Clinical and Radiographic Outcomes of Anterior Lumbar Interbody Fusions Using a Titanium Cage with a Biomimetic Surface.

BACKGROUND: We analyzed clinical and radiographic outcomes in patients undergoing anterior lumbar interbody fusions (ALIFs) using a new biomimetic titanium fusion cage (Titan nanoLOCK interbody, Medtronic, Minneapolis, Minnesota, United States). This specialized cage employs precise nanotechnology to stimulate inherent biochemical and cellular osteogenic reactions to the implant, aiming to amplify the rate of fusion. To our knowledge, this is the only study to assess early clinical and radiographic results in ALIFs. METHODS: We conducted a retrospective review of data for patients who underwent single or multilevel ALIF using this implant between October 2016 and April 2021. Indications for treatment were spondylolisthesis, postlaminectomy syndrome, or spinal deformity. Clinical and radiographic outcome data for these patients were collected and assessed. RESULTS: A total of 84 patients were included. The mean clinical follow-up was 36.6 ± 14 months. At 6 months, solid fusion was seen in 97.6% of patients. At 12 months, solid fusion was seen in 98.8% of patients. Significant improvements were seen in patient-reported outcome measures (PROMs; visual analog scale and Oswestry Disability Index) at 6 and 12 months compared with the preoperative scores (p < 0.001). One patient required reoperation for broken pedicle screws 2 days after the ALIF. None of the patients required readmission within 90 days of surgery. No patients experienced an infection. CONCLUSIONS: ALIF using a new titanium interbody fusion implant with a biomimetic surface technology demonstrated high fusion rates (97.6%) as early as 6 months. There was significant improvement in PROMs at 6 and 12 months.

Outcomes of 2-Level Versus 3- or 4-Level Anterior Cervical Discectomy and Fusion Using a Biomimetic Surface Titanium Cage: Multicenter Experience.

OBJECTIVE: Interbody cages for spinal fusions are primarily constructed from polyetheretherketone or titanium compositions. However, these crude macroscopic materials pose limitations for improving the rates of bony fusions. The authors aimed to compare the fusion rates and postoperative complications in patients who underwent 2-level or 3-or 4-level anterior cervical discectomy and fusion (ACDF) performed with the use of a novel biomimetic surface titanium cage. METHODS: A retrospective multicenter study was conducted that included all patients who underwent multilevel ACDF with this cage between January 2017 and April 2021. Patient demographics and procedure-related, radiographic, and postoperative complication data were collected. RESULTS: A total of 124 patients were identified; 69 (55.6%) had a 3-or 4-level fusion and 55 (44.4%) had a 2-level fusion. The demographics of the 2 groups differed significantly only in terms of age (P = 0.01). At 3 months, a significantly higher solid fusion rate was found for 2-level fusions than 3-or 4-level fusions (83.7% vs. 56.3%, P = 0.004); however, significance was lost at 6-months (98.2% vs. 88.4%, respectively; P = 0.08). No patients required posterior supplemental fixation. Transient dysphagia was the only postoperative complication that was significantly increased in the 3-or 4-level fusion group compared to the 2-level group (27.5% vs. 9.1%, P = 0.02). CONCLUSIONS: Radiographic and clinical outcomes were equivalent in 3-or 4-level and 2-level ACDFs in which these biomimetic surface titanium cages were used. Furthermore, the use of this technology led to high fusion rates with no requirement for posterior supplemental fusions.

Bone marrow stromal cells generate an osteoinductive microenvironment when cultured on titanium-aluminum-vanadium substrates with biomimetic multiscale surface roughness.

Osseointegration of titanium-based implants possessing complex macroscale/microscale/mesoscale/nanoscale (multiscale) topographies support a direct and functional connection with native bone tissue by promoting recruitment, attachment and osteoblastic differentiation of bone marrow stromal cells (MSCs). Recent studies show that the MSCs on these surfaces produce factors, including bone morphogenetic protein 2 (BMP2) that can cause MSCs not on the surface to undergo osteoblast differentiation, suggesting they may produce an osteogenic environmentin vivo. This study examined if soluble factors produced by MSCs in contact with titanium-aluminum-vanadium (Ti6Al4V) implants possessing a complex multiscale biomimetic topography are able to induce osteogenesis ectopically. Ti6Al4V disks were grit-blasted and acid-etched to create surfaces possessing macroscale and microscale roughness (MM), micro/meso/nanoscale topography (MN), and macro/micro/meso/nanoscale topography (MMNTM). Polyether-ether-ketone (PEEK) disks were also fabricated by machining to medical-grade specifications. Surface properties were assessed by scanning electron microscopy, contact angle, optical profilometry, and x-ray photoelectron spectroscopy. MSCs were cultured in growth media (GM). Proteins and local factors in their conditioned media (CM) were measured on days 4, 8, 10 and 14: osteocalcin, osteopontin, osteoprotegerin, BMP2, BMP4, and cytokines interleukins 6, 4 and 10 (IL6, IL4, and IL10). CM was collected from D14 MSCs on MMNTMand tissue culture polystyrene (TCPS) and lyophilized. Gel capsules containing active demineralized bone matrix (DBM), heat-inactivated DBM (iDBM), and iDBM + MMN-GM were implanted bilaterally in the gastrocnemius of athymic nude mice (N= 8 capsules/group). Controls included iDBM + GM; iDBM + TCPS-CM from D5 to D10 MSCs; iDBM + MMN-CM from D5 to D10; and iDBM + rhBMP2 (R&D Systems) at a concentration similar to D5-D10 production of MSCs on MMNTMsurfaces. Legs were harvested at 35D. Bone formation was assessed by micro computed tomography and histomorphometry (hematoxylin and eosin staining) with the histology scored according to ASTM 2529-13. DNA was greatest on PEEK at all time points; DNA was lowest on MN at early time points, but increased with time. Cells on PEEK exhibited small changes in differentiation with reduced production of BMP2. Osteoblast differentiation was greatest on the MN and MMNTM, reflecting increased production of BMP2 and BMP4. Pro-regenerative cytokines IL4 and IL10 were increased on Ti-based surfaces; IL6 was reduced compared to PEEK. None of the media from TCPS cultures was osteoinductive. However, MMN-CM exhibited increased bone formation compared to iDBM and iDBM + rhBMP2. Furthermore, exogenous rhBMP2 alone, at the concentration found in MMN-CM collected from D5 to D10 cultures, failed to induce new bone, indicating that other factors in the CM play a critical role in that osteoinductive microenvironment. MSCs cultured on MMNTMTi6Al4V surfaces differentiate and produce an increase in local factors, including BMP2, and the CM from these cultures can induce ectopic bone formation compared to control groups, indicating that the increased bone formation arises from the local response by MSCs to a biomimetic, multiscale surface topography.

Interobserver agreement using computed tomography to assess radiographic fusion criteria with a unique titanium interbody device.

The accuracy of using computed tomography (CT) to assess interbody fusion in patients with titanium implants has been questioned in the past. Radiologists have reported difficulty assessing fusion bone quality because of metal artifact and small graft windows. A new titanium interbody implant with a large footprint and a wide graft aperture has been developed. We conducted a study to determine the interobserver reliability of using CT to assess radiographic fusion variables with the new titanium interbody device. Patients underwent anterior lumbar interbody fusion with the same titanium interbody implant. Reconstructed CT images were obtained randomly at 6, 9, or 12 months. Two independent radiologists reviewed the scans. Interobserver reliability was calculated using the κ statistic. Fifty-six spinal fusion levels (33 patients) were analyzed. The radiologists agreed on 345 of the 392 fusion data points reviewed (κ = .88). Agreement for solid fusion formation was 0.77. This interbody device demonstrated minimal artifact and minimal subsidence, and trabecular bone was easily identified throughout the implant in the vast majority of cases reviewed. High interobserver agreement was noted across all radiographic variables assessed.

