Vertebral Columns, Fall 2019

Vertebral Columns International Society for the Advancement of Spine Surgery

Fall 2019

San Juan Sunset, credit: Quilldancer, Flickr. Cover: San Juan, Playa de Balerma, credit: Antonio Hidalgo. ISASS20 will be at San Juan, Puerto Rico.

In This Issue EDITOR’S NOTE Robotic Spine Surgery: True Necessity or Marketing Gimmick?........... 3 PHARMA CBD in Spine Surgery, Part 1: What is CBD?......................................... 5 MEDICOLEGAL Liability and Litigation in Spine Surgery: What Spine Surgeons Should Know...................................................................................................... 7 NEW TECHNOLOGY Wearables in Spine Surgery....................................................................9

Editor in Chief Kern Singh, MD Editorial Board Peter Derman, MD, MBA Brandon Hirsch, MD Sravisht Iyer, MD Safdar Khan, MD Yu-Po Lee, MD Grant Shifflett, MD Sheeraz Qureshi, MD Publisher Jonny Dover

BIOLOGICS Update on Biologics for Spinal Fusion...................................................11

Vertebral Columns is published quarterly by the International Society for the Advancement of Spine Surgery. © 2019 ISASS. All rights reserved.

Opinions of authors and editors do not necessarily reflect positions taken by the Society.

This publication is available digitally at https://vertebralcolumns.com.

ISSN 2414-6277.

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EDITOR’S NOTE

Robotic Spine Surgery: True Necessity or Marketing Gimmick?

Kern Singh, MD Although robotic surgery has been discussed hypothetically for decades, the applications of robotic spine surgery have just recently begun to accelerate. With a brief reflection on the first applications of robotic surgery in the early 1980s, we can clearly see advances--though many are still coming to terms with feasibility. In its earliest form, surgical robots were prototyped from industrial robots and then transitioned into the medical field. The PUMA 560 was one of these first robotic apparatuses--a surgical arm used to aid in delicate neurosurgery. While early efforts led by NASA, the Ames Research Centre, and Stanford focused on medical “telepresence”, it was the US military that foresaw a role for robotic surgery. The initial vision was to link distant surgeons to injured soldiers on the battlefield via remotely operating robotic platforms.4 Many of these original researchers started private enterprises that began to materialize by the early 2000s.2,7 One such successful project was the da Vinci System, which at present, has become successfully utilized in many surgical subspecialties and implemented at institutions around the globe. Mazor Robotics was the first company to successfully bring a robot for spine surgery to market in the early 2000s.

There are a number of potential advantages to using robotics in spine surgery. Numerous studies have demonstrated the increased accuracy and decreased intraoperative radiation exposure of robotic-assisted pedicle screw placement in comparison to historic freehand placement.1,3,5 Removing surgeon-induced tremors may allow junior surgeons to focus on more technical aspects of the procedure, thereby decreasing an already steep learning curve found in spine surgery--perhaps even more so in minimally invasive spine surgery.

The da Vinci System demonstrated a modification of learning curves for many laparoscopic procedures, which had a positive effect on junior surgeons and their ability to increase surgical volume. The unlimited steadiness offered by a robot could allow tenured surgeons to continue to practice beyond their current expected career timelines.

With an aging population requiring evermore care and increasing number of orthopaedic procedures, a secure workforce of surgeons is necessary.

As promising technology continues to emerge, a primary concern is protecting patient interests against consequences from potentially aggressive and unsubstantiated marketing. Institutional pressures for the latest technology can also result in questionable procurements. The decision to include robotics into one’s practice must be based on

scientific results demonstrating improved safety and outcomes for the desired procedure, and with thorough cost/benefit analysis. The increased initial overhead costs of robotic surgery may pose a burden to interested surgeons. Therefore, it is imperative to balance high margin cases with large volume procedures to help ameliorate operating costs.

The attempt to meet such rigid marketing demands has captivated--now--generations of spine surgery endeavors. Mazor Robotics (Caesarea, Israel) was the first company to develop a surgical robot focused on spine surgery in 2001.

The company released SpineAssist in 2004. Medtronics ultimately acquired Mazor, releasing the Mazor X and the Renaissance. Although numerous robotic systems are in use today, only a limited number focus on spine surgery. Other robot offerings include Globus Medical’s Excelsius GPS, Zimmer biomet’s ROSA, and a new Chinese robot from Tinavi Medical Technology.

Robotic surgery will become a necessity due to (1) the increased accuracy of instrumentation; (2) decreased intraoperative radiation exposure to surgeons, OR staff, and patients; (3) shortening the learning curve and; (4) maximizing spine surgeon career length. As robotic technology evolves, other advantages will materialize. Undoubtedly, robotic surgery will serve as a main-

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stay in many future spine surgery procedures and practices. Our challenge, however, is to eschew this change no faster than makes sense based on demonstrated advantages, and while in keeping our patients at the forefront of our healthcare system.

References 1. Fan Y, Du JP, Liu JJ, Zhang JN, Qiao HH, Liu SC, et al: Accuracy of pedicle screw placement comparing robot-assisted technology and the free-hand with fluoroscopy-guided method in spine surgery: An updated meta-analysis.

Medicine 97:e10970, 2018 2. Felger JE, Wiley Nifong L, Randolph Chitwood W: The Evolution of and Early Experience With Robot-Assisted Mitral Valve Surgery. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques 12:58–63, 2002 Available: http://dx.doi.org/10.1097/00129689200202000-00010.

3. Gao S, Lv Z, Fang H: Robot-assisted and conventional freehand pedicle screw placement: a systematic review and meta-analysis of randomized controlled trials. Eur Spine J 27:921–930, 2018 4. Lane T: A short history of robotic surgery.

Ann R Coll Surg Engl 100:5–7, 2018 5. Molliqaj G, Schatlo B, Alaid A, Solomiichuk V, Rohde V, Schaller K, et al: Accuracy of robot-guided versus freehand fluoroscopy-assisted pedicle screw insertion in thoracolumbar spinal surgery. Neurosurg Focus 42:E14, 2017 6. Prasad S: Applications of Robotics.

Spine 43:2018 Available: https://journals. lww.com/spinejournal/fulltext/10.1097/ BRS.0000000000002557.

7. Satava RM: Surgical robotics: the early chronicles: a personal historical perspective.

Surg Laparosc Endosc Percutan Tech 12:6–16, 2002

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PHARMA

CBD In Spine Surgery, Part 1: What is CBD?

Peter Derman, MD, MBA Cannabis, a genus of flowering plants indigenous to parts of Asia, has been cultivated and used by humans for thousands of years.1 Numerous emotional, psychological, and physical benefits have been attributed to it. Cannabis contains numerous cannabinoids, chemical compounds that interact with the body’s endogenous endocannabinoid system via G protein-coupled cannabinoid receptors located in numerous tissues including the central and peripheral nervous systems, immune tissues, and both osteoplasts and osteoclasts.2–4 Delta 9-tetrahydrocannabinol (THC) is the principal psychoactive constituent of Cannabis. Cannabidiol (CBD), a major non-psychotropic component, has recently made headlines as a natural remedy for a seemingly endless array of ailments including acne, insomnia, post-traumatic stress disorder, inflammatory conditions, anxiety, depression, and even cancer despite a lack of robust data. The mechanism of action for CBD is not fully understood, but it is known to have low-binding affinity to cannabinoid receptors and instead indirectly affects downstream signaling. However, it does demonstrate affinity for binding dopamine, opioid, and serotonin receptors.

CBD use appears to be relatively safe, with studies indicating that it does not induce catalepsy or euphoria, affect gastrointestinal transit, alter physiological parameters (blood pressure, heart rate, and body temperature), or affect psychological or psychomotor functions5. It does not generate withdrawal symptoms and is not believed to be addictive6. Chronic use and doses as high as 1,500 mg/ day have been well tolerated in humans without significant adverse effects. However, CBD has been associated with somnolence, diarrhea, decreased appetite, elevated liver function tests, and decreased fertilization capacity.5,7 CBD acts as a competitive inhibitor of the hepatic cytochrome P450 enzyme and may therefore impair degradation of drugs utilizing this same pathway8. Close International Normalized Ratio (INR) monitoring is therefore advised during initiation and titration of CBD in patients taking warfarin.

CBD exists in a regulatory gray zone. Cannabis varietals with THC content below 0.3% are classified as hemp, while those with higher THC concentrations are considered marijuana.9 The 2018 Farm Bill removed hemp from the list of federally controlled substances.

Epidiolex, an anti-epileptic, is the only CBD-based drug approved by the Food and Drug Administration (FDA). While sale and consumption of hemp-derived CBD is not prohibited by the federal government, CBD cannot otherwise be marketed as a therapeutic or as a

dietary supplement.9 The FDA has sent warning letters over the past several years to firms making health claims relating to their CBD-based products.10 Individual states may have their own laws relating to CBD, and it is currently banned altogether in Idaho, South Dakota, and Nebrasa.9 To further complicate matters, interstate commerce involving CBD-containing products is prohibited, which may impact online purchasing.

Because hemp-derived CBD products may contain small quantities of THC (or even relatively high amounts if there has been THC cross contamination from marijuana-derived products), consumption could result in a positive drug screen11. This risk can be minimized by utilizing reputable vendors and products with a Certificate of Analysis demonstrating that the product contains zero THC. The World Anti-Doping Agency recently removed CBD from its list of banned substances for international competition.12 Given the general public’s growing awareness of CBD and its purported health benefits, physicians are increasingly being asked about it, including in the realm of spine care. It is important for doctors to provide up-to-date, evidence-based recommendations whenever possible. To that end, the spine-related literature on CBD will be reviewed in the next edition of Vertebral Columns. Spoiler alert: Despite some intriguing pre-clinical studies, there is currently insufficient evidence

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to recommend CBD for use in the treatment of spinal pathology.

References 1. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis‐based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;2018(3). doi:10.1002/14651858.CD012182.pub2 2. Maroon J, Bost J. Review of the neurological benefits of phytocannabinoids. Surg Neurol Int. 2018;9:91. doi:10.4103/sni.sni_45_18 3. Napimoga MH, Benatti BB, Lima FO, et al. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int Immunopharmacol. 2009;9(2):216-222. doi:10.1016/j. intimp.2008.11.010

public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-questions-and-answers. Accessed September 1, 2019.

10. Commissioner O of the. Warning Letters and Test Results for Cannabidiol-Related Products. FDA. July 2019. http://www.fda.gov/ news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Accessed September 1, 2019.

11. Gill LL. Can You Take CBD and Pass a Drug Test? Consumer Reports. https://www. consumerreports.org/cbd/can-you-take-cbdand-pass-a-drug-test/. Accessed August 26, 2019.

12. What is Prohibited. World Anti-Doping Agency. https://www.wada-ama.org/en/content/what-is-prohibited/prohibited-in-competition/cannabinoids. Accessed August 26, 2019.

4. Kogan NM, Melamed E, Wasserman E, et al.

Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts. J Bone Miner Res. 2015;30(10):19051913. doi:10.1002/jbmr.2513 5. Bergamaschi MM, Queiroz RHC, Zuardi AW, Crippa JAS. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237-249.

6. Viudez-Martínez A, García-Gutiérrez MS, Medrano-Relinque J, Navarrón CM, Navarrete F, Manzanares J. Cannabidiol does not display drug abuse potential in mice behavior.

