Recent Advances in Orthopaedics 4 Gregg R Klein, P Maxwell Courtney
INDEX
×
Chapter Notes

Save Clear

What is new in spine surgery?Chapter 1

Zachary T Grace,
John D Koerner
 
TRENDS IN SURGICAL TREATMENT
With advances in techniques and technology as well as an ageing population, the rate of spine surgery continues to increase, particularly for lumbar spine pathology. In an analysis of the National Inpatient Sample (NIS) in the United States (US) from 2004 to 2015, Martin et al found the number of elective lumbar fusion cases to increase by 62.3% (122,769 cases in 2004 to 199,140 in 2015), with the highest increase in patients >65 years of age [1]. The largest increases in fusion in the US for this time period were seen for the indications of spondylolisthesis and scoliosis [1], but the accuracy of diagnosis codes in the NIS given for lumbar fusion procedures is questionable [2]. Another study using the same database found an increasing number of lumbar fusion procedures among octogenarians from 2004 to 2013, but the length of hospital stay decreased (from 6 to 4.5 days) with increases in hospital charges [3]. There are also fewer isolated decompressions being done. The percentage of patients with lumbar spinal stenosis undergoing decompression alone decreased from 47.5 to 34.6% from 2010 to 2014 in the NIS database, with increases in both simple fusions (35.3–47.2%) and complex fusions (>3 vertebrae or 360°) (5.7 to 7.1%) [4]. These findings of an increasing number of fusions in an older population are consistent around the world. A database analysis from Japan between 2004 and 2015 found a 1.9 times increase in the total number of spine surgeries, with patients in their 70s being the most popular age group [5].
These findings of fewer decompressions and more fusions are not limited to the elderly. For patients with continuous 12-month insurance coverage aged 40–64 years between 2010 and 2014, the proportion of patients with lumbar stenosis undergoing decompression alone decreased linearly. The rates of complex arthrodesis also increased significantly each year, along with increased complications and higher costs [6]. There are also significant regional differences in the rates of arthrodesis, being more commonly performed in the South (48%), the Midwest (42%), versus the Northeast (36%) and the West (31%) [7].
The rate of cervical spine surgery has actually decreased slightly over the course of 2001–2013 (75.34 to 72.20 per 100,000 adults) [8] (Figure 1.1).
_________________
Zachary T Grace BS, Hackensack Meridian School of Medicine, Nutley, New Jersey, US Email: zachary.grace@hmhn.org
John D Koerner MD, Rothman Orthopaedic Institute, Paramus, New Jersey, US Email: john.koerner@rothmanortho.com
2
zoom view
Figure 1.1: Cervical spinal surgery rates (per 100,000 adults) categorised by region and year through 2001 to 2013 from the NIS database. US geography was divided between northeast (depicted in red), midwest (green), south (light blue), and western (purple) regions. NIS, National Inpatient Sample.Source: Liu CY, Zygourakis CC, Yoon S, et al. Trends in Utilization and Cost of Cervical Spine Surgery Using the National Inpatient Sample Database, 2001 to 2013. Spine (Phila Pa 1976) 2017; 42:E906–E913.
However, the total number of fusion procedures still increased when looking at cervical spondylotic myelopathy (CSM) (3,879–8,181 from 2003 to 2013), with slight increase in the average age (58.2–60.6 years), and significant increases in hospital charges [$49,445 to $92,040 (p < 0.001)] [9]. Trends in surgical treatment for single-level cervical radiculopathy have changed recently. Based on data from the National Surgical Quality Improvement Program (NSQIP) database from 2010 to 2016, there was an increase in the percentage of cervical disc replacement (7.7–16.1%), with a decrease in posterior cervical foraminotomy (20.3–10.6%), and relatively stable rate of anterior cervical discectomy and fusion (ACDF) procedures (72.0–73.3%) [10].
