interface with bone. Finally, data were also taken in the implant center. The data were compared with reference values obtained from patients with healthy bone by measurement at 25 mm from the bone/implant interface.
Before undergoing surgical procedures, the patient gave informed consent. The patient has consented to the publication of this case report.
Results
Case 1
Numerous granules of bone matrix were found in the right frontotemporal region of the implant, particularly in the cranial segment and at the interface with the implant, highlighted by the dark spots (Fig. 1a). A second analysis was carried out after 3 years, revealing accumulation of the blood pool with late fixation of the osteotropic drug. The interface of the implant with bone appears less defined than the previous analysis, thus suggesting extensive bone migration into the porous implant structure (Fig. 1b).
Case 1: scintigraphic analysis of cranial implants. (A) Patient R.I., after 7 months; (B) patient R.I., after 36 months; (C) patient C.F., after 6 months; (D) patient C.F., after 24 months. Red circles highlight the area interested by the new bone formation.
In the case of C.F., the first scintigraphic analysis was carried out 6 months after surgery, revealing accumulation of the radioisotope at the cranial and caudal site of the porous implant with diffuse marginal trabeculation (Fig. 1c). After 2 years a second scintigraphic analysis was performed, revealing homogeneous colonization of the porous scaffold with no significant variations in the distribution of the radioisotope in the left frontotemporoparietal region. In addition, the isotope distribution appears more homogeneous in the remaining part of the scaffold compared to the previous analysis (Fig. 1d). Scintigraphic analyses were carried out by equipment provided by Molecular Imaging Systems (Siemens Healthcare).
Case 2
The 3D CT scans confirm the optimal reconstruction of the cranial bone defect (Fig. 2). Figure 3 presents the densitometric scan and profile, reported with the Hounsfield Scale, to assess the extent and quality of the penetrated bone and the osteointegration. In particular, Figure 3a shows calcification spots at the interface of the scaffold with the dura mater, which confirms the presence of neoforming bone tissue induced by the subdural bleeding. In this case the presence of a healthy dura enhanced the process of bone neoformation since the bleeding could occur from both the perimetral and the dural sides. Figure 3a also shows that many scaffold pores are filled with new bone. Empty pores are also visible, possibly due to the absence of any interconnection. Figure 3b shows the densitometric profile at both sides of the bone-implant interface, taken in correspondence of the two paths highlighted by the violet (Profile 1) and green (Profile 2) lines. The graph confirms abundant bone formation, including at the interface where the level in the Hounsfield Scale is well above the baseline. Also, the densitometric profile at the center of the implant demonstrates extensive bone penetration in the region of the skull as well, far from the region at the interface with the margin of the defect.
Case 2: CT Scan of the patient after 2 months from implant.
Case 2 (A) Densitometric scan; the colored arrows indicate the scanned areas, while the red circle highlights the new regenerated bone tissue; (B) profiles of the healthy and operated sites of the skull (corresponding to the colored arrows in Fig. 3a) at 12 months from implant.
Discussion
The studies reported in this paper further confirm the safety of custom-made porous HA scaffolds and their ability to tightly bind with the surrounding bone and establish excellent osteointegration in relatively short times (no longer than 2 years according to our observation times), by progressive colonization with healthy bone. Hydroxyapatite is reported to have lower mechanical strength and stiffness than acrylic or metal implants; therefore HA implants may not have sufficient resistance to withstand shocks in the postoperative period. However, due to their bioinertness, metals and plastics do not allow bone penetration and osteointegration, thus their mechanical performance remains unchanged with time. In this respect, in the case of secondary trauma, metals and plastics do not undergo breakage but they absorb the elastic waves that are then transmitted to the surrounding bone. This can cause bone failure can occur, particularly at the proximity of the anchorage points, thus resulting in displacement of the implant, even involving the underlying soft tissues and the brain, with potential dural and cerebral damage. Porous osteointegrative scaffolds can instead improve mechanical responses over time, since the filling of the pores with the new bone can progressively increase mechanical strength. This commonly occurs in the case of composites based on porous high-modulus matrices filled with lower-modulus compounds (31). Therefore, upon secondary trauma, the bone/scaffold construct can display mechanisms of fracture dynamics closer to that of bone, thus exhibiting physiological-like responses to shocks and preventing the possible complete failure of the implant inside the cranium. Furthermore, in the case of posttraumatic fracture of the scaffold, in many cases the damage can be self-repaired by the growth and penetration of new bone into the crack (18, 19). This ability promises new potential applications in the field of cranial reconstruction in children, where the continuous bone growth prevents the use of inert implants that are stable over time (32-33-34-35-36).
