Use of ceramic synthetic allografts in spine surgery: a narrative review with early basic science and clinic data of novel nanosynthetic bone graft

Introduction

Degenerative spinal disorders continue to increase as the global population ages, spurring continued focus on optimizing current therapies and developing more targeted therapies (1). Several studies have demonstrated excellent fusion rates and patient outcomes using iliac crest bone autograft in both cervical and lumbar fusion surgeries (2-4). However, given the recognized donor site morbidity associated as well as increasing issue in bone quality with an aging population, there has been emphasis on investigating synthetic allograft options to reduce the need for autograft to achieve appropriate fusion (5-9).

There are four principles often necessary for a successful fusion: osteoconductivity, osteoinductivity, osteogenesis, and osteointegration (6). Osteoconduction is the process by which a graft acts as a scaffold that passively hosts cells and factors necessary for eventual bone formation. Osteoinduction is the process of recruitment, proliferation, and differentiation of host mesenchymal stem cells into bone-forming cells. This has been demonstrated through bone morphogenetic proteins, fibroblast growth factor, platelet derived- and vascular derived growth factors (10,11). Osteogenesis is the process of bone growth; osteogenic bone grafts have all the cellular elements, growth factors and scaffolding required to form new bone. Osteointegration describes the process by which bony ingrowth provides a secure connection between a material’s surface and bone (12). Bone grafts that demonstrate these properties have historically been associated with successful spinal fusion.

While autografts are considered the gold standard for encouraging fusion due to their inherent osteoconductive, osteoinductive, and osteogenic properties, their use has been associated with complications including pain, neurovascular injury, infection, fracture, and hematoma (13). The use of local bone grafting does help limit these adverse events but is often limited due to lack of availability of bone volume. The combination of allograft, which generally demonstrates only osteoconductive properties, with autograft has been increasingly used in spine surgery and has been shown in several anatomic areas to produce similar radiographic and clinical outcomes to autografts, often with lower complication rates (10,14). Concern regarding cost and potential risks of allograft—including disease transmission—has spurred interest in synthetic materials.

Purported benefits of synthetic materials for encouraging bony fusion include potentially decreased cost, more readily available supply, and nanoproperties that can be specifically adjusted to improve bone growth (8). Many synthetic materials are available with a variety of biomechanical and handling properties, biodegradability, and microscale architecture properties (15), with general categories including ceramics, synthetic polymers, synthetic peptides, bioactive glass, and peptide amphiphiles (16). As synthetics like ceramics are generally considered to have osteoconductive properties but generally not osteoinductive potential, they are often combined with osteoinductive substances like autograft or orthobiologics to ensure adequate osteogenic potential (17).

The purpose of this narrative review is to evaluate ceramic-based synthetic materials used to facilitate spinal fusion. We present this article in accordance with the Narrative Review reporting checklist (available at https://jss.amegroups.com/article/view/10.21037/jss-24-55/rc).

Methods

A review of national databases (PubMed and Scopus) was performed using literature from 1900 to 2024. Keywords included terms “allograft”, “nanosynthetic”, “spine”, and “surgery”. Studies that aimed to describe the types of devices, clinical and radiological outcomes, limitations, and future directions were included. Studies unavailable in English were excluded (Table 1).

Ceramics

Ceramic materials are increasingly utilized as synthetic graft extenders, often in concert with bioactive materials to encourage bone growth. Touted for their osteoinductive properties, biocompatibility, and biodegradability, these nontoxic materials do not elicit an immune response and can be made into porous or compact forms, with porous forms proving more amenable to cell adhesion cell growth, and distribution of nutrients (18). Moreover, in comparison to alternative graft materials, ceramics are considered to be more cost-effective (10). However, disadvantages of ceramics include inherent low mechanical strength—particularly with increased porosity—as well as brittleness with low fracture resistance, low tensile strength, and lack of vigorous osteoinductive properties (17,19). Commonly used ceramics include calcium sulfates (CSs), calcium phosphates, beta tricalcium phosphate, and hydroxyapatites (HAs) (19).

CSs

CS is a low-cost biodegradable ceramic that allows for an osteoconductive matrix for bony ingrowth; this is due in part to a crystalline structure that is similar to that of cancellous bone, therefore providing a scaffold for the migration of capillaries and mesenchymal stem cells (11). It requires a dry environment and has been shown to soften with moisture exposure, which leads to decreased strength and increased tendency for fragmentation (11).

As it tends to break down faster than bone deposition can occur (it usually dissolves at 5–7 weeks after implantation), its use in spinal fusion is generally limited to smaller defects (8,19,20). Moreover, its dissolution has been shown to cause serous drainage from the surgical site (21).