 
ROBOTICS
Robot-assisted spine surgery has become increasingly popular over the past several years. Pedicle screw placement by free hand or fluoroscopic guidance is relatively safe, but still has a risk of misplacement which can lead to neurologic or vascular injury, dural tear, or inadequate fixation. The accuracy of free hand versus robot-assisted pedicle screw placement has been evaluated by many studies and numerous robotic platforms. A meta-analysis of ten articles demonstrated significantly greater accuracy with the 3robot-assisted group compared to free hand with fluoroscopic guidance (odds ratio 95%, “perfect accuracy” confidence interval 1.38–2.07, p < 0.01; odds ratio 95% “clinically acceptable” confidence interval: 1.17–2.08, p < 0.01) [11]. This analysis only included studies with postoperative computed tomography (CT), and had two separate accuracy measurements: perfect accuracy (completely within the pedicle) and clinical acceptance (<3 mm of screw outside the pedicle without complication). In addition to the potential benefit of accuracy within the pedicle, there may be a decreased rate of proximal facet violation when using robotic assistance. In a randomised control trial of minimally invasive posterior lumbar interbody fusion (MIS-PLIF) comparing the Mazor robot with freehand technique, there were no proximal joint violations when using the robot (74 screws), but 13/82 (15.9%) in the freehand technique [12].
The ROSA robot (Medtech) uses an intraoperative O-arm (Medtronic Inc.) to produce a 3D reconstruction. The Globus Medical Excelsius GPS (Globus Medical, Audobon, PA) system uses similar techniques requiring a pre-operative CT, but uses a rigid arm without the need for k-wire placement, and provides real-time feedback (Figure 1.2). One study evaluating the first 54 cases performed using this system demonstrated a 98.3% accuracy with minimal offset from the pre-operative plan and no complications [13]. These platforms are gaining popularity but cost may be a limiting factor to widespread use.
 
SPINAL CORD INJURY TRIALS
There have been two recent clinical trials for acute spinal cord injury (SCI), evaluating the Rho inhibitor VX-210 and Riluzole. The enzyme Rho is activated after SCI during the secondary inflammatory phase. This enzyme can inhibit axonal regeneration and, therefore, an investigational agent VX-210 which inhibits Rho was the focus of a clinical trial of SCI [14]. The initial phase 1/2a safety trial included 48 patients with acute SCI with an American Spinal Injury Association Impairment Scale (AIS) grade A undergoing surgery where a single dose of VX-210 was applied to the dura mater [15]. Initial results were promising with improvement in motor strength in patients with cervical SCI. The phase 2b/3 Spinal Cord Injury Rho Inhibition Investigation (SPRING) trial then investigated the safety and efficacy of VX-210 treatment [14] (Figure 1.3). Unfortunately, the interim analysis failed to demonstrate efficacy and the trial was terminated.
zoom view
Figure 1.2: Intraoperative utilisation of the Globus Medical Excelsius GPS (Globus Medical, Audobon PA) system. Arrows depicting robotic arm assistance with 4-panel interactive user interface for real-time feedback. With permission from Benech CA, et al. (2019)
4
zoom view
Figure 1.3: Depiction of acute spinal cord injury (SCI) treatment using VX-210. (A) Topical administration of VX-210 in a fibrin sealant to the extradural surface of the spinal cord. (B) Time-sensitive gradient levels were measured to assess 1-mg dose of VX-210 penetration in a post-mortem pig model. With permission from Fehlings MG, et al. (2018)
Riluzole, a sodium channel-blocking agent, demonstrated safety and possible efficacy for treatment of acute SCI in a phase I trial, and the subsequent phase IIB/III double-blinded randomised controlled trial [Riluzole in Acute Spinal Cord Injury Study (RISCIS)] is ongoing [16]. Currently, no results are available.
Numerous trials evaluating stem cell treatment for chronic SCI have been completed with significant variability in results [17]. One acute-phase trial used allogenic umbilical cord-derived mesenchymal stem cells (MSCs) within 24 hours of injury and found recovery of two patients from American Spinal Cord Injury Association (ASIA) A to ASIA C [18]. However, there is significant variability in the types of cells, methods, and timing of implantation to make any definitive conclusions at this time.
