Bone grafting and biologics for spinal fusion in the pediatric population: current understanding and future perspective

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  • 1 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland;
  • | 2 Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia;
  • | 3 Department of Neurological Surgery, University of California, San Francisco, California;
  • | 4 Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona; and
  • | 5 Department of Neurosurgery, Children’s National Hospital, Washington, DC
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Pediatric spinal fusions have been associated with nonunion rates of approximately 25%, putting patients at risk for neurological complications while simultaneously incurring significant costs for revision surgery. In an effort to decrease nonunion rates, various bone grafts and biologics have been developed to increase osseous formation and arthrosis. The current gold-standard bone graft is autologous bone taken from the iliac crest or ribs, but this procedure is associated with significant morbidity and postoperative pain due to an additional graft harvesting procedure. Other bone graft substitutes and biologics include allografts, demineralized bone matrix, bone morphogenetic protein, and bioactive glass. Ultimately, these substitutes have been studied more extensively in the adult population, and there is a paucity of strong evidence for the use of these agents within the pediatric population. In this review, the authors will discuss in detail the characteristics of the various bone graft substitutes, their fusion efficacy, and their safety profile in this subpopulation.

ABBREVIATIONS

AIS = adolescent idiopathic scoliosis; BMP = bone morphogenetic protein; DBM = demineralized bone matrix; NIS = Nationwide Inpatient Sample; OCF = occipitocervical fusion; PCF = posterior cervical fusion; rhBMP-2 = recombinant human BMP-2.

Pediatric spinal fusions have been associated with nonunion rates of approximately 25%, putting patients at risk for neurological complications while simultaneously incurring significant costs for revision surgery. In an effort to decrease nonunion rates, various bone grafts and biologics have been developed to increase osseous formation and arthrosis. The current gold-standard bone graft is autologous bone taken from the iliac crest or ribs, but this procedure is associated with significant morbidity and postoperative pain due to an additional graft harvesting procedure. Other bone graft substitutes and biologics include allografts, demineralized bone matrix, bone morphogenetic protein, and bioactive glass. Ultimately, these substitutes have been studied more extensively in the adult population, and there is a paucity of strong evidence for the use of these agents within the pediatric population. In this review, the authors will discuss in detail the characteristics of the various bone graft substitutes, their fusion efficacy, and their safety profile in this subpopulation.

ABBREVIATIONS

AIS = adolescent idiopathic scoliosis; BMP = bone morphogenetic protein; DBM = demineralized bone matrix; NIS = Nationwide Inpatient Sample; OCF = occipitocervical fusion; PCF = posterior cervical fusion; rhBMP-2 = recombinant human BMP-2.

Spinal fusion remains the gold-standard surgical intervention for the management of spinal conditions caused by degeneration, deformity, infection, or trauma.1–6 Current surgical procedures involve fixation systems complemented by bone grafts or bone graft substitutes in an effort to promote adequate fusion.2 Pediatric spinal corrective surgery is a relatively frequent pediatric procedure, with an estimated 14,264 cases conducted in 2009.7 A majority of pediatric spinal fusions are performed for severe cases of idiopathic scoliosis, neuromuscular scoliosis, spondylolisthesis, and traumatic injuries of the spine.8–11 Though fusion rates have improved significantly over the past 10 years, pseudarthrosis, or nonunion, occurs in approximately 5%–45% of fusions in adult populations.12 In the pediatric population, large studies have not established nonunion rates, though numerous case series have reported nonunion rates ranging between 0% and 33% in pediatric patients.13–19 Nonunion leads to potential neurological complications and the need for repetitive fusion procedures in an attempt to achieve fusion, which can incur significant costs per revision.20 Given the unacceptably high rates of nonunion, a variety of biologics and bone augmentation devices have been developed in an attempt to improve fusion rates.

Bone formation after spinal fusion has been described as occurring through intramembranous and endochondral ossification.21 While autologous bone grafts are the current gold standard, the procedure has significant limitations such as donor site morbidity, limited supply, and imperfect success rate; these limitations have led to the development of different bone graft substitutes and commercial products.12,22 There are a number of key factors that must be weighed when deciding on a bone graft substitute, including the substitute’s osteoconductive, osteoinductive, and osteogenic properties (Fig. 1).2,12 An osteoconductive substitute acts as a scaffold to deliver bone growth factors, while an osteoinductive substitute contains one or more growth factors that are capable of inducing osteogenesis through independent attraction of osteogenic precursor cells. An osteogenic substitute contains osteogenic precursor cells itself and does not rely on the differentiation of precursor cells.2,12,23

FIG. 1.
FIG. 1.

Properties of biologics for pediatric spinal fusion. Representative illustrations of top vertebra (A), intervertebral space containing structural biomaterial (B), bottom vertebra (C), and rigid internal fixation structure (D).

