Porous tantalum cage loaded with CGF promotes interbody fusion in a rat XLIF model

Porous tantalum cage loaded with CGF promotes interbody fusion in a rat XLIF model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Porous tantalum cage loaded with CGF promotes interbody fusion in a rat XLIF model Han Wu, Weijian Wang, Shaorong Li, Jianshi Song, Sidong Yang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7337688/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 21 You are reading this latest preprint version Abstract This study addresses the clinical challenge of nonunion in spinal interbody fusion by developing a novel composite implant: a porous tantalum (PTa) cage loaded with concentrated growth factors (CGF). The CGF-PTa cage synergistically combines the mechanical strength and osteoconductivity of chemically vapor-deposited PTa with the sustained release of angiogenic and osteogenic factors from CGF. Using a rat extreme lateral interbody fusion (XLIF) model, the research systematically evaluates the efficacy of this composite in promoting bone regeneration and spinal fusion. Results from radiography, micro-CT, biomechanical testing, histological staining, and immunohistochemistry consistently show that CGF-PTa significantly enhances bone ingrowth, fusion rate, and mechanical stability compared to PTa alone. The findings also reveal that CGF facilitates angiogenesis and osteogenesis by modulating the local healing microenvironment and promoting vascular–osteogenic coupling. Importantly, the CGF-PTa system demonstrated excellent biocompatibility and biodegradability in vivo, with no observed systemic toxicity. This work highlights the potential of combining bioactive factors with porous metallic scaffolds to overcome the limitations of inert implants in avascular environments, offering a promising strategy for functional optimization of interbody fusion devices and their future clinical application. Biological sciences/Biotechnology Physical sciences/Materials science Health sciences/Medical research interbody fusion concentrated growth factors Chemical vapor deposition Porous tantalum cage XLIF Rat model Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction With the accelerating global trend of population aging, the incidence of lumbar degenerative diseases such as lumbar disc herniation, spinal stenosis, and spondylolisthesis has significantly increased, posing major challenges to healthcare systems worldwide 1 . These conditions are often accompanied by persistent low back pain and progressive neurological dysfunction. When conservative treatments fail, surgical intervention becomes necessary 2 . Interbody fusion, a key surgical technique for managing degenerative spinal disorders, aims to restore spinal stability and relieve nerve compression. However, its long-term efficacy remains limited by complications such as pseudarthrosis and nonunion 3 . Currently, autologous bone grafting is considered the gold standard for interbody fusion due to its superior osteoconductive and osteoinductive properties. Nevertheless, its clinical application is restricted by donor site pain, infection, and limited bone availability 4 . Moreover, the surgical approach significantly influences the feasibility of harvesting autologous bone. Unlike traditional posterior lumbar interbody fusion (PLIF), lateral approaches such as XLIF avoid extensive resection of posterior bony structures, making it difficult to obtain sufficient autologous graft material. Surgeons often resort to harvesting bone from distant sites such as the iliac crest, which increases operative time and the risk of donor-site complications. Under such circumstances, allogeneic bone grafting is also widely used as an alternative approach, but it carries risks of immune rejection and disease transmission, and generally exhibits weak osteoinductive properties 5 . These clinical limitations have spurred the development of biomaterials for spinal fusion. Among them, PTa has emerged as a promising candidate owing to its excellent biocompatibility, corrosion resistance, and an elastic modulus similar to that of cancellous bone 6 . The elastic modulus of PTa is approximately 3–4 GPa, closely matching cancellous bone and thus mitigating issues such as stress shielding and implant subsidence commonly observed with conventional titanium-based implants 7 . Furthermore, PTa fabricated via CVD can achieve a porosity of 75–80%, and its interconnected three-dimensional structure facilitates cellular adhesion and bone tissue ingrowth 8–10 . In fact, osteoconduction and osteoinduction are two essential characteristics of bone implants 11 . While CVD-derived PTa possesses excellent osteoconductivity due to its structural and material properties, its bioinert nature limits its capacity to actively induce bone formation. Studies suggest that ideal porous implants should incorporate bioactive cells or growth factors to promote both angiogenesis and osteogenesis 12 . Therefore, enhancing the osteoinductive capacity of PTa is crucial for its application in interbody fusion, especially given the avascular and complex microenvironment of the interbody space. CGF, representing the third generation of autologous platelet concentrates, are enriched with multiple growth factors such as VEGF, PDGF, TGF-β, and IGF-1, which play essential roles in angiogenesis and osteogenic differentiation 13,14 . Produced via a variable-speed centrifugation process, CGF forms a dense, cross-linked fibrin matrix with a three-dimensional network structure. This matrix acts as an ideal biological carrier for growth factors, allowing for sustained, sequential release during degradation 15 . Previous studies have shown that CGF's fibrin network enables a controlled release of growth factors for up to 14 days, thereby maintaining a stable local concentration gradient essential for tissue regeneration 16,17 . This “high-concentration reservoir–programmed release” mechanism makes CGF a highly effective autologous biomaterial for promoting tissue regeneration and vascularization 18,19 . As a result, CGF has been widely applied in oral and maxillofacial surgery, plastic and reconstructive procedures, wound healing, and bone defect repair 20–22 . In theory, the combination of CGF’s osteoinductive potential with PTa’s osteoconductive structure can provide a physical cage for cell adhesion while delivering bioactive factors that promote angiogenesis and bone healing, thereby enhancing interbody fusion. However, such a strategy remains underexplored in the context of spinal fusion. In particular, the regulation of the "angiogenesis–osteogenesis coupling" mechanism to improve fusion outcomes warrants further investigation. We hypothesize that the biological activity of CGF can complement the bioinertness of PTa to synergistically enhance osteogenesis and vascularization, ultimately improving fusion rates and reducing the time required for spinal fusion.Therefore, this study proposes an innovative approach by combining PTa and CGF to fabricate a dual-functional composite cage capable of simultaneously promoting bone regeneration and neovascularization. The efficacy of this cage in facilitating interbody fusion was systematically evaluated in a rat XLIF model (Scheme 1), offering a novel strategy for optimizing interbody fusion cage design and advancing the treatment of degenerative spinal diseases. 2. Materials and methods 2.1. Animal source, care, ethics statement, and euthanasia In this study, male SD rats (3 months old, weighing 350 ± 50 g; sourced from the Animal Experiment Center of Hebei Medical University, China) were used. The rats were housed in an enriched environment, individually in separate cages, with a 12-hour light/dark cycle. After 2–3 days of acclimatization, all experiments were performed at the Animal Experiment Center of the Third Hospital of Hebei Medical University, approved by the Animal Ethics Committee of the Third Hospital of Hebei Medical University (approval number: Z2024-057-1), and strictly followed the NIH ARRIVE Guidelines for the Care and Use of Laboratory Animals. All methods were conducted in accordance with relevant institutional, national, and international guidelines and regulations. At the end of the study, all rats were euthanized using sodium pentobarbital and phenytoin sodium (100 mg/kg, intraperitoneal injection). 2.2. Fabrication of the PTa interbody fusion cage The porous tantalum interbody fusion cages were fabricated using the classical CVD technique developed by Implex-Zimmer. Based on the anatomical data of rat lumbar vertebrae, customizedcages were designed and manufactured. The resulting PTa cage had a porosity of approximately 80% and an average pore diameter of 440 µm.The fabrication process included the following steps: open-cell polyurethane foam with pore sizes ranging from 400–600 µm and a total porosity of ~ 80% was first degreased and resin-infiltrated, then pyrolyzed at 950°C in an inert atmosphere to form a three-dimensional reticulated vitreous carbon (RVC) skeleton. Tantalum sponge was chlorinated at ~ 330°C in a Cl₂ atmosphere to produce volatile TaCl₅. The reduction reaction 2TaCl₅ + 5H₂ → 2Ta + 10HCl was carried out at 980–1030°C, 2–8 Torr, and ≥ 92 vol% H₂. Tantalum atoms deposited uniformly along the pore walls for 60 minutes, forming a pure tantalum layer (~ 80 µm thick), resulting in a trabecular-like architecture with a dodecahedral lattice topology consisting of 98 wt% Ta and 2 wt% RVC.After deposition, the samples were cooled under inert gas, ultrasonically cleaned to remove residual chlorine, and subjected to vacuum annealing at 300°C for 30 min and 1000°C for 60 min to release residual stress and densify the tantalum layer. Final cleaning was performed sequentially using acetone, anhydrous ethanol, and ultrapure water. The qualified porous tantalum blocks were provided by Zimmer Biomet and subsequently cut using Wire-cut machining into rectangular shapes (3.5 mm × 1 mm × 1 mm) suitable for implantation in the rat spine. 2.3. Preparation of CGF CGF was prepared according to a previously established protocol. Approximately 7 mL of whole blood was collected from the hearts of rats under isoflurane anesthesia into sterile glass tubes without anticoagulants. A specialized centrifuge with a variable-speed program was used for separation: initial acceleration for 30 s, followed by 2 min at 2700 rpm (600 g), 4 min at 2400 rpm (500 g), another 4 min at 2700 rpm, and 3 min at 3000 rpm (800 g), ending with deceleration over 36 s. The resulting layers were: top—platelet-poor plasma (PPP), middle—CGF gel, and bottom—red blood cells (RBCs). 2.4. Preparation of CGF-PTa interbody fusion cage To ensure uniform distribution and surface coverage of gel-form CGF within the PTa cage, the following procedure was performed. The cage was first ultrasonically cleaned in acetone, anhydrous ethanol, and ultrapure water for 15 minutes each. Surface hydrophilicity was then enhanced using low-temperature oxygen plasma treatment (50 W, 5 min). During vacuum perfusion, the pretreated PTa cage was placed in a sterile chamber. An initial vacuum of − 0.03 MPa was applied for 10 seconds to remove air from the pores, followed by the slow addition of CGF gel. The vacuum was increased to − 0.06 MPa and maintained for 10 minutes to promote deep infiltration. Finally, the cage was tilted at a 45° angle under atmospheric pressure and slowly rotated to ensure even distribution of excess surface CGF. The construct was left undisturbed for 10 minutes to allow stable deposition within the cage. 2.5. Characterization of the CGF-PTa interbody fusion cage The surface morphology and porous microstructure of PTa and CGF-PTa cages were observed under a scanning electron microscope (SEM, Hitachi SU-8100, Japan) after gold sputter-coating, with accelerating voltage set at 20 kV and magnifications ranging from ×50 to ×20,000.To evaluate the sustained release profile of the CGF-PTa cage, ELISA was used to detect the concentrations of growth factors released over time. Cages loaded with CGF were immersed in 3 mL of PBS, and samples were collected and replaced at predefined time points (days 1, 3, 5, 7, and 14). Concentrations of VEGF, IGF-1, and TGF-β were measured, and release curves were plotted accordingly. 2.6. Animal model and surgical procedures This study employed the novel rat XLIF interbody fusion model that our team has successfully established 23 . A total of 48 male SD rats (3 months old, 350 ± 50 g) were randomly assigned to the PTa group or the CGF-PTa group. Anesthesia was induced with 5% isoflurane at a flow rate of 300 mL/min and maintained at 2% isoflurane. Anesthetic depth was monitored and adjusted by assessing tail, ear, and limb responses to pinch stimuli. After successful anesthesia, the rats were placed in the right lateral decubitus position, and the lumbar region was shaved and disinfected. The L4–L5 interbody space was located based on the iliac crest level, approximately corresponding to the surface projection of the sixth lumbar vertebra. A 4 cm arcuate skin incision was made approximately 3–4 cm lateral to the midline on the left flank. The external oblique, internal oblique, and transversus abdominis muscles were sequentially dissected to expose the quadratus lumborum and retroperitoneal fat. The retroperitoneal space was bluntly dissected to reach the dorsal side of the psoas major and the iliolumbar vessels, which were ligated. The retroperitoneal fat was retracted using saline-soaked gauze to expose the anterior-lateral border of the L4–L5 disc along the level of the L5 vertebral body.The annulus fibrosus was incised, and the nucleus pulposus was thoroughly removed. The cartilaginous endplates were scraped until punctate bleeding was observed. The PTa or CGF-PTa cage was then implanted, followed by lateral fixation of the L4–L5 segment using a titanium plate. After confirming adequate hemostasis, the surgical layers were closed in sequence, and the wound was covered with sterile dressing. Postoperative care included intraperitoneal injection of penicillin sodium (8U) for three consecutive days. Rats were monitored closely for neurological function and wound healing. 2.7. X-ray analysis Lateral radiographs of the lumbar spine were obtained postoperatively to assess implant displacement or subsidence. Fusion status was evaluated radiographically using a modified Bridwell grading system based on postoperative X-ray images. All grading was performed independently by two blinded spinal surgeons. The criteria were as follows:Grade 0, No new bone formation; no visible bone bridging across the disc space;Grade 1, New bone formation present, but no continuous bone bridge༛Grade 2, Partial but evident bone bridging, with clear fusion progression༛Grade 3, Continuous and uniform bone bridge formation between adjacent vertebral bodies, indicating complete radiographic fusion. 2.8. Manual palpation examination At postoperative weeks 4 and 8, rats were euthanized, and surrounding muscles and ligaments were removed to harvest spinal segments. After removing all internal fixation hardware, the L4–L5 fusion segment and adjacent levels were manually assessed for mobility by two blinded spinal surgeons. Flexion, extension, lateral bending, and rotation were performed to evaluate motion between segments.Segments exhibiting no obvious movement were classified as fused;Segments with visible mobility were classified as non-fused.Manual palpation results were used as a supplemental assessment of fusion and were analyzed in conjunction with radiographic scoring. 2.9. Micro-CT measurement At postoperative weeks 4 and 8, six samples from each group were randomly selected for high-resolution micro-CT imaging (SkyScan 1176, Bruker, Germany). The scanning parameters were set as follows: resolution of 18 µm, X-ray tube voltage of 65 kV, current of 385 µA, and exposure time of 340 ms per projection for a complete 360°rotation scan.Reconstruction was performed using Dataviewer and 3D visualization using CTvox. The interbody fusion region was defined as the region of interest (ROI), and 3D bone microstructural parameters were quantified using CTAn software:Bone volume to total volume (BV/TV), Bone surface to total volume (BS/TV), Trabecular number (Tb.N), Trabecular thickness (Tb.Th), Trabecular separation (Tb.Sp) and Bone mineral density (BMD). 