Contemporary research highlights enhanced pedicle screw stabilization through CS augmentation in cases of unstable thoracolumbar burst fractures (22-24). Studies using sheep models have indicated that CS injections can mitigate fracture risks in osteoporotic vertebral bodies (25). Buser et al.’s review, which assessed the effectiveness and safety of synthetic bone graft alternatives compared to autografts or allografts in treating lumbar and cervical degenerative spinal conditions, found comparable outcomes between CS and autologous grafts for lumbar fusion. However, this systematic review’s overall evidence quality was deemed low or inadequate, mainly due to potential biases and the small sizes of study samples (26).

In a prospective study, Xie et al. evaluated 68 patients with cervical degenerative disc disorders undergoing one- or two-level discectomy. The study found similar outcomes between groups using polyether-ether-ketone (PEEK) interbody cages filled with CS/demineralized bone matrix (DBM) and those using autogenous iliac cancellous bone. At a 12-month evaluation, fusion rates were 94.3% for the CS/DBM group and 100% for the iliac crest bone graft (ICBG) group, with both achieving 100% fusion at the 24-month final follow-up. Follow-up assessments showed no notable differences in clinical symptom scores or lordotic angles. Notably, the complication rate was lower in the CS/DBM group (8.6%) compared to the ICBG group (18.2%) (27).

Calcium phosphate

Unlike CS, calcium phosphate has been shown to possess osteoconductive and osteointegrative properties (19). Calcium phosphate has demonstrated strength under compressive forces, while relative weakness under tension and shear forces, and brittleness when used individually (19). Examples of these materials include beta-tricalcium phosphate and calcium phosphate cement. Beta-tricalcium phosphate is an example of a porous phosphate with compressive and tensile properties similar to those of cancellous bone and demonstrates a slower rate of degradation (6 to 18 months) compared to CS (5 to 7 weeks). As bone growth may be incomplete in that time frame, cement formulations of calcium phosphate have been developed that demonstrate longer degradation of approximately 24 months (8,17,18).

In a randomized controlled trial, Dai et al. assessed fusion rates among patients undergoing instrumented posterolateral fusion for degenerative lumbar stenosis, comparing the efficacy of beta-tricalcium phosphate with local autograft versus ICBG (28). All 62 patients (32 in the beta-tricalcium phosphate group, 30 in ICBG group) demonstrated radiographic fusion within 3-year postoperative follow-up. Nickoli et al.’s systematic review evaluating 30 studies using ceramics as bone graft extenders in patients undergoing posterolateral fusion demonstrated a fusion rate for beta-tricalcium phosphate of 92.5% (319 of 348 patients), exceeding the fusion rates observed with all ceramic-based bone grafts, which stood at 86.4% (17). Abbasi et al. employed beta-tricalcium phosphate combined with autologous bone marrow aspirate in a cohort of 24 patients undergoing oblique lateral lumbar interbody fusion (LLIF) in which all available disc space after discectomy was packed with beta-tricalcium phosphate and bone marrow aspirate; fusion was confirmed radiographically in all 24 patients at 1-year follow-up (29).

Silicated calcium phosphate

A new generation of ceramics includes silicate-substituted calcium phosphate (Si-CaP), which is formed by partial substitution of phosphate with silicate (30). Research indicates that silicates enhance bone metabolism by upregulating osteoblast proliferation and differentiation, fostering osteoinductive gene expression, and boosting type I collagen synthesis (18,31,32). The integration of silicate into ceramics is believed to augment the material’s negative surface charge, thus attracting osteoblasts to its surface and enhancing porosity and neovascularization, thereby enhancing its osteoinductive properties (33).

Wheeler et al.’s comparison of iliac crest autografts with Si-CaP showed a higher fusion mass in the Si-CaP group, with comparable bony bridging (32). Additionally, Jenis et al. reported a 76.5% fusion rate at 24 months post-operation in posterolateral lumbar fusions (34). In a study of 234 patients (516 spinal fusion levels) undergoing spinal fusion by cervical, thoracic, or lumbar procedures, Alimi et al. demonstrated fusion rates in 82.9% of patients and 86.8% of levels using only Si-CaP as bone graft substance; highest fusion rate was observed in the cervical region (35). In a considerably smaller study, Licina et al. conducted a comparison between Si-CaP and rhBMP-2 in posterolateral lumbar fusion, observing fusion in all nine patients with Si-CaP and eight of nine with rhBMP-2, alongside comparable pain relief and quality of life improvements (36). Pimenta et al. performed a prospective study comparing Si-CaP with rhBMP-2 bone graft in standalone extreme lateral interbody fusion (XLIF), demonstrating fusion with both graft materials but more rapid early postoperative fusion with use of rhBMP-2 (37). Recently, Mokawem et al. (38) reported a high combined fusion rate of 98.9% in transforaminal lumbar interbody fusion (TLIF) and LLIF procedures involving 93 adults using SiCaP-packed 3D-printed lamellar titanium cages. Similarly, Bolger et al. observed an 86.3% fusion rate at 12 months in patients undergoing instrumented posterolateral fusion with Si-CaP (39).

HA

HA, a key component of the inorganic bone matrix, features a porous structure conducive to osteoconductivity (8,19). The synthetic version of HA is designed to replicate this matrix, enhancing its compressive strength and toughness through sintering (40,41). HA is inert, easily sterilized, and readily available, though disadvantages include its inherent lack of strength and slow bioabsorbability, as it remains in vivo indefinitely with estimated resorption of 1–2% per year (19). HA is therefore not typically used alone as bone substitute and is often frequently augmented with instrumented fusion to ensure incorporation in surrounding native bone.

Studies have demonstrated that HA achieves substantial fusion rates within the cervical spine. Yoshii et al. investigated the efficacy of a synthetic porous/dense composite HA with percutaneously harvested ICBG versus tricortical ICBG in anterior cervical discectomy and fusion (ACDF). At 2-year follow-up fusion rates, sagittal alignment, and recovery rates were comparable between both groups (42). Intraoperative blood loss in the HA groups was significantly less than the ICBG group. While the ICBG group demonstrated donor site complications in 29.2% of patients, there was no donor site morbidity reported in the HA group.

HA has also been shown to achieve high fusion rates in the lumbar spine. Korovessis et al. performed a prospective randomized controlled trial in which 60 patients with degenerative lumbar stenosis undergoing posterolateral lumbar or lumbosacral fusion were randomized into three study groups: (I) autologous ICBG bilaterally; (II) ICBG unilaterally with HA and local bone and bone marrow on the contralateral side; or (III) HA with local bone graft and bone marrow bilaterally. All of the study groups demonstrated fusion on radiographs and computed tomography (CT) scans obtained 12 months postoperatively (43). Of note, the authors acknowledged incomplete fusion between transverse processes, thought to be associated with resorption of HA; this was not associated with overall fusion rate or subsequent functional outcomes.

Multiple studies have demonstrated the efficacy of HA as a bone graft extender to address morbidities associated with ICBG harvest; these studies all demonstrated comparable fusion rates to the “gold standard” ICBG (17,44,45). Yoo et al. investigated how the HA mixture ratio and the volume of bone graft affected fusion rates in 88 patients who underwent minimally invasive TLIF (46). Patients were divided into three groups: (I) local autograft only; (II) mixture of HA and >50% autograft; (III) HA and <50% autograft. Additionally, patients were subdivided into those who received graft volume <12 mL (Group A) or >12 mL (Group B). There were no significant differences in fusion rates between groups 1–3. However, there was a notable increase in fusion rates when the bone graft volume exceeded 12 mL (81.5% in Group A and 92.0% in Group B, P=0.03) (46).

Ceramic grafts + biomaterial

Given that ceramic grafts inherently lack osteoinductivity, they have been combined with bioactive materials like bone marrow aspirate, ICBG, or local autograft. Commercial ceramic grafts such as Mastergraft (Medtronic, Minneapolis, MN, USA), BoneSave (Stryker, Kalamazoo, MI, USA), Nanoss (Surgalign, Deerfield, IL, USA) and others have demonstrated efficacy as bone graft extenders (47-51). Nickoli et al. performed systematic reviews demonstrating that mean fusion rate using ceramic grafts in conjunction with bioactive materials for lumbar fusion was 86.4% (17). Fusion rates ranged from 72.5% to 96.2% upon combining ceramic with bone marrow aspirate or ICBG with DBM, respectively. Interestingly, there was no significant difference in fusion rates based on type of ceramic used (8,17).

Nanosynthetic graft

Novel synthetic grafts developed within the past decade have sought to better replicate the microstructure of the mineral component of bone by incorporating nanoscale granules. This increases surface area of the synthetic graft to allow for increased bone formation and increased resorption of the synthetic material. One such nanosynthetic bone graft is OssDsign^™ Catalyst (OssDsign, Uppsala, Sweden) that consists of nanoscale calcium phosphate with silicate substitution (5.8 wt% silicon) (52). Conway et al. compared fusion rates between nanosynthetic graft plus autograft with a collagen-biphasic calcium phosphate putty plus autograft in a rabbit model (53). Histology demonstrated bone formation via endochondral ossification, with new bone formation directly on the nanosynthetic granules. Endochondral ossification is a process that occurs during surgical spinal fusion to create new bone in the hypoxic zones of the fusion bed and requires the replacement of hyaline cartilage with bone. This process initiates as mesenchymal cells differentiate into chondrocytes, rapidly proliferating and secreting an extracellular matrix that forms the cartilage model for bone development. In this study, there was increased bone formation in the nanosynthetic graft group at all time points, as well as decreased lateral bending range of motion and increased fusion rates with 100% fusion at 26 weeks, which was comparable to autograft alone (53).

Recently, Varga et al. described in a case report the first use of OssDsign^™ Catalyst in a spinal fusion patient (54). Varga et al. assessed postoperative outcomes for a 40-year-old woman with L5–S1 degenerative disk disease and mild radicular symptoms. She underwent an L5–S1 TLIF with posterior instrumentation using OssDsign™ Catalyst nanosynthetic bone graft as a standalone graft anteriorly (2 mL) and within (1 mL) the interbody PEEK cage, and bilaterally (4 mL per side) in the posterolateral fusion area. The construct, stabilized by titanium internal fixation with 2 rods and 4 screws, showed significant bone growth and healing by 3 months postoperatively, achieving interbody and posterolateral spine fusion by 6 months (54). These preliminary results suggest that OssDsign^™ Catalyst could potentially be beneficial for bone growth and healing in human patients, echoing positive outcomes seen in pre-clinical studies. Additionally, the ease of use of the graft material was highlighted, particularly its handling characteristics and application within various areas of the surgical construct (54).

An ongoing study known as the OssDsign Spine Registry Study, or “Propel”, is a multi-center, post-market, prospective, observational spine fusion registry designed to evaluate the outcomes of patients undergoing spine fusion with OssDsign bone grafts (55). This study aims to enroll around 300 participants, who will be followed for a period of 24 months ± 90 days post-surgery. It is structured to assess the rate of bone fusion through imaging techniques like CT and X-rays, as well as patient-reported outcomes related to quality of life and pain, which are measured by standardized indexes and scales such as the Oswestry Disability Index and Visual Analog Scale. This is estimated to be completed by 2027 (55).

Finally, preclinical data from the granules that make up OssDsign^™ Catalyst in an intramuscular defect model, mimicking the center of a fusion mass given absence of adjacent host bone, has demonstrated that in the absence of local highly vascularised host bone, the material properties of OssDsign^™ Catalyst play a key role in recapitulating the highly effective bone healing response of autograft (56). Using appropriate control materials, the high silicate content of OssDsign^™ Catalyst was shown to result in rapid bone formation in these challenging defects, with bone forming by both intramembranous and endochondral ossification pathways; this bone formation was shown to be associated with recruitment of mesenchymal stem cells to the graft area and endogenous expression of BMP-2 by these cells (Figures 1,2).

Figure 1 Tissue response was assessed from decalcified paraffin histology, utilizing tetrachrome staining to identify any formation of osteoid in the defect, with positive staining of osteoid appearing as a deep blue color. (A) When a control material is made with nanoscale structure alone, without silicate ions, this does not result in bone formation. (B) When autograft is tested in this type of model, initial rapid bone formation occurs, followed by graft remodelling (44). FT, fibrous tissue; NB, new bone; G, granule of graft material; EB, endochondral bone.

Figure 2 Immunohistochemical staining of decalcified sections for BMP-2 expression. The rapid formation of new bone with OssDsign™ Catalyst in this intramuscular defect model ( (A) was associated with recruitment of host mesenchymal stem cells to the graft area, and subsequent endogenous expression of BMP-2 by these cells (positive staining of cells, brown), mimicking the role of endogenous BMPs in bone fracture repair (45). An osteoconductive control, a coral-derived bone graft (B), shows no positive staining for BMP-2. FT, fibrous tissue; NB, new bone; G, granule of graft material.

Conclusions

There have been considerable advancements in synthetic ceramic materials available for use in spine surgery. Nanosynthetic materials such as Catalyst have shown promise in animal models and early clinical applications as an autograft extender, with ongoing research assessing clinical outcomes on a larger scale. Future clinical studies will be necessary to determine differences in outcomes between the various types of synthetic materials available to optimize fusion rates while minimizing cost and complications associated with autograft.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Spine Surgery, for the series “Minimally Invasive Techniques in Spine Surgery and Trend Toward Ambulatory Surgery”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jss.amegroups.com/article/view/10.21037/jss-24-55/rc

Peer Review File: Available at https://jss.amegroups.com/article/view/10.21037/jss-24-55/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-24-55/coif). The series “Minimally Invasive Techniques in Spine Surgery and Trend Toward Ambulatory Surgery” was commissioned by the editorial office without any funding or sponsorship. C.K. served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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