A frequent drawback in cranioplasty procedures, particularly with titanium plates, is the occurrence of graft infections that force surgeons to a second surgery for the implant removal, application of antibacterial therapies and a new cranioplasty (5). Indeed, metal and plastic implants do not enable the loading of antibiotics, whereas porous hydroxyapatite is characterized by a high exposed surface with high affinity with many kinds of drugs and bioactive molecules (37-38-39-40) that can be loaded in situ, thus preventing a second surgery.
Altogether, the aspects discussed in this paper confirm porous HA scaffolds as a significant opportunity for satisfactory regeneration of large cranial bone defects. However, the intrinsic features of porous HA and the physiological phenomena previously observed in the presence of these scaffolds suggest that porous HA is specifically indicated for patients still possessing adequate regenerative potential, and a healthy dura, which enable extensive bleeding and enhanced bone formation and penetration. Nevertheless, even in the case of patients with serious damage involving the soft tissues and the dura, bleeding with bone penetration can always occur from the peripheral areas thus also sustaining osteointegration. It can be also observed that, due to the initial limited strength of porous HA, its implantation may not be recommended in the case of patients with possible alteration of motion control such as epileptics. The features of limited initial strength of porous HA, and the ability to improve the mechanical behavior with time towards bone-like performance, paint a picture in which the follow-up of porous HA can be considered critical within the first year, but in the long term porous HA can guarantee increasing safety (19, 20) and, possibly, complete solution of the defect. Conversely, the possible release of ions from metallic and plastic implants in the long term poses several concerns regarding their long-term safety, along with the potential need for revision surgery (41).
In spite of the importance of osteointegration in cranial defects, it was observed that the degree of satisfaction of the patients and the degree of osteointegration were not correlated in patients of different ages implanted with custom-made porous HA (42). From the above considerations it can also be concluded that the use of porous HA scaffolds, which gives undeniable benefits to patients, should be considered in terms of a cost-benefit assessment, on the basis of the physiologic state of the patient. The above considerations are motivated by the first evidence of the performance of HA scaffolds after postsurgery analysis in patients. Understandably, since the new approach based on osteointegrative scaffolds is in its infancy, the low number of cases available cannot yet generate a statistically relevant population. However, the outcome of the clinical cases so far reported is promising and no serious cases of failure specifically attributable to the nature of the porous HA scaffolds have been reported to date.
Conclusions
The new data presented in this work support the numerous studies published thus far on the safety and reliability of custom-made porous HA scaffolds in the reconstruction of large cranial bone defects. Importantly, porous HA scaffolds exhibit good mimicry of the bone mineral composition, promoting new bone formation and the establishment of a tight bone-implant interface within weeks from surgery. The highly porous structure also facilitates extensive bone penetration throughout the whole scaffold, with excellent osteointegration and positive effects on the overall biomechanical performance. An interesting feature of porous HA is related to the intrinsic hydrophilic character of hydroxyapatite and its diffuse microporosity, both of which permit extensive adsorption of fluids to the scaffold. This allows cranioplasty procedures to be implemented with the use of osteoinductive agents such as piastrinic gels or autologous stem cells to enhance the bone regeneration process. In the case of postsurgical infections, porous HA scaffolds may also be directly loaded with antibiotic drugs, thus preventing the need for a second surgery to completely replace the implant. The effective enhancement of bone regeneration with factors such as platelet-rich plasma is a matter worthy of investigation in future comparative clinical studies since it may represent a significant boosting of the healing process, particularly in patients with reduced endogenous potential.
Disclosures
Financial support: No grants or funding have been received for this study.
Conflict of interest: Angelo Nataloni is a full-time employee of Fin-Ceramica Faenza S.p.A.
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Institute of Science and Technology for Ceramics, National Research Council, ISTEC – CNR, Faenza - Italy
Department of Neurosurgery, Cannizzaro University Hospital of Catania, Catania - Italy
Department of Neurosurgery, Di Summa - Antonio Perrino Hospital, Brindisi - Italy
Fin-Ceramica Faenza S.p.A., Faenza - Italy
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