Osteointegration in Custom-made Porous Hydroxyapatite Cranial Implants: From Reconstructive Surgery to Regenerative Medicine

doi:10.1016/j.wneu.2015.03.027

World Neurosurgery

Volume 84, Issue 2, August 2015, Pages 591.e11-591.e16

https://doi.org/10.1016/j.wneu.2015.03.027 Get rights and content

Background

Custom-made porous hydroxyapatite (HA) implant (Fin-Ceramica Faenza S.p.A., Italy) is a biomimetic, osteoconductive material. Margin fusion at the bone-implant edge, cell proliferation within implant pores, and osteointegration in an animal model have already been described.

Case Description

Radiological, microtomographical, and histological analyses were performed on two patients who underwent surgical explantation of cranial implants after postoperative complication.

Primary devices explanted after 2 years showed areas of newly formed bone strictly osteointegrated with pores of the prosthesis. These prostheses showed a focal zone of resorption in correspondence of the newly formed bone, and no signs of inflammation or cytotoxicity were observed. A back-up prosthesis, explanted from the same patient after 6 months because of an infection, did not show presence of newly formed bone both on the surface and in the internal part of the prosthesis.

Conclusions

Custom-made porous HA implant is an osteoconductive material able to promote osteogenesis, osteointegrate with bone tissue, provide an effective cranial reconstruction, and restore functional features of the skull. However, complete bone healing is still a complex and long process.

Introduction

Bone tissue regeneration is an important challenge in the field of orthopedic and craniofacial surgery. Due to the increasing need of clinical solutions able to recover the functional properties of missing or diseased bone, the past implants design is increasingly evolving into scaffolds intended to sustain and assist extensive cell colonization and anchorage to the existing bone, finally leading to osteointegration, which also allows the bone/biomaterial construct to gather biomechanical competence 3, 17.

To do this, regenerative bone scaffolds must exhibit good biocompatibility without inducing inflammation or toxic reactions and exchange suitable chemical signals with the surrounding extracellular matrix in order to activate and promote the series of events at the cell level, thus triggering the formation and organization of new bone tissue (13). In this respect, the first interactions between the cells and the scaffold surface define the quality of the tissue implant interface, which is a key issue for the regenerative ability of the bio-device. The implantation of a three-dimensional (3D) porous scaffold is required, with characteristics of bioactivity and osteoconductivity associated to bio-mechanic performance suitable for the specific implant site 1, 15. More specifically, scaffolds have to provide the space for new bone formation and the necessary support for cells to proliferate and maintain their differential function. Moreover, they should exhibit suitable architectures for inducing the formation and maturation of well-organized tissue (2).

In an attempt to find a balance among composition, structure, porosity, and mechanical strength, biomedical engineers and material scientists developed many different approaches to create structures with open and interconnected pores by imposing different geometries or by forming complex microstructures through the use of natural templates.

Pore volume and size, both at the macroscopic and the microscopic level, are important morphological properties of a scaffold for bone regeneration 7, 10, 11. Macroscopic porosity (i.e., several hundreds of μm), which promotes activation and enhancement of bone ingrowth and osteointegration of the implant after surgery, should also be interconnected with channel-like microporosity that enables fluid exchange throughout the whole scaffold, thus providing a supply of nutrients and the elimination of metabolic waste products. The pore interconnection in a bone scaffold is relevant to avoid a spatially discontinuous ingrowth of the new bone with the formation of bone islands throughout the whole scaffold.

A preclinical study on an animal model implanted with porous HA devices has been recently published by Martini et al (10). The in vivo assessment of this prosthetic device with functions of cranial bone substitute made of porous HA showed the actual capacity of osteointegration of the device with the margins of the host bone and the capability of the device to be hosted by the newly formed bone over time.

The osteointegration process of porous HA device in human patients has been described particularly in the proximity of the bone/implant interface (6). This also affects the mechanical performance of the bone/implant construct. Spontaneous healing of fractured HA devices has been shown, indicating that viable bone and cells had fully colonized the implants (16). In recent years, the behavior of the CustomBone HA prosthesis in humans has also been characterized in 57-year-old and 69-year-old women 5, 12. In both cases the etiology of craniotomy was meningioma, and HA prostheses were explanted because of tumor relapse and subsequent cranioplasty with back-up CustomBone used to repair skull defect. Explantations occurred 3 years and 1 year, respectively, after CustomBone implant. Histological results detected the presence of newly formed bone on the inner perimeter and internal pores of the prostheses. These were the first reported human cases of effective bone-HA integration, but the etiology of treatment, meningioma, should leave open questions about potential tumor infiltration capability.

