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

Abstract

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.

Introduction

The current focus of AO-GO is the use of osteobiologics in Anterior Cervical Fusion and Decompression (ACDF) procedures for cervical degenerative conditions. There are three phases to the AO-GO work: Phase 1- evidence synthesis; Phase 2- recommendation development based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach; Phase 3- recommendation dissemination and ongoing evidence collection based on DegenPRO, a prospective data collection of spine degenerative surgery hosted by the AO Spine Knowledge Forum Degenerative (KF Degen) and the Bone Osteobiologics and Evidence classification (BOnE Classification) developed by the KF Degen, ¹ and development of a clinical decision support tool. This Special Issue addresses the following objectives for Phase 1 and Phase 2:

• 1. To identify and evaluate the existing osteobiologics and their use in ACDF procedures.

• 2. To identify patient characteristics/risk factors guiding the decision on use of osteobiologics and evaluate clinical outcomes in these patient subgroups.

• 3. To develop evidence-based recommendations for the use of osteobiologics in ACDF procedure based on Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. ²

A multidisciplinary international team representing spine surgeons, researchers, and clinical practitioners was established. Conflicts of interest of the team members were obtained and disclosed, and the key roles were defined including a Core Team, the Topic leads of the systematic reviews, the systematic review teams, guideline panelists, and observers. It was important to determine a priori who would be able to provide advice and who could vote on the final recommendations. The structure of the team and distinct responsibilities during the guideline development process are detailed in Table 1. Training to make recommendations using the GRADE approach was provided during the first guideline meeting. AO Spine Knowledge Forum Degenerative Steering Committee also oversaw the guideline development process and monitored the activities. To achieve stringent quality control and acceptability among the spine community, the guideline development process was modeled according to the guideline development process proposed by WHO ³ and the Guideline International Network (GIN)-McMaster Guideline Development Checklist (https://cebgrade.mcmaster.ca/guidecheck).

Table 1.

Role of Participants in the Guideline Development.

Team Structure	Primary Responsibilities	Main Functions	Participation Timeline	Essential Expertise	Disclosure
Steering group AO-GO project (Meisel, Buser, and Jain) and AO Spine knowledge forum degenerative (KF degen) steering committee (SC) (https://www.aofoundation.org/spine/research/research-programs/knowledge-forum-degenerative)	Oversee the evidence collection and guideline development process	Administration, peer review, oversee the whole study group and the study activities	Start-end (phase 1 and 2)	Leadership in the overall project and expertise in the topic (spinal surgery, ACDF, biologics, etc.)	Yes
Project manager (Wu) on behalf of the AO Spine KF degen SC	Oversee the evidence collection and guideline development process	Coordinate all systematic reviews and guideline development process, attend meetings, record and disseminate meeting minutes	Start-end (phase 1 and 2)	Project management	Yes
Methodologist (Santesso) for GRADE approach	Guide the evidence-based process for guideline development using GRADE approach	Assess systematic reviews, attend meetings, moderate guideline development according to the GRADE approach	After the systematic review starts till guideline development (phase 1 and 2)	GRADE approach	Yes
Systematic review teams (Table 2)	Each team to perform evidence based systematic review to form the basis of the evidence part of the guideline	Review and key questions, perform systematic reviews, and assess evidence collected Team leads also participate in guideline development process, especially focusing on providing insights of the evidence collected of the respective topics	After the first draft of the scope with key study questions till the completion of systematic reviews and guideline development (phase 1 and 2)	Systematic review	Yes
Guideline development panel (Table 4)	Formulate guidelines; define scope and content	Review, revise, and approve the final guideline based on the evidence collected following GRADE approach	After the first draft of the guideline till the completion of the guideline development (phase 2)	Expertise in the topic (spinal surgery, ACDF, biologics, etc.)	Yes
External reviewers/observers (Alini and Van Hooff)	Critically assess the process of systematic review and guideline development as independent reviewers.	Observe and assess the study process and methodology used. Attend meetings, review study documentations, etc.	After the preliminary results are available from the systematic review till the completion of guideline development (phase 1 and 2).	Expertise in the topic (spinal surgery, ACDF, biologics, etc.) and methodology.	Yes

Phase 1- Evidence Synthesis

The aim of Phase 1 was to identify and critically evaluate evidence for the use of osteobiologics in ACDF procedures for cervical spine degenerative cases, in terms of their functionality and clinical outcomes. It is clear, that high quality evidence is lacking for use of different biologics, particularly, in challenging clinical cases with comorbidities, or in multi-level surgeries. The systematic review, ⁴ which analyzed synthetic grafts (HA, β-TCP/HA, polymethylmethacrylate (PMMA)), and biocompatible osteoconductive polymer (BOP) for cervical degenerative conditions, showed there is insufficient evidence to derive recommendations regarding their use. Therefore, it was decided to focus on osteobiologics used in ACDF and factors influencing the decision-making process such as patient characteristics including age, BMI, smoking status, comorbidities, as well as cost effectiveness and regional availability. Next, a list of research questions (Table 2) were developed by a subgroup of the core leaders with a focus on clinically relevant topics with deficits in the literature or topics that had clinical equipoise, such as use of allograft vs mechanical cages with osteobiologics in ACDF surgery. These research questions were then vetted with the larger group at the AO Spine Knowledge Forum meeting, and once agreed upon, were developed into PICO (Population, Intervention, Comparator and Outcomes) format (Table 3). The larger group agreed that in addition to outcomes such as fusion and medical or surgical complications, patient important outcomes such as function, pain and quality of life, should be analyzed in the systematic reviews. The research questions addressed all the factors individually and were later integrated together to formulate the recommendations (Table 2). A systematic review team was created to conduct each review for a PICO and included researchers with expertise in conducting systematic reviews and clinical experience. Each team had monthly contact with members of the Steering Committee to ensure progress and to discuss methods and challenges with their review.

Table 2.

AOGO Research Topics/Questions and Team Leaders (list of team members can be found as the co-authors of the respective systematic review manuscripts of the AOGO Focus Issue).

	Topic Leaders	Topics/Questions
Topic 1	Arun Kumar V. MBBS, MS Reva Spine Centre, Visakhapatnam, India	Do osteobiologics augment fusion in ACDF surgery performed with mechanical interbody devices (PEEK, carbon fiber, metal cages) and is the fusion rate comparable to that with autograft?
Topic 2	Amit Jain MD, MBA Johns Hopkins University, Baltimore, MD, USA	Structural Allograft Versus Mechanical Interbody Devices Augmented with Osteobiologics in Anterior Cervical Discectomy and Fusion
Topic 3	Gianluca Vadalà MD, PhD Campus Bio-Medico University of Rome, Rome, Italy	The role of osteobiologics in augmenting spine fusion in zero-profile and unplated anterior cervical discectomy and fusion compared to plated constructs
Topic 4a	Sathish Muthu MS, MD Government Medical College, Dindigul, India	Does the use of Autograft influence the Fusion and Complication Rates in patients undergoing 1 or 2-level Anterior Cervical Discectomy and Fusion Surgery?
Topic 4b	Ricardo Rodrigues-Pinto MD, PhD, FEBOT Centro Hospitalar Universitário do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal Hospital CUF Trindade, Porto, Portugal	Complications of the use allograft in 1- or 2-level anterior cervical discectomy and fusion
Topic 4c	Juan P. Cabrera MD Hospital Clínico Regional de Concepción, Concepción, Chile	Complications with Demineralized Bone Matrix, Hydroxyapatite, and Beta-Tricalcium Phosphate in Single and Two-level Anterior Cervical Discectomy and Fusion Surgery
Topic 4d	Juan P. Cabrera MD Hospital Clínico Regional de Concepción, Concepción, Chile	Analysis of Complications in Multilevel Anterior Cervical Discectomy and Fusion using Osteobiologics other than Bone Morphogenetic Protein
Topic 5	Christopher Thomas Martin MD University of Minnesota, Minneapolis, MN, USA	Comparative Complications Associated with BMP Use in Patients Undergoing ACDF for Degenerative Spinal Conditions
Topic 6	Pieter-Paul A. Vergroesen MD, PhD, MBA The University Medical Center Utrecht, Utrecht, the Netherlands	The Use of Osteobiologics in Single Versus Multi-Level Anterior Cervical Discectomy and Fusion
Topic 7	Chris Arts PhD Maastricht University Medical Centre, Maastricht, the Netherlands Eindhoven University of Technology, Eindhoven, the Netherlands	The evidence for the use of osteobiologics in hybrid constructs (Anterior Cervical Discectomy and Fusion (ACDF) and total disc replacement (TDR)) in multilevel cervical degenerative disc disease
Topic 8	Waeel O. Hamouda MSc, MD, FEBNS, FRCS(SN) Research, and Teaching Hospitals - Cairo University, Cairo, Egypt	Dosing Strategy For Osteobiologics Used In ACDF Surgery, Influence On Fusion Rates And Associated Complications
Topic 9	Patrick Hsieh MD University of Southern California, Los Angeles, CA, USA.	Cervical Spine Fusion – Comparison of Different Osteobiologics and Different Imaging Modalities and Time Frames for Fusion Assessment
Topic 10	Andreas K. Demetriades FRCS Royal Infirmary Edinburgh, Edinburgh, United Kingdom	What is the evidence surrounding the cost-effectiveness of osteobiologic use in ACDF surgery?
Topic 11	Stipe Ćorluka MD University of Applied Health Sciences Zagreb, Zagreb, Croatia	How Do Patient Comorbidities Affect the Choice of Osteobiologics for Anterior Cervical Discectomy and Fusion?
Topic 12	Ricardo Rodrigues-Pinto MD, PhD, FEBOT Centro Hospitalar Universitário do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal Hospital CUF Trindade, Porto, Portugal	What is the Evidence Supporting Osteobiologic Use in Revision Anterior Cervical Discectomy and Fusion?

Table 3.

AOGO PICO Table.

Study Component	Inclusion	Exclusion
Participants	• Adult patients (18–80 years old) • Patients with herniated or degenerative cervical neck discs	• History of tumour • Infection • SCI • Trauma/Fracture • Skeletally immature patients • Scoliosis or cervical deformity
Intervention	Topic 1–6 and 8–13: 1–4 levels ACDF (grouping into 1-2 levels and 3-4 levels)	• Anterior and posterior cervical fusions • Anterior cervical corpectomy and fusion
	Topic 7: 2–4 levels ACDF+ TDR
Comparator(s)	Topic 1: Osteobiologics and mechanical interbody devices (PEEK, carbon fibre, metal cages) VS. Autograft	Topic 1: NA
	Topic 2: Osteobiologics and mechanical interbody devices (PEEK, carbon fibre, metal cages) VS. Allograft	Topic 2: NA
	Topic 3: Zero-profile and unplated cage augmented with osteobiologics VS. Zero-profile and plated cage augmented with osteobiologics Different numbers of surgical level With neck bracing VS. Without neck bracing	Topic 3: NA
	Topic 4: Compare different osteobiologics according to Appendix 2 Different numbers of surgical level	Topic 4: Use of BMP
	Topic 5: With VS. without BMP Compare different BMPs Different numbers of surgical level (The study should include BMP at least in one study group, with or without other osteobiologics)	Topic 5: Studies that do not include any patients in whom BMP was used
	Topic 6: Single level vs. multi-level ACDF surgeries with synthetic cages and others (PEEK, carbon fibre, metal cages)	Topic 6: Studies that only include autograft or allograft and no osteobiologics, extracorporal bone stimulation due to High intensity ultrasound. and those are not treated by the golden standard i.e., standalone plate or cage
	Topic 7: Hybrid construct (ACDF + TDR) with biologics VS. ACDF alone with biologics	Topic 7: PEEK cage alone, Titanium cage alone, Surface modified cages alone without osteobiologics added
	Topic 8: Compare different dosing strategy Compare use of volume/concentration	Topic 8: NA
	Topic 9: Compare different biologics Compare different imaging modalities and time frames	Topic 9: NA
	Topic 10: Use of osteobiologic VS. no osteobiologic Compare different types of osteobiologics to each other Compare osteobiologic use in ACDF with plate VS. without plate	Topic 10: NA
	Topic 11: Patient use a specific biologic (autograft, allograft, DBM, BMP2, ceramics, cell-based) that have risk factor (s) VS. without a risk factor, within the same study	Topic 11: Studies that do not include risk factor analysis
	Topic 12: Compare revision ACDF surgeries with different biologics Revision ACDF surgery with osteobiologics VS. without, within the same study	Topic 12: Studies that do not include any patient undergoing revision surgery
	Topic 13: Use of BMP VS. autograft bone	Topic 13: Studies that do not include any patients in whom BMP was used or perform implantation of rhBMP-2 or rhBMP-7 into sites other than the spine.
Outcomes	Topic 1: Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3);	Topic 1: No radiographic assessment of fusion
	Topic 2: Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3);	Topic 2: No radiographic assessment of fusion
	Topic 3: Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3); PROs (EQ5D, SF36, NDI, NRS/VAS, mJOA); Complications (Appendix 1)	Topic 3: No radiographic assessment of fusion
	Topic 4: Complications (Appendix 1)	Topic 4: No complications reported
	Topic 5: Complications (Appendix 1)	Topic 5: No complications reported
	Topic 6: Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3); PROs (EQ5D, SF36, NDI, NRS/VAS, mJOA)	Topic 6: No radiographic assessment of fusion
	Topic 7: Primary outcomes • Radiographical assessment of cervical range of motion (ROM), fusion rate, adjacent segment degeneration and post-operative complications Secondary outcomes • Visual analogue scale • Neck disability index (NDI) • Odom criteria	Topic 7: No radiographic assessment of fusion
	Topic 8: Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3); Comorbidities; Complications (Appendix 1)	Topic 8: No radiographic assessment of fusion
	Topic 9: Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3);	Topic 9: No radiographic assessment of fusion
	Topic 10: Cost incl of biologic, of surgery, hospitalization, follow ups, Incl for complications, revisions. Indirect costs: return to work, physiotherapy, rehabilitation, medication, etc.	Topic 10: No direct or indirect cost related information
	Topic 11: Direct outcome are osteobiologics. Means to look at the biologics: • Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3); • PROs (EQ5D, SF36, NDI, NRS/VAS, mJOA) • Complications (Appendix 1)	Topic 11: No radiographic assessment of fusion
	Topic 12: Direct outcome are revisions. Means to look at the revisions: • Radiographic fusion (either X-ray/CT/both) with at least 6- month FU (Appendix 3); • PROs (EQ5D, SF36, NDI, NRS/VAS, mJOA) • Complications (Appendix 1)	Topic 12: No radiographic assessment of fusion
	Topic 13: Incidence of cancer	Topic 13: Studies that did not mention cancer as a potential outcome
Study Design	• RCTs, cohort studies, prospective or retrospective studies with ≥10 patients per group	• In vitro studies, animal studies • Case reports • Comparative studies with <10 patients per treatment group
Publication	Studies published in English in peer reviewed journals, publicly published HTAs or available FDA reports. (Each publication with a full review should be indicated whether or not it is an industry supported study.) Databases to be searched: PubMed, EMBASE, Cochrane, clinicaltrial.gov	Abstracts, editorials, letters • Duplicate publications of the same study which do not report on different outcomes • Single reports from multicentre trials • Studies reporting on the technical aspects of biologics use in fusion surgery • White papers • Narrative and systematic reviews • Articles identified as preliminary reports when results are published in later versions
Timing	Published in 2000 or later

Subsequently, a series of systematic reviews synthesizing and appraising the evidence for osteobiologics were conducted. When possible study protocols for the systemetic reviews were registered in PROSPERO, the international prospective register for systematic reviews – link: https://www.crd.york.ac.uk/prospero/. For many PICOs, randomized controlled trials were not available that directly compared autograft, allograft, or a cage with osteobiologic to each other. Instead, indirect comparisons using case series of each were pooled and then compared to each other. Meta-analysis was also not possible in most comparisons and results were summarized by range of effects. Unfortunately, there was also very little data about outcomes in specific populations based on comorbidities and these analyses were not conducted. The overall strength of evidence for the clinical outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ⁵ As per GRADE, the body of evidence was specified in four categories (high, moderate, low and very low) and reflect the level of certainty in the effect estimates to support a recommendation. Several factors can increase or reduce the confidence in the effect, such as the risk of bias of the studies, the precision and consistency of the effect, the directness of the evidence and the risk of publication bias.^6–11 For most outcomes, the certainty in the evidence was rated down for risk of bias because prognostic balance was likely not possible when comparing results from case series. There was often very few people across studies resulting in imprecise results.

Phase 2- Recommendation Development based on GRADE

Phase 2 was conducted together with the Guideline Development Panel (Table 4) under the guidance of the GRADE methodologist. Using the evidence from the systematic reviews, the GRADE methodologist created GRADE Evidence-to-Decision (EtD) frameworks, using the GRADEpro Guideline Development Tool (www.gradepro.org). Each EtD table described the benefits and harms of the osteobiologics compared to autograft or allograft or compared to each other, and the costs/resources and cost-effectiveness, patient values and preferences, equity, acceptability, and feasibility. EtDs for the use of osteobiologics or not in single or multi-level surgery, or in ACDF - TDR hybrid constructs were also compiled from the systematic reviews. While EtDs are typically used in person to facilitate decision making, we instead created these EtDs in GRADEpro and first sent them out to the guideline group and systematic review teams to provide initial feedback online (referred to in GRADEpro as Panel Voice). The EtD asked respondents to make a series of judgements, for example to judge whether the benefits and harms are substantial, whether the costs are large or negligible, and whether osteogiologics or other grafts are feasible or acceptable. The intention of asking for these judgements was to identify areas where there was agreement and areas where discussion would be necessary during meetings. For all recommendations, an in-person or virtual meeting occurred and areas of potential controversy were discussed. Judgements were reviewed and the panelists reached consensus in favor or against the use of osteobiologics or other grafts in a particular clinical scenario. Voting was not necessary. Recommendations were drafted using GRADE terminology: recommendations could be strong or conditional (https://gdt.gradepro.org/app/handbook/handbook.html). Important remarks were also added to aid clinicians when applying the recommendation. After the meetings, the Core Team prepared the final list of recommendations, assessed them for consistency, and sent them to the panelists, the systematic review teams, and an external group for review.

Table 4.

AOGO Guideline Development Panel.

Name	Title	Institution	City	Country
Samuel K. Cho	MD	Department of Orthopaedic Surgery, Icahn School of Medicine at Mount Sinai	New York, NY	USA
Peter G. Passias	MD	Departments of Orthopaedic and Neurosurgery, Division of Spinal Surgery, NYU Langone Medical Center, NY Spine Institute, Department of Neurological Surgery, Weill Cornell Medical College, Cornell University	New York, NY	USA
K. Daniel Riew	MD	Department of Orthopedic Surgery, Columbia University College of Physicians and Surgeons	New York, NY	USA
John H. Shin	MD	Department of Neurosurgery, Massachusetts General Hospital	Boston, MA	USA
Jeffrey C. Wang	MD	USC Spine Center, Keck School of Medicine at the University of Southern California	Los Angeles, CA	USA
S. Tim Yoon	MD, PhD	Department of Orthopedic Surgery, Emory University	Atlanta, GA	USA
Mohammad El-Sharkawi	MD, PhD	Department of Orthopaedic and Trauma Surgery, Faculty of Medicine, Assiut University	Assiut	Egypt
Atiq Uz Zaman	MBBS, FCPS, MME	Lahore Medical and Dental College, Ghurki Trust Teaching Hospital	Lahore	Pakistan
Ashish D Diwan	MBBS PhD FRACS FAOrthA	SpineLabs & Spine Service, Discipline of Surgery, St George & Sutherland Campus, University of New South Wales	Sydney	Australia
Gabriel Liu	M.B.B.Ch., BAO, M.Sc., F.R.C.S., F.R.C.S. Ed. (Orth), F.A.M.S., (Orth)	Department of Orthopedic Surgery, National University Hospital	Singapore	Singapore
Zhuojing Luo	MD, PhD	Department of Orthopaedic Surgery, Xijing Hospital	Xi'an	China
Daisuke Sakai	MD, PhD	Department of Orthopaedic Surgery, Tokai University School of Medicine	Isehara	Japan
Yu Sun	MD, PhD	Department of Orthopaedics, Peking University Third Hospital	Beijing	China
Kota Watanabe	MD, PhD	Department of Orthopaedic Surgery, Keio University School of Medicine	Tokyo	Japan
Sashin Ahuja	MBBS, MS Orth, DNB Orth, FRCS, FRCS Orth, MSc Orth Engin.	University Hospital of Wales	Cardiff	United Kingdom
Tamás Fekete	MD, PhD	Spine Center Division, Schulthess Klinik	Zürich	Switzerland
Luca Papavero	MD, PhD	Schoen Clinic Hamburg Eilbek	Hamburg	Germany
Veranis Sotiris	MD	251 General Air Force and Reserve Hospital	Athens	Greece
Emiliano Vialle	MD	Spine Surgery Group, Department of Orthopaedics, Cajuru University Hospital, Catholic University of Parana	Curitaba	Brazil

Discussion

AO-GO is aiming to help various stakeholders, including surgeons, to choose and use appropriate osteobiologics, companies to develop and advance osteobiologics products, hospitals to use suitable osteobiologics products, and regulatory authorities to oversee osteobiologics development and usage. By developing a guideline for osteobiologics use, we also aim to encourage evidence-based research on osteobiologics and related products.

The methods used ensured that the guideline development complied with accepted methodology and standards. Despite the paucity of studies directly comparing autograft, allograft and osteobiologics to each other, and the lack of data for the use of osteobiologics in populations with comorbidities, the guideline group balanced available evidence of benefits and harms with costs and other factors and made clinically useful recommendations that will be disseminated and validated in Phase 3. The group of experts identified for the guideline development ensured participation of clinical experts, key opinion leaders, stakeholders, and policy makers who will facilitate implementation into routine clinical practice. The systematic reviews and evidence-based guideline will also be presented in conferences and published in international peer-reviewed journals.

Compared to artificial intelligence (AI) and medical learning (ML) applications such as diagnostic imaging and classification in spine research, predictive analytics and clinical decision support tools are in their infancy. Advances in AI novel technologies and availability of data registries have enabled outcome prediction analysis and development of a clinical decision support system to some extent. Nijmegen Decision Tool for Chronic Low back pain is a recent decision support tool based on predictors such as patient’s demographics and symptoms, which is yet under development.^5,12–14 In fact, to date there is no application of ML in a decision support tool for spine surgeries. Accountability, risk of bias, ethics and data protection are the major hurdles for implementing ML technology in health care. Availability of large datasets for algorithm training, validation and accuracy testing pose other major challenges.

This paper presents Phase 1 and Phase 2 for guideline development, the AOGO osteobiologics grading system is currently being developed and Phase 3 is in preparation. In future, the systematic reviews will need to be updated and the recommendations revised if needed.

Appendix.

Appendix 1: List of Complications

For a consistent reporting among all 13 topics, please categorize each reported complication according to the below listing:

Peri-Operative Surgical Complications

• 1. Neurologic deterioration ≥1 motor grade in ASIA motor scale

• 2. New Post-Op Radiculitis or Neuropathic Pain

• 3. Wound dehiscence

• 4. Superficial wound infection

• 5. Deep wound infection

• 6. Airway Compromise Requiring Surgical Intervention

• 7. Dysphagia

• 8. Dysphonia

• 9. Anterior Cervical Hematoma/Seroma

• 10. Epidural Hematoma/Seroma

• 11. CSF leak/meningocele

• 12. Vertebral Artery Injury

• 13. Esophoageal Perforation

• 14. Horners Syndrome

• 15. Peri-Operative Death

Mid or Long Term Outcomes

• 1. Nonunion

• 2. Construct failure with loss of correction (cage subsidence, screw pull out, plate dislodgement)

• 3. Construct failure without loss of correction (cage subsidence, screw pull out, plate dislodgement)

• 4. Surgical Revision of Cervical Arthroplasty

• 5. Revision Surgery for Incomplete Neurologic Decompression and Persistent Symptoms

Medical Complications

• 1. Cardiac arrest/failure/arrhythmia

• 2. Deep vein thrombosis

• 3. Delirium

• 4. Gastrointestinal bleeding

• 5. Myocardial infarction

• 6. Pneumonia

• 7. Pressure sores

• 8. Pulmonary embolism

• 9. Systemic infection

• 10. Urinary tract infection

Other

• 1. Specify

Appendix 2: List of Osteobiologics

For a consistent reporting among all 13 topics, please categorize each studied osteobiologics according to the below listing:

• Autologous bone graft such as autologous iliac crest bone (AICB)

• Allogenic bone graft; Bone marrow aspirate (BMA)

• Demineralized bone matrix (DBM)

• Hydroxyapatite (HA)

• Bone morphogenetic protein (BMP)

• Platelet-rich plasma (PRP)

• Ceramic-based bone graft

• Mesenchymal stem cells (MSC)

• Other synthetic materials (Synthetic grafts-β-TCP, bioglass, etc.)

Appendix 3: The Definition of Fusion

Please refer to the definition provided here:

https://pubmed.ncbi.nlm.nih.gov/25893344/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232720/

In all the systematic reviews where fusion is evaluated, please list in the table:

• 1) what specific fusion criteria was used by the study

• 2) whether the study’s fusion criteria was consistent with the fusion criteria as defined by the Rhee/Riew study in the link above

ORCID iDs

Zorica Buser https://orcid.org/0000-0002-5680-0643

Hans Jörg Meisel https://orcid.org/0000-0003-3838-1489

Yabin Wu https://orcid.org/0000-0002-1836-7674

Amit Jain https://orcid.org/0000-0002-9983-3365

Sangwook Tim Yoon https://orcid.org/0000-0003-1010-6952