The ideal bone graft substitute is one that mimics the osteoconductive, osteoinductive, and osteogenic properties of autologous bone. A variety of biologics have been developed and used to augment bone formation, including allografts, bone morphogenetic protein (BMP), demineralized bone matrix (DBM), and various ceramic-based agents.2 Despite the lack of strong clinical evidence for bone graft substitutes, there has been an exponential rise in the number of bone graft substitutes in the commercial spine arena, largely contributing to the increasing costs associated with the procedure.22

While these agents have been studied more extensively in the adult population, there is a significant paucity of information regarding their safety and efficacy in the pediatric population.8,20 An important consideration in the pediatric population is the risk of long-term effects, along with weight-, age-, and level-dependent dosing recommendations.15,20 Although there is significant heterogeneity regarding the indications for pediatric spinal fusion, in this review, we will discuss characteristics of the various bone graft substitutes, their fusion efficacy, and their safety profile in this subpopulation.

Autografts in the Pediatric Population

Autologous bone, harvested from the iliac crest or ribs, is the current gold standard in both adult and pediatric populations due to its inherent osteoconductive, osteoinductive, and osteogenic characteristics (Fig. 1).24–26 However, despite its frequent use in practice, few studies and no randomized controlled trials have been conducted in pediatric populations assessing its efficacy. A recent meta-analysis by Reintjes et al. evaluated 539 pediatric patients who underwent posterior cervical fusion (PCF) or occipitocervical fusion (OCF) interventions using autograft.26 The authors demonstrated high rates of fusion in the pediatric population with a 94% overall fusion rate with autologous bone graft, and a 99% fusion rate when using autologous bone in combination with rigid internal fixation. In a retrospective analysis of 2154 pediatric patients with neuromuscular scoliosis, Rumalla et al. identified a significant increase in autograft use from 2002 to 2011 (31.3% and 59.8%, respectively).11 The authors further noted that autograft use led to decreased complications, but a longer length of stay, compared with not using autograft.

Though autografts provide excellent fusion rates, due to the need for an additional graft harvesting procedure, they are not without significant complications that are especially troubling in the pediatric population.11,26 Grafts are frequently harvested in children from either the iliac crest or the ribs. Common complications involve graft site morbidity, increased operation time, postoperative pain, increased infection risk, seroma formation, pelvic fractures, and the risk of peripheral nerve injury.26–28 Graft site morbidity remains one of the most concerning and common complications, with 17%–39% of iliac crest graft patients and 4% of rib graft patients experiencing complications.29–31 In a cohort of 214 pediatric patients, Skaggs et al. identified a perioperative complication rate of 2% following iliac crest bone grafting. Additionally, 24% of the patients experienced pain, with 15% experiencing severe pain interfering with daily activity at the 4-year follow-up.32 These known complications have driven the commercial development of bone graft substitutes that are more attractive for use in the pediatric population. Though bone grafting in the pediatric population is lauded as the best treatment option, larger, more well-designed studies are needed to fully understand the efficacy and complications associated with autografts in this population.

Allografts in the Pediatric Population

Allografts are derived from cadavers and have been commonly used in the past when autologous bone grafts were not available. Key features that make allografts tempting as autograft substitutes are their easy harvest and relative unlimited supply. Limitations, however, center around the risk of disease transfer, decreased mechanical strength, and poor osteogenic abilities (Fig. 1).33,34 Another important consideration when using allografts is the antigenicity of the bone. Frozen allografts have a higher risk of antigenicity compared with freeze-dried bone; however, freeze drying reduces the strength of cortical bone.35 Studies that have compared the integration of allograft bone with that of autograft bone have demonstrated slow integration of the allograft cohort with incomplete vascularization and decreased osteoinduction and osteoconduction.33,36,37 While frequently used in the adult population, relatively few studies have been conducted in the pediatric population.34,38–40

In the 1980s, 2 studies noted the inferiority of allograft bone material in pediatric cervical fusion compared with autografts.41,42 However, in recent years, numerous studies have demonstrated the potential efficacy of allografts in pediatric spinal fusion.26,27,43 Despite these studies, surgeons tend to preferentially choose autografts over allografts for pediatric spinal fusion.26,44 Hood et al. demonstrated a 100% fusion rate following the combined use of allograft with BMP in the C1–2 screw fixation in 2 children.43 In 2017, Murphy et al. demonstrated a fusion rate of 88% following freeze-dried allograft use for subaxial cervical fusion in 18 children.45 In a meta-analysis, Reintjes et al. evaluated 14 studies involving a total of 65 pediatric patients who underwent PCF or OCF using allograft without local autograft.26 There was an overall fusion rate of 80% compared with 94% in the autograft cohort. The fusion rate lessened significantly if allograft was used without rigid internal fixation, with 0% and 36% fusion rates in the OCF and PCF cohorts, respectively. A subgroup analysis for rigid internal fixation revealed a smaller difference between the autograft and allograft cohorts (99% vs 94%), indicating the need for internal rigid fixation regardless of the bone graft material.26,44