Here we report two cases of patients who were implanted with custom-made bioceramic porous hydroxyapatite prosthesis after cranial decompression. Both patients experienced postoperative wound complications that required removal of the cranial prosthesis. Both cases subsequently underwent cranial repair using back-up custom-made devices. One patient also went through an intervention of back-up prosthesis removal. To evaluate quantitatively and qualitatively the ossification of HA prosthesis before explantation, computed tomography (CT) scans were carried out. Finally, the three explants obtained from two different patients were analyzed microtomographically and histologically.

Section snippets

Surgical Procedures

Each implant was placed according to the standard manufacturer protocol and as described by Staffa et al. (16). Bone margins were freshened in order to guarantee the maximum contact between the device and cranium. Dural substitutes or growth factors were not used.

Radiological Analysis and Hounsfield Measures

Postoperative CT scans were performed to evaluate implant positioning and margin adhesion. Further radiologic evaluations on bone/implant density were performed using Mimics software (Mimics Innovation Suite v17.0 Medical, Materialise,

Radiologic Evaluation (Positioning, Hounsfield Values at Bone-Implant Margin)

The radiological examination confirmed that the correct position (Figure 1A) of the cranial bone substitute in the implant was maintained over time and that HA implant was completely merged with the host bone. The Hounsfield bone density graph showed a continuity between the implant and host bone: The implant bone density (Hounsfield unit value above 2000 HU) was higher than the host bone density (400–1000 HU) without values below bone threshold (Figure 1B). We also excluded the formation of

Discussion

The aim of the study was to evaluate the repair trend and the osteointegration of custom-made porous HA implants for cranioplasty. Radiological, microtomographical, and histological analyses were performed on two patients who underwent surgical explantation of cranial implants after postoperative complication.

The search for osteointegration using inorganic bone substitutes in cranioplasty should be considered useless because cranial repair is mainly considered a replacement of cranial voids

Acknowledgement

Dr. Fricia and Dr. Passanisi performed the surgeries and collected the clinical cases. Histological and microtomographical analysis were performed at Rizzoli Orthopaedic Institute.