2.10. Biomechanical evaluation The biomechanical testing was conducted following a modified protocol based on Reference 24 . Spinal segment stiffness was evaluated by measuring displacement distance using an Instron 5543 mechanical testing system (INSTRON, Norwood, MA, USA) equipped with a cantilever loading setup.Following micro-CT scanning, three specimens per group were selected and prepared by removing surrounding soft tissues, titanium plates, and screws, while preserving discs, ligaments, and joint capsules.Screws were inserted into the cranial and caudal vertebrae and fixed in polymethyl methacrylate (PMMA). A PMMA loading block was adhered to the superior surface of L4 and connected to the testing apparatus. The loading parameters were set at 22 N·mm torque with a 22 mm moment arm, and a 1 N load was applied to the cement block through the loading head. Flexion, extension, and left/right lateral bending were tested with 30 s relaxation between cycles. Each specimen underwent three loading cycles; stiffness values were calculated from the final cycle and reported as N·mm/°. 2.11. Histological analysis To evaluate bone regeneration within the fusion zone, undecalcified sections of bone were prepared and stained with Van-Gieson. At weeks 4 and 8 postoperatively, spinal specimens were harvested and fixed in 4% paraformaldehyde, dehydrated, and embedded in resin. Sections (~ 30 µm thick) were prepared using a cutting-grinding system and stained with Van-Gieson. Digital microscopy (DSX 500, Olympus, Japan) was used for imaging. ImageJ software was used for semi-quantitative analysis of new bone area within the cage (defined ROI). A uniform color threshold was set to identify mineralized bone and calculate its area fraction within the ROI. 2.12. Immunohistochemistry Bone tissues surrounding the interbody fusion cage were harvested at 4 and 8 weeks post-operation. Immunohistochemical staining was performed to detect the relative expression of CD31, VEGF, OCN, and RUNX2 in bone tissues at the interbody fusion sites, evaluating osteogenic activity and angiogenesis in each group. Tissue was fixed in 4% paraformaldehyde, decalcified in 10% EDTA for 3 weeks, paraffin-embedded, and sectioned at 5 µm. Sections were incubated overnight at 4°C with primary antibodies (Servicebio, China), followed by HRP-conjugated goat anti-rabbit IgG as the secondary antibody. Immunoreactive cells were identified by brown cytoplasmic staining and counterstained with hematoxylin. Positive cell counts were recorded under a light microscope. 2.13. Degradability and Local Biocompatibility of CGF Twelve 3-month-old male SD rats were anesthetized with 2% isoflurane and subcutaneously injected with 0.5 g of gel-form CGF in the dorsal region. Rats were randomly divided into four groups (n = 3 per time point) and euthanized at days 0, 3, 7, and 14. Residual CGF was harvested and weighed (Wt) to calculate degradation rate:Degradation rate (%) = (Wa − Wt) / Wa×100%,where Wa = initial CGF weight (0.5g). Adjacent skin tissue was fixed in 4% paraformaldehyde and stained with HE for histological examination to assess local biocompatibility. 2.14. Biocompatibility assay At 8 weeks post-surgery, rats were euthanized, and major organs (heart, liver, spleen, lungs, kidneys) were collected. Tissues were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with HE. Histological evaluation was performed to detect any systemic toxicity or pathological alterations resulting from cage implantation. 2.15. Statistical analysis Statistical analyses were conducted using SPSS 26.0 software (IBM, USA). Normality of data distribution was assessed using the Shapiro-Wilk test. For normally distributed data, parametric tests ( t-test or ANOVA) were used; otherwise, the Mann–Whitney U test was applied. All data are expressed as mean ± standard deviation (SD), with statistical significance defined as *p < 0.05, **p < 0.01, and ***p < 0.001. 3. Results 3.1. Characterization of the CGF-PTa interbody fusion cage As shown in Fig. 1 A, centrifugation of autologous rat blood resulted in three distinct layers: the upper layer was PPP, the middle layer was CGF, and the bottom layer consisted of RBCs. The extracted CGF gel appeared translucent. SEM revealed that CGF exhibited a dense fibrin matrix interwoven with platelets and red blood cells. Figure 1 A displays the macroscopic view of the CVD-fabricated porous cage prepared according to rat lumbar anatomical measurements. The prepared porous tantalum fusion device demonstrates intact overall architecture and surface morphology without observable manufacturing defects or cracks. SEM imaging confirmed that the porouscages exhibited a trabecular-like, dodecahedral lattice topology derived from RVC composite, with a porosity of approximately 80% and an average pore diameter of 440 µm. The cage columns showed uniform, continuous 3D interconnected pores, morphologically resembling cancellous bone, and featured micron-to-nanoscale surface roughness (Fig. 1 B). No unmelted particles or structural irregularities were observed, and the pore sizes matched macroscopic measurements. It is generally accepted that pore diameters of 300–500 µm and porosity of 75–90% are optimal for bone ingrowth. In this study, the pore size and porosity of the tantalum metalcage were 440 µm and 80%, respectively. As shown in the figure, the CGF gel can uniformly fill the pore structure of the porous tantalum metalcage. The local magnified SEM image shows that under negative pressure perfusion conditions, the CGF gel can penetrate deep into the internal pores of the cage and still maintain a dense and uniform fibrous network structure in the deep area. The ELISA results indicated that the angiogenic and osteogenic-related factors VEGF, TGF-β, and IGF-1 were continuously released within 14 days (Fig. 1 C). This indicated that CGF provides sustained delivery of bioactive factors, aligning with the prolonged and complex process of bone regeneration. Previous studies have described a biphasic release pattern from CGF: an initial burst release due to platelet activation and free diffusion, followed by a sustained release governed by gradual fibrincage degradation 25 . Our findings support this mechanism, suggesting that the release of growth factors is predominantly driven by the degradation of the fibrin network, during which embedded platelets disintegrate and slowly release their contents into the local microenvironment. 3.2. X-ray imaging and assessment of interbody fusion To evaluate fusion efficacy, lateral X-ray imaging was performed at predefined time points in all 48 SD rats (Fig. 2 A). No signs of cage displacement or subsidence were observed in any animals, and the titanium plates and screws remained intact without evidence of fracture, deformation, or loosening. Over time, both the PTa and CGF-PTa groups exhibited progressive formation of new bone bridging anterior and posterior to the cage, integrating with adjacent vertebral bodies (Fig. 2 B).According to the modified Bridwell scoring system, at 1 month postoperatively, the mean fusion scores were 0.92 ± 0.63 in the PTa group and 1.42 ± 0.63 in the CGF-PTa group. Although the difference was not statistically significant (p = 0.164), the CGF-PTa group showed a trend toward higher fusion grades. At 2 months, fusion scores increased to 2.25 ± 1.11 in the PTa group and 2.75 ± 0.35 in the CGF-PTa group; however, the difference remained statistically non-significant (p = 0.182) (Table 1 ). Despite the lack of statistical significance, the CGF-PTa group exhibited a higher proportion of Grade 3 fusions (complete bony bridging) at both time points, indicating a more robust fusion trend (Fig. 2 C). The non-significant results may be attributed to factors such as limited sample size (n = 12 per group), inter-animal variability in healing, and the semiquantitative nature of radiographic scoring, which can be subjective. Nevertheless, the CGF-PTa group consistently outperformed the PTa group in radiographic fusion scores, suggesting that CGF may facilitate enhanced spinal fusion. o further validate this observation, additional assessments, including manual palpation, micro-CT, biomechanical testing, and histological analysis, were conducted. 3.3. Manual palpation of interbody fusion Manual palpation was performed at 4 and 8 weeks postoperatively to assess spinal segment stability. At week 4, the complete fusion rate in the PTa group was 0.0% (0/12), whereas the CGF-PTa group showed a higher rate of 16.7% (2/12). By week 8, the fusion rate increased to 41.7% (5/12) in the PTa group and reached 91.7% (11/12) in the CGF-PTa group (Table 1 ).The trend observed in manual palpation results was consistent with the radiographic fusion scores, both showing time-dependent improvement in fusion status. Moreover, at both time points, the CGF-PTa group exhibited higher fusion rates than the PTa group. At week 4, the difference was not statistically significant, as determined by Fisher’s exact test (p = 0.478). However, at week 8, the intergroup difference reached statistical significance (p = 0.027), indicating that CGF loading significantly enhanced interbody fusion during the later stage of healing. Table 1 Radiographic fusion scores and Manual palpation fusion rate PTa(n = 12) CGF-PTa(n = 12) p Fusion score(4W) 0.92 ± 0.63 1.42 ± 0.63 p = 0.164 Fusion score(8W) 2.25 ± 1.11 2.75 ± 0.35 p = 0.182 Fusion rate(4W) 0.0% 16.7% p = 0.478 Fusion rate(8W) 41.7% 91.7% p = 0.027 Fusion status was assessed using the modified Bridwell grading system based on lateral X-ray images, which classifies interbody fusion into four levels: Grade 0 indicates no new bone formation and no evidence of bony bridging between adjacent vertebral bodies; Grade 1 represents the presence of new bone formation without a continuous bone bridge; Grade 2 reflects partial but substantial bone bridging with a clear tendency toward fusion; and Grade 3 denotes the formation of a continuous and uniform bone bridge across the interbody space, suggesting complete radiographic fusion. Fusion outcomes were further confirmed by manual palpation to evaluate segmental stability. 3.4. Micro-CT scanning and analysis To further evaluate the osteogenic performance of the CGF-PTa cage in vivo, micro-CT was performed on harvested spinal segments at 4 and 8 weeks postoperatively. As shown in Fig. 3 A, representative sagittal and coronal slices, along with 3D reconstructions, demonstrated new bone formation at the L4–L5 interbody fusion site in both groups.At 4 weeks, preliminary bone ingrowth was observed in both the PTa and CGF-PTa groups, with the CGF-PTa group showing a more robust bone healing trend, although continuous fusion had not yet been achieved. At 8 weeks postoperatively, both groups demonstrated more evident new bone formation compared to the 4-week time point, and a stable bridging union across the interbody space had formed. Notably, the CGF-PTa group exhibited significantly superior bone tissue regeneration than the PTa group.To quantify the micro-CT findings, bone microarchitectural parameters including BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD were analyzed (Fig. 3 B). The results showed that both groups exhibited a general trend of improvement in bone structural parameters as the healing process progressed over time. Statistically significant enhancements were observed in BV/TV(PTa: 4w, 5.06 ± 0.59% vs 8w, 9.54 ± 0.85%, p < 0.001 ;CGF-PTa༚4w, 7.04 ± 0.55% vs 8w, 14.99 ± 0.83%, p < 0.001)、Tb.Th༈PTa༚4w, 0.02 ± 0.01mm vs 8w, 0.04 ± 0.01 mm, p < 0.001 ༛CGF-PTa༚4w, 0.03 ± 0.01mm vs 8w, 0.05 ± 0.01 mm, p < 0.001༉、Tb.N༈PTa༚4w, 1.26 ± 0.08 1/mm vs 8w, 2.86 ± 0.26 1/mm, p < 0.001 ༛CGF-PTa༚4w, 1.56 ± 0.16 1/mm vs 8w, 3.24 ± 0.28 1/mm, p < 0.001༉、Tb.Sp༈PTa༚4w, 0.43 ± 0.03mm vs 8w, 0.35 ± 0.03mm, p < 0.001 ༛CGF-PTa༚4w, 0.43 ± 0.04mm vs 8w, 0.30 ± 0.03mm, p < 0.001༉和BMD༈PTa༚4w, 0.36 ± 0.03g/cm³ vs 8w, 0.90 ± 0.10g/cm³, p < 0.001 ༛CGF-PTa༚4w, 0.51 ± 0.04g/cm³ vs 8w, 1.11 ± 0.06g/cm³, p < 0.001༉. For BS/TV, a significant increase was observed in the PTa group from 12.00 ± 0.68 1/mm at 4 weeks to 14.65 ± 0.76 1/mm at 8 weeks (p < 0.001). In contrast, no statistically significant change was found in the CGF-PTa group, where BS/TV increased from 11.27 ± 1.00 1/mm to 12.12 ± 0.71 1/mm (p = 0.121). To further determine whether the CGF-PTa group exhibited an improving trend in bone fusion quality over time, intergroup comparisons between the PTa and CGF-PTa groups were conducted at different time points. At 4 weeks, although both groups showed similar trends in BV/TV, Tb.Th, and BMD, the CGF-PTa group demonstrated significantly greater improvements in all three parameters (p < 0.001). In addition, Tb.N in the CGF-PTa group (1.56 ± 0.16 1/mm) was significantly higher than that in the PTa group (1.26 ± 0.08 1/mm, p = 0.002). In fact, these differences became more pronounced by week 8. Compared to the PTa group, the CGF-PTa group exhibited significantly higher values in BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD (p < 0.001). Notably, BMD remained significantly elevated in the CGF-PTa group (p = 0.004), further supporting the enhancement of bone quality. Even for parameters such as Tb.N (p = 0.036) and Tb.Sp (p = 0.012), which showed smaller absolute differences, the CGF-PTa group still demonstrated statistically significant improvements. Taken together, these results suggest that the CGF-PTa cage significantly promotes new bone formation in vivo and exhibits progressively enhanced osteogenic performance over time. 3.5. Biomechanical evaluation Biomechanical testing of spinal specimens at 4 and 8 weeks postoperatively further demonstrated that with the progression of the fusion process, bone fusion quality was markedly improved by week 8. Moreover, the incorporation of CGF into the PTa cage significantly enhanced the interbody fusion strength compared to PTa alone(Fig. 4 ). At 4 weeks, compared with the PTa group, the PTa-CGF group exhibited a 54.74% increase in flexural stiffness.༈13.37 ± 1.05 Nmm/Deg vs 8.64 ± 1.37 Nmm/Deg, p = 0.009༉;An improvement of 39.45% in extension stiffness was also observed.༈11.67 ± 1.18Nmm/Deg vs 8.37 ± 1.06 Nmm/Deg, p = 0.023༉༛During lateral bending, stiffness was improved by 18.54% (14.26 ± 1.00 N·mm/deg vs 12.03 ± 1.42 N·mm/deg, p = 0.09) on the left side and by 23.92% (14.41 ± 1.13 N·mm/deg vs 11.63 ± 1.30 N·mm/deg, p = 0.049) on the right side.At 8 weeks, compared with the PTa group, the PTa-CGF group exhibited a 32.45% improvement in flexion stiffness (26.46 ± 2.46 N·mm/deg vs 19.97 ± 2.60 N·mm/deg, p = 0.035), and a 14.73% improvement in extension stiffness (21.27 ± 2.49 N·mm/deg vs 18.54 ± 1.71 N·mm/deg, p = 0.192). During lateral bending, stiffness increased by 23.67% on the left side (25.52 ± 2.41 N·mm/deg vs 20.63 ± 2.22 N·mm/deg, p = 0.061) and by 23.38% on the right side (25.34 ± 2.15 N·mm/deg vs 20.54 ± 2.47 N·mm/deg, p = 0.064). 3.6. Osseointegration assessment by histomorphometry analysis To assess the osteogenic performance of CGF-PTa, Van-Gieson staining was performed on bone tissue within the interbody fusion region (Fig. 5 A). During the early phase of bone formation, new bone tissue began to grow along the surface of the tantalum cage from the surrounding bone. As the healing process progressed, bone gradually infiltrated the inner pores of the cage. Compared to the PTa group without CGF, the CGF-PTa group exhibited more rapid and evident bone ingrowth. At 4 weeks postoperatively, partial new bone formation was observed along the outer surface of the cage in the PTa group, while in the CGF-PTa group, early bone ingrowth into the internal pores of the cage was already evident. By 8 weeks, both groups showed substantial bone ingrowth into the porous structure, suggesting a continuous and progressive bone regeneration process. The CGF-PTa group exhibited denser and more continuous mineralized bone, consistent with the micro-CT results shown in Fig. 3 , indicating that CGF-loaded porous tantalum significantly promotes bone growth within the interbody fusion region. Subsequent quantitative analysis of bone area fraction within the cage (defined as the region of interest, ROI) showed that at 4 weeks postoperatively, the CGF-PTa group exhibited a bone area fraction of 8.73 ± 1.81%, representing an approximately 59.9% increase compared to 5.46 ± 0.84% in the PTa group (p = 0.0024). By 8 weeks, the bone area fraction increased to 41.38 ± 5.17% in the CGF-PTa group and 25.65 ± 2.79% in the PTa group. Notably, the CGF-PTa group demonstrated a significantly stronger trend in bone formation, with a 61.3% increase in bone area compared to the PTa group (p < 0.001) (Fig. 5 B). 