A significant amount of the research in this field focuses on the grafted material. However, surgical technique may also play a significant role in the success of the fusion.27,44 A recent study by Iyer et al. demonstrated that using a structural allograft can produce a 100% fusion rate in adolescents. Eighteen pediatric patients (mean age 8.5 ± 4.3 years) underwent OCF with a structural cadaveric tricortical iliac crest allograft and standard rigid internal fixation.27 This cohort demonstrated significant bony healing within 6 months postsurgery and progressive osseous union as the follow-up time increased. While their study was conducted in a small cohort without randomization, Iyer et al. demonstrated the potential of allografts in the pediatric population, with an excellent fusion rate and high safety profile.27 Results reported by Groen et al. supported the importance of surgical technique by demonstrating a 100% fusion rate following OCF using a modified Gallie technique to fuse tightly wired allograft bone blocks.44 There is a relative paucity of information involving the use of allograft alone for pediatric spinal fusion; however, it may be of significant use in cases of minimal autograft availability, which is seen frequently in the pediatric population.

DBM in the Pediatric Population

Developed as a type of allogenic bone substitute, DBM is a decalcified product that is void of mineral products but retains some osteoinductive growth factors, collagen, noncollagen proteins, and varying quantities of cellular debris.40 First implemented in 1965 by Urist, DBM has been used frequently in spine surgeries and has been identified as having both osteoconductive and osteoinductive properties (Fig. 1).33,46 Since then, a number of studies have demonstrated the efficacy of DBM in animal models and adult populations. However, only one clinical series has been conducted in the pediatric population using DBM as the sole graft substitute. Betz et al. retrospectively reviewed 17 patients with adolescent idiopathic scoliosis (AIS) who underwent posterior spinal fusion using DBM only and demonstrated a 100% fusion rate.8 Furthermore, these authors compared the fusion efficacy of DBM alone with that of allograft alone and demonstrated identical fusion rates but a 60% faster fusion rate in the DBM cohort.

DBM has been implemented in a number of other pediatric surgical specialties, including plastic surgery for craniofacial reconstruction and orthopedic surgery.47–50 DBM has demonstrated consistent osseous formation without significant perioperative or long-term complications in the reconstruction of large calvarial defects in children.47 Additionally, it has shown efficacy in a number of pediatric orthopedic procedures such as for the treatment of bone cysts or subtrochanteric femoral nonunion.48,50 Ultimately, there is a severe lack of scientific evidence for the use of DBM in the pediatric population, specifically regarding spinal fusion. Studies examining its efficacy and safety profile are required prior to any widespread use of DBM as a pediatric spinal fusion bone graft substitute.

BMP in the Pediatric Population

BMPs are members of the transforming growth factor–beta family and have been extensively studied for their role in osseous formation. BMP stimulates endochondral ossification by binding to receptors on osteogenic progenitor cells and triggering an intracellular cascade;33 it has shown both osteoinductive and osteogenic properties (Fig. 1). For instance, the osteoinductive properties of recombinant human BMP-2 (rhBMP-2) are due to its ability to act as a chemotactic agent, growth factor, and a differentiation factor.2,7,51 Given the lack of osteoconductive properties within BMP, it cannot be administered as a monotherapy and must be used alongside a bone graft substitute with osteoconductive properties. The unlimited quantity and immediate availability of rhBMP-2 during surgery contribute to the appeal of its use within the pediatric population.52 From a clinical standpoint, a number of studies have examined the efficacy of rhBMP-2 in both adult and pediatric populations, and it gained approval from the US FDA in 2002 for anterior lumbar spine fusion in adults.20 The rate of rhBMP-2 use in the pediatric population for spinal fusion has been estimated to range from 2% to 38%.7,53–56 Although there is no FDA-approved use of rhBMP-2 in the pediatric population, it is often used off label in the treatment of scoliosis or kyphosis; however, it presents significant safety concerns, including bony overgrowth, toxicity, immunogenicity, interaction with exposed dura mater, osteoclastic activation, and carcinogenesis.57