Acta Pharmacol Sin. 2019;40(3):358-364. doi:10.1038/s41401-018-0032-8 7. VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ Guide to Cannabidiol and Hemp Oils. Mayo Clinic Proceedings. 2019;0(0). doi:10.1016/j.mayocp.2019.01.003 8. Grayson L, Vines B, Nichol K, Szaflarski JP. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 2017;9:10-11. doi:10.1016/j.ebcr.2017.10.001 9. Commissioner O of the. FDA Regulation of Cannabis and Cannabis-Derived Products: Questions and Answers. FDA. June 2019. http://www.fda.gov/news-events/

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MEDICOLEGAL

Liability and Litigation Related to Spine Surgery: What Spine Surgeons Should Know Brandon Hirsch, MD Malpractice litigation is an often-cited cause of defensive medical practice, increased healthcare costs, and physician dissatisfaction.

A 2011 study of more than 40,000 US physicians found a 7.4% annual incidence of malpractice claims, with significant variation amongst specialties.1 Not surprisingly, neurosurgeons and orthopaedic surgeons were amongst the specialists most often involved in malpractice claims (annual incidence, 19% and 14% respectively). In fact, the study projected that 99% of physicians in “high-risk” specialties would face at least one malpractice claim by age 65.

Medicolegal risk is inherent to spine surgery given its complication profile. Despite this, the topic of liability is rarely discussed during training and many young spine surgeons lack an understanding of malpractice litigation within their specialty. The vast majority of litigation related to spine surgery involves the legal concept of civil liability. Civil liability is established when all of the following elements exist: duty, breach of duty, harm (i.e. injury), and causation.2 Duty generally refers to acting toward fellow citizens with reasonable regard for their interests.

Professional duty is specific to medical malpractice and is present in virtually all cases related to spine surgery. Professional duty can

be thought of as the obligation to provide care that society and other professionals within the field would reasonably expect. Professional duty is established whenever a doctor-patient relationship is formed (as is universally the case for a patient undergoing spine surgery).

A breach of professional duty occurs when a surgeon deviates from the care and judgement that a peer would exercise in an equivalent scenario. This element requires defining the “standard of care,” which involves expert testimony and can vary between jurisdictions. Harm is established when physical injury or death occurs. Harm can also include economic loss assuming it stems from an injury. Causation refers to the fact that the plaintiff must demonstrate that the harm involved in the case occurred as a direct result of the breach of duty.

the post-operative period. Decision making related to workup of these symptoms with advanced imaging is amongst the most challenging aspects of managing patients after spine surgery, particularly early in a surgeon’s career. While being proactive in these scenarios can help avoid delays in diagnosis and treatment of complications, one must balance this against the urge to practice “defensive medicine.”

Ordering imaging studies with the primary goal of protecting oneself against litigation is not advisable as this increases the cost of care and can lead to unnecessary intervention for incidental findings that are not clinically relevant. If possible, seeking the input of colleagues and mentors regarding untoward postoperative events is encouraged, however uncomfortable this might be for the operating surgeon.

Recent study of legal research databases offers some insight into the reasons for litigation related to spine surgery.3,4 Intraoperative, surgically-related complications are cited in 50-60% of cases. As one might expect, cases involving nerve and/or spinal cord injury account for the large majority (85%) of suits involving surgical complications.4 Beyond these intraoperative causes, the next most frequently cited reasons for litigation involve delays in diagnosis (32%) and/or treatment (33%).3 This fact underscores the obvious importance of careful attention to patient complaints and changes in neurologic status during

Another commonly cited reason for malpractice suits in spine surgery is inadequate informed consent.

The prevalence of this complaint varies in the literature. Grauberger et al performed the largest study of the topic, evaluating 233 patient claims over a 25 year period.5 The authors identified allegations of inadequate informed consent in 153 (66%) of cases. Amongst these claims, the most common allegation was related to a failure to explain risks (30%) followed by failure to explain alternative treatment options (10%). Other allegations related to consent accounted for a smaller proportion of cases

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and were related to a discussion of the surgeon’s experience level and use of non-FDA approved devices.

The study further analyzed how cases with a complaint related to informed consent differed from the 80 cases that did not. Interestingly, claims related to informed consent had a significantly lower proportion of severe and permanent injuries and were significantly associated with verdicts in favor of the defense (vs. settlement or plaintiff verdict).

Although somewhat subjective and under-studied in the literature, adequate informed consent must include a discussion of the risks of the procedure and alternatives to the proposed surgery. Surgeons should be directly involved in this discussion rather than delegating to mid-level providers or trainees.

While written documents and multimedia can be helpful during the consent process, they should not be considered a substitute for verbal discussion. Given the prevalence of this type of complaint in liability claims related to spine surgery, it would be beneficial for training to programs to place greater emphasis on teaching this skill as a part of residency and fellowship programs.

Although litigation is more prevalent in spine surgery relative to other specialties, judgements are made in favor of the defendant in most cases (54-75%, depending on the series).3,4,6 Studies by Daniels et al. and Makhni et al. looked in detail at factors associated with case outcomes. Both studies found no differences in outcome based upon surgeon specialty (neurosurgery vs. orthopaedic spine). Cases involving a delay in diagnosis or treatment are significantly more likely to end in a settlement or ruling in favor of the plaintiff. As expected, verdicts in favor of the plaintiff were also 8

significantly more likely in the setting of catastrophic injuries to the patient (i.e. spinal cord injury, anoxic brain injury, or death) vs. non-catastrophic injuries.4 The duration of malpractice litigation related to spine surgery averages 5.3 years. Cases resulting in a defense verdict tend to take longer than those ending in settlement or a plaintiff verdict (5.5 vs. 4.4 years).6 The overwhelming majority of spine surgeons will encounter one or more liability claims over the course of their career. The process of defending a malpractice claim is typically stressful, time consuming, and expensive. Despite this, judgements are made in favor of the surgeon more often than not. Obtaining adequate informed consent and avoiding delays in diagnosis/ treatment of complications is critical in reducing the likelihood of an unfavorable verdict. Further research and education regarding what defines adequate informed consent in spine surgery would be of great benefit to spine surgeons and their patients moving forward.

References 1. Jena AB, Seabury S, Lakdawalla D, et al.

Malpractice risk according to physician specialty. N Engl J Med. Epub ahead of print 2011.

DOI: 10.1056/NEJMsa1012370.

2. Bal BS, Brenner L. Essential Legal Knowledge for the Orthoaedic Surgeon. AAOS Business, Policy, and Practice Management in Orthopaedics Lecture Series. Available at https://www.aaos.org/advocacy/ols/.

3. Agarwal N, Gupta R, Agarwal P, et al. Descriptive analysis of state and federal spine surgery malpractice litigation in the United States.

Spine (Phila Pa 1976). Epub ahead of print 2018. DOI: 10.1097/BRS.0000000000002510.

4. Daniels AH, Ruttiman R, Eltorai AEM, et al.

Malpractice litigation following spine surgery. J Neurosurg Spine 2017;27:470–5.

5. Grauberger J, Kerezoudis P, Choudhry AJ, et al. Allegations of Failure to Obtain Informed

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Consent in Spinal Surgery Medical Malpractice Claims. JAMA Surg 2017;152:e170544.

6. Makhni MC, Park PJ, Jimenez J, et al. The medicolegal landscape of spine surgery: how do surgeons fare? Spine J 2018;18:209–15.

NEW TECHNOLOGY

Wearables in Spine Surgery Sravisht Iyer, MD When you think of Apple, what is the first thing that comes to mind?

For most people – it is likely to be the phone in their pocket. Over just the past 12 years, the iPhone has become an indispensable part of our day to day life; the first thing you reach for in the morning and often the last thing you put down before bed. There is no question that the iPhone has defined Apple’s last decade. The next decade, however, is likely to belong to a different device category: wearables.

In their 2019 third quarter results, Apple reported growth of over 50% in sales of their wearable devices.

This segment – which includes devices like the Apple Watch, AirPods and Beats-branded headphones – represents the fastest growing segment of the company. As we move from swiping our phones to glancing at our wrist and chatting via our AirPods, it is not difficult to imagine a future where much of our day to day attire has a “smart” component. As this transition unfolds, it provides healthcare providers with an unprecedented opportunity: the ability to receive real-time feedback on our patients’ health and recovery.

Apple and Wall Street realize the value of this transformation.

Fortune magazine estimates that Apple could generate as much as $300 billion in revenue from its healthcare services by 2027. While these numbers must, admittedly, be consumed with a healthy dose of

skepticism; healthcare applications form the core value proposition for Apple Watch and its’ competitors. The latest generation of the Apple Watch, for example, already provides real time heart rate monitoring with alarms for tachycardia, bradycardia and certain arrhythmias. What’s more, the Watch’s gyroscope allows for real-time fall detection. The next generation of Watches may include blood pressure and glucose monitoring amongst a bevy of healthcare-centric tools.

driven by patient-reported declines in walking tolerance. To describe the trajectory of recovery following surgery for lumbar spinal stenosis would be tremendously valuable both to spine surgeons and to patients considering surgical intervention.

In many ways, the growth in wearable technology represents an opportunity to add an extra dimension to patient-reported outcomes.

In addition to providing objective data, wearable technology has the advantage of being a passive, remote These capabilities have not gone data collection method. They do unnoticed by the orthopedic comnot require patients to return for munity. In 2018, Apple and Zimmer appointments, complete questionBiomet launched a collaboration naires or answer phone calls. Once to improve the “joint replacement a patient opts-in, the collection, journey.” This collaboration – evaluation and tracking of their centered on an app – is anchored data requires little or no effort. by a clinical study that uses the This enables robust, long-term data continuous data collected by the collection that is not limited by Apple Watch to provide insights selection bias. (Perhaps I am being into patients’ recovery from joint too optimistic because we know evreplacement surgery. By leverageryone will upgrade when the new ing the ubiquity of the iPhone and Watch comes out).

Apple Watch, Apple seeks to enroll as many as 10,000 patients in the There are, of course, significant United States – an effort that would privacy implications as we move put this trial on par with some of toward this new paradigm. It is critthe largest clinical trials in mediical that we remain vigilant about cine. these concerns, and are proactive in enacting appropriate ethical stanIt is not difficult to envision a simi- dards and safeguards. It will also be lar trial in spine surgery. While the important to clearly define which pathology we treat in spine surgery entity (the hospital, the technology is more varied than a typical arthro- company, the individual researchplasty practice, the most common er) “owns” the data and who is procedures we perform (lumbar responsible for enforcing these laminectomy for spinal stenosis safeguards. and/or fusion for degenerative spondylolisthesis) are frequently Existing efforts to use similar Vertebral Columns • Spring 2017

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outcome measures in spine surgery have been woefully limited. The body of evidence in the literature is limited, principally, to a single study with small sample size (38 patients) and patchy data collection (only 7 days at two specific time points).1 Adding data from even the current generation of wearables would represent a substantial step forward.

By following patients from their pre-operative state through their post-operative recovery – from their (likely) initial decline in activity to their eventual improvement - it is easy to envision a “normative” curve for recovery averaged across thousands of patients. The construction of such a curve could result in important cost savings to the health care system. It would be possible, for example, to increase the duration between routine office visits; more frequent visits could be reserved only for patients that deviate from these normative curves (slow recovery) or those who have a change in their trajectory suggesting an acute complication.

The concept of change is an important one. One of the challenges in the current healthcare environment is demonstrating the efficacy of new technologies compared to the existing options. Detractors of minimally invasive spine surgery, for example, will claim that there are no differences in post-operative outcome measures. While they may be true when these outcome measures are sampled at individual time points 6 months and 1 year post-operatively, the trajectory of improvement may be substantially different with minimally invasive procedures. Measuring and quantifying these changes would allow us to more accurately measure the

incremental value of new interventions ranging from the exotic (new implant or technique) to the mundane (post-op physical therapy).

Wearable technologies will undoubtedly become more widely used across various fields of medicine. While a typical spine surgeon sees patients with a variety of complaints, the use of wearable technologies has the potential to significantly enhance our ability to measure the objective value of our interventions and justify incremental advances in technology.

1. Smuck M, Muaremi A, Zheng P, et al. Objective measurement of function following lumbar spinal stenosis decompression reveals improved functional capacity with stagnant real-life physical activity.

Spine J 2018;18:15–21.

BIOLOGICS

Update on Biologics for Spinal Fusion Yu Po Lee, MD

use of DBM as an autograft extender in anterior and posterior spinal Bony fusion is a highly regulated fusions but it has not been shown cellular and molecular event that is to be an effective bone graft subdependent on various host and graft stitute at this point.1 Fresh frozen factors. Iliac crest one graft is the allograft is less commonly used. ideal bone graft because it contains But there are studies, which show osteogenic, osteoinductive, and os- good results with its use. In a study teoconductive elements.1 But there by Urrutia et al., the authors evalis a limited supply of iliac crest uated the efficacy of a fresh frozen bone graft and harvesting iliac crest femoral head as a structural interbone graft has been associated with body graft substitute. The authors significant morbidity. An osteocon- noted a 93.6% fusion rate with the ductive element serves as a scaffold fresh frozen femoral head allograft for bony ingrowth. Osteoinductive without any graft subsidence. So factors induce recruitment and allografts continue to be used as differentiation of osteogenic cells. bone graft extenders. But fresh Osteogenic cells can be turned into frozen allograft may be feasible as a osteoblasts to form bone. The ideal bone graft substitute in some cases. bone graft substitute or extender has one or all of these elements to Synthetics are another alternative promote bone formation. to autograft for spinal fusions.

Examples of more commonly used Allograft, or allogenic bone, is synthetics include beta-tricalcium one of the most commonly used phosphate, hydroxyapatite (HA), autograft alternatives for spinal and calcium sulfate. Synthetic fusions. Allograft is obtained from serve primarily as an osteoconduccadavers and is readily available. tive scaffold. They are most comCortical grafts serve as good struc- monly used in posterolateral spinal tural grafts. Cortical grafts are regfusions. Their use is limited in the ularly used in anterior cervical and anterior spine because of the need lumbar fusions. Cancellous chips to shield them from compressive are also used to augment posterior forces, which can cause them to spinal fusions. Demineralized bone crack. Because they are relatively matrix (DBM) is another cadavinert and only serve as an osteoconeric allograft option. DBM is less ductive scaffold. Because of this, osteoconductive but retains more they cannot be considered as bone osteoinductive properties. DBM is graft substitutes and they are often processed by removal of minerals combined with other grafts which by acid extraction (decalcified), have osteoinductive and osteogenic leaving the extracellular matrix and properties. a mixture of proteins and collagen, and variable amounts of bone mor- Tantalum is a porous metal with phogenic protein (BMP) and bone open-cell structure resembling growth factors. Data supports the cancellous bone with a porosity

between 75% and 85%. It has a low modulus of elasticity similar to endochondral bone. The porous structure encourages bony integration, remodeling, and vascularlization. Tantalum, however, is biologically inert and has limited direct bonding to bone. At this time, there are a few studies evaluating the use of tantalum in cervical fusion. But the data has been mixed. In on study Kasliwal et al, the patients were randomized to tantalum ring with autograft, tantalum alone, or ICBG. The fusion rates at 24 months in the tantalum group was only 44% versus 100% in the iliac crest group.3 However, in another study by King et al., the authors noted a 100% fusion rate at two years in their retrospective review.4 So, more studies are necessary to better understand the use of tantalum as a bone graft substitute.

The bone morphogenic proteins (BMP) are members of the transforming growth factor-beta (TGF-b) superfamily and were first discovered by Urist and colleagues in the 1960s.5 These proteins are osteoinductive by inducing pluripotent mesenchymal stem cells (MSC) to become osteoblasts.

Several clinical studies have examined the efficacy of rhBMPs.6 With scientific advances BMP can now be produced with recombinant gene technology for clinical use.

So BMP can now be produced in mass quantities. BMP was initially studied in anterior lumbar interbody fusions (ALIF) in humans. In a multicenter, prospective randomized controlled trial, fusion

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rates were 94.5% for rhBMP-2 and 88.7% for ICBG at 24 months. So BMP can be used as a bone graft substitute. However, there are concerns regarding cancer risk, radiculitis, ectopic bone formation, and vertebral osteolysis. retrograde ejaculation, seroma/hematoma, and prevertebral swelling. So BMP should be used judiciously and should not be used in patients with existing or a previous history of cancer. Another osteoinductive protein, initially discovered in the 1980s, is BMP-7, also known as osteogenic protein-1 (OP-1). However an early clinical trial failed to show efficacy. In this study by Vaccaro et al., the authors noted a fusion rate of 55% in posterolateral fusions.7 A relatively new bone growth protein is i-Factor. I-Factor is composite bone graft substitute, which contains the P-15 collagen fragment on a hydrogel carrier. In one study, the authors compared i-Factor to local autograft in a cortical ring allograft for anterior cervical fusions.8 The fusion rates for i-Factor in this model was 88.97% versus 85.82% in the autograft group.

In one study evaluating the use of allogenic stems cells in a cervical fusion, the authors noted fusion rates of 87%. Significant research remains and is ongoing utilizing MSC products.

Autologous bone marrow aspirate (BMA) is one potential source of osteoinductive factors and osteogenic cells. BMA added to an osteoconductive matrix potentially contains all three components of bone graft. In a recent human study, eight patients underwent a combined posterolateral fusion and interbody fusion with BMA and demineralized bone matrix.9 The authors reported a 81.3% fusion rate.

3. Kasliwal MK, Baskin DS, Traynelis VC. Failure of porous tantalum cervical interbody fusion devices: two-year results from a prospective, randomized, multicenter clinical study. J Spinal Disord Tech. 2013 Jul;26(5):239-45.

Allogenic MSC-derived are also available for clinical use. These products significantly vary in regard to total MSC concentration, donor age, shelf life, and cell viability.

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In conclusion, many promising technologies are currently in use or under development for improving the outcomes of spinal fusions.

Allograft is still commonly used.

But there are many alternatives available to utilize as bone graft extenders and substitutes. Knowledge about the risks and benefits of each of these products will help the surgeon choose the best bone graft substitute or extender. But more studies are necessary to improve our knowledge of each of these products.

References 1. Morris MT, Tarpada SP, Cho W. Bone graft materials for posterolateral fusion made simple: a systematic review. Eur Spine J. 2018 Aug;27(8):1856-1867.

2. Urrutia J, Molina M. Fresh-frozen femoral head allograft as lumbar interbody graft material allows high fusion rate without subsidence. Orthop Traumatol Surg Res. 2013 Jun;99(4):413-8.

4. King V, Swart A, Winder MJ. Tantalum trabecular metal implants in anterior cervical corpectomy and fusion: 2-year prospective analysis. J Clin Neurosci. 2016 Oct;32:91-4.

5. Urist MR, Dowell TA, Hay PH, Strates BS. Inductive substrates for bone formation. Clin Orthop Relat Res. 1968 Jul-Aug;59:59-96.

6. Burkus JK, Transfeldt EE, Kitchel SH, et al.

Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002 Nov 1;27(21):2396-408.

7. Vaccaro AR, Anderson DG, Patel T, et al.

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