3.7. Immunohistochemistry To evaluate the effects of CGF-PTa on angiogenesis and osteogenesis, immunohistochemical analysis was performed on bone tissue from the interbody fusion region (Fig. 6 A). CD31 and VEGF were selected as representative markers for angiogenesis. CD31 is a typical endothelial cell marker involved in maintaining vascular integrity and permeability, while VEGF is a key mediator of angiogenesis, capable of significantly promoting the formation and expansion of new capillaries, thereby improving local blood supply 26 .In parallel, Runx2 and OCN were selected as osteogenic markers reflecting early and late stages of bone formation, respectively. Runx2 is a core transcription factor required for osteoprogenitor cell differentiation, with increased expression indicating activation of osteogenesis. OCN, a late-stage matrix protein secreted by osteoblasts, reflects ongoing matrix maturation and mineralization 27 . As shown in Fig. 6 B, at 4 weeks postoperatively, the proportions of CD31 and VEGF positive cells in the CGF-PTa group were significantly higher than those in the PTa group (both p < 0.001), indicating that the involvement of CGF notably enhanced local angiogenic activity in the early stage of bone healing. By 8 weeks, although the difference between the two groups had decreased, the expression levels of CD31 and VEGF in the CGF-PTa group remained higher than in the PTa group (p < 0.05, p < 0.01), suggesting a sustained angiogenic effect in the mid-to-late healing stage. As shown in Fig. 6 C, at 4 weeks postoperatively, the proportions of OCN and Runx2 positive cells in the CGF-PTa group were also higher than those in the PTa group (p < 0.05), indicating that CGF application not only activated osteoblast differentiation early but also promoted the expression of bone matrix proteins. This trend further increased by 8 weeks, with a significant increase in OCN-positive cells (p < 0.01), and Runx2 expression reaching statistical significance (p < 0.001), suggesting that CGF-PTa continued to enhance osteogenic activity and bone remodeling in the mid-to-late healing stage. Overall, the pro-angiogenic effect of CGF-PTa became evident in the early postoperative period and provided a favorable microenvironment for subsequent bone repair. Over time, its osteogenic-promoting effect gradually increased, showing stronger tissue regeneration capacity during the later phase of bone healing. This synergistic enhancement of angiogenesis and osteogenesis reveals a potential mechanism by which CGF promotes angiogenic–osteogenic coupling during interbody fusion. 3.8. Degradation and Local Biocompatibility Evaluation of CGF The degradation process of the CGF gel is shown in the Fig. S1 . The results indicated that the subcutaneously implanted CGF gel gradually decreased in size on days 0, 3, 7, and 14, with no visible signs of inflammation observed on the skin surface at any time point. The degradation curve showed that the initial mass of the CGF gel was 0.50 ± 0.01 g, which decreased to 0.35 ± 0.02 g on day 3, 0.20 ± 0.01 g on day 7, and further to 0.05 ± 0.01 g on day 14. This degradation process is likely associated with the gradual absorption and breakdown of fibrin components in CGF by host tissues. Overall, the CGF gel showed a continuous degradation trend after implantation, with a cumulative degradation rate of 90.6% by day 14. 3.9. Osseointegration assessment by histomorphometry analysis Tissue sections of major organs were prepared and stained with HE to assess whether the implantation of the fusion cage caused any pathological changes (Fig.S2). At 2 months postoperatively, no obvious pathological abnormalities were observed in the CGF-PTa group compared with the non-operated control group. These results indicate that the porous tantalumcage loaded with CGF, as well as any potential degradation products, did not induce significant toxicity in the major organs of SD rats, demonstrating good in vivo biocompatibility. 4. Discussion Delayed healing and nonunion following interbody fusion remain major challenges in the field of spinal surgery 28 . Compared to conventional bone repair processes such as maxillofacial defects or long bone fractures, spinal fusion presents greater complexity and challenges, primarily due to the unique interbody microenvironment and complex biomechanical conditions 29 . Unlike conventional bone defects, the interbody fusion site is subjected to continuous axial loading and shear stress; excessive mechanical stimulation may lead to fibrous tissue proliferation, thereby interfering with the formation of bony bridging 24 . Moreover, successful interbody fusion relies on bone regeneration between the vertebral endplates, a region characterized by chronically limited blood supply, which further constrains the bone healing process 30 . To address the challenges posed by the complex mechanical environment and insufficient blood supply during interbody fusion, this study is the first to apply a combination of PTa cage fabricated by chemical vapor deposition, characterized by a high friction coefficient and rough surface morphology, with CGF in a rat lateral interbody fusion model based on the XLIF technique. Results from X-ray imaging, Micro-CT, biomechanical testing, and subsequent histological analyses demonstrated that implantation of CGF-loaded porous tantalum cages within the interbody space significantly accelerated the process of bone fusion and improved the quality of interbody bone integration. Furthermore, biocompatibility evaluations revealed no significant pathological abnormalities in the subcutaneous tissues surrounding the implants or in major organs such as the heart, liver, spleen, lungs, and kidneys after surgery, indicating that the CGF-PTa construct exhibits favorable biocompatibility for interbody fusion applications. In fact, a common strategy in bone tissue engineering for promoting bone regeneration involves the combination of biomaterials and growth factors to create an optimal microenvironment for cell adhesion, vascularization, and signal transduction necessary for new bone formation 31 . Currently, biomaterials used in the field of bone repair can be broadly classified into four categories: ceramics, polymers, metals, and composites, each possessing distinct mechanical and biological advantages 32 , 33 . Tantalum, owing to its corrosion resistance, elastic modulus similar to that of cancellous bone, and excellent biocompatibility, has achieved favorable clinical outcomes and widespread recognition as a metal coating and a substitute for bone grafts 34 . Studies have shown that porous tantalum cages, due to their high friction coefficient and rough surface morphology, significantly enhance cell adhesion and provide ideal anchorage points for osteoblasts, thereby improving osteoconductivity. Additionally, the naturally formed surface oxide layer (Ta₂O₅) exhibits inherent antibacterial properties while maintaining excellent biocompatibility. Together, these features contribute to a biomimetic microenvironment that promotes cell proliferation and extracellular matrix deposition 35 . Porous tantalum possesses a Young’s modulus of approximately 3–4 GPa, closely matching that of cancellous bone. Combined with a three-dimensional interconnected porosity exceeding 75%, it offers additional space and attachment sites for cellular proliferation and growth within the cage, thereby facilitating inward bone tissue ingrowth, as demonstrated in previous studies 36 . In addition, high porosity enhances the transport of blood and oxygen, reduces stress shielding, and provides pathways for the inward growth of cells and blood vessels 37 , 38 . Based on these advantages, tantalum has been widely applied in recent years in joint replacement, treatment of traumatic fractures, post-tumor resection bone reconstruction, and interbody fusion, among other related fields 39 , 40 . However, due to the inherent bioinertness of tantalum, it lacks sufficient osteoinductive capacity. When implanted alone into the avascular and complex interbody microenvironment, the rate and quality of bone formation remain inferior to that achieved with autologous bone grafts. Meanwhile, in clinical applications, growth factors from the TGF-β superfamily, particularly bone morphogenetic proteins (BMPs), are among the most commonly used in combination with various biomaterials. However, exogenous growth factors such as BMPs are associated with complications, including radiculitis and ectopic bone formation caused by burst release, in addition to their high economic cost 41 , 42 . As a result, researchers have increasingly shifted their focus toward platelet concentrates and their combination with bone substitute materials as an alternative strategy, aiming to achieve more stable and controllable bone regeneration. CGF was first developed by Sacco in 2005 and is prepared from fresh whole blood using variable-speed centrifugation technology. It belongs to the third generation of platelet concentrates 43 . Compared with first-generation platelet-rich plasma (PRP) and second-generation platelet-rich fibrin (PRF), CGF possess not only a higher concentration of growth factors but also a more sustained and stable release profile. As a result, CGF has been widely applied in research fields related to tissue repair and bone regeneration 16 , 44 , 45 . Studies have shown that during the variable-speed centrifugation of fresh whole blood, platelets undergo lysis as a result of continuous shear stress and collision forces. A large number of ruptured platelets, along with leukocytes and erythrocytes, become embedded within the subsequently formed dense fibrin network 46 . Meanwhile, the dense fibrin network structure formed through variable-speed centrifugation in CGF enables the sustained release of multiple multilineage growth factors, including VEGF, TGF-β, and IGF-1, with a release duration of up to 14 days 15 . The synergistic action of these bioactive factors can induce macrophage polarization toward the M2 phenotype, promote angiogenesis, and drive the osteogenic differentiation of mesenchymal stem cells (MSCs), thereby creating a favorable cellular and molecular environment for bone tissue regeneration 47 . Therefore, autologous platelet concentrates (APCs), with CGF as a representative, can be considered biomimetic hematomas that have been artificially optimized to achieve high concentrations and controlled release of growth factors. Their mechanism of action is similar to that of hematomas naturally formed at fracture or bone defect sites, but the standardized preparation of CGF significantly enhances the concentration and bioavailability of these active factors. Moreover, SEM analysis of the CGF-PTa composite scaffold, prepared via vacuum perfusion, confirmed that the gel-form CGF was uniformly distributed and thoroughly infiltrated the porous structure of the tantalum scaffold. We hypothesize that this combination establishes a vascular–osteogenic coupling microenvironment, in which the dense fibrin matrix and multiple growth factors contained within the CGF permeate along the tantalum pores, promoting the synchronized ingrowth of vascular structures and trabecular bone into the scaffold interior. This process results in the simultaneous enhancement of both mechanical support and biological functionality. In this study, porous tantalum metal cages were fabricated using a CVD technique and subsequently loaded with gel-form CGF through negative pressure infusion. The cages were characterized by SEM. The struts of the porous tantalum cages were uniform and structurally intact, exhibiting an interconnected pore architecture similar to that of cancellous bone, with a highly regular dodecahedral geometry in terms of pore size and shape. The surface morphology demonstrated micro- and nanoscale roughness. The CGF, prepared from allogeneic rat cardiac blood, displayed a uniform and dense fibrin network structure, within which platelets, red blood cells, and white blood cells were visibly embedded. In the CGF-PTa composite cage, SEM imaging revealed that the porous structure was extensively coated with dense fibrin matrix. Fibrin fibers of varying sizes adhered to and penetrated deeply into the cage's internal pore network. High-magnification observations of the gel-filled pores showed a complex internal structure composed of densely woven fibrin networks, platelets, and red blood cells. Previous studies have demonstrated that high-viscosity fibrin scaffolds can act as temporary “nesting” matrices for platelets, erythrocytes, leukocytes, and CD34⁺ cells, enabling their initial retention and the gradual release of growth factors. This controlled release mechanism helps to avoid early-stage burst release and instead delivers cytokines in a more physiologically regulated manner 48 , 49 . “On-demand” release not only holds the potential to amplify biological effects but also reduces the risk of tissue edema and inflammation caused by high local concentrations of growth factors 50 . Subsequent ELISA results further confirmed that angiogenic and osteogenic growth factors, including VEGF, TGF-β, and IGF-1, were continuously and gradually released from the CGF-PTa composite cage over a period of 14 days, supporting the feasibility of the proposed release mechanism. To evaluate the therapeutic efficacy of CGF-loaded tantalum cages fabricated via CVD in spinal fusion procedures, the selection of an appropriate animal model is critical. In spinal fusion research, small animal models have become ideal tools for high-throughput screening and mechanistic studies due to their short observation periods, low cost, and high reproducibility 51 . Therefore, rat models of spinal fusion are widely used in related research. However, due to the small body size of rats and technical limitations in surgical procedures, commonly employed spinal fusion models are primarily limited to intertransverse process fusion and coccygeal interbody fusion 52 , 53 . It is important to note that the applicability of these two models has long been a subject of debate. Some researchers argue that intertransverse process fusion more closely resembles conventional bone defect models and does not adequately reflect the biological processes of interbody fusion. Others contend that coccygeal interbody fusion fails to accurately replicate the axial loading and shear stress experienced during the interbody fusion process 54 . To address this issue, our research team developed a rat lumbar interbody fusion model based on the anatomical characteristics of rats, utilizing a lateral extraperitoneal approach(XLIF technique). This model more accurately simulates the biomechanical conditions of human interbody fusion 23 . X-ray results showed that no evident loosening or displacement of the implants or internal fixation devices was observed in either the PTa or CGF-PTa groups during the postoperative follow-up period. At both 4 and 8 weeks postoperatively, interbody fusion scores in the CGF-PTa group were consistently higher than those in the PTa group. Manual palpation findings were consistent with the radiographic fusion scores, showing higher fusion rates in the CGF-PTa group at both time points. Notably, at 8 weeks postoperatively, the fusion rate in the CGF-PTa group reached 91.7%, which was significantly higher than the 41.7% observed in the PTa group. Micro-CT assessments at 4 and 8 weeks revealed initial bone ingrowth in both groups at the 4-week time point, with the CGF-PTa group demonstrating superior bone healing, particularly in terms of new bone formation and tissue ingrowth, despite the absence of complete interbody fusion. As healing progressed to 8 weeks, more pronounced new bone formation and the establishment of stable bony bridging across the interbody space were observed in both groups. Bone structural parameters, including BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD, generally improved over time, indicating ongoing bone regeneration. Although both groups showed favorable healing trends, the CGF-PTa group consistently exhibited superior outcomes, suggesting greater potential for CGF-PTa in promoting bone regeneration and interbody fusion. At 4 and 8 weeks postoperatively, animals were euthanized, and the spinal segments were harvested after removal of the screws and titanium plates. Biomechanical testing, including flexion-extension and lateral bending, was performed on both the PTa and CGF-PTa groups. The results showed that the CGF-PTa group exhibited greater structural stiffness in all loading directions compared to the PTa group, indicating superior mechanical stability of the fused segment. Notably, although the differences between the groups were slightly reduced at 8 weeks, the CGF-PTa group continued to demonstrate a significant mechanical advantage, reflecting the sustained contribution of the material throughout the bone healing process.Subsequently, hard tissue grinding sectioning combined with Van-Gieson staining was used to evaluate changes in bone volume within the fusion region. The results revealed that the bone area fraction within the scaffold in the CGF-PTa group was 8.73% at 4 weeks and 41.38% at 8 weeks, significantly higher than the 5.46% and 25.65% observed in the PTa group, corresponding to increases of approximately 59.9% and 61.3%, respectively. These findings were highly consistent with the micro-CT results, indicating that CGF loading not only facilitates early-stage adhesion and colonization of new bone tissue but also promotes more extensive and deeper bone infiltration and remodeling within the scaffold at later stages.The above biomechanical and histological findings further validate the effectiveness of CGF in enhancing the osteogenic performance of interbody fusion scaffolds. These results are also consistent with previous studies that support the osteogenic potential of CGF, highlighting its favorable regenerative capacity and promising application prospects.To further investigate the underlying biological mechanisms, immunohistochemical analysis was conducted to assess the expression of angiogenesis and osteogenesis related markers in the fusion region. The results demonstrated a higher proportion of CD31 and VEGF positive cells in the CGF-PTa group at both 4 and 8 weeks, suggesting enhanced local angiogenesis that may support new bone formation. In parallel, the expression of osteogenic markers Runx2 and OCN was significantly upregulated, indicating that CGF facilitates osteoblast differentiation and extracellular matrix maturation.These findings are consistent with previous reports showing that CGF is rich in multiple growth factors, such as VEGF, TGF-β, and IGF-1, which promote both angiogenesis and osteogenesis. The results provide further evidence, at the cellular and molecular levels, supporting the potential of CGF in bone tissue engineering. In addition, histological examination of the tissue surrounding the implant and major organs confirmed the favorable in vivo biocompatibility of the CGF-PTa construct, laying a foundation for its future clinical translation.In summary, the incorporation of CGF into porous tantalum cage establishes a favorable microenvironment that synergistically promotes both neovascularization and bone formation, offering an effective strategy to enhance the bioactivity of porous metal fusion devices. Although this study systematically evaluated the osteogenic effects and biocompatibility of CGF-PTa in interbody fusion, several limitations remain and should be addressed in future research. (1)Due to the limited interbody space in rats, the volume of the tantalum scaffold used in this study was relatively small. As a result, only one histological section could be obtained per sample, which restricted the sample size and allowed for only a single staining method in histopathological analysis. Future studies may consider incorporating customized drilling techniques to enlarge the interbody space, thereby improving the operability and evaluation efficiency of the model. (2)Although CGF should ideally be prepared from autologous blood to ensure immunocompatibility, the limited blood volume in rats necessitated the use of allogeneic blood sources in this study, which may have introduced confounding factors affecting the outcomes. (3)While CGF inherently exhibits a certain degree of sustained release capability, previous studies have shown that combining CGF with hydrogels or nanomaterials can further prolong the release duration of bioactive factors. However, to enhance clinical translatability, this study deliberately avoided introducing exogenous materials that may pose a risk of biological toxicity, which may have limited the optimization of sustained release.Overall, these limitations provide clear directions for further optimization of the model and lay the groundwork for future studies in large animal models or preclinical settings. 5. Conclusion In this study, a composite system comprising porous tantalum cage loaded with CGF was developed and systematically evaluated in a rat interbody fusion model. The results demonstrated that CGF-PTa exhibited excellent performance in terms of fusion rate, biomechanical stability, biocompatibility, osteogenic capacity, and bone integration, significantly enhancing the long-term stability of the fusion segment. The synergistic effect between CGF and the porous tantalum cage enabled coordinated promotion of both angiogenesis and bone regeneration within the interbody fusion microenvironment, highlighting its promising potential in the field of tissue engineering. This strategy offers a novel approach and theoretical foundation for the functional optimization and clinical translation of porous metal fusion devices. Declarations Conflicts of interest There are no conflicts to declare. Author Contribution H.W. Writing – original draft. W. W. Data curation. S. L. Writing – review & editing. J. S.: Writing – review & editing. S.Y. Writing – review & editing. Q.Y. Visualization. L.L. Visualization. R.Z. Conceptualization. Haoyu Wu: Investigation. W.Zhang. Supervision,Funding acquisition. Acknowledgements Not applicable. 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Exploring an innovative augmentation strategy in spinal fusion: A novel selective prostaglandin EP4 receptor agonist as a potential osteopromotive factor to enhance lumbar posterolateral fusion. Biomaterials 320 https://doi.org:10.1016/j.biomaterials.2025.123278 (2025). Gantenbein, B. et al. The bone morphogenetic protein 2 analogue L51P enhances spinal fusion in combination with BMP2 in an in vivo rat tail model. Acta Biomater. 177 , 148–156. https://doi.org:10.1016/j.actbio.2024.01.039 (2024). Drespe, I. H., Polzhofer, G. K., Turner, A. S. & Grauer, J. N. Animal models for spinal fusion. Spine J. 5 , 209–S216. https://doi.org:10.1016/j.spinee.2005.02.013 (2005). Scheme Scheme 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Supplementaryinformation.docx floatimage1.jpeg Cite Share Download PDF Status: Published Journal Publication published 12 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 13 Oct, 2025 Reviewers agreed at journal 06 Oct, 2025 Reviews received at journal 05 Oct, 2025 Reviews received at journal 03 Oct, 2025 Reviewers agreed at journal 23 Sep, 2025 Reviewers agreed at journal 21 Sep, 2025 Reviewers agreed at journal 18 Sep, 2025 Reviews received at journal 18 Sep, 2025 Reviewers agreed at journal 17 Sep, 2025 Reviewers agreed at journal 16 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers agreed at journal 08 Sep, 2025 Reviews received at journal 04 Sep, 2025 Reviewers agreed at journal 25 Aug, 2025 Reviewers agreed at journal 22 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers invited by journal 20 Aug, 2025 Editor assigned by journal 20 Aug, 2025 Editor invited by journal 20 Aug, 2025 Submission checks completed at journal 14 Aug, 2025 First submitted to journal 14 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7337688","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":505278976,"identity":"f861b887-0da1-479a-9145-9043e51cd3ee","order_by":0,"name":"Han Wu","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Wu","suffix":""},{"id":505278977,"identity":"07011989-1403-4c21-9631-2827e856e12c","order_by":1,"name":"Weijian Wang","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Weijian","middleName":"","lastName":"Wang","suffix":""},{"id":505278978,"identity":"d1668be7-1d56-4a74-be67-ba0fb0fb1dbc","order_by":2,"name":"Shaorong Li","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shaorong","middleName":"","lastName":"Li","suffix":""},{"id":505278979,"identity":"9009a010-7387-4a96-b82c-536d20c68642","order_by":3,"name":"Jianshi Song","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jianshi","middleName":"","lastName":"Song","suffix":""},{"id":505278980,"identity":"1b981d8e-9b6c-4091-a80d-51268477d844","order_by":4,"name":"Sidong Yang","email":"","orcid":"","institution":"The Third hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Sidong","middleName":"","lastName":"Yang","suffix":""},{"id":505278981,"identity":"0cde8be2-6740-4ce6-afe6-4cadd21974c2","order_by":5,"name":"Qiang Yang","email":"","orcid":"","institution":"Tianjin University","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Yang","suffix":""},{"id":505278982,"identity":"3bbdc71d-c76c-4258-9c09-ea2c22b69daa","order_by":6,"name":"Liang Li","email":"","orcid":"","institution":"The Third hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Li","suffix":""},{"id":505278983,"identity":"2fdde029-e0e7-4e89-998b-adc3feb5be11","order_by":7,"name":"Ruixin Zhen","email":"","orcid":"","institution":"The First Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruixin","middleName":"","lastName":"Zhen","suffix":""},{"id":505278984,"identity":"6cc356af-37eb-454a-a950-8e4a25398581","order_by":8,"name":"Haoyu Wu","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haoyu","middleName":"","lastName":"Wu","suffix":""},{"id":505278985,"identity":"1ffb6ac3-5449-41e2-9719-51058406b091","order_by":9,"name":"Wei Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBACefnnBw4k/KiR45dgYIMIHSCgxbAhJ/HBx55jxpIziNXCcCDB2HAGG3PihhvEamFsOJAmzcPDxrj5dvOxRzfbGOT4biQwfi7Ao4WdsfGYNI+FDLPZnWPpxrltDMaSNxKYpWfgs6WZAWwLm9mNHDNpoBagCxPYmHnwuewYg5k0D1CN8Yz8byAt9YS1nGEAe1/CQCKHDaQlwYCQFsMZPOBANpC4kWZunHNOwnDmmYfN0vi0yEuwg6Oyvn9G8rPHOWU28nzHkw9+xuswNCDBAAp4EjSMglEwCkbBKMAGAJvFS4T+BDRPAAAAAElFTkSuQmCC","orcid":"","institution":"The Third hospital of Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-08-10 08:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7337688/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7337688/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-31736-1","type":"published","date":"2025-12-12T15:59:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90154974,"identity":"dbd9e9ad-439a-4fe6-b29f-d3ccb661f7d2","added_by":"auto","created_at":"2025-08-29 07:57:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2007019,"visible":true,"origin":"","legend":"\u003cp\u003eCharacterization of the CGF-PTa cage. (A) Photographic and SEM images of CGF gel, along with the interbody fusion cage (3.5 mm × 1 mm × 1 mm) used for in vivo experiments. (B) Scanning electron microscopy images of the PTa cage and the CGF-PTa cage. (C) Cumulative release profiles of TGF-β, IGF-1, and VEGF from the CGF-loaded PTa cage (n = 3).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/41c8da26a160de68a05a4699.png"},{"id":90154972,"identity":"c49245f0-b393-438a-8f4d-ea055fb02c01","added_by":"auto","created_at":"2025-08-29 07:57:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":486274,"visible":true,"origin":"","legend":"\u003cp\u003eExperimental design of the SD rat interbody fusion model and X-ray based fusion score analysis. (A) Schematic illustration of the surgical and analytical procedures for the rat interbody fusion model. (B) Representative X-ray images obtained immediately postoperatively and at 1 and 2 months after surgery. (C) Modified Bridwell scoring analysis of interbody fusion outcomes at 1 and 2 months postoperatively in SD rats.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/c6315179be04a0163611f860.png"},{"id":90156142,"identity":"ee3a4e6f-4291-432d-a284-92dc6a83bac0","added_by":"auto","created_at":"2025-08-29 08:13:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":938710,"visible":true,"origin":"","legend":"\u003cp\u003eMicro-CT evaluation of interbody fusion at 4 and 8 weeks postoperatively. (A) Representative μCT images of the L4–L5 segment, including sagittal CT slices, 3D reconstructed coronal views, 3D reconstructions of the cage region (gray indicates the porous tantalum cage), and binarized images illustrating bone ingrowth within the cage. (B) Quantitative analysis of trabecular bone microarchitectural parameters, including BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD, in each group at 4 and 8 weeks postoperatively. (n = 6; data are presented as mean ± standard deviation. * indicates intergroup comparisons: p \u0026lt; 0.05, *p \u0026lt; 0.01, **p \u0026lt; 0.001; # indicates intragroup comparisons between time points: #p \u0026lt; 0.05, ##p \u0026lt; 0.01, ###p \u0026lt; 0.001)\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/37dc3feef2df8c3d364b68e2.png"},{"id":90154975,"identity":"fe145665-7a83-4940-a57c-1543ba06de7a","added_by":"auto","created_at":"2025-08-29 07:57:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":378316,"visible":true,"origin":"","legend":"\u003cp\u003eBiomechanical stiffness analysis to evaluate segmental stability of the operated lumbar spine at 4 and 8 weeks postoperatively.Comparison of stiffness between the CGF-PTa and PTa groups in (A) flexion/extension and (B) left/right lateral bending.(n = 3; data are presented as mean ± standard deviation. *p \u0026lt; 0.05, **p \u0026lt; 0.01.)\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/185fe6e387707617ed596117.png"},{"id":90154979,"identity":"a66bb10b-19ee-42ec-b57c-8616b20b2137","added_by":"auto","created_at":"2025-08-29 07:57:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1568156,"visible":true,"origin":"","legend":"\u003cp\u003eHistological analysis of the interbody fusion region at 4 and 8 weeks postoperatively.(A) Representative Van-Gieson stained images of the interbody fusion region in the PTa and CGF-PTa groups at 4 and 8 weeks after cage implantation. Red indicates newly formed bone, black representscage pores, and yellow denotes surrounding background tissue.(B) Quantitative analysis of bone area fraction within the cage based on Van-Gieson staining.(n = 6; * indicates significant difference between groups: *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001.)\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/5b9c553f4d44feb37bad1203.png"},{"id":90155167,"identity":"16948809-1c94-44d8-a619-50c0fa68da15","added_by":"auto","created_at":"2025-08-29 08:05:18","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2170612,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical analysis of the interbody fusion region at 4 and 8 weeks postoperatively. (A) Representative immunohistochemical staining images showing the expression of CD31, VEGF, OCN, and RUNX2 at 4 and 8 weeks after surgery. Cytoplasmic staining of positive cells appears brown, while nuclei are stained dark blue. (B) Quantitative analysis of the proportions of CD31 and VEGF positive cells. (C) Quantitative analysis of the proportions of OCN and RUNX2 positive cells. (n = 6; * indicates significant difference between groups: *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/25c9ec87847b9e2a4393dde0.png"},{"id":98244779,"identity":"d0f4cedb-abc6-4608-91b6-f480c95c3d92","added_by":"auto","created_at":"2025-12-15 16:15:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8678169,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/9feb7d54-8d22-4b23-9507-ff3e8238a6ef.pdf"},{"id":90156143,"identity":"027127f3-e767-41dd-ab17-ac65492846c2","added_by":"auto","created_at":"2025-08-29 08:13:18","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":5054838,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/689294510e3b08a168710ac4.docx"},{"id":90154978,"identity":"cda1195f-8713-4e66-9b5d-edf3aeb35fb1","added_by":"auto","created_at":"2025-08-29 07:57:18","extension":"jpeg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":656044,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7337688/v1/79a44603509c96150421509c.jpeg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Porous tantalum cage loaded with CGF promotes interbody fusion in a rat XLIF model","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eWith the accelerating global trend of population aging, the incidence of lumbar degenerative diseases such as lumbar disc herniation, spinal stenosis, and spondylolisthesis has significantly increased, posing major challenges to healthcare systems worldwide \u003csup\u003e1\u003c/sup\u003e. These conditions are often accompanied by persistent low back pain and progressive neurological dysfunction. When conservative treatments fail, surgical intervention becomes necessary \u003csup\u003e2\u003c/sup\u003e. Interbody fusion, a key surgical technique for managing degenerative spinal disorders, aims to restore spinal stability and relieve nerve compression. However, its long-term efficacy remains limited by complications such as pseudarthrosis and nonunion \u003csup\u003e3\u003c/sup\u003e. Currently, autologous bone grafting is considered the gold standard for interbody fusion due to its superior osteoconductive and osteoinductive properties. Nevertheless, its clinical application is restricted by donor site pain, infection, and limited bone availability \u003csup\u003e4\u003c/sup\u003e. Moreover, the surgical approach significantly influences the feasibility of harvesting autologous bone.\u003c/p\u003e\n\u003cp\u003eUnlike traditional posterior lumbar interbody fusion (PLIF), lateral approaches such as XLIF avoid extensive resection of posterior bony structures, making it difficult to obtain sufficient autologous graft material. Surgeons often resort to harvesting bone from distant sites such as the iliac crest, which increases operative time and the risk of donor-site complications. Under such circumstances, allogeneic bone grafting is also widely used as an alternative approach, but it carries risks of immune rejection and disease transmission, and generally exhibits weak osteoinductive properties \u003csup\u003e5\u003c/sup\u003e. These clinical limitations have spurred the development of biomaterials for spinal fusion. Among them, PTa has emerged as a promising candidate owing to its excellent biocompatibility, corrosion resistance, and an elastic modulus similar to that of cancellous bone \u003csup\u003e6\u003c/sup\u003e. The elastic modulus of PTa is approximately 3\u0026ndash;4 GPa, closely matching cancellous bone and thus mitigating issues such as stress shielding and implant subsidence commonly observed with conventional titanium-based implants \u003csup\u003e7\u003c/sup\u003e. Furthermore, PTa fabricated via CVD can achieve a porosity of 75\u0026ndash;80%, and its interconnected three-dimensional structure facilitates cellular adhesion and bone tissue ingrowth \u003csup\u003e8\u0026ndash;10\u003c/sup\u003e. In fact, osteoconduction and osteoinduction are two essential characteristics of bone implants \u003csup\u003e11\u003c/sup\u003e. While CVD-derived PTa possesses excellent osteoconductivity due to its structural and material properties, its bioinert nature limits its capacity to actively induce bone formation. Studies suggest that ideal porous implants should incorporate bioactive cells or growth factors to promote both angiogenesis and osteogenesis \u003csup\u003e12\u003c/sup\u003e. Therefore, enhancing the osteoinductive capacity of PTa is crucial for its application in interbody fusion, especially given the avascular and complex microenvironment of the interbody space.\u003c/p\u003e\n\u003cp\u003eCGF, representing the third generation of autologous platelet concentrates, are enriched with multiple growth factors such as VEGF, PDGF, TGF-\u0026beta;, and IGF-1, which play essential roles in angiogenesis and osteogenic differentiation\u003csup\u003e13,14\u003c/sup\u003e. Produced via a variable-speed centrifugation process, CGF forms a dense, cross-linked fibrin matrix with a three-dimensional network structure. This matrix acts as an ideal biological carrier for growth factors, allowing for sustained, sequential release during degradation \u003csup\u003e15\u003c/sup\u003e. Previous studies have shown that CGF\u0026apos;s fibrin network enables a controlled release of growth factors for up to 14 days, thereby maintaining a stable local concentration gradient essential for tissue regeneration \u003csup\u003e16,17\u003c/sup\u003e. This \u0026ldquo;high-concentration reservoir\u0026ndash;programmed release\u0026rdquo; mechanism makes CGF a highly effective autologous biomaterial for promoting tissue regeneration and vascularization \u003csup\u003e18,19\u003c/sup\u003e. As a result, CGF has been widely applied in oral and maxillofacial surgery, plastic and reconstructive procedures, wound healing, and bone defect repair \u003csup\u003e20\u0026ndash;22\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn theory, the combination of CGF\u0026rsquo;s osteoinductive potential with PTa\u0026rsquo;s osteoconductive structure can provide a physical cage for cell adhesion while delivering bioactive factors that promote angiogenesis and bone healing, thereby enhancing interbody fusion. However, such a strategy remains underexplored in the context of spinal fusion. In particular, the regulation of the \u0026quot;angiogenesis\u0026ndash;osteogenesis coupling\u0026quot; mechanism to improve fusion outcomes warrants further investigation. We hypothesize that the biological activity of CGF can complement the bioinertness of PTa to synergistically enhance osteogenesis and vascularization, ultimately improving fusion rates and reducing the time required for spinal fusion.Therefore, this study proposes an innovative approach by combining PTa and CGF to fabricate a dual-functional composite cage capable of simultaneously promoting bone regeneration and neovascularization. The efficacy of this cage in facilitating interbody fusion was systematically evaluated in a rat XLIF model (Scheme 1), offering a novel strategy for optimizing interbody fusion cage design and advancing the treatment of degenerative spinal diseases.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003e2.1. Animal source, care, ethics statement, and euthanasia\u003c/h2\u003e\n \u003cp\u003eIn this study, male SD rats (3 months old, weighing 350\u0026thinsp;\u0026plusmn;\u0026thinsp;50 g; sourced from the Animal Experiment Center of Hebei Medical University, China) were used. The rats were housed in an enriched environment, individually in separate cages, with a 12-hour light/dark cycle. After 2\u0026ndash;3 days of acclimatization, all experiments were performed at the Animal Experiment Center of the Third Hospital of Hebei Medical University, approved by the Animal Ethics Committee of the Third Hospital of Hebei Medical University (approval number: Z2024-057-1), and strictly followed the NIH ARRIVE Guidelines for the Care and Use of Laboratory Animals. All methods were conducted in accordance with relevant institutional, national, and international guidelines and regulations. At the end of the study, all rats were euthanized using sodium pentobarbital and phenytoin sodium (100 mg/kg, intraperitoneal injection).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\"\u003e\n \u003ch2\u003e2.2. Fabrication of the PTa interbody fusion cage\u003c/h2\u003e\n \u003cp\u003eThe porous tantalum interbody fusion cages were fabricated using the classical CVD technique developed by Implex-Zimmer. Based on the anatomical data of rat lumbar vertebrae, customizedcages were designed and manufactured. The resulting PTa cage had a porosity of approximately 80% and an average pore diameter of 440 \u0026micro;m.The fabrication process included the following steps: open-cell polyurethane foam with pore sizes ranging from 400\u0026ndash;600 \u0026micro;m and a total porosity of ~\u0026thinsp;80% was first degreased and resin-infiltrated, then pyrolyzed at 950\u0026deg;C in an inert atmosphere to form a three-dimensional reticulated vitreous carbon (RVC) skeleton. Tantalum sponge was chlorinated at ~\u0026thinsp;330\u0026deg;C in a Cl₂ atmosphere to produce volatile TaCl₅. The reduction reaction 2TaCl₅ + 5H₂ \u0026rarr; 2Ta\u0026thinsp;+\u0026thinsp;10HCl was carried out at 980\u0026ndash;1030\u0026deg;C, 2\u0026ndash;8 Torr, and \u0026ge;\u0026thinsp;92 vol% H₂. Tantalum atoms deposited uniformly along the pore walls for 60 minutes, forming a pure tantalum layer (~\u0026thinsp;80 \u0026micro;m thick), resulting in a trabecular-like architecture with a dodecahedral lattice topology consisting of 98 wt% Ta and 2 wt% RVC.After deposition, the samples were cooled under inert gas, ultrasonically cleaned to remove residual chlorine, and subjected to vacuum annealing at 300\u0026deg;C for 30 min and 1000\u0026deg;C for 60 min to release residual stress and densify the tantalum layer. Final cleaning was performed sequentially using acetone, anhydrous ethanol, and ultrapure water. The qualified porous tantalum blocks were provided by Zimmer Biomet and subsequently cut using Wire-cut machining into rectangular shapes (3.5 mm \u0026times; 1 mm \u0026times; 1 mm) suitable for implantation in the rat spine.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003e2.3. Preparation of CGF\u003c/h2\u003e\n \u003cp\u003eCGF was prepared according to a previously established protocol. Approximately 7 mL of whole blood was collected from the hearts of rats under isoflurane anesthesia into sterile glass tubes without anticoagulants. A specialized centrifuge with a variable-speed program was used for separation: initial acceleration for 30 s, followed by 2 min at 2700 rpm (600 g), 4 min at 2400 rpm (500 g), another 4 min at 2700 rpm, and 3 min at 3000 rpm (800 g), ending with deceleration over 36 s. The resulting layers were: top\u0026mdash;platelet-poor plasma (PPP), middle\u0026mdash;CGF gel, and bottom\u0026mdash;red blood cells (RBCs).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\"\u003e\n \u003ch2\u003e2.4. Preparation of CGF-PTa interbody fusion cage\u003c/h2\u003e\n \u003cp\u003eTo ensure uniform distribution and surface coverage of gel-form CGF within the PTa cage, the following procedure was performed. The cage was first ultrasonically cleaned in acetone, anhydrous ethanol, and ultrapure water for 15 minutes each. Surface hydrophilicity was then enhanced using low-temperature oxygen plasma treatment (50 W, 5 min). During vacuum perfusion, the pretreated PTa cage was placed in a sterile chamber. An initial vacuum of \u0026minus;\u0026thinsp;0.03 MPa was applied for 10 seconds to remove air from the pores, followed by the slow addition of CGF gel. The vacuum was increased to \u0026minus;\u0026thinsp;0.06 MPa and maintained for 10 minutes to promote deep infiltration. Finally, the cage was tilted at a 45\u0026deg; angle under atmospheric pressure and slowly rotated to ensure even distribution of excess surface CGF. The construct was left undisturbed for 10 minutes to allow stable deposition within the cage.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003e2.5. Characterization of the CGF-PTa interbody fusion cage\u003c/h2\u003e\n \u003cp\u003eThe surface morphology and porous microstructure of PTa and CGF-PTa cages were observed under a scanning electron microscope (SEM, Hitachi SU-8100, Japan) after gold sputter-coating, with accelerating voltage set at 20 kV and magnifications ranging from \u0026times;50 to \u0026times;20,000.To evaluate the sustained release profile of the CGF-PTa cage, ELISA was used to detect the concentrations of growth factors released over time. Cages loaded with CGF were immersed in 3 mL of PBS, and samples were collected and replaced at predefined time points (days 1, 3, 5, 7, and 14). Concentrations of VEGF, IGF-1, and TGF-\u0026beta; were measured, and release curves were plotted accordingly.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003e2.6. Animal model and surgical procedures\u003c/h2\u003e\n \u003cp\u003eThis study employed the novel rat XLIF interbody fusion model that our team has successfully established\u003csup\u003e23\u003c/sup\u003e. A total of 48 male SD rats (3 months old, 350\u0026thinsp;\u0026plusmn;\u0026thinsp;50 g) were randomly assigned to the PTa group or the CGF-PTa group. Anesthesia was induced with 5% isoflurane at a flow rate of 300 mL/min and maintained at 2% isoflurane. Anesthetic depth was monitored and adjusted by assessing tail, ear, and limb responses to pinch stimuli. After successful anesthesia, the rats were placed in the right lateral decubitus position, and the lumbar region was shaved and disinfected. The L4\u0026ndash;L5 interbody space was located based on the iliac crest level, approximately corresponding to the surface projection of the sixth lumbar vertebra. A 4 cm arcuate skin incision was made approximately 3\u0026ndash;4 cm lateral to the midline on the left flank. The external oblique, internal oblique, and transversus abdominis muscles were sequentially dissected to expose the quadratus lumborum and retroperitoneal fat. The retroperitoneal space was bluntly dissected to reach the dorsal side of the psoas major and the iliolumbar vessels, which were ligated. The retroperitoneal fat was retracted using saline-soaked gauze to expose the anterior-lateral border of the L4\u0026ndash;L5 disc along the level of the L5 vertebral body.The annulus fibrosus was incised, and the nucleus pulposus was thoroughly removed. The cartilaginous endplates were scraped until punctate bleeding was observed. The PTa or CGF-PTa cage was then implanted, followed by lateral fixation of the L4\u0026ndash;L5 segment using a titanium plate. After confirming adequate hemostasis, the surgical layers were closed in sequence, and the wound was covered with sterile dressing. Postoperative care included intraperitoneal injection of penicillin sodium (8U) for three consecutive days. Rats were monitored closely for neurological function and wound healing.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003e2.7. X-ray analysis\u003c/h2\u003e\n \u003cp\u003eLateral radiographs of the lumbar spine were obtained postoperatively to assess implant displacement or subsidence. Fusion status was evaluated radiographically using a modified Bridwell grading system based on postoperative X-ray images. All grading was performed independently by two blinded spinal surgeons. The criteria were as follows:Grade 0, No new bone formation; no visible bone bridging across the disc space;Grade 1, New bone formation present, but no continuous bone bridge༛Grade 2, Partial but evident bone bridging, with clear fusion progression༛Grade 3, Continuous and uniform bone bridge formation between adjacent vertebral bodies, indicating complete radiographic fusion.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003e2.8. Manual palpation examination\u003c/h2\u003e\n \u003cp\u003eAt postoperative weeks 4 and 8, rats were euthanized, and surrounding muscles and ligaments were removed to harvest spinal segments. After removing all internal fixation hardware, the L4\u0026ndash;L5 fusion segment and adjacent levels were manually assessed for mobility by two blinded spinal surgeons. Flexion, extension, lateral bending, and rotation were performed to evaluate motion between segments.Segments exhibiting no obvious movement were classified as fused;Segments with visible mobility were classified as non-fused.Manual palpation results were used as a supplemental assessment of fusion and were analyzed in conjunction with radiographic scoring.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003e2.9. Micro-CT measurement\u003c/h2\u003e\n \u003cp\u003eAt postoperative weeks 4 and 8, six samples from each group were randomly selected for high-resolution micro-CT imaging (SkyScan 1176, Bruker, Germany). The scanning parameters were set as follows: resolution of 18 \u0026micro;m, X-ray tube voltage of 65 kV, current of 385 \u0026micro;A, and exposure time of 340 ms per projection for a complete 360\u0026deg;rotation scan.Reconstruction was performed using Dataviewer and 3D visualization using CTvox. The interbody fusion region was defined as the region of interest (ROI), and 3D bone microstructural parameters were quantified using CTAn software:Bone volume to total volume (BV/TV), Bone surface to total volume (BS/TV), Trabecular number (Tb.N), Trabecular thickness (Tb.Th), Trabecular separation (Tb.Sp) and Bone mineral density (BMD).