The use of steroids for acute SCI is still controversial, and popularity today has decreased. However, a systematic review on the use of methylprednisolone sodium succinate for the treatment of acute SCI led to the creation of three suggested guidelines: (1) do not offer steroids to adult SCI patients presenting after 8 hours; (2) offer patients 5presenting within 8 hours of acute SCI steroids as a treatment for 24 hours; and (3) do not offer a 48 hour infusion of steroids [19]. It is important to note that these are “suggestions” only, and are not strong recommendations.
 
SPINAL CORD INJURY: PRECLINICAL
There are numerous preclinical studies evaluating methods of treatment for acute SCI. Electrical stimulation has been evaluated in animal models as a treatment for SCI. In a rat SCI model, epidural electrical stimulation stimulated the Wnt signalling pathway and increased brain-derived neurotrophic factor (BDNF) and fatty-acid amide hydrolase (FAAH), which may help in recovery after SCI [20] (Figures 1.4 and 1.5). Electro-acupuncture also demonstrated benefits in reducing oxidative stress in a rat SCI model [21]. Other preclinical studies have evaluated the role of tumour necrosis factor-α-induced protein 8 (TNFAIP8) in SCI [22], selective agonists of the P2Y purinergic receptor [23], and proanthocyanidins (PACS) to inhibit ferroptosis in SCI and promote recovery [24], as well as ascorbic acid to promote axonal sprouting in SCI [25].
Mesenchymal stem cells have been studied for the treatment of neurodegenerative diseases [26]. The ideal timing of therapeutic treatment for SCI is still unknown.
zoom view
Figure 1.4: Electrical stimulation (ES) use on fatty-acid amide hydrolase (FAAH) expression in a rat model after spinal cord injury (SCI). (A) Immunohistochemical stain of FAAH among different groups. (B) FAAH expression levels among different groups.
6
zoom view
Figure 1.5: Summarisation of molecular and gene pathways involved and the effects of spinal cord injury (SCI) and electrical stimulation (ES). With permission from Ghorbani M, et al (2020) (FAAH, fatty-acid amid hydrolase; BDNF, brain-derived neurotrophic factor).
A rat study attempted to measure the chondroitin sulphate (CS) and dermatan sulphate (DS) levels at different time periods in order to identify the ideal timing for intervention, and found higher levels of DS compared to CS starting at 2 weeks after SCI, which suggests that week 2 after SCI may be ideal [27]. Adipose-derived mesenchymal stem cell (ADSC) transplantation for SCI has been studied in several animal models. In a mouse SCI model, ADSCs were injected into the lesion site immediately after injury and were found to survive at least 28 days. Several pathways were studied resulting in decreases in proinflammatory cytokines and increased neuron survival [28].
 
PREDICTIVE ANALYTICS
Predictive modelling and machine-based learning have been applied to the field of spinal surgery to predict outcomes post-operatively. One such framework called “SpineCloud” used perioperative imaging along with post-operative functional and pain outcomes to try to predict outcomes. By incorporating the preoperative demographics, there was significant improvement in prediction ability [29]. Another study attempted to predict outcomes, surgical parameters, and reoperations for patients undergoing decompression for lumbar stenosis using machine learning. The authors were able to predict patients achieving minimal clinical important difference (MCID) from 51 to 85% in various outcome measures, predict rate of reoperation in 63–69% of cases, predict with 78% accuracy cases that were prolonged surgery, and predict 77% of patients that required an extended hospital stay [30]. Machine learning can also be used to aid in medical decision making using electronic medical records [31]. These are promising 7technologies that may help physicians and patients to better understand peri-operative risks and post-operative outcomes.
 
DISC REPLACEMENT
Motion preservation techniques continue to gain momentum, but the number of fusion procedures still greatly outnumbers non-fusion procedures. Based on data from the NIS database from 2006 to 2013, approximately 132,000 ACDFs are performed each year versus only 1,600 cervical disc arthroplasties (CDAs), but the number of CDAs performed over that time period increased by 190% versus 5.7% for ACDF [32].
