A new bioinspired collagen-hydroxyapatite bone graft substitute in adult scoliosis surgery: results at 3-year follow-up

Introduction

Adult scoliosis is a spinal deformity in a skeletally mature patient with a Cobb angle of more than 10° in the coronal plain. Deformity in the adult spine can be a consequence of an adolescent deformity, a new presentation of deformity due to a degenerative process of the motion segment of the spine or the result of other causes such as tumor or osteoporotic fractures. Aebi scores describe 3 types of adult scoliosis: (i) primary degenerative scoliosis (de novo), (ii) progressive idiopathic scoliosis; (iii) secondary degenerative scoliosis (1).

In adult scoliosis, pain and disability correlate with segment degeneration, and sagittal imbalance are the most relevant findings to make a decision to undertake surgical treatment (2). Progression of neurological deficits or symptoms not responsive to conservative treatment for more than 6 months are additional indications to surgery. Instrumented spinal fusion is an effective treatment; however, the relatively limited amount of autologous local bone available for the graft makes it necessary to use bone from other sources or synthetic biomaterials.

Among the available graft options, an autologous iliac crest bone graft (ICBG) is considered the gold standard option for achieving arthrodesis, thanks to its excellent osteoinductive, osteoconductive and osteogenic properties. However, drawbacks such as morbidity at the harvesting site and limited availability may limit its use (3-4-5-6).

Local autograft bone (LAB), harvested from the lamina and the spinous processes during surgery, shows excellent fusion rates, reduced morbidity rates and shorter times in surgery (3, 7, 8); however, despite these excellent characteristics, the quantity and quality of LAB can be influenced by patient-related factors, particularly in children and older patients, resulting in a lack of material in sufficient amounts. Other bone graft substitutes developed as alternatives to autologous bone (i.e., allograft, bone morphogenetic proteins, demineralized bone matrix, platelet gel, mesenchymal stem cells) have shown variable results and disagreement in their clinical indications, being still the focus of investigations concerning their safety and efficacy in spinal applications (7, 9-10-11-12).

In this scenario, synthetic bone graft substitutes (BGSs) have been proposed and have available on the market since the 1980s as alternative osteoconductive materials to fill bony defects and smooth contour irregularities (3, 10, 13, 14). Usually derived from naturally occurring ceramics, these materials have been developed to provide porous scaffolds with a structural framework and mechanical stability, able to act as a cell anchorage site and thus enable new bone ingrowth.

The most common examples of ceramic-based materials are hydroxyapatite (HA), tricalcium phosphate (TCP) and calcium sulphate (CS), which have structural compositions that closely mimic the inorganic phase of bone. In spinal applications, the use of BGSs as viable replacements for autologous bone has been well-documented, showing how these materials, used as graft extenders, can provide comparable fusion rates to autologous bone, while avoiding donor site complications (15-16-17-18-19).

In particular, among the ceramic-based alternatives available, HA accounts for nearly 70 wt% of the mineral (inorganic) component of bone and teeth (20, 21), and is thus the most suitable material for bone replacement. In recent decades, new-generation BGSs have been developed to obtain enhanced mimicry of the biochemical and biophysical properties of the human bone. These “biomimetic” materials are manufactured by an assembling and mineralization process mimicking the cascade of phenomena yielding new bone formation in vivo (22), using equine-derived type I collagen, subjected to self-assembly and simultaneous mineralization with an apatite nanophase. In this complex process of biomineralization, therefore, an extracellular matrix (ECM)–mimicking matrix acts as an active template for the deposition of the mineral phase, and is also able to direct mineral deposition and limit crystal growth. The activation of these control mechanisms occurs through the linking of collagen functional groups (e.g., carbonyl groups) with calcium ions, which are then the nucleation sites for the mineral part. The highly regulated chemical-physical interaction between the inorganic (HA) and organic (type I collagen) phase is fundamental to allowing the formation of a composite material (bone) with unique properties of both stiffness (minerals) and elasticity (collagen) (23, 24).

The information stored in the organic phase (type I collagen) drives the mineralization process toward the development of nanostructured apatite platelets orientated along the long axis of the collagen, which is a feature considered to promote osteoblasts’ adhesion (25) (Fig. 1). Studies have also demonstrated that a multitude of doping ions (i.e., carbonate, magnesium), substituting either calcium (Ca) or phosphate (P) ions in the crystal lattice, characterize the formation of new bone (26-27-28). This phenomenon represents the major source of structural disorder in the mineral bone component, increasing its chemical reactivity and dissolution ability while maintaining a good affinity with osteoblast cells. Among the doping ions taking part to this process, Mg²⁺ ions, partially substituting calcium ions, are associated with the first stages and the very fast turnover of newly bone formation. The presence of Mg²⁺ ions increases the nucleation kinetic of the new mineral bone component while delaying the crystallization process, thus making it extremely active during remodeling (23). For the purpose of manufacturing a 3D fibrous mineralized construct which exhibits a very high degree of mimicry of the natural bone tissue, the assembling and simultaneous mineralization of type I collagen fibrils with biomimetic Mg-HA in aqueous media is provided, thus obtaining a newly developed 3D scaffold for bone regeneration made of magnesium-doped hydroxyapatite/type I collagen (MHA/Coll) (Fig. 2). The capability of this new-generation biomimetic BGS to promote bone regeneration and to assist new bone formation has been demonstrated in preliminary studies in animal models (29, 30), showing interesting results and therefore representing a valid alternative to ICBG for spinal applications – in particular for those procedures requiring enormous amounts of bone graft to be available for the treatment of long spinal segments (i.e., degenerative scoliosis).

In light of these considerations, we retrospectively reviewed a case series of patients who underwent long spinal fusion with the use of a synthetic MHA/Coll composite scaffold (provided by Fin-Ceramica Faenza S.p.A., Faenza, Italy) mixed with LAB graft for the treatment of adult degenerative scoliosis. The final outcome was evaluated by the analysis of posterolateral fusion rates and clinical parameters. A number of patient-related factors were also considered in order to evidence their possible influence on the final outcome.

Materials and methods

Results

According to the inclusion criteria, 41 patients were included in this retrospective study. Table III shows the patients’ demographic characteristics. There were 31 women and 10 men. The mean patient age was 62.9 years (standard deviation [SD] = 8.21 years). There were 22 participants younger than 65 years. Mean BMI (kg/m²) was 24.5 (SD = 3.6). Smokers comprised 29.3% of the sample population. Twelve patients (29.3%) had had previous surgical treatments for degenerative scoliosis. Thirteen patients (31.7%) had undergone an interbody fusion. The type of adult scoliosis was evaluated according to the Aebi classification system (Tab. III). Mean preoperative VAS score was 8.6. The mean preoperative ODI score was 72.

All of the patients underwent at least the fusion of 2 vertebral levels (Tab. IV). The postoperative radiographs (Figs. 5 and 6) showed the progressive incorporation of synthetic bone graft in the fusion area with time. Table V reports bony fusion as evaluated by the Lenke classification system. After 6 months, a good level of arthrodesis was achieved by the majority of patients (grade A or B). Only 1 patient showed no fusion (Lenke grade D). At 12-month follow-up, more than half of the patients (56%) already showed complete fusion mass (grade A). Only 2 patients still manifested partial and incomplete fusion (grade C). There were no patients showing a bone union failure. After 36 months, the majority of patients showed complete (grade A, 61%) (Fig. 7) or almost complete (grade B, 34%) bone union. Only 2 patients still manifested partial and incomplete fusion (grade C). The lack of bone union failure was confirmed at 36 months of follow-up. No baseline or clinical differences affected the outcome of patients with a delayed fusion as compared with patients already showing Lenke grade A or B at 6 months (Fisher’s exact test: 2-sided p>0.05).

Maximum flexion-extension postoperative radiographs, performed at 36 months after surgery, did not show any mechanical instability. No hardware failure was recorded. Correction of the scoliosis deformity and sagittal balance were maintained similarly and satisfactorily at final follow-up in all patients. SVA was between 0 and 5 points in all patients, and was also evaluated at 36-month follow-up (Tab. VI) (34). According to the Schwab criteria for good sagittal alignment, all patients showed SVA of between 0 and 5 cm (35).

The mean ODI decreased from 72 (baseline value) to 34.6, 25.5 and 23, at 6, 12 and 36 months, respectively (p<0.0001 for all time points vs. pre-op measure) (Tab. VII).

Mean pain intensity, measured on the 10-point VAS, was 8.6 at baseline. The mean VAS score decreased from 8.6 to 4.5 after 6 months post-op, then from 4.5 to 2.8 at 12-month follow-up, and from 2.8 to 2.2 at 36-month follow-up. At the different time points, the decrease of VAS score was significant, compared with the pre-op measure (p<0.0001) (Tab. VIII). No demographic or surgical factors affected either fusion or clinical values, which were all statistically significantly different at the follow-up periods (6, 12 and 36 months) compared with their preoperative values (p≤0.0005, at least). No intraoperative or postoperative complications were recorded.

Discussion

Currently, no BGS is better than an autologous bone graft. In long spinal fusion, the relatively limited quantity of local bone LAB graft means there is a need for other sources. Harvesting autologous bone graft from the iliac crest is one of the standard procedures, but possible complications associated with this technique are well known: donor site morbidity, postoperative pain, hematoma, infections and increased blood loss, which may occur in 25%-30% of patients, thus limiting its use (3). Another alternative is the use of allograft bone (harvested from a cadaveric donor), but this is often associated with potential risk of disease transmission, bacterial contamination or host-related reactions (36).

The results of the present study demonstrated that the use of the newly developed MHA/Coll 3D scaffold (RegenOss; provided by Fin-Ceramica Faenza S.p.A., Faenza, Italy) as BGS for bone regeneration is effective to achieve long spinal fusion in the surgical treatment of adult scoliosis. Moreover, this material can safely be mixed with autologous bone, as demonstrated by the absence of any adverse events recorded. We also considered a number of patient-related risk factors, which might influence the final outcome, but no correlations with either the degree of fusion or any clinical parameters were found.

The RegenOss scaffold evaluated in the present work was obtained by a bioinspired synthesis method (biomineralization) enabling the mineralization of type I collagen fibrils with an ion-doped apatitic nanophase, similar to what occurs during the formation of natural bone (22). Therefore, the scaffold exhibits physicochemical, morphological, structural and ultrastructural features very close to those of newly formed bone tissue (37).; as a result, the presence of a plethora of compositional and morphological cues offered by this scaffold can trigger several biochemical mechanisms instructing cells toward tissue regeneration.

In particular, the osteointegrative capabilities of this new scaffold have been recently reported by Grigolo and colleagues (38). The author reported the clinical case of a 65-year-old patient who underwent a long posterolateral fusion for treatment of adult scoliosis with severe sagittal imbalance and, 1 year later, revision surgery due to the rupture of a metallic bar. During the revision surgery, a histological examination was performed, showing the complete osteointegration of the graft, and evidencing the safety and efficacy of the implanted material (Fig. 8).

The use of ceramic-based BGSs in spinal applications has been widely investigated during recent years. Nickoli and colleagues (39) reviewed 30 clinical studies using ceramic-based materials as bone graft extenders in the lumbar spine. In 10 studies, involving more than 450 patients, the use of ceramics plus local autograft evidenced a fusion rate of around 90%. Lee and coworkers (40) reported no difference between the patient group treated with HA (87%) and the control group treated with ICBG (89%) in terms of fusion rates. Korovessis et al (41) concluded that HA together with the use of instrumentation and autologous bone provides good performance and a solid dorsal fusion within the expected time. Mashhadinezhad et al (42) evaluated the degree of fusion after applying HA inserted into cages for interbody fusion. The authors reported no difference between fusion rates achieved with HA compared with ICGB at 12-month follow-up, showing that application of HA granules, even inserted in cages, proved to be an effective treatment also for interbody fusion applications.

All of these data again confirm the safety and effectiveness of HA-based bone grafts in different spinal applications. From this perspective, data from the present retrospective study, in which we showed an improvement of bony fusion of about more than 90% at 36 months after surgery, are in line with results reported above. Moreover, the safety and efficacy of RegenOss in providing bone union was reiterated by the lack of baseline or clinical factors affecting the final outcome, as measured by Lenke grades A and B, at 6-month follow-up.

HA provides an osteoconductive matrix and shows osteogenic properties, but it generally lacks osteoinductive potential. For this reason, rates of successful arthrodesis can be increased by using bioceramics in conjunction with a source of cells such as a local autograft, which can be indicated to reduce the need for ICBG and concomitantly increase the quantity of bone graft available during surgery. The advantages provided by the use of synthetic bone grafts include their immediate availability and their unlimited quantity and good safety profile, which make them an essential resource, especially for those surgical procedures requiring a large amount of available bone graft.

In this retrospective study, we evidenced the safety and efficacy of this new-generation BGS for long fusion in spinal surgery. This BGS, by virtue of its malleability which makes it adaptable to cover complex shape defects, is particularly recommended for overlapping long segments of the spinal column. In addition, its regenerative properties, which allow bone ingrowth and tissue remodeling, are of relevant interest in scoliosis surgery.

One limitation of this study was the lack of a control group treated with autologous bone alone. Furthermore, a longer-term observation is needed to evaluate the fate of the synthetic bone graft–assisted spinal fusion, because a rigid spinal system can mask possible pseudoarthrosis during the first few years after surgery.

Conclusion

This study suggests that the use of this newly developed MHA/Coll 3D scaffold as a BGS in long spinal fusion for the treatment of adult scoliosis was safe and effective in providing spinal arthrodesis without any adverse effects or inflammatory response in all of the 41 patients treated for adult degenerative scoliosis. Surgical results showed equivalent or superior results compared with previous published data associated with the use of the gold standard ICBG. No patient-related factors affected the final outcome, underlying the notion that the use of this bone graft is effective independently of the patient’s clinical condition, and it can be safely associated with autologous bone in this surgery. Use of the 3D scaffold provided new bone formation, allowing spinal arthrodesis and therefore representing a valid support to instrumentation devices for the achievement of spinal fusion. Further investigations are needed to support long-term efficacy and additional indications for its use.