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003e2.10. Biomechanical evaluation\u003c/h2\u003e\n \u003cp\u003eThe biomechanical testing was conducted following a modified protocol based on Reference \u003csup\u003e24\u003c/sup\u003e. Spinal segment stiffness was evaluated by measuring displacement distance using an Instron 5543 mechanical testing system (INSTRON, Norwood, MA, USA) equipped with a cantilever loading setup.Following micro-CT scanning, three specimens per group were selected and prepared by removing surrounding soft tissues, titanium plates, and screws, while preserving discs, ligaments, and joint capsules.Screws were inserted into the cranial and caudal vertebrae and fixed in polymethyl methacrylate (PMMA). A PMMA loading block was adhered to the superior surface of L4 and connected to the testing apparatus. The loading parameters were set at 22 N\u0026middot;mm torque with a 22 mm moment arm, and a 1 N load was applied to the cement block through the loading head. Flexion, extension, and left/right lateral bending were tested with 30 s relaxation between cycles. Each specimen underwent three loading cycles; stiffness values were calculated from the final cycle and reported as N\u0026middot;mm/\u0026deg;.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003e2.11. Histological analysis\u003c/h2\u003e\n \u003cp\u003eTo evaluate bone regeneration within the fusion zone, undecalcified sections of bone were prepared and stained with Van-Gieson. At weeks 4 and 8 postoperatively, spinal specimens were harvested and fixed in 4% paraformaldehyde, dehydrated, and embedded in resin. Sections (~\u0026thinsp;30 \u0026micro;m thick) were prepared using a cutting-grinding system and stained with Van-Gieson. Digital microscopy (DSX 500, Olympus, Japan) was used for imaging. ImageJ software was used for semi-quantitative analysis of new bone area within the cage (defined ROI). A uniform color threshold was set to identify mineralized bone and calculate its area fraction within the ROI.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003e2.12. Immunohistochemistry\u003c/h2\u003e\n \u003cp\u003eBone tissues surrounding the interbody fusion cage were harvested at 4 and 8 weeks post-operation. Immunohistochemical staining was performed to detect the relative expression of CD31, VEGF, OCN, and RUNX2 in bone tissues at the interbody fusion sites, evaluating osteogenic activity and angiogenesis in each group. Tissue was fixed in 4% paraformaldehyde, decalcified in 10% EDTA for 3 weeks, paraffin-embedded, and sectioned at 5 \u0026micro;m. Sections were incubated overnight at 4\u0026deg;C with primary antibodies (Servicebio, China), followed by HRP-conjugated goat anti-rabbit IgG as the secondary antibody. Immunoreactive cells were identified by brown cytoplasmic staining and counterstained with hematoxylin. Positive cell counts were recorded under a light microscope.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003e2.13. Degradability and Local Biocompatibility of CGF\u003c/h2\u003e\n \u003cp\u003eTwelve 3-month-old male SD rats were anesthetized with 2% isoflurane and subcutaneously injected with 0.5 g of gel-form CGF in the dorsal region. Rats were randomly divided into four groups (n\u0026thinsp;=\u0026thinsp;3 per time point) and euthanized at days 0, 3, 7, and 14. Residual CGF was harvested and weighed (Wt) to calculate degradation rate:Degradation rate (%) = (Wa\u0026thinsp;\u0026minus;\u0026thinsp;Wt) / Wa\u0026times;100%,where Wa\u0026thinsp;=\u0026thinsp;initial CGF weight (0.5g). Adjacent skin tissue was fixed in 4% paraformaldehyde and stained with HE for histological examination to assess local biocompatibility.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\"\u003e\n \u003ch2\u003e2.14. Biocompatibility assay\u003c/h2\u003e\n \u003cp\u003eAt 8 weeks post-surgery, rats were euthanized, and major organs (heart, liver, spleen, lungs, kidneys) were collected. Tissues were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with HE. Histological evaluation was performed to detect any systemic toxicity or pathological alterations resulting from cage implantation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\"\u003e\n \u003ch2\u003e2.15. Statistical analysis\u003c/h2\u003e\n \u003cp\u003eStatistical analyses were conducted using SPSS 26.0 software (IBM, USA). Normality of data distribution was assessed using the Shapiro-Wilk test. For normally distributed data, parametric tests ( t-test or ANOVA) were used; otherwise, the Mann\u0026ndash;Whitney U test was applied. All data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), with statistical significance defined as *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, and ***p\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1. Characterization of the CGF-PTa interbody fusion cage\u003c/h2\u003e\n \u003cp\u003eAs shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA, centrifugation of autologous rat blood resulted in three distinct layers: the upper layer was PPP, the middle layer was CGF, and the bottom layer consisted of RBCs. The extracted CGF gel appeared translucent. SEM revealed that CGF exhibited a dense fibrin matrix interwoven with platelets and red blood cells.\u003c/p\u003e\n \u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA displays the macroscopic view of the CVD-fabricated porous cage prepared according to rat lumbar anatomical measurements. The prepared porous tantalum fusion device demonstrates intact overall architecture and surface morphology without observable manufacturing defects or cracks. SEM imaging confirmed that the porouscages exhibited a trabecular-like, dodecahedral lattice topology derived from RVC composite, with a porosity of approximately 80% and an average pore diameter of 440 \u0026micro;m. The cage columns showed uniform, continuous 3D interconnected pores, morphologically resembling cancellous bone, and featured micron-to-nanoscale surface roughness (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). No unmelted particles or structural irregularities were observed, and the pore sizes matched macroscopic measurements. It is generally accepted that pore diameters of 300\u0026ndash;500 \u0026micro;m and porosity of 75\u0026ndash;90% are optimal for bone ingrowth. In this study, the pore size and porosity of the tantalum metalcage were 440 \u0026micro;m and 80%, respectively. As shown in the figure, the CGF gel can uniformly fill the pore structure of the porous tantalum metalcage. The local magnified SEM image shows that under negative pressure perfusion conditions, the CGF gel can penetrate deep into the internal pores of the cage and still maintain a dense and uniform fibrous network structure in the deep area.\u003c/p\u003e\n \u003cp\u003eThe ELISA results indicated that the angiogenic and osteogenic-related factors VEGF, TGF-\u0026beta;, and IGF-1 were continuously released within 14 days (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC). This indicated that CGF provides sustained delivery of bioactive factors, aligning with the prolonged and complex process of bone regeneration. Previous studies have described a biphasic release pattern from CGF: an initial burst release due to platelet activation and free diffusion, followed by a sustained release governed by gradual fibrincage degradation\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Our findings support this mechanism, suggesting that the release of growth factors is predominantly driven by the degradation of the fibrin network, during which embedded platelets disintegrate and slowly release their contents into the local microenvironment.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2. X-ray imaging and assessment of interbody fusion\u003c/h2\u003e\n \u003cp\u003eTo evaluate fusion efficacy, lateral X-ray imaging was performed at predefined time points in all 48 SD rats (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). No signs of cage displacement or subsidence were observed in any animals, and the titanium plates and screws remained intact without evidence of fracture, deformation, or loosening. Over time, both the PTa and CGF-PTa groups exhibited progressive formation of new bone bridging anterior and posterior to the cage, integrating with adjacent vertebral bodies (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB).According to the modified Bridwell scoring system, at 1 month postoperatively, the mean fusion scores were 0.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63 in the PTa group and 1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63 in the CGF-PTa group. Although the difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.164), the CGF-PTa group showed a trend toward higher fusion grades. At 2 months, fusion scores increased to 2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11 in the PTa group and 2.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35 in the CGF-PTa group; however, the difference remained statistically non-significant (p\u0026thinsp;=\u0026thinsp;0.182) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eDespite the lack of statistical significance, the CGF-PTa group exhibited a higher proportion of Grade 3 fusions (complete bony bridging) at both time points, indicating a more robust fusion trend (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). The non-significant results may be attributed to factors such as limited sample size (n\u0026thinsp;=\u0026thinsp;12 per group), inter-animal variability in healing, and the semiquantitative nature of radiographic scoring, which can be subjective. Nevertheless, the CGF-PTa group consistently outperformed the PTa group in radiographic fusion scores, suggesting that CGF may facilitate enhanced spinal fusion. o further validate this observation, additional assessments, including manual palpation, micro-CT, biomechanical testing, and histological analysis, were conducted.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3. Manual palpation of interbody fusion\u003c/h2\u003e\n \u003cp\u003eManual palpation was performed at 4 and 8 weeks postoperatively to assess spinal segment stability. At week 4, the complete fusion rate in the PTa group was 0.0% (0/12), whereas the CGF-PTa group showed a higher rate of 16.7% (2/12). By week 8, the fusion rate increased to 41.7% (5/12) in the PTa group and reached 91.7% (11/12) in the CGF-PTa group (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).The trend observed in manual palpation results was consistent with the radiographic fusion scores, both showing time-dependent improvement in fusion status. Moreover, at both time points, the CGF-PTa group exhibited higher fusion rates than the PTa group. At week 4, the difference was not statistically significant, as determined by Fisher\u0026rsquo;s exact test (p\u0026thinsp;=\u0026thinsp;0.478). However, at week 8, the intergroup difference reached statistical significance (p\u0026thinsp;=\u0026thinsp;0.027), indicating that CGF loading significantly enhanced interbody fusion during the later stage of healing.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRadiographic fusion scores and Manual palpation fusion rate\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePTa(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCGF-PTa(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFusion score(4W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.164\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFusion score(8W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.182\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFusion rate(4W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.478\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFusion rate(8W)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eFusion status was assessed using the modified Bridwell grading system based on lateral X-ray images, which classifies interbody fusion into four levels: Grade 0 indicates no new bone formation and no evidence of bony bridging between adjacent vertebral bodies; Grade 1 represents the presence of new bone formation without a continuous bone bridge; Grade 2 reflects partial but substantial bone bridging with a clear tendency toward fusion; and Grade 3 denotes the formation of a continuous and uniform bone bridge across the interbody space, suggesting complete radiographic fusion. Fusion outcomes were further confirmed by manual palpation to evaluate segmental stability.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4. Micro-CT scanning and analysis\u003c/h2\u003e\n \u003cp\u003eTo further evaluate the osteogenic performance of the CGF-PTa cage in vivo, micro-CT was performed on harvested spinal segments at 4 and 8 weeks postoperatively. As shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA, representative sagittal and coronal slices, along with 3D reconstructions, demonstrated new bone formation at the L4\u0026ndash;L5 interbody fusion site in both groups.At 4 weeks, preliminary bone ingrowth was observed in both the PTa and CGF-PTa groups, with the CGF-PTa group showing a more robust bone healing trend, although continuous fusion had not yet been achieved. At 8 weeks postoperatively, both groups demonstrated more evident new bone formation compared to the 4-week time point, and a stable bridging union across the interbody space had formed. Notably, the CGF-PTa group exhibited significantly superior bone tissue regeneration than the PTa group.To quantify the micro-CT findings, bone microarchitectural parameters including BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD were analyzed (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB). The results showed that both groups exhibited a general trend of improvement in bone structural parameters as the healing process progressed over time. Statistically significant enhancements were observed in BV/TV(PTa: 4w, 5.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59% vs 8w, 9.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ;CGF-PTa༚4w, 7.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55% vs 8w, 14.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.83%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)、Tb.Th༈PTa༚4w, 0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01mm vs 8w, 0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ༛CGF-PTa༚4w, 0.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01mm vs 8w, 0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001༉、Tb.N༈PTa༚4w, 1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08 1/mm vs 8w, 2.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 1/mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ༛CGF-PTa༚4w, 1.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 1/mm vs 8w, 3.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 1/mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001༉、Tb.Sp༈PTa༚4w, 0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03mm vs 8w, 0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ༛CGF-PTa༚4w, 0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04mm vs 8w, 0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001༉和BMD༈PTa༚4w, 0.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03g/cm\u0026sup3; vs 8w, 0.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10g/cm\u0026sup3;, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ༛CGF-PTa༚4w, 0.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04g/cm\u0026sup3; vs 8w, 1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06g/cm\u0026sup3;, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001༉. For BS/TV, a significant increase was observed in the PTa group from 12.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68 1/mm at 4 weeks to 14.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76 1/mm at 8 weeks (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, no statistically significant change was found in the CGF-PTa group, where BS/TV increased from 11.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00 1/mm to 12.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71 1/mm (p\u0026thinsp;=\u0026thinsp;0.121).\u003c/p\u003e\n \u003cp\u003eTo further determine whether the CGF-PTa group exhibited an improving trend in bone fusion quality over time, intergroup comparisons between the PTa and CGF-PTa groups were conducted at different time points. At 4 weeks, although both groups showed similar trends in BV/TV, Tb.Th, and BMD, the CGF-PTa group demonstrated significantly greater improvements in all three parameters (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In addition, Tb.N in the CGF-PTa group (1.