While a number of case series and retrospective studies have examined the prevalence of rhBMP-2 use in the pediatric population for spinal fusion, no high-quality randomized controlled studies have been conducted.7,20,52–54,57 Utilizing the Kids’ Inpatient Database, Dodwell et al. reported an 11% rate of BMP use in pediatric spinal fusion cases nationwide.53 Subsequently, querying the Nationwide Inpatient Sample (NIS), Jain et al. reported the rate of off-label rhBMP-2 use in pediatric spinal fusion to have increased from 2.7% in 2003 to 9.3% in 2009, despite the lack of an FDA-approved indication.54 The odds of BMP use are significantly higher in patients with congenital scoliosis (OR 1.3, p = 0.04), thoracolumbar fractures (OR 2.8, p < 0.01), or spondylolisthesis (OR 5.0, p < 0.01).54 Interestingly, Lam et al. reported decreased frequency of the use of rhBMP-2 in anterior cervical fusion surgery, likely due to the recognized increased risk of dysphagia.7,58 Of note, BMP use has been reported at higher rates in patients with private insurance and at nonteaching institutions.7,54

With regard to its fusion efficacy, the use of BMP has been shown to increase the risk of nonunion compared with the gold-standard autografts.52 In a retrospective cohort of 34 children who underwent either occipitocervical or atlantoaxial fusions with adjunct rhBMP-2, nonunion was seen in 11% of cases after 12 months.52 A retrospective analysis of 13 patients revealed a fusion rate of 85% when supplementing autografts or allografts with 12 mg of rhBMP-2.20 Despite poor reported fusion rates, a recent retrospective study of BMP efficacy for revision cervical spinal fusion in 8 children with Down syndrome reported a 100% fusion rate. However, the high fusion rate following BMP use may be confounded by the use of iliac crest autograft, more rigid construct, and prolonged halo vest use in a majority of the patients. A few BMP-related complications have been noted, with only 1 patient developing a sterile BMP-induced seroma.59 Factors such as age, sex, BMP dose, graft material, number of fused levels, or postoperative orthosis have not been shown to have any association with fusion rate when utilizing rhBMP-2. Additionally, contrary to the common belief that BMP can be cost-prohibitive, Sayama et al. did not find any statistically significant difference in average hospital costs between the two cohorts.52

One of the most significant concerns regarding the use of BMP in children is the perceived increased cancer risk due to the presence of BMP receptors on human tumors and its potential to affect processes regulating cellular division.7,52 In the retrospective NIS analysis evaluating 9538 patients conducted by Lam et al., there were no reported malignancies.7 Sayama et al. conducted a retrospective evaluation of 50 pediatric patients following posterior instrumented spinal fusion using rhBMP-2 and did not find any cases of new malignancy, degeneration, or metastasis of existing tumors during the 2-year follow-up period.57 Apart from malignancy, studies have suggested the safety of rhBMP-2 in the pediatric population, with a low rate of complications attributed to BMP.20,56 However, contrary to the reported minimal complications following BMP use in some studies, serious complications have been reported in the pediatric literature, including wound infections, adjacent-segment kyphosis, osseous overgrowth causing spinal cord compression, dysphagia, seromas, and heterotopic bone development resulting in cervicomedullary compression necessitating reoperation.54,60–64 Recent studies in pediatric orthopedics, not limited to spinal fusion, have noted that BMP-related complications have occurred in 39% of cases.64 Importantly, the long-term toxicities of BMP use in children remain unknown.65

Ultimately, incorporation of BMP results in fusion rates approaching, but still potentially inferior to, those seen with autograft alone.26,45,52 Additionally, retrospective studies have not established an association with improved fusion rates following BMP use, adding doubt regarding the necessity of its application.52 Despite the lack of strong evidence advocating for the use of BMP in the pediatric population, it may be useful to augment fusion rates in younger patients with a lower autograft harvest volume or other factors resulting in poor osteogenesis.45,52 While there are data suggesting the potential efficacy and safety of BMP in pediatric spinal fusion, it should be used carefully. Its potential significant risks must be discussed thoroughly with the patient’s caregivers, given the lack of prospective data and unknown long-term effects.20

Bioactive Glass in the Pediatric Population

Bioactive glasses have been known to be extremely biocompatible and do not evoke an inflammatory response when implanted into humans. Bioactive glass has been reported to upregulate genes crucial for new bone formation such as insulin-like growth factor, vascular endothelial growth factor, and other angiogenic growth factors. Furthermore, it has both osteoconductive and osteoinductive properties (Fig. 1).33,66 Bioactive glass has also shown osteostimulatory effects, with higher rates of osteoblastic activity than seen with hydroxyapatite.67,68 It has also demonstrated antibacterial properties that may reduce the potential of graft bacterial colonization.66,67

Although a number of studies have demonstrated fusion rates of up to 90% with bioactive glass–local autograft mixtures in adult populations, few studies have been done to evaluate the efficacy of bioactive glasses in pediatric spinal fusion.66 In 2008, Ilharreborde et al. retrospectively compared the fusion efficacy of bioactive glass with iliac crest autograft in 88 patients with progressive thoracic AIS.67 They demonstrated a fusion rate of 98% in the bioactive glass cohort and noted a trