Allogenic bone marrow-derived mesenchymal stromal cell-based therapy for patients with chronic low back pain: a prospective, multicentre, randomised placebo controlled trial (RESPINE study).

OBJECTIVES: To assess the efficacy of a single intradiscal injection of allogeneic bone marrow mesenchymal stromal cells (BM-MSCs) versus a sham placebo in patients with chronic low back pain (LBP). METHODS: Participants were randomised in a prospective, double-blind, controlled study to receive either sham injection or intradiscal injection of 20 million allogeneic BM-MSC, between April 2018 and December 2022. The first co-primary endpoint was the rate of responders defined by improvement of the Visual Analogue Scale (VAS) for pain of at least 20% and 20 mm, or improvement of the Oswestry Disability Index (ODI) of 20% between baseline and month 12. The secondary structural co-primary endpoint was assessed by the disc fluid content measured by quantitative MRI T2, between baseline and month 12. Secondary endpoints included pain VAS, ODI, the Short Form (SF)-36 and the minimal clinically important difference in all timepoints (1, 3, 6, 12 and 24 months). We determined the immune response associated with allogeneic cell injection between baseline and 6 months. Serious adverse events (SAEs) were recorded. RESULTS: 114 patients were randomised (n=58, BM-MSC group; n=56, sham placebo group). At 12 months, the primary outcome was not reached (74% in the BM-MSC group vs 69% in the placebo group; p=0.77). The groups did not differ in all secondary outcomes. No SAE related to the intervention occurred. CONCLUSIONS: While our study did not conclusively demonstrate the efficacy of allogeneic BM-MSCs for LBP, the procedure was safe. Long-term outcomes of MSC therapy for LBP are still being studied. TRIAL REGISTRATION NUMBER: EudraCT 2017-002092-25/ClinicalTrials.gov: NCT03737461.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of Phase I-a short report.

NOVOCART® Disk plus, an autologous cell compound for autologous disk chondrocyte transplantation, was developed to reduce the degenerative sequel after lumbar disk surgery or to prophylactically avoid degeneration in adjacent disks, if present. The NDisc trial is an ongoing multi-center, randomized study with a sequential phase I study within the combined phase I/II trial with close monitoring of tolerability and safety. Twenty-four adult patients were randomized and treated with the investigational medicinal product NDisc plus or the carrier material only. Rates of adverse events in Phase I of this trial were comparable with those expected in the early time course after elective disk surgery. There was one reherniation 7 months after transplantation, which corresponds to an expected reherniation rate. Immunological markers like CRP and IL-6 were not significantly elevated and there were no imaging abnormalities. No indications of harmful material extrusion or immunological consequences due to the investigational medicinal product NDplus were observed. Therefore, the study appears to be safe and feasible. Safety analyses of Phase I of this trial indicate a relatively low risk considering the benefits that patients with debilitating degenerative disk disease may gain.

Migrational changes of mesenchymal stem cells in response to cytokines, growth factors, hypoxia, and aging.

Mesenchymal stem cells (MSCs) are non-immunogenic, multipotent cells with at least trilineage differentiation potential. They promote wound healing, improve regeneration of injured tissue, and mediate numerous other health effects. MSCs migrate to sites of injury and stimulate repair either through direct differentiation or indirectly through the stimulation of endogenous repair mechanisms. Using the in vitro scratch assay, we show that the inflammatory cytokines, chemokines, and growth factors TNF-α, SDF-1, PDGF, and bFGF enhance migration of rat MSCs under normoxic conditions, while TNF-α, IFN-γ, PDGF, and bFGF promote MSC migration under hypoxic conditions. This indicates that the oxygen concentration affects how MSCs will migrate in response to specific factors and, consistent with this, differential expression of cytokines was observed under hypoxic versus normoxic conditions. Using the transwell migration assay, we find that TNF-α, IFN-γ, bFGF, IGF-1, PDGF, and SDF-1 significantly increase transmigration of rat MSCs compared to unstimulated medium. MSCs derived from aged rats exhibited comparable migration to MSCs derived from young rats under hypoxic and normoxic conditions, even after application with specific factors. Similarly, migration in MSCs from aged, human donors did not statistically differ compared to migration in MSCs derived from human umbilical cord tissue or younger donors.

Patient Comorbidities, Their Influence on Lumbar Spinal Fusion Surgery, and Recommendations to Reduce Unfavorable Outcomes.

Improvements in healthcare management have led to a decrease in perioperative and postoperative complications. However, perioperative medical complications and mortality rates continue to increase in patients undergoing elective spinal surgeries. This trend is driven by the increase in the older population and the rise in the number of patients with more than two comorbidities. Managing patients with multiple comorbidities requires additional resources, augmenting the financial and societal burden. Despite the high risk of complications and mortality, patients with multiple comorbidities undergo spinal surgery for degenerative spinal conditions daily. These findings highlight the need for heightened awareness, patient education, and management of comorbidities before elective spinal surgeries. This article comprehensively reviews literature on the effects of medical comorbidities on spinal fusion surgery outcomes to increase awareness of the surgical complications associated with comorbidities. In addition, suggested preoperative and postoperative comorbidity management strategies are outlined.

What Is the Evidence Surrounding the Cost-Effectiveness of Osteobiologic Use in ACDF Surgery? A Systematic Review of the Literature.

STUDY DESIGN: This study constitutes a systematic review of the literature. OBJECTIVE: The aim of this study was to identify and present all available studies that report on the costs of osteobiologics used in anterior cervical discectomy and fusion (ACDF). METHODS: The literature was systematically reviewed to identify studies with specific inclusion criteria: (1) randomized controlled trials and observational studies, (2) in adult patients, (3) with herniated disc(s) or degenerative cervical spine disease, (4) reporting on either direct or indirect costs of using specific osteobiologics in an ACDF operation. (5) Only studies in English were included. The quality of the included studies was assessed using the MINORS and RoB 2.0 tools. RESULTS: Overall, 14 articles were included; one randomized controlled trial and 13 observational studies. The most commonly used osteobiologics other than autograft/iliac crest bone graft (ICBG) were allograft and bone morphogenetic protein (BMP). None of the studies was reported to be industry-supported. There was considerable heterogeneity on the reported costs. Overall, most studies reported on surgery-related costs, such as anesthesia, operating room, surgical materials and surgeon's fee. Only two studies, both using allograft, reported the exact cost of the osteobiologic used (450 GBP, $700). Some of the studies reported on the cost of care during hospitalization for the surgical operation, such as radiology studies, emergency room costs, cardiologic evaluation, laboratory studies, pharmacy costs, and room costs. Only a few studies reported on the cost of follow-up, reoperation, and physical therapy and rehabilitation. CONCLUSION: Based on the data of this current systematic review, no recommendations can be made regarding the cost-effectiveness of using osteobiologics in ACDF. Given the high costs of osteobiologics, this remains a topic of importance. The design of future studies on the subject should include cost effectiveness.

Discectomy versus sequestrectomy in the treatment of lumbar disc herniation: a systematic review and meta-analysis.

BACKGROUND CONTEXT: Lumbar disc herniation (LDH) is a leading cause of low back pain (LBP) and leg pain and may require surgical treatment in case of persistent pain and/or neurological deficits. Conventional discectomy involves removing the herniated fragment and additional material from the disc space, potentially accelerating disc degeneration and contributing to chronic LBP. Conversely, by resecting the herniated fragment only, sequestrectomy may reduce postoperative LBP while increasing the risk of LDH recurrence. PURPOSE: To compare discectomy versus sequestrectomy in terms of risk of reherniation, reoperation rate, complications, pain, satisfaction, and perioperative outcomes (operative time, blood loss, length of stay [LOS]). STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic search of PubMed/MEDLINE and Scopus databases was performed through May 1, 2024 for both randomized and nonrandomized studies. The search was conducted according to PRISMA guidelines. The RoB-2 and MINORS tools were utilized to assess the risk of bias in included studies. The quality of the evidence was evaluated according to the GRADE approach. Relevant outcomes were pooled for meta-analysis. RESULTS: A total of 16 articles (1 randomized controlled trial with 2 follow-up studies, 6 prospective studies, and 7 retrospective studies) published between 1991 and 2020 involving 2009 patients were included for analysis. No significant differences were noted between discectomy versus sequestrectomy in terms of risk of reherniation (OR: 0.85, 95% CI: 0.57 to 1.26, p=.42), reoperation rate (OR: 0.95, 95% CI: 0.64 to 1.40, p=.78), and complications (OR: 1.03, 95% CI: 0.50 to 2.11, p=.94). Although LBP (MD: -0.06, 95% CI: -0.39 to 0.28, p=.74) and leg pain intensity (MD: 0.11, 95% CI: -0.21 to 0.42, p=.50) were similar postoperatively, significantly better outcomes were reported by patients treated with sequestrectomy at 1 year (leg pain: MD: 0.37, 95% CI: 0.19 to 0.54, p<.0001) and 2 years (LBP: MD: 0.19, 95% CI: 0.03 to 0.34, p=.02; leg pain: MD: 0.20, 95% CI: 0.09 to 0.31, p=.0005). Sequestrectomy also resulted in a higher patient satisfaction (OR: 0.60, 95% CI: 0.40 to 0.90, p=.01) and shorter operative time (MD: 8.71, 95% CI: 1.66 to 15.75, p=.02), while blood loss (MD: 0.18, 95% CI: -2.31 to 2.67, p=.89) and LOS (MD: 0.02 days, 95% CI: -0.07 to 0.12, p=.60) did not significantly differ compared to discectomy. CONCLUSIONS: Based on the current evidence, discectomy and sequestrectomy do not significantly differ in terms of risk of reherniation, reoperation rate, and postoperative complications. Patients treated with sequestrectomy may benefit from a marginally higher pain improvement, better satisfaction outcomes, and a shorter operative time, although the clinical relevance of these differences needs to be validated in larger, prospective, randomized studies.

Analysis of Complications in Multilevel Anterior Cervical Discectomy and Fusion Using Osteobiologics Other than Bone Morphogenetic Protein: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVES: The aim of this study is to analyze the complications related to multilevel anterior cervical discectomy and fusion (ACDF) using osteobiologics other than bone morphogenetic protein (BMP). METHODS: A systematic review of the literature was conducted using PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov databases. The search to identify studies reporting complications in multilevel ACDF surgery using osteobiologics other than bone morphogenetic protein was performed in August 2020. The study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). RESULTS: A total of 584 articles were found after searching the databases and removing duplicates. Next, screening was performed in a double reviewer process, and 153 eligible articles-with 4 retrospective studies-in full-text were selected; these met all inclusion criteria. A total of 197 patients received 3-level ACDF, while 72 patients received 4-level ACDF. Osteobiologics were used in all selected articles, allograft was used in 4 studies, autologous bone graft was utilized in 3 articles, and hydroxyapatite was used in 1 article. The main complications reported were dysphagia, adjacent segment disease, and pseudarthrosis. CONCLUSIONS: Given the limited evidence, no conclusions on complications in multilevel ACDF using osteobiologics other than BMP could be made. However, descriptively, the most common complications found were dysphagia, adjacent segment disease, and pseudoarthrosis. Further prospective studies separately analyzing complications in multilevel ACDF by osteobiologics and a number of treated levels are needed.

Complications of the Use Allograft in 1- or 2-Level Anterior Cervical Discectomy and Fusion: A Systematic Review.

Study Design: Systematic literature reviewObjective: To critically analyze the literature and describe the complications associated with the use of allograft in 1- or 2- level anterior cervical discectomy and fusion (ACDF)Methods: A systematic search of PubMed/MEDLINE, EMBASE, and ClinicalTrials.gov databases was conducted for literature published between January 2000 and August 2020 reporting complications associated with the use of allograft in 1- or 2- level ACDF.Results: From 584 potentially relevant citations, 21 met the inclusion criteria (4 randomized controlled trials (RCT), 4 prospective, and 13 retrospective studies). The patient number varied between 26 and 463 in comparative studies (RCT and non-RCT) and between 29 and 345 in non-comparative studies. Fusion rate was reported in 14 studies and ranged between 68.5-100%. The most frequently reported complication was post-operative dysphagia or dysphonia, with incidences ranging between .5% and 14.4%. Revision surgery was the second most reported complication (14 studies) and ranged between 0% and 10.3%. Wound-related complications were reported in 6 studies and ranged between 0% and 22.8%.Conclusion: The overall reporting of complications was low with very few comparative studies. Reported complications with allografts are within the range of other osteobiologics and autografts and in most cases may not attributable to the use of osteobiologics and may be complications of the procedure itself. Comparative studies with a more robust methodology analyzing complications with allograft and other osteobiologics are needed to inform current practice with strong recommendations.