Implant materials generate different peri-implant inflammatory factors: poly-ether-ether-ketone promotes fibrosis and microtextured titanium promotes osteogenic factors.

STUDY DESIGN: An in vitro study examining factors produced by human mesenchymal stem cells on spine implant materials. OBJECTIVE: The aim of this study was to examine whether the inflammatory microenvironment generated by cells on titanium-aluminum-vanadium (Ti-alloy, TiAlV) surfaces is affected by surface microtexture and whether it differs from that generated on poly-ether-ether-ketone (PEEK). SUMMARY OF BACKGROUND DATA: Histologically, implants fabricated from PEEK have a fibrous connective tissue surface interface whereas Ti-alloy implants demonstrate close approximation with surrounding bone. Ti-alloy surfaces with complex micron/submicron scale roughness promote osteoblastic differentiation and foster a specific cellular environment that favors bone formation whereas PEEK favors fibrous tissue formation. METHODS: Human mesenchymal stem cells were cultured on tissue culture polystyrene, PEEK, smooth TiAlV, or macro-/micro-/nano-textured rough TiAlV (mmnTiAlV) disks. Osteoblastic differentiation and secreted inflammatory interleukins were assessed after 7 days. Fold changes in mRNAs for inflammation, necrosis, DNA damage, or apoptosis with respect to tissue culture polystyrene were measured by low-density polymerase chain reaction array. Data were analyzed by analysis of variance, followed by Bonferroni's correction of Student's t-test. RESULTS: Cells on PEEK upregulated mRNAs for chemokine ligand-2, interleukin (IL) 1ß, IL6, IL8, and tumor necrosis factor. Cells grown on the mmnTiAlV had an 8-fold reduction in mRNAs for toll-like receptor-4. Cells grown on mmnTiAlV had reduced levels of proinflammatory interleukins. Cells on PEEK had higher mRNAs for factors strongly associated with cell death/apoptosis, whereas cells on mmnTiAlV exhibited reduced cytokine factor levels. All results were significant (P < 0.05). CONCLUSION: These results suggest that fibrous tissue around PEEK implants may be due to several factors: reduced osteoblastic differentiation of progenitor cells and production of an inflammatory environment that favors cell death via apoptosis and necrosis. Ti alloy surfaces with complex macro/micro/nanoscale roughness promote osteoblastic differentiation and foster a specific cellular environment that favors bone formation. LEVEL OF EVIDENCE: N/A.

Rough titanium alloys regulate osteoblast production of angiogenic factors.

BACKGROUND CONTEXT: Polyether-ether-ketone (PEEK) and titanium-aluminum-vanadium (titanium alloy) are used frequently in lumbar spine interbody fusion. Osteoblasts cultured on microstructured titanium generate an environment characterized by increased angiogenic factors and factors that inhibit osteoclast activity mediated by integrin α2ß1 signaling. It is not known if this is also true of osteoblasts on titanium alloy or PEEK. PURPOSE: The purpose of this study was to determine if osteoblasts generate an environment that supports angiogenesis and reduces osteoclastic activity when grown on smooth titanium alloy, rough titanium alloy, or PEEK. STUDY DESIGN: This in vitro study compared angiogenic factor production and integrin gene expression of human osteoblast-like MG63 cells cultured on PEEK or titanium-aluminum-vanadium (titanium alloy). METHODS: MG63 cells were grown on PEEK, smooth titanium alloy, or rough titanium alloy. Osteogenic microenvironment was characterized by secretion of osteoprotegerin and transforming growth factor beta-1 (TGF-ß1), which inhibit osteoclast activity and angiogenic factors including vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), and angiopoietin-1 (ANG-1). Expression of integrins, transmembrane extracellular matrix recognition proteins, was measured by real-time polymerase chain reaction. RESULTS: Culture on titanium alloy stimulated osteoprotegerin, TGF-ß1, VEGF-A, FGF-2, and angiopoietin-1 production, and levels were greater on rough titanium alloy than on smooth titanium alloy. All factors measured were significantly lower on PEEK than on smooth or rough titanium alloy. Culture on titanium alloy stimulated expression of messenger RNA for integrins that recognize Type I collagen in comparison with PEEK. CONCLUSIONS: Rough titanium alloy stimulated cells to create an osteogenic-angiogenic microenvironment. The osteogenic-angiogenic responses to titanium alloy were greater than PEEK and greater on rough titanium alloy than on smooth titanium alloy. Surface features regulated expression of integrins important in collagen recognition. These factors may increase bone formation, enhance integration, and improve implant stability in interbody spinal fusions.

Lumbar spine fusion for chronic low back pain due to degenerative disc disease: a systematic review.

STUDY DESIGN: Systematic literature review. OBJECTIVE: To categorize published evidence systematically for lumbar fusion for chronic low back pain (LBP) in order to provide an updated and comprehensive analysis of the clinical outcomes. SUMMARY OF BACKGROUND DATA: Despite a large number of publications of outcomes of spinal fusion surgery for chronic LBP, there is little consensus on efficacy. METHODS: A MEDLINE and Cochrane database search was performed to identify published articles reporting on validated patient-reported clinical outcomes measures (2 or more of visual analogue scale, Oswestry Disability Index, Short Form [36] Health Survey [SF-36] PCS, and patient satisfaction) with minimum 12 months of follow-up after lumbar fusion surgery in adult patients with LBP due to degenerative disc disease. Twenty-six total articles were identified and stratified by level of evidence: 18 level 1 (6 studies of surgery vs. nonoperative treatment, 12 studies of alternative surgical procedures), 2 level 2, 2 level 3, and 4 level 4 (2 prospective, 2 retrospective). Weighted averages of each outcomes measure were computed and compared with established minimal clinically important difference values. RESULTS: Fusion cohorts included a total of 3060 patients. The weighted average improvement in visual analogue scale back pain was 36.8/100 (standard deviation [SD], 14.8); in Oswestry Disability Index 22.2 (SD, 14.1); in SF-36 Physical Component Scale 12.5 (SD, 4.3). Patient satisfaction averaged 71.1% (SD, 5.2%) across studies. Radiographical fusion rates averaged 89.1% (SD, 13.5%), and reoperation rates 12.5% (SD, 12.4%) overall, 9.2% (SD, 7.5%) at the index level. The results of the collective studies did not differ statistically in any of the outcome measures based on level of evidence (analysis of variance, P > 0.05). CONCLUSION: The body of literature supports fusion surgery as a viable treatment option for reducing pain and improving function in patients with chronic LBP refractory to nonsurgical care when a diagnosis of disc degeneration can be made.

Blood serum antibody analysis and long-term follow-up of patients treated with recombinant human bone morphogenetic protein-2 in the lumbar spine.

STUDY DESIGN: Prospective, longitudinal cohort study. OBJECTIVE: To examine the incidence of bone morphogenetic protein (BMP)-2 antibody formation in lumbar spine applications and to determine the clinical significance of an antibody response. SUMMARY OF BACKGROUND DATA: Immune responses can affect the safety and efficacy profile of recombinant proteins. Type, incidence, and time course of antibody formation were evaluated in clinical studies investigating recombinant human bone morphogenetic protein (rhBMP)-2 in spinal arthrodesis. METHODS: Analysis of antibody formation to BMP-2, bovine collagen, and human collagen was performed after three prospective clinical studies investigating rhBMP-2 in single-level lumbar spinal arthrodesis. Two studies investigated rhBMP-2 applied to an absorbable collagen sponge at 1.5 mg/cm3 in lumbar interbody fusion (n=449); one study investigated rhBMP-2 applied to a ceramic and collagen compression-resistant matrix at 2.0 mg/cm3 in instrumented posterolateral fusion (n=239). Control patients received iliac crest bone graft (n=360). Two validated enzyme-linked immunosorbent assays were used to test for BMP-2 antibodies. Neutralizing antibodies were assessed using a cell bioassay. The incidence of antibodies to bovine and human collagen was determined. Radiographic and clinical outcome data were assessed to determine whether antibodies were correlated to patient outcomes. RESULTS: BMP-2 antibody rates ranged from 0.8% to 6.4% in rhBMP-2 patients and from 0% to 2.3% in control patients. Formation of BMP-2 antibodies peaked within the first 3 months and returned toward baseline values by 12 months. No neutralizing antibodies were detected. Bovine collagen antibody rates ranged from 12.7% to 18.8% in the rhBMP-2 patients and from 12.9% to 21.2% in the control patients. No antibodies to human collagen were detected. Adverse event rates were similar in antibody-positive and antibody-negative patients. BMP-2 antibodies did not affect bridging bone rates. CONCLUSION: Formation of anti-BMP-2 antibodies was low and transient. No neutralizing antibodies were observed. Formation of antibodies did not affect fusion success or appear to have clinical sequelae.

Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of interbody fusion rates and clinical outcomes.

BACKGROUND CONTEXT: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive protein approved for use in the anterior lumbar interspace. High fusion rates with rhBMP-2 have been reported with threaded interbody allograft dowels. There may be a clinical benefit for the patient by adding rhBMP-2 to the allograft. PURPOSE: To compare the fusion rates and clinical outcomes of patients treated with allograft interbody fusions with and without the addition of rhBMP-2. STUDY DESIGN: Prospective consecutive patient enrollment with minimum 24-month follow-up. PATIENT SAMPLE: Seventy-five patients with lumbar interbody fusions at 1-3 spinal segments. OUTCOMES MEASURES: Clinical: Numerical Rating Scale (NRS) and Oswestry Disability Index (ODI). Radiographic: X-ray and computed tomographic scan analysis using the Molinari-Bridwell fusion scale. METHODS: Seventy-five patients scheduled for lumbar fusion were enrolled sequentially. Group 1: 30 patients had anterior interbody allografts alone. Group 2: 45 patients had anterior interbody allograft filled with rhBMP-2. All cases had posterior pedicle screw instrumentation. A total of 165 surgical levels (62 allograft alone/103 allograft+BMP) were included. Fusion data and clinical outcomes were collected for a minimum of 2 years after surgery. RESULTS: Statistically higher fusion rates were observed in the patients with BMP at all time points compared with allograft alone. Group 2 (+ BMP) fusion rates were 94%, 100%, and 100% at 6, 12, and 24 months after surgery. Group 1 (-BMP) fusion rates were 66%, 84%, and 89% at the same time intervals. Clinical outcomes were significantly improved in Group 2 compared with Group 1 at 6 months. There were no revisions (0%) in the BMP group and 4 revision fusion surgeries (13%) in the allograft group. No untoward effects were attributable to the rhBMP-2. CONCLUSIONS: Our study confirms the efficacy of an innovative lumbar fusion technique: an interbody femoral ring allograft, combined with an osteoinductive stimulant (rhBMP-2), protected by pedicle screws. This combination of a structural interbody allograft with rhBMP-2 eliminates the insult of iliac crest harvest, allows for reliable radiographic analysis, and results in successful fusion formation in 100% of the cases in this study.

Indications and outcomes of reconstructive surgery in chronic pain of spinal origin.

STUDY DESIGN: Peer-reviewed literature was reviewed and summarized. OBJECTIVE: To synthesize the indications and published outcomes of reconstructive lumbar spine surgery for the treatment of chronic pain of spinal origin. METHODS: A literature review was conducted. RESULTS: The most common indication for reconstructive lumbar surgery is pain that is refractory to nonsurgical treatment. Lumbar fusion has been shown to improve symptoms in carefully selected patients with incapacitating pain. CONCLUSIONS: A successful arthrodesis is the fundamental surgical goal for patients with chronic pain of spinal origin. However, a successful fusion does not always correlate with a successful clinical result.