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 1/mm) was significantly higher than that in the PTa group (1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08 1/mm, p\u0026thinsp;=\u0026thinsp;0.002). In fact, these differences became more pronounced by week 8. Compared to the PTa group, the CGF-PTa group exhibited significantly higher values in BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Notably, BMD remained significantly elevated in the CGF-PTa group (p\u0026thinsp;=\u0026thinsp;0.004), further supporting the enhancement of bone quality. Even for parameters such as Tb.N (p\u0026thinsp;=\u0026thinsp;0.036) and Tb.Sp (p\u0026thinsp;=\u0026thinsp;0.012), which showed smaller absolute differences, the CGF-PTa group still demonstrated statistically significant improvements. Taken together, these results suggest that the CGF-PTa cage significantly promotes new bone formation in vivo and exhibits progressively enhanced osteogenic performance over time.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5. Biomechanical evaluation\u003c/h2\u003e\n \u003cp\u003eBiomechanical testing of spinal specimens at 4 and 8 weeks postoperatively further demonstrated that with the progression of the fusion process, bone fusion quality was markedly improved by week 8. Moreover, the incorporation of CGF into the PTa cage significantly enhanced the interbody fusion strength compared to PTa alone(Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). At 4 weeks, compared with the PTa group, the PTa-CGF group exhibited a 54.74% increase in flexural stiffness.༈13.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05 Nmm/Deg vs 8.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37 Nmm/Deg, p\u0026thinsp;=\u0026thinsp;0.009༉;An improvement of 39.45% in extension stiffness was also observed.༈11.67\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18Nmm/Deg vs 8.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06 Nmm/Deg, p\u0026thinsp;=\u0026thinsp;0.023༉༛During lateral bending, stiffness was improved by 18.54% (14.26\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00 N\u0026middot;mm/deg vs 12.03\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42 N\u0026middot;mm/deg, p\u0026thinsp;=\u0026thinsp;0.09) on the left side and by 23.92% (14.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.13 N\u0026middot;mm/deg vs 11.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30 N\u0026middot;mm/deg, p\u0026thinsp;=\u0026thinsp;0.049) on the right side.At 8 weeks, compared with the PTa group, the PTa-CGF group exhibited a 32.45% improvement in flexion stiffness (26.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.46 N\u0026middot;mm/deg vs 19.97\u0026thinsp;\u0026plusmn;\u0026thinsp;2.60 N\u0026middot;mm/deg, p\u0026thinsp;=\u0026thinsp;0.035), and a 14.73% improvement in extension stiffness (21.27\u0026thinsp;\u0026plusmn;\u0026thinsp;2.49 N\u0026middot;mm/deg vs 18.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.71 N\u0026middot;mm/deg, p\u0026thinsp;=\u0026thinsp;0.192). During lateral bending, stiffness increased by 23.67% on the left side (25.52\u0026thinsp;\u0026plusmn;\u0026thinsp;2.41 N\u0026middot;mm/deg vs 20.63\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22 N\u0026middot;mm/deg, p\u0026thinsp;=\u0026thinsp;0.061) and by 23.38% on the right side (25.34\u0026thinsp;\u0026plusmn;\u0026thinsp;2.15 N\u0026middot;mm/deg vs 20.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.47 N\u0026middot;mm/deg, p\u0026thinsp;=\u0026thinsp;0.064).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6. Osseointegration assessment by histomorphometry analysis\u003c/h2\u003e\n \u003cp\u003eTo assess the osteogenic performance of CGF-PTa, Van-Gieson staining was performed on bone tissue within the interbody fusion region (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eA). During the early phase of bone formation, new bone tissue began to grow along the surface of the tantalum cage from the surrounding bone. As the healing process progressed, bone gradually infiltrated the inner pores of the cage. Compared to the PTa group without CGF, the CGF-PTa group exhibited more rapid and evident bone ingrowth. At 4 weeks postoperatively, partial new bone formation was observed along the outer surface of the cage in the PTa group, while in the CGF-PTa group, early bone ingrowth into the internal pores of the cage was already evident. By 8 weeks, both groups showed substantial bone ingrowth into the porous structure, suggesting a continuous and progressive bone regeneration process. The CGF-PTa group exhibited denser and more continuous mineralized bone, consistent with the micro-CT results shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, indicating that CGF-loaded porous tantalum significantly promotes bone growth within the interbody fusion region.\u003c/p\u003e\n \u003cp\u003eSubsequent quantitative analysis of bone area fraction within the cage (defined as the region of interest, ROI) showed that at 4 weeks postoperatively, the CGF-PTa group exhibited a bone area fraction of 8.73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.81%, representing an approximately 59.9% increase compared to 5.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84% in the PTa group (p\u0026thinsp;=\u0026thinsp;0.0024). By 8 weeks, the bone area fraction increased to 41.38\u0026thinsp;\u0026plusmn;\u0026thinsp;5.17% in the CGF-PTa group and 25.65\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79% in the PTa group. Notably, the CGF-PTa group demonstrated a significantly stronger trend in bone formation, with a 61.3% increase in bone area compared to the PTa group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eB).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\n \u003ch2\u003e3.7. Immunohistochemistry\u003c/h2\u003e\n \u003cp\u003eTo evaluate the effects of CGF-PTa on angiogenesis and osteogenesis, immunohistochemical analysis was performed on bone tissue from the interbody fusion region (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eA). CD31 and VEGF were selected as representative markers for angiogenesis. CD31 is a typical endothelial cell marker involved in maintaining vascular integrity and permeability, while VEGF is a key mediator of angiogenesis, capable of significantly promoting the formation and expansion of new capillaries, thereby improving local blood supply\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.In parallel, Runx2 and OCN were selected as osteogenic markers reflecting early and late stages of bone formation, respectively. Runx2 is a core transcription factor required for osteoprogenitor cell differentiation, with increased expression indicating activation of osteogenesis. OCN, a late-stage matrix protein secreted by osteoblasts, reflects ongoing matrix maturation and mineralization\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eAs shown in Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eB, at 4 weeks postoperatively, the proportions of CD31 and VEGF positive cells in the CGF-PTa group were significantly higher than those in the PTa group (both p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating that the involvement of CGF notably enhanced local angiogenic activity in the early stage of bone healing. By 8 weeks, although the difference between the two groups had decreased, the expression levels of CD31 and VEGF in the CGF-PTa group remained higher than in the PTa group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), suggesting a sustained angiogenic effect in the mid-to-late healing stage. As shown in Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eC, at 4 weeks postoperatively, the proportions of OCN and Runx2 positive cells in the CGF-PTa group were also higher than those in the PTa group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating that CGF application not only activated osteoblast differentiation early but also promoted the expression of bone matrix proteins. This trend further increased by 8 weeks, with a significant increase in OCN-positive cells (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and Runx2 expression reaching statistical significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suggesting that CGF-PTa continued to enhance osteogenic activity and bone remodeling in the mid-to-late healing stage. Overall, the pro-angiogenic effect of CGF-PTa became evident in the early postoperative period and provided a favorable microenvironment for subsequent bone repair. Over time, its osteogenic-promoting effect gradually increased, showing stronger tissue regeneration capacity during the later phase of bone healing. This synergistic enhancement of angiogenesis and osteogenesis reveals a potential mechanism by which CGF promotes angiogenic\u0026ndash;osteogenic coupling during interbody fusion.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e\n \u003ch2\u003e3.8. Degradation and Local Biocompatibility Evaluation of CGF\u003c/h2\u003e\n \u003cp\u003eThe degradation process of the CGF gel is shown in the Fig.\u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e. The results indicated that the subcutaneously implanted CGF gel gradually decreased in size on days 0, 3, 7, and 14, with no visible signs of inflammation observed on the skin surface at any time point. The degradation curve showed that the initial mass of the CGF gel was 0.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 g, which decreased to 0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 g on day 3, 0.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 g on day 7, and further to 0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 g on day 14. This degradation process is likely associated with the gradual absorption and breakdown of fibrin components in CGF by host tissues. Overall, the CGF gel showed a continuous degradation trend after implantation, with a cumulative degradation rate of 90.6% by day 14.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\n \u003ch2\u003e3.9. Osseointegration assessment by histomorphometry analysis\u003c/h2\u003e\n \u003cp\u003eTissue sections of major organs were prepared and stained with HE to assess whether the implantation of the fusion cage caused any pathological changes (Fig.S2). At 2 months postoperatively, no obvious pathological abnormalities were observed in the CGF-PTa group compared with the non-operated control group. These results indicate that the porous tantalumcage loaded with CGF, as well as any potential degradation products, did not induce significant toxicity in the major organs of SD rats, demonstrating good in vivo biocompatibility.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eDelayed healing and nonunion following interbody fusion remain major challenges in the field of spinal surgery\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Compared to conventional bone repair processes such as maxillofacial defects or long bone fractures, spinal fusion presents greater complexity and challenges, primarily due to the unique interbody microenvironment and complex biomechanical conditions\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Unlike conventional bone defects, the interbody fusion site is subjected to continuous axial loading and shear stress; excessive mechanical stimulation may lead to fibrous tissue proliferation, thereby interfering with the formation of bony bridging\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Moreover, successful interbody fusion relies on bone regeneration between the vertebral endplates, a region characterized by chronically limited blood supply, which further constrains the bone healing process\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. To address the challenges posed by the complex mechanical environment and insufficient blood supply during interbody fusion, this study is the first to apply a combination of PTa cage fabricated by chemical vapor deposition, characterized by a high friction coefficient and rough surface morphology, with CGF in a rat lateral interbody fusion model based on the XLIF technique. Results from X-ray imaging, Micro-CT, biomechanical testing, and subsequent histological analyses demonstrated that implantation of CGF-loaded porous tantalum cages within the interbody space significantly accelerated the process of bone fusion and improved the quality of interbody bone integration. Furthermore, biocompatibility evaluations revealed no significant pathological abnormalities in the subcutaneous tissues surrounding the implants or in major organs such as the heart, liver, spleen, lungs, and kidneys after surgery, indicating that the CGF-PTa construct exhibits favorable biocompatibility for interbody fusion applications.\u003c/p\u003e\n\u003cp\u003eIn fact, a common strategy in bone tissue engineering for promoting bone regeneration involves the combination of biomaterials and growth factors to create an optimal microenvironment for cell adhesion, vascularization, and signal transduction necessary for new bone formation\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Currently, biomaterials used in the field of bone repair can be broadly classified into four categories: ceramics, polymers, metals, and composites, each possessing distinct mechanical and biological advantages\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Tantalum, owing to its corrosion resistance, elastic modulus similar to that of cancellous bone, and excellent biocompatibility, has achieved favorable clinical outcomes and widespread recognition as a metal coating and a substitute for bone grafts\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Studies have shown that porous tantalum cages, due to their high friction coefficient and rough surface morphology, significantly enhance cell adhesion and provide ideal anchorage points for osteoblasts, thereby improving osteoconductivity. Additionally, the naturally formed surface oxide layer (Ta₂O₅) exhibits inherent antibacterial properties while maintaining excellent biocompatibility. Together, these features contribute to a biomimetic microenvironment that promotes cell proliferation and extracellular matrix deposition\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Porous tantalum possesses a Young\u0026rsquo;s modulus of approximately 3\u0026ndash;4 GPa, closely matching that of cancellous bone. Combined with a three-dimensional interconnected porosity exceeding 75%, it offers additional space and attachment sites for cellular proliferation and growth within the cage, thereby facilitating inward bone tissue ingrowth, as demonstrated in previous studies\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. In addition, high porosity enhances the transport of blood and oxygen, reduces stress shielding, and provides pathways for the inward growth of cells and blood vessels\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Based on these advantages, tantalum has been widely applied in recent years in joint replacement, treatment of traumatic fractures, post-tumor resection bone reconstruction, and interbody fusion, among other related fields\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. However, due to the inherent bioinertness of tantalum, it lacks sufficient osteoinductive capacity. When implanted alone into the avascular and complex interbody microenvironment, the rate and quality of bone formation remain inferior to that achieved with autologous bone grafts.\u003c/p\u003e\n\u003cp\u003eMeanwhile, in clinical applications, growth factors from the TGF-\u0026beta; superfamily, particularly bone morphogenetic proteins (BMPs), are among the most commonly used in combination with various biomaterials. However, exogenous growth factors such as BMPs are associated with complications, including radiculitis and ectopic bone formation caused by burst release, in addition to their high economic cost\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. As a result, researchers have increasingly shifted their focus toward platelet concentrates and their combination with bone substitute materials as an alternative strategy, aiming to achieve more stable and controllable bone regeneration. CGF was first developed by Sacco in 2005 and is prepared from fresh whole blood using variable-speed centrifugation technology. It belongs to the third generation of platelet concentrates\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Compared with first-generation platelet-rich plasma (PRP) and second-generation platelet-rich fibrin (PRF), CGF possess not only a higher concentration of growth factors but also a more sustained and stable release profile. As a result, CGF has been widely applied in research fields related to tissue repair and bone regeneration\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Studies have shown that during the variable-speed centrifugation of fresh whole blood, platelets undergo lysis as a result of continuous shear stress and collision forces. A large number of ruptured platelets, along with leukocytes and erythrocytes, become embedded within the subsequently formed dense fibrin network\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Meanwhile, the dense fibrin network structure formed through variable-speed centrifugation in CGF enables the sustained release of multiple multilineage growth factors, including VEGF, TGF-\u0026beta;, and IGF-1, with a release duration of up to 14 days\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The synergistic action of these bioactive factors can induce macrophage polarization toward the M2 phenotype, promote angiogenesis, and drive the osteogenic differentiation of mesenchymal stem cells (MSCs), thereby creating a favorable cellular and molecular environment for bone tissue regeneration\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Therefore, autologous platelet concentrates (APCs), with CGF as a representative, can be considered biomimetic hematomas that have been artificially optimized to achieve high concentrations and controlled release of growth factors. Their mechanism of action is similar to that of hematomas naturally formed at fracture or bone defect sites, but the standardized preparation of CGF significantly enhances the concentration and bioavailability of these active factors. Moreover, SEM analysis of the CGF-PTa composite scaffold, prepared via vacuum perfusion, confirmed that the gel-form CGF was uniformly distributed and thoroughly infiltrated the porous structure of the tantalum scaffold. We hypothesize that this combination establishes a vascular\u0026ndash;osteogenic coupling microenvironment, in which the dense fibrin matrix and multiple growth factors contained within the CGF permeate along the tantalum pores, promoting the synchronized ingrowth of vascular structures and trabecular bone into the scaffold interior. This process results in the simultaneous enhancement of both mechanical support and biological functionality.\u003c/p\u003e\n\u003cp\u003eIn this study, porous tantalum metal cages were fabricated using a CVD technique and subsequently loaded with gel-form CGF through negative pressure infusion. The cages were characterized by SEM. The struts of the porous tantalum cages were uniform and structurally intact, exhibiting an interconnected pore architecture similar to that of cancellous bone, with a highly regular dodecahedral geometry in terms of pore size and shape. The surface morphology demonstrated micro- and nanoscale roughness. The CGF, prepared from allogeneic rat cardiac blood, displayed a uniform and dense fibrin network structure, within which platelets, red blood cells, and white blood cells were visibly embedded. In the CGF-PTa composite cage, SEM imaging revealed that the porous structure was extensively coated with dense fibrin matrix. Fibrin fibers of varying sizes adhered to and penetrated deeply into the cage\u0026apos;s internal pore network. High-magnification observations of the gel-filled pores showed a complex internal structure composed of densely woven fibrin networks, platelets, and red blood cells. Previous studies have demonstrated that high-viscosity fibrin scaffolds can act as temporary \u0026ldquo;nesting\u0026rdquo; matrices for platelets, erythrocytes, leukocytes, and CD34⁺ cells, enabling their initial retention and the gradual release of growth factors. This controlled release mechanism helps to avoid early-stage burst release and instead delivers cytokines in a more physiologically regulated manner\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. \u0026ldquo;On-demand\u0026rdquo; release not only holds the potential to amplify biological effects but also reduces the risk of tissue edema and inflammation caused by high local concentrations of growth factors\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Subsequent ELISA results further confirmed that angiogenic and osteogenic growth factors, including VEGF, TGF-\u0026beta;, and IGF-1, were continuously and gradually released from the CGF-PTa composite cage over a period of 14 days, supporting the feasibility of the proposed release mechanism.\u003c/p\u003e\n\u003cp\u003eTo evaluate the therapeutic efficacy of CGF-loaded tantalum cages fabricated via CVD in spinal fusion procedures, the selection of an appropriate animal model is critical. In spinal fusion research, small animal models have become ideal tools for high-throughput screening and mechanistic studies due to their short observation periods, low cost, and high reproducibility\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. Therefore, rat models of spinal fusion are widely used in related research. However, due to the small body size of rats and technical limitations in surgical procedures, commonly employed spinal fusion models are primarily limited to intertransverse process fusion and coccygeal interbody fusion\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. It is important to note that the applicability of these two models has long been a subject of debate. Some researchers argue that intertransverse process fusion more closely resembles conventional bone defect models and does not adequately reflect the biological processes of interbody fusion. Others contend that coccygeal interbody fusion fails to accurately replicate the axial loading and shear stress experienced during the interbody fusion process\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. To address this issue, our research team developed a rat lumbar interbody fusion model based on the anatomical characteristics of rats, utilizing a lateral extraperitoneal approach(XLIF technique). This model more accurately simulates the biomechanical conditions of human interbody fusion\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. X-ray results showed that no evident loosening or displacement of the implants or internal fixation devices was observed in either the PTa or CGF-PTa groups during the postoperative follow-up period. At both 4 and 8 weeks postoperatively, interbody fusion scores in the CGF-PTa group were consistently higher than those in the PTa group. Manual palpation findings were consistent with the radiographic fusion scores, showing higher fusion rates in the CGF-PTa group at both time points. Notably, at 8 weeks postoperatively, the fusion rate in the CGF-PTa group reached 91.7%, which was significantly higher than the 41.7% observed in the PTa group. Micro-CT assessments at 4 and 8 weeks revealed initial bone ingrowth in both groups at the 4-week time point, with the CGF-PTa group demonstrating superior bone healing, particularly in terms of new bone formation and tissue ingrowth, despite the absence of complete interbody fusion. As healing progressed to 8 weeks, more pronounced new bone formation and the establishment of stable bony bridging across the interbody space were observed in both groups. Bone structural parameters, including BV/TV, BS/TV, Tb.Th, Tb.N, Tb.Sp, and BMD, generally improved over time, indicating ongoing bone regeneration. Although both groups showed favorable healing trends, the CGF-PTa group consistently exhibited superior outcomes, suggesting greater potential for CGF-PTa in promoting bone regeneration and interbody fusion.\u003c/p\u003e\n\u003cp\u003eAt 4 and 8 weeks postoperatively, animals were euthanized, and the spinal segments were harvested after removal of the screws and titanium plates. Biomechanical testing, including flexion-extension and lateral bending, was performed on both the PTa and CGF-PTa groups. The results showed that the CGF-PTa group exhibited greater structural stiffness in all loading directions compared to the PTa group, indicating superior mechanical stability of the fused segment. Notably, although the differences between the groups were slightly reduced at 8 weeks, the CGF-PTa group continued to demonstrate a significant mechanical advantage, reflecting the sustained contribution of the material throughout the bone healing process.Subsequently, hard tissue grinding sectioning combined with Van-Gieson staining was used to evaluate changes in bone volume within the fusion region. The results revealed that the bone area fraction within the scaffold in the CGF-PTa group was 8.73% at 4 weeks and 41.38% at 8 weeks, significantly higher than the 5.46% and 25.65% observed in the PTa group, corresponding to increases of approximately 59.9% and 61.3%, respectively. These findings were highly consistent with the micro-CT results, indicating that CGF loading not only facilitates early-stage adhesion and colonization of new bone tissue but also promotes more extensive and deeper bone infiltration and remodeling within the scaffold at later stages.The above biomechanical and histological findings further validate the effectiveness of CGF in enhancing the osteogenic performance of interbody fusion scaffolds. These results are also consistent with previous studies that support the osteogenic potential of CGF, highlighting its favorable regenerative capacity and promising application prospects.To further investigate the underlying biological mechanisms, immunohistochemical analysis was conducted to assess the expression of angiogenesis and osteogenesis related markers in the fusion region. The results demonstrated a higher proportion of CD31 and VEGF positive cells in the CGF-PTa group at both 4 and 8 weeks, suggesting enhanced local angiogenesis that may support new bone formation. In parallel, the expression of osteogenic markers Runx2 and OCN was significantly upregulated, indicating that CGF facilitates osteoblast differentiation and extracellular matrix maturation.These findings are consistent with previous reports showing that CGF is rich in multiple growth factors, such as VEGF, TGF-\u0026beta;, and IGF-1, which promote both angiogenesis and osteogenesis. The results provide further evidence, at the cellular and molecular levels, supporting the potential of CGF in bone tissue engineering. In addition, histological examination of the tissue surrounding the implant and major organs confirmed the favorable in vivo biocompatibility of the CGF-PTa construct, laying a foundation for its future clinical translation.In summary, the incorporation of CGF into porous tantalum cage establishes a favorable microenvironment that synergistically promotes both neovascularization and bone formation, offering an effective strategy to enhance the bioactivity of porous metal fusion devices.\u003c/p\u003e\n\u003cp\u003eAlthough this study systematically evaluated the osteogenic effects and biocompatibility of CGF-PTa in interbody fusion, several limitations remain and should be addressed in future research. (1)Due to the limited interbody space in rats, the volume of the tantalum scaffold used in this study was relatively small. As a result, only one histological section could be obtained per sample, which restricted the sample size and allowed for only a single staining method in histopathological analysis. Future studies may consider incorporating customized drilling techniques to enlarge the interbody space, thereby improving the operability and evaluation efficiency of the model. (2)Although CGF should ideally be prepared from autologous blood to ensure immunocompatibility, the limited blood volume in rats necessitated the use of allogeneic blood sources in this study, which may have introduced confounding factors affecting the outcomes. (3)While CGF inherently exhibits a certain degree of sustained release capability, previous studies have shown that combining CGF with hydrogels or nanomaterials can further prolong the release duration of bioactive factors. However, to enhance clinical translatability, this study deliberately avoided introducing exogenous materials that may pose a risk of biological toxicity, which may have limited the optimization of sustained release.Overall, these limitations provide clear directions for further optimization of the model and lay the groundwork for future studies in large animal models or preclinical settings.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn this study, a composite system comprising porous tantalum cage loaded with CGF was developed and systematically evaluated in a rat interbody fusion model. The results demonstrated that CGF-PTa exhibited excellent performance in terms of fusion rate, biomechanical stability, biocompatibility, osteogenic capacity, and bone integration, significantly enhancing the long-term stability of the fusion segment. The synergistic effect between CGF and the porous tantalum cage enabled coordinated promotion of both angiogenesis and bone regeneration within the interbody fusion microenvironment, highlighting its promising potential in the field of tissue engineering. This strategy offers a novel approach and theoretical foundation for the functional optimization and clinical translation of porous metal fusion devices.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflicts of interest\u003c/h2\u003e\u003cp\u003eThere are no conflicts to declare.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eH.W. Writing \u0026ndash; original draft. W. W. Data curation. S. L. Writing \u0026ndash; review \u0026amp; editing. J. S.: Writing \u0026ndash; review \u0026amp; editing. S.Y. Writing \u0026ndash; review \u0026amp; editing. Q.Y. Visualization. L.L. Visualization. R.Z. Conceptualization. Haoyu Wu: Investigation. W.Zhang. Supervision,Funding acquisition.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request and can also be accessed as supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRavindra, V. M. et al. 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Animal models for spinal fusion. \u003cem\u003eSpine J.\u003c/em\u003e \u003cb\u003e5\u003c/b\u003e, 209\u0026ndash;S216. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1016/j.spinee.2005.02.013\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1016/j.spinee.2005.02.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2005).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Scheme ","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"interbody fusion, concentrated growth factors, Chemical vapor deposition, Porous tantalum cage, XLIF, Rat model","lastPublishedDoi":"10.21203/rs.3.rs-7337688/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7337688/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study addresses the clinical challenge of nonunion in spinal interbody fusion by developing a novel composite implant: a porous tantalum (PTa) cage loaded with concentrated growth factors (CGF). The CGF-PTa cage synergistically combines the mechanical strength and osteoconductivity of chemically vapor-deposited PTa with the sustained release of angiogenic and osteogenic factors from CGF. Using a rat extreme lateral interbody fusion (XLIF) model, the research systematically evaluates the efficacy of this composite in promoting bone regeneration and spinal fusion. Results from radiography, micro-CT, biomechanical testing, histological staining, and immunohistochemistry consistently show that CGF-PTa significantly enhances bone ingrowth, fusion rate, and mechanical stability compared to PTa alone. The findings also reveal that CGF facilitates angiogenesis and osteogenesis by modulating the local healing microenvironment and promoting vascular\u0026ndash;osteogenic coupling. Importantly, the CGF-PTa system demonstrated excellent biocompatibility and biodegradability in vivo, with no observed systemic toxicity. This work highlights the potential of combining bioactive factors with porous metallic scaffolds to overcome the limitations of inert implants in avascular environments, offering a promising strategy for functional optimization of interbody fusion devices and their future clinical application.\u003c/p\u003e","manuscriptTitle":"Porous tantalum cage loaded with CGF promotes interbody fusion in a rat XLIF model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-29 07:57:13","doi":"10.21203/rs.3.rs-7337688/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision 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