Development of an International AO Spine Guideline for the Use of Osteobiologics in Anterior Cervical Fusion and Decompression (AO-GO).

STUDY DESIGN: Methodological study for guideline development. OBJECTIVE: AO Spine Guideline for Using Osteobiologics (AO-GO) project for spine degenerative pathologies was an international, multidisciplinary collaborative initiative to identify and evaluate evidence on existing use of osteobiologics in Anterior Cervical Fusion and Decompression (ACDF). The aim was to formulate precisely defined, clinically relevant and internationally applicable guidelines ensuring evidence-based, safe and effective use of osteobiologics, considering regional preferences and cost-effectiveness. METHODS: Guideline was completed in two phases: Phase 1- evidence synthesis; Phase 2- recommendation development based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. In Phase 1, key questions identified by a panel of experts were addressed in a series of systematic reviews of randomized and non-randomized studies. In Phase 2, the GRADE approach was used to formulate a series of recommendations, including expert panel discussions via web calls and face-to-face meetings. DISCUSSION: AO-GO aims to bridge an important gap between evidence and use of osteobiologics in spine fusion surgeries. Owing to differences in osteobiologics preparation and functional characteristics, regulatory requirements for approval may vary, therefore it is highly likely that these products enter market without quality clinical trials. With a holistic approach the guideline aims to facilitate evidence-based, patient-oriented decision-making processes in clinical practice, thus stimulating further evidence-based studies regarding osteobiologics usage in spine surgeries. In Phase 3, the guideline will be disseminated and validated using prospectively collected clinical data in a separate effort of the AO Spine Knowledge Forum Degenerative in a global multicenter clinical study.

The Evidence for the Use of Osteobiologics in Hybrid Constructs (Anterior Cervical Discectomy and Fusion and Total Disc Replacement) in Multilevel Cervical Degenerative Disc Disease: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVE: Examine the clinical evidence for the use of osteobiologics in hybrid surgery (combined anterior cervical discectomy and fusion (ACDF) and total disc replacement (TDR)) in patients with multilevel cervical degenerative disc disease (DDD). METHODS: PubMed and Embase were searched between January 2000 and August 2020. Clinical studies investigating 18-80 year old patients with multilevel cervical DDD who underwent hybrid surgery with or without the use of osteobiologics were considered eligible. Two reviewers independently screened and assessed the identified articles. The methodological index for non-randomized studies (MINORS) tool and the risk of bias (RoB 2.0) assessment tool were used to assess risk of bias. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to evaluate quality of evidence across studies per outcome. RESULTS: Eleven studies were included. A decrease in cervical range of motion was observed in most studies for both the hybrid surgery and the control groups consisting of stand-alone ACDF or TDR. Fusion rates of 70-100% were reported in both the hybrid surgery and control groups consisting of stand-alone ACDF. The hybrid surgery group performed better or comparable to the control group in terms of adjacent segment degeneration. Studies reported an improvement in visual analogue scale for pain and neck disability index values after surgery compared to preoperative scores for both treatment groups. The included studies had moderate methodological quality. CONCLUSIONS: There is insufficient evidence for assessing the use of osteobiologics in multilevel hybrid surgery and additional high quality and controlled research is deemed essential.

The Role of Osteobiologics in Augmenting Spine Fusion in Unplated Anterior Cervical Discectomy and Fusion Compared to Plated Constructs: A Systematic Review and Meta-analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To compare clinical and radiographic outcomes as well as complications of unplated vs plated anterior cervical discectomy and fusion (ACDF) surgery considering the role of osteobiologics in single- and multi-level procedures. METHODS: A systematic search of PubMed/MEDLINE, Scopus, CINAHL, EMBASE, CENTRAL, Cochrane and ClinicalTrials.gov databases was performed. Briefly, we sought to identify studies comparing unplated vs. plated ACDF for cervical degenerative disc disease reporting the use of osteobiologics in terms of clinical outcomes, radiographic fusion, and complications. Data on study population, follow-up time, type of cage and plate used, type of osteobiologic employed, number of levels treated, patient-reported outcomes (PROs), radiographic outcomes and complications were collected and compared. Relevant information was pooled for meta-analyses. RESULTS: Thirty-eight studies met the inclusion criteria. No significant difference was found in terms of clinical outcomes between groups. Unplated ACDF was characterized by reduced blood loss, operation time and length of hospital stay. Fusion was achieved by the majority of patients in both groups, with no evidence of any specific contribution depending on the osteobiologics used. Dysphagia was more commonly associated with anterior plating, while cage subsidence prevailed in the unplated group. CONCLUSION: Unplated and plated ACDF seem to provide similar outcomes irrespective of the osteobiologic used, with minor differences with doubtful clinical significance. However, the heterogeneity and high risk of bias affecting included studies markedly prevent significant conclusions.

Do Osteobiologics Augment Fusion in Anterior Cervical Discectomy and Fusion Surgery Performed With Mechanical Interbody Devices (Polyether ether ketone, Carbon Fiber, Metal Cages) and is the Fusion Rate Comparable to that With Autograft? A Systematic Review.

STUDY DESIGN: Systematic Review of the Literature. OBJECTIVE: The purpose of this study was to perform a systematic review describing fusion rates for anterior cervical discectomy and fusion (ACDF) using autograft vs various interbody devices augmented with different osteobiologic materials. METHODS: A systematic review limited to the English language was performed in Medline, Embase and Cochrane library using Medical Subject Heading (MeSH) terms. Studies that evaluated fusion after ACDF using autografts and osteobiologics combined with PEEK, carbon fibre, or metal cages were searched for. Articles in full text that met the criteria were included in the review. The main outcomes evaluated were the time taken to merge, the definition of the fusion assessment, and the modality of the fusion assessment. The risk of bias of each article was assessed by the MINORS score or ROB 2.0 depending on the randomisation process. RESULTS: The total number of references reviewed was six hundred and eighty-two. After applying the inclusion criteria, 54 were selected for the retrieval of the full text. Eight studies were selected and included for final analysis in this study. Fusion rates were reported between 83.3% and 100% for autograft groups compared to 46.5% and 100% for various interbody device/osteobiological combinations. The overall quality of the evidence in all radiographic fusion studies was considered insufficient due to a serious risk of bias. CONCLUSION: Mechanical interbody devices augmented with osteobiologics performed similarly to autografts in terms of reliability and efficacy. Their time to fusion and fusion rate were comparable to autografts at the end of the final follow-up.

Structural Allograft Versus Mechanical Interbody Devices Augmented With Osteobiologics in Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic Literature Review. OBJECTIVE: Perform a systematic review evaluating postoperative fusion rates for anterior cervical discectomy and fusion (ACDF) using structural allograft vs various interbody devices augmented with different osteobiologic materials. METHODS: Comprehensive literature search using PubMed, Embase, The Cochrane Library, and Web of Science was performed. Included studies were those that reported results of 1-4 levels ACDF using pure structural allograft compared with a mechanical interbody device augmented with an osteobiologic. Excluded studies were those that reported on ACDF with cervical corpectomy; anterior and posterior cervical fusions; circumferential (360° or 540°) fusion or revision ACDF for nonunion or other conditions. Risk of bias was determined using the Cochrane review guidelines. RESULTS: 8 articles reporting fusion rates of structural allograft and an interbody device/osteobiologic pair were included. All included studies compared fusion rates following ACDF among structural allograft vs non-allograft interbody device/osteobiologic pairs. Fusion rates were reported between 84% and 100% for structural allograft, while fusion rates for various interbody device/osteobiologic combinations ranged from 26% to 100%. Among non-allograft cage groups fusion rates varied from 73-100%. One study found PEEK cages filled with combinations of autograft, allograft, and demineralized bone matrix (DBM) to have an overall fusion rate of 26%. In one study comparing plate and zero-profile constructs, there was no difference in fusion rates for two-level fusions. CONCLUSION: There was limited data comparing fusion outcomes of patients undergoing ACDF using structural allograft vs interbody devices augmented with osteobiologic materials to support superiority of one method.

Comparison of Different Osteobiologics in Terms of Imaging Modalities and Time Frames for Fusion Assessment in Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVES: The study's primary objective was to determine how osteobiologic choice affects fusion rates in patients undergoing anterior cervical discectomy and fusion (ACDF). The study's secondary objectives were to 1) determine the optimal timing of fusion assessment following ACDF and 2) determine if osteobiologic type affects the timing and optimal modality of fusion assessment. METHODS: A systematic search of PubMed/MEDLINE was conducted for literature published from 2000 through October 2020 comparing anterior fusion in the cervical spine with various osteobiologics. Both comparative studies and case series of ≥10 patients were included. RESULTS: A total of 74 studies met the inclusion criteria. Seventeen studies evaluated the efficacy of autograft on fusion outcomes, and 23 studies assessed the efficacy of allograft on fusion outcomes. 3 studies evaluated the efficacy of demineralized bone matrix, and seven assessed the efficacy of rhBMP-2 on fusion outcomes. Other limited studies evaluated the efficacy of ceramics and bioactive glasses on fusion outcomes, and 4 assessed the efficacy of stem cell products. Most studies utilized dynamic radiographs for the assessment of fusion. Overall, there was a general lack of supportive data to determine the optimal timing of fusion assessment meaningfully or if osteobiologic type influenced fusion timing. CONCLUSIONS: Achieving fusion following ACDF appears to remain an intricate interplay between host biology and various surgical factors, including the selection of osteobiologics. While alternative osteobiologics to autograft exist and may produce acceptable fusion rates, limitations in study methodology prevent any definitive conclusions from existing literature.

The Use of Osteobiologics in Single versus Multi-Level Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic literature review. OBJECTIVES: In this study we assessed evidence for the use of osteobiologics in single vs multi-level anterior cervical discectomy and fusion (ACDF) in patients with cervical spine degeneration. The primary objective was to compare fusion rates after single and multi-level surgery with different osteobiologics. Secondary objectives were to compare differences in patient reported outcome measures (PROMs) and complications. METHODS: After a global team of reviewers was selected, a systematic review using different repositories was performed, confirming to PRISMA and GRADE guidelines. In total 1206 articles were identified and after applying inclusion and exclusion criteria, 11 articles were eligible for analysis. Extracted data included fusion rates, definition of fusion, patient reported outcome measures, types of osteobiologics used, complications, adverse events and revisions. RESULTS: Fusion rates ranged from 87.7% to 100% for bone morphogenetic protein 2 (BMP-2) and 88.6% to 94.7% for demineralized bone matrix, while fusion rates reported for other osteobiologics were lower. All included studies showed PROMs improved significantly for each osteobiologic. However, no differences were reported when comparing osteobiologics, or when comparing single vs multi-level surgery specifically. CONCLUSION: The highest fusion rates after 2-level ACDF for cervical spine degeneration were reported when BMP-2 was used. However, PROMs did not differ between the different osteobiologics. Further blinded randomized trials should be performed to compare the use of BMP-2 in single vs multi-level ACDF specifically.

Dosing Strategy for Osteobiologics Used in ACDF Surgery: Influence on Fusion Rates and Associated Complications. A Systematic Literature Review.

STUDY DESIGN: Systematic review. OBJECTIVE: To assess the available evidence related to dose-dependent effectiveness (i.e., bone fusion) and morbidity of osteobiologics used in anterior cervical discectomy and fusion (ACDF). METHODS: Studies with more than 9 adult patients with degenerated/herniated cervical discs operated for one-to four-levels ACDF reporting used osteobiologics doses, fusion rates at six months or later, and related comorbidities were included. PubMed, EMBASE, ClinicalTrials, and Cochrane were searched through September 2021. Data extracted in spread sheet and risk of bias assessed using MINORS and Rob-2. RESULTS: Sixteen studies were selected and sub-grouped into BMP and non-BMP osteobiologics. For the 10 BMP studies, doses varied from 0.26 to 2.1 mg in 649 patients with fusion rates of 95.3 to 100% at 12 months. For other osteobiologics, each of six studies reported one type of osteobiologic in certain dose/concentration/volume in a total of 580 patients with fusion rates of 6.8 to 96.9% at 12 months. Risk of bias was low in three of the 13 non-randomized (18.75%) and in all the three randomized studies (100%). CONCLUSIONS: Taking into account the inconsistent reporting within available literature, for BMP usage in ACDF, doses lower than 0.7 mg per level can achieve equal successful fusion rates as higher doses, and there is no complication-free dose proved yet. It seems that the lower the dose the lower the incidence of serious complications. As for non-BMP osteobiologics the studies are very limited for each osteobiologic and thus conclusions must be drawn individually and with caution.

Muscle activity and rehabilitation in spinal stenosis (MARSS) after conservative therapy and surgical decompression with or without fusion: Protocol for a partially randomized patient preference trial on rehabilitation timing.

Background: Patients affected by lumbar spinal stenosis (LSS) suffer from a multifactorial degeneration of the lumbar spine resulting in narrowing of the neuroforamina and spinal canal, leading to various functional limitations. It remains unclear whether LSS patients after surgery would benefit from early post-operative rehabilitation, or if a delayed rehabilitation would be more advantageous. The purpose of this partially randomized patient preference trial is to evaluate the impact of post-operative rehabilitation timing as well as surgical intervention type on psychometric properties and functional outcomes in patients with LSS. Methods: Data for this patient preference trial are collected before and after surgical (decompression only or decompression and fusion) and rehabilitative interventions as well as six, 12 and 24 months after completing rehabilitation. The study participants are patients diagnosed with LSS who are at least 18 years old. After a medical check-up, participants will complete patient-reported outcome measures (PAREMO-20, SIBAR, FREM-8, SF-12, SFI, ODI) and different functional assessments (functional reach test, loaded reach test, handgrip strength, standing balance control, 6-min walk test). Ethics and dissemination: The results of this study will be published through peer-reviewed publications and scientific contributions at national and international conferences. This research has been approved by the Institutional Review Board of Martin Luther University Halle-Wittenberg (reference number: 2022-128).

Do the Choice of Fusion Construct With and Without Autograft Influence the Fusion and Complication Rates in Patients Undergoing 1 or 2-Level Anterior Cervical Discectomy and Fusion Surgery? A PRISMA-Compliant Network Meta-Analysis.

STUDY DESIGN: Network meta-analysis. OBJECTIVES: To compare the fusion outcome and complications of different 1 or 2-level anterior cervical decompression and fusion (ACDF) constructs performed with and without the application of autografts. METHODS: We performed an independent and duplicate search in electronic databases including PubMed, Embase, Web of Science, Cochrane, and Scopus for relevant articles published between 2000 and 2020. We included comparative studies reporting fusion rate and complications with and without the use of autografts in ACDF across 5 different fusion constructs. A network meta-analysis was performed in Stata, categorized based on the type of fusion constructs utilized. Fusion constructs were ranked based on p-score approach and surface under cumulative ranking curve (SUCRA) scores. The confidence of results from the analysis was appraised with Cochrane's CINeMA approach. RESULTS: A total of 2216 patients from 22-studies including 6 Randomized Controlled Trials (RCTs) and 16 non-RCTs were included in network analysis. The mean age of included patients was 49.3 (±3.62) years. Based on our meta-analysis, we could conclude that use of autograft in 1- or 2-level ACDF did not affect the fusion and mechanical implant-related complications. The final fusion and mechanical complication rates were also not significantly different across the different fusion constructs. The use of plated constructs was associated with a significant increase in post-ACDF dysphagia rates [OR 3.42; 95%CI (.01,2.45)], as compared to stand-alone constructs analysed. CONCLUSION: The choice of fusion constructs and use of autografts does not significantly affect the fusion and overall complication rates following 1 or 2-level ACDF surgery.