Longer follow-up studies are becoming available as well and have shown good results and durability. 10-year outcomes of the single-level Prestige LP cervical disc remained stable compared to the 7-year data, with patient satisfaction above 90% [33]. Additional benefits may be seen with disc replacement with multilevel procedures. The two-level Prestige LP cervical disc at 10 years also demonstrated a higher rate of overall success compared to ACDF (80.4% vs. 62.2%), as well as fewer secondary surgeries at adjacent levels (9.0% vs. 17.9%) [34]. Similarly, in the 7-year follow-up study for the Mobi-C Cervical Disc, the overall success analysis demonstrated clinical superiority of two-level disc replacement versus ACDF, and non-inferiority of single level [35] (Figure 1.6).
A meta-analysis of eleven randomised controlled trials of CDA versus ACDF with at least 4-year follow-up showed no difference in neurological improvement, but significantly greater improvement in Neck Disability Index (NDI) and Short Form 36 Health Survey physical component [36]. The authors also found a lower rate of secondary surgical procedures in the CDA group, but similar rates of adjacent segment degeneration. Another meta-analysis started to find differences of adjacent-level operation at 5 years favouring CDA for single level pathology, which was also evident at 7 years (4.3% vs. 10.8%) [37]. Similar findings were seen with two-level CDA at 7 years for adjacent-level operation (5.1% vs. 10.0%) (Figure 1.7).
A 10-year follow-up study of the Bryan CDA found significantly higher incidence of adjacent level ossification disease (ALOD) after ACDF compared to CDA (68.2% vs. 11.1%, p = 0.0003) but there were no significant differences in NDI, VAS-arm, or neck pain in high- versus low-grade ALOD.
zoom view
Figure 1.6: Overall treatment success of Mobi-C© cervical disc in two-level disc replacement versus anterior cervical discectomy and fusion (ACDF) surgery among 330 patients. TDR, total disc replacement. With permission from Radcliff K, et al (2017).
8
zoom view
Figure 1.7: Data from nine randomised trials comparing rates of adjacent-level reoperation for cervical disc arthroplasty (CDA) with anterior cervical discectomy and fusion (ACDF) in one-level cervical spondylosis. With permission from Badhiwala JH, et al (2020).
This suggests that ALOD is only a radiographic finding which does not affect outcomes [38]. Heterotopic ossification was also assessed at 10 years following Prestige LP cervical disc at the index levels. The authors found a 39% incidence of severe (grade 3 or 4) HO at 10 years, but no differences were found in outcomes compared to those with less severe or no HO (grades 0–2) [39].
 
BIOLOGICS FOR SPINAL FUSION
Biologics to enhance fusion rates continue to be developed. Platelet-rich plasma (PRP) is one augment that has been used extensively to enhance fusion rates; however, there is conflicting evidence on its efficacy. A recent meta-analysis of 11 studies and 741 patients actually found a higher fusion rate in patients treated without PRP, with no significant changes in VAS scores or estimated blood loss [40]. However, another meta-analysis of 14 studies found a higher fusion rate in the studies that used a high-platelet concentration compared to those that used a low concentrate [41]. One prospective randomised study of 50 patients found a significantly higher fusion rate (94% vs. 74%, p = 0.002) in patients undergoing one- or two-level posterolateral fusion (PLF) for lumbar spondylosis, as well as a greater fusion mass and faster time to fusion in those treated with PRP versus not [42]. Another meta-analysis of seven studies with patients undergoing posterior lumbar interbody fusion found no difference in fusion rate with PRP, but a shorter time to union (1.62 months) as well as lower back pain in those treated with PRP [43]. Another meta-analysis of 12 studies found no difference in fusion rate or pain levels with treatment of PRP [44]. There may be variability in the platelet concentration or technique that can explain the contradicting results from many of these studies.9
Recombinant human bone morphogenetic protein-2 (rhBMP-2) continues to be a popular augment for spinal fusion procedures, but there is still concern for potential complications. A retrospective cohort study of 191 patients undergoing transforaminal lumbar interbody fusion (TLIF) showed high fusion rates with or without the use of rhBMP-2 (92.7% vs. 92.3%), with a slightly higher rate of seroma and radiculitis in the rhBMP-2 group [45]. The optimal dosage of rhBMP-2 is still unknown for posterior lumbar procedures. In a systematic review and meta-analysis of 22 articles and 2,729 patients undergoing PLIF or TLIF, the fusion and complication rates were not different between different dosages of rhBMP-2, and the minimally effective dose was found to be as low as 1.28 mg/level [46].
Allogeneic cellular bone grafts have also become more popular with varying degrees of clinical efficacy. One retrospective study from 150 consecutive patients undergoing posterolateral lumbar fusion found a successful fusion rate of 98.7% based on radiographs with Vivigen allograft (Lifenet Health) [47]. Osteocel (Nuvasive, San Diego, CA), Trinity Evolution (Orthofix, Lewisville, TX), and Bio4 (Stryker, Kalamazoo, MI) are allograft tissue products that contain live stem cells and have shown success in several studies [48]. However, the cost associated with these products can be substantial, and further evidence is needed before widespread acceptance.
 
DISC DEGENERATION TREATMENT
Intervertebral disc (IVD) degeneration continues to be a widely studied topic with numerous approaches. IVD degeneration is known to be at least partially due to an increase in cytokines and matrix metalloproteases, which is mediated by the nuclear factor kappa B (NF-kB) pathway. In a study of discarded human lumbar discs and rat discs, the NF-kB inhibitor NEMOE-binding domain peptide was found to reduce interleukin-1β (IL-1β) and matrix metalloprotease levels, increase cell viability, and downregulate IL-6 [49]. This may represent a potential target to prevent and treat disc degeneration.
Mesenchymal stem cells have also been evaluated for the treatment of IVD degeneration, but it is still unclear as what the exact mechanism. One study demonstrated a paracrine effect of MSCs, and not ECM remodelling in a disc degeneration model [50]. Growth factors have also been studied as a potential treatment to prevent or reverse degeneration of discs. The growth differentiation factor (GDF) family has been shown to promote disc regeneration by upregulating healthy cell marker genes in degenerated discs and by MSC induction to nucleus pulposus cells [51].
Autologous PRP has also been studied for chronic discogenic back pain. In one laboratory study, human bone marrow-derived mesenchymal stem cells (hMSCs) with leucocyte-poor PRP, enhanced hMSC proliferation, and hyaluronic acid production compared to leucocyte-rich PRP [52] (Figures 1.8 and 1.9).
 
SPINE REGISTRIES
The American Spine Registry and the North American Spine Society (NASS) Registry have both been established to improve patient outcomes. The American Spine Registry is a collaboration of the American Association of Neurological Surgeons (AANS) and the American Academy of Orthopaedic Surgeons (AAOS), and will incorporate the Quality Outcomes Database Spine Registry.10
zoom view
Figure 1.8: Human mesenchymal stem cell (hMSC) proliferation using normalised absorbance of PrestoBlue 570-nm across 6 days. (LP, leucocyte poor; LR, leucocyte rich; PRP, platelet-rich plasma).
zoom view
Figure 1.9: Hyaluronic acid levels among platelet preparation across 6 days. With permission from Dregalla RC, et al (2020). (LP, leucocyte poor; LR, leucocyte rich, PRP, platelet-rich plasma; hMSC, human mesenchymal stem cell, PR, platelet rich).
The key distinction between the two registries is that the American Spine Registry is procedural based and the NASS Registry is diagnosis based. Both registries will allow providers to compare their results to others within the registry.
 
NORTH AMERICAN SPINE SOCIETY GUIDELINES
The NASS publishes evidenced-based clinical guidelines on topics that are important to clinicians and can be found on their website (https://www.spine.org/Research-Clinical-Care/Quality-Improvement/Clinical-Guidelines). Previous guidelines have included antithrombotic therapies in spine surgery, diagnosis, and treatment of cervical radiculopathy from degenerative disorders, diagnosis, and treatment of degenerative lumbar spine stenosis, diagnosis, and treatment of lumbar disc herniation with radiculopathy, diagnosis, and treatment of degenerative spondylolisthesis, diagnosis, and treatment of adult isthmic spondylolisthesis. The most recent guideline is on the diagnosis and treatment of low back pain. The guidelines address several questions regarding low back pain including the diagnosis, imaging, medical and psychological treatment, physical medicine and rehabilitation, interventional treatment, surgical treatment, and cost utility. Several additional topics are under development including the diagnosis and treatment of neoplastic vertebral fractures in adults, diagnosis and treatment of osteoporotic vertebral compression fractures in adults, and a revision to the anti-thrombotic therapies in spine surgery.11
REFERENCES
  1. Martin BI, Mirza SK, Spina N, et al. Trends in lumbar fusion procedure rates and associated hospital costs for degenerative spinal diseases in the United States, 2004 to 2015. Spine (Phila Pa 1976) 2019; 44:369–376.
  1. Gologorsky Y, Knightly JJ, Chi JH, et al. The nationwide inpatient sample database does not accurately reflect surgical indications for fusion. J Neurosurg Spine 2014; 21:984–993.
  1. Kha ST, Ilyas H, Tanenbaum JE, et al. Trends in lumbar fusion surgery among octogenarians: a nationwide inpatient sample study from 2004 to 2013. Glob Spine J 2018; 8:593–599.
  1. Al Jammal OM, Delavar A, Maguire KR, et al. National trends in the surgical management of lumbar spinal stenosis in adult spinal deformity patients. Spine (Phila Pa 1976) 2019; 44:E1369–E1378.
  1. Kobayashi K, Ando K, Nishida Y, et al. Epidemiological trends in spine surgery over 10 years in a multicenter database. Eur Spine J 2018; 27:1698–1703.
  1. Raad M, Donaldson CJ, El Dafrawy MH, et al. Trends in isolated lumbar spinal stenosis surgery among working US adults aged 40-64 years, 2010-2014. J Neurosurg Spine 2018; 29:169–175.
  1. Raad M, Reidler JS, El Dafrawy MH, et al. US regional variations in rates, outcomes, and costs of spinal arthrodesis for lumbar spinal stenosis in working adults aged 40–65 years. J Neurosurg Spine 2019; 30:83–90.
  1. Liu CY, Zygourakis CC, Yoon S, et al. Trends in utilization and cost of cervical spine surgery using the national inpatient sample database, 2001 to 2013. Spine (Phila Pa 1976) 2017; 42:E906–E913.
  1. Vonck CE, Tanenbaum JE, Smith GA, et al. National trends in demographics and outcomes following cervical fusion for cervical spondylotic myelopathy. Glob Spine J 2018; 8:244–253.
  1. Mok JK, Sheha ED, Samuel AM, et al. Evaluation of current trends in treatment of single-level cervical radiculopathy. Clin Spine Surg 2019; 32:E241–E245.
  1. Fan Y, Du JP, Liu JJ, et al. Accuracy of pedicle screw placement comparing robot-Assisted technology and the free-hand with fluoroscopy-guided method in spine surgery. Medicine (United States) 2018; 97:e10970.
  1. Kim HJ, Jung WI, Chang BS, et al. A prospective, randomized, controlled trial of robot-assisted vs freehand pedicle screw fixation in spine surgery. Int J Med Robot Comput Assist Surg 2017; 97:e10970.
  1. Benech CA, Perez R, Benech F, et al. Navigated robotic assistance results in improved screw accuracy and positive clinical outcomes: an evaluation of the first 54 cases. J Robot Surg 2019; 14:431–437.
  1. Fehlings MG, Kim KD, Aarabi B, et al. Rho inhibitor VX-210 in Acute Traumatic Subaxial Cervical Spinal Cord Injury: Design of the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) Clinical Trial. J Neurotrauma 2018; 35:1049–1056.
  1. Fehlings MG, Theodore N, Harrop J, et al. A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma 2011; 28:787–796.
  1. Fehlings MG, Nakashima H, Nagoshi N, et al. Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): A randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord 2016; 54:8–15.
  1. Yamazaki K, Kawabori M, Seki T, et al. Clinical trials of stem cell treatment for spinal cord injury. Int J Mol Sci 2020; 21:3994.
  1. Xiao Z, Tang F, Zhao Y, et al. Significant Improvement of Acute Complete Spinal Cord Injury Patients Diagnosed by a Combined Criteria Implanted with NeuroRegen Scaffolds and Mesenchymal Stem Cells. Cell Transplant 2018; 27:907–915.
  1. Fehlings MG, Wilson JR, Tetreault LA, et al. A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Use of Methylprednisolone Sodium Succinate. Glob Spine J 2017; 7:203S–211S.
  1. Ghorbani M, Shahabi P, Karimi P, et al. Impacts of epidural electrical stimulation on Wnt signaling, FAAH, and BDNF following thoracic spinal cord injury in rat. J Cell Physiol 2020; 235:9795–9805.
  1. Cheng M, Wu X, Wang F, et al. Electro-Acupuncture Inhibits p66Shc-Mediated Oxidative Stress to Facilitate Functional Recovery After Spinal Cord Injury. J Mol Neurosci 2020; 70:2031–2040.
  1. Xue W, Tan W, Dong L, et al. TNFAIP8 influences the motor function in mice after spinal cord injury (SCI) through meditating inflammation dependent on AKT. Biochem Biophys Res Commun 2020; 528:234–241.
  1. Zhao Z, Hu X, Wu Z, et al. A Selective P2Y Purinergic Receptor Agonist 2-MesADP Enhances Locomotor Recovery after Acute Spinal Cord Injury. Eur Neurol 2020; 83:195–212.
  1. Zhou H, Yin C, Zhang Z, et al. Proanthocyanidin promotes functional recovery of spinal cord injury via inhibiting ferroptosis. J Chem Neuroanat 2020; 107:101807.
  1. 12 Hong JY, Davaa G, Yoo H, et al. Ascorbic acid promotes functional restoration after spinal cord injury partly by epigenetic modulation. Cells 2020; 9:1310.
  1. Reyhani S, Abbaspanah B, Mousavi SH. Umbilical cord-derived mesenchymal stem cells in neurodegenerative disorders: from literature to clinical practice. Regen Med 2020; 15:1561–1578.
  1. Rezaei S, Bakhtiyari S, Assadollahi K, et al. Evaluating chondroitin sulfate and dermatan sulfate expression in glial scar to determine appropriate intervention time in rats. Basic Clin Neurosci 2020; 11:31–40.
  1. Zhou Z, Tian X, Mo B, et al. Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway. Stem Cell Res Ther 2020; 11:212.
  1. De Silva T, Vedula SS, Perdomo-Pantoja A, et al. SpineCloud: image analytics for predictive modeling of spine surgery outcomes. J Med Imaging 2020; 7:031502.
  1. Siccoli A, de Wispelaere MP, Schröder ML, et al. Machine learning-based preoperative predictive analytics for lumbar spinal stenosis. Neurosurg Focus 2019; 46:E5.
  1. Schwartz JT, Gao M, Geng EA, et al. Applications of machine learning using electronic medical records in spine surgery. Neurospine 2019; 16:643–653.
  1. Saifi C, Fein AW, Cazzulino A, et al. Trends in resource utilization and rate of cervical disc arthroplasty and anterior cervical discectomy and fusion throughout the United States from 2006 to 2013. Spine J 2018; 18:1022–1029.
  1. Gornet MF, Burkus JK, Shaffrey ME, et al. Cervical disc arthroplasty: 10-year outcomes of the Prestige LP cervical disc at a single level. J Neurosurg Spine 2019; 31:317–325.
  1. Gornet MF, Lanman TH, Kenneth Burkus J, et al. Two-level cervical disc arthroplasty versus anterior cervical discectomy and fusion: 10-year outcomes of a prospective, randomized investigational device exemption clinical trial. J Neurosurg Spine 2019; Online ahead of print.