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These adverse events led to hospitalization extension for 5 patients (4.5%, p = 0.02) and revision surgery for 1 patient (p = 0.02). The CUSTOMBONE device is supported by a growing number of scientific projects concerning implanted patients both adults and children [15–29] demonstrating the clinical performance and reliability of the device in craniofacial procedures. For many years, series and reviews of the literature have multiplied to study and compare cranioplasty implants; whether they be made of titanium, poly-methyl-methacrylate (PMMA), polyetheretherketone (PEEK), autologous bone or hydroxyapatite (25 articles in 2000 to 168 in 2017) [30,31].
Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis.
To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years.
Mean age of patients included in the study was 42 ± 15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p < 0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection.
Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (> 1 year). Thus assiduous, regular and long-term surveillances are necessary.
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The choice of specific CaP-derived biomaterial depends on the targeted applications. For example, biocompatible ceramics, such as stoichiometric hydroxyapatite (HA) or biphasic calcium phosphate (BCP), are used as commercial bone substitutes [13–21]. In view of the brittleness of CaP ceramics, organic-inorganic composite CaP-derived materials such as chitosan-reinforced calcium phosphate cements [22] or apatite-collagen nanocomposites [23,24] have also been introduced to improve the mechanical properties of the device [25–31].
In this work, we show that sono-electrodeposition is an efficient and versatile process for the coating of activated carbon fiber cloth (ACC) with biocompatible calcium phosphate (CaP) phases. The chemical composition, microtexture and structure of the coating were investigated by FTIR, SEM, TEM, XRD and solid-state NMR, highlighting the influence of cathodic polarization and water electrolysis on the coating characteristics. At low current density, the process leads to the formation of calcium-deficient hydroxyapatite (CDA) and octacalcium phosphate (OCP) phases with plate-like microtextures. At higher current density, the CaP coating consists of carbonated hydroxyapatite with a needle-like microtexture while, at intermediate regimes, both plate-like and needle-like microtextures are formed. The coatings were not uniform, however, for all the current density values employed, either on carbon fiber or ACC surfaces. Alternatively, it is shown that a uniform coating with a well-defined thickness can be obtained by using a constant potential value close to that of water electrolysis. In that case, the deposit consists of a homogeneous CDA phase with a plate-like nanocrystalline microtexture which exhibits a highly biomimetic structural character.
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We discuss the hereditary behavior of hydroxyapatite-based composites used for cranioplasty surgery in the context of material isotropy. We classify mixtures of collagen and hydroxiapatite composites as biomimetic ceramic composites with hereditary properties modeled by fractional-order calculus. We assume isotropy of the biomimetic ceramic is assumed and provide thermodynamic of restrictions for the material parameters. We exploit the proposed formulation of the fractional-order isotropic hereditariness further by means of a novel mechanical hierarchy corresponding exactly to the three-dimensional fractional-order constitutive model introduced.
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The above differences may reflect the different characteristics of the implanted materials: bioinertia (such as in titanium, which offers direct contact with bone tissue), biotolerance (such as in polyether ether ketone or polymethyl methacrylate, which create fibrous tissue at the interface with bone), and bioactivity (such as in autologous graft or PHA, which induces osseointegration by chemical bonding of bone tissue with the implant). In 2015, Fricia et al.34 demonstrated bony cell colonization of the graft in a 2-year histologic analysis of PHA CP with newly formed bone remarking PHA bony-induction capacity. In our series, we had an infection rate of 6.7%, of which 4.8% of patients required surgical revision.
Despite the mixed evidence regarding the effect of decompressive craniectomy in terms of outcome, a tremendous increase in related reports has been observed in the last years. Cranioplasty plays a key role in restoring function and anatomy of the cranial vault. Considering that cranioplasty is not exempt from risks, the identification of the safest technique becomes crucial to achieve better patients' recovery. Porous hydroxyapatite (PHA) has received growing attention for its potential in bony integration. Here we report a multicenter prospective follow-up analysis of 149 patients who underwent cranioplasty with PHA prostheses. In particular, we focus on the incidence of adverse events and implant removal.
From January 2001 to December 2015 we conducted a prospective multicenter study of 149 patients who underwent cranioplasty with custom-made PHA flaps after decompressive craniectomy for several reasons. The endpoints were the incidence of adverse events after cranioplasty and of related implant removal.
66 patients (44%) were treated within 6 months from decompression, and only 2 patients had a bifrontal bilateral reconstruction. Of those, 25 patients reported complications (16.8%), and 9 of them (6% of the whole case series) required removal of the prosthesis. The only significant factor predicting cranioplasty removal was a previous infection.
Hydroxyapatite for cranial implants is fully comparable to other heterologous materials. It has a biologic potential of bony integration. The risk of explants seems to be significantly higher in second-line patients, data not shown in previous studies.
Long-Term Follow-Up Comparative Study of Hydroxyapatite and Autologous Cranioplasties: Complications, Cosmetic Results, Osseointegration
2018, World Neurosurgery
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The animal study of the CB prosthesis demonstrated a colonization of the pores by bone cells, spreading from the periphery toward the center of the implant over 12 months, with only very partial resorption.24 Only isolated clinical case reports have described osseointegration limited to partial colonization of the pores, insufficient to ensure adequate resistance.11,15,22,24,25,30,31 To date, there is no validated method to assess the osseointegration of CB prostheses in patients.
A three-dimensional reconstruction technique using the CustomBone (CB) prosthesis allows custom-made cranioplasty (CP) possessing osseointegration properties owing to its porous hydroxyapatite (HA) composition. This reconstruction technique has replaced less expensive techniques such as subcutaneously preserved autologous bone (SP). Our primary objective was to evaluate complications between CB and SP CP techniques. A secondary objective was to assess cosmetic results and osseointegration of CPs.
This single-center study comprised patients undergoing delayed CB or SP CP after craniectomy between 2007 and 2014. A prospective interview was conducted to collect all data, including 2-year follow-up clinical and radiologic data. Cosmetic results were assessed by a qualitative score, and osseointegration was assessed by measuring relative fusion at the CP margins.
Of 100 patients undergoing CB or SP CP between 2007 and 2014, 92 (CB, n = 44; SP, n = 48) participated in the prospective interview. No significant difference in complication rates was observed between the 2 groups. The main complication specific to the CB group was fracture of the prosthesis observed in 20.8% patients. A higher rate of good cosmetic results was observed in the CB group (92.5% vs. 74.3%, P = 0.031). In the CB group, 51% of patients demonstrated no signs of bone fusion of the CP.
Although the CB prosthesis is associated with cosmetic advantages, the porous hydroxyapatite composition makes it fragile in the short-term and long-term, and effective osseointegration remains uncertain.

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: Conflict of interest statement: The authors declare that they have no conflicts of interest.

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Case ReportOsteointegration in Custom-made Porous Hydroxyapatite Cranial Implants: From Reconstructive Surgery to Regenerative Medicine

Background

Case Description

Conclusions

Introduction

Section snippets

Surgical Procedures

Radiological Analysis and Hounsfield Measures

Radiologic Evaluation (Positioning, Hounsfield Values at Bone-Implant Margin)

Discussion

Acknowledgement

Injury

Biomaterial

Adv Drug Deliv Rev

Clin Neurol Neurosurg

Neurochirurgie

Biomaterials

Oral Surg Oral Med Oral Pathol Oral Radiol

Biomaterials

Case Report
Osteointegration in Custom-made Porous Hydroxyapatite Cranial Implants: From Reconstructive Surgery to Regenerative Medicine