  1. Radcliff K, Davis RJ, Hisey MS, et al. Long-term evaluation of cervical disc arthroplasty with the Mobi-C© cervical disc: A randomized, prospective, multicenter clinical trial with seven-year follow-up. Int J Spine Surg 2017; 11:31.
  1. Byvaltsev VA, Stepanov IA, Riew DK. Mid-term to long-term outcomes after total cervical disk arthroplasty compared with anterior diskectomy and fusion. Clin Spine Surg 2020; 33:192–200.
  1. Badhiwala JH, Platt A, Witiw CD, et al. Cervical disc arthroplasty versus anterior cervical discectomy and fusion: a meta-analysis of rates of adjacent-level surgery to 7-year follow-up. J Spine Surg 2020; 6:217–232.
  1. Boody BS, Lee EN, Sasso WR, et al. Functional outcomes associated with adjacent-level ossification disease 10 years after cervical disc arthroplasty or ACDF. Clin Spine Surg 2020; 33:E420–E425.
  1. Gornet MF, Lanman TH, Burkus JK, et al. Occurrence and clinical implications of heterotopic ossification after cervical disc arthroplasty with the Prestige LP Cervical Disc at 2 contiguous levels. J Neurosurg Spine 2020; Online ahead of print.
  1. Yolcu YU, Wahood W, Eissa AT, et al. The impact of platelet-rich plasma on postoperative outcomes after spinal fusion: a systematic review and meta-analysis. J Neurosurg Spine 2020; Online ahead of print.
  1. Manini DR, Shega FD, Guo C, et al. Role of platelet-rich plasma in spinal fusion surgery: systematic review and meta-analysis. Adv Orthop 2020; 2020:8361798.
  1. Kubota G, Kamoda H, Orita S, et al. Platelet-rich plasma enhances bone union in posterolateral lumbar fusion: A prospective randomized controlled trial. Spine J 2019; 19:e34–e40.
  1. Pairuchvej S, Muljadi JA, Arirachakaran A, et al. Efficacy of platelet-rich plasma in posterior lumbar interbody fusion: systematic review and meta-analysis. Eur J Orthop Surg Traumatol 2020; 30:583–593.
  1. Ji-jun H, Hui-hui S, Qing L, et al. Efficacy of using platelet-rich plasma in spinal fusion surgery—a preferred reporting items for systematic reviews and meta-analyses–compliant meta-analysis. World Neurosurg 2020; 30:583–593.
  1. Khan TR, Pearce KR, McAnany SJ, et al. Comparison of transforaminal lumbar interbody fusion outcomes in patients receiving rhBMP-2 versus autograft. Spine J 2018; 18:439–446.
  1. Lytle EJ, Lawless MH, Paik G, et al. The minimally effective dose of bone morphogenetic protein in posterior lumbar interbody fusion: a systematic review and meta-analysis. Spine J. 2020; 20:1286–1304.
  1. Hall JF, McLean JB, Jones SM, et al. Multilevel instrumented posterolateral lumbar spine fusion with an allogeneic cellular bone graft. J Orthop Surg Res 2019; 14:372.
  1. Shah VP, Hsu WK. Stem cells and spinal fusion. Neurosurg Clin N Am 2020; 31:65–72.
  1. Glaeser JD, Salehi K, Kanim LEA, et al. NF-κB inhibitor, NEMO-binding domain peptide attenuates intervertebral disc degeneration. Spine J 2020; 20:1480–1491.
  1. 13 Teixeira GQ, Pereira CL, Ferreira JR, et al. Immunomodulation of human mesenchymal stem/stromal cells in intervertebral disc degeneration insights from a proinflammatory/degenerative ex vivo model. Spine (Phila Pa 1976) 2018; 43:E673–E682.
  1. Hodgkinson T, Shen B, Diwan A, et al. Therapeutic potential of growth differentiation factors in the treatment of degenerative disc diseases. JOR Spine 2019; 2:e1045.
  1. Dregalla RC, Uribe Y, Bodor M. Human mesenchymal stem cells respond differentially to platelet preparations and synthesize hyaluronic acid in nucleus pulposus extracellular matrix. Spine J 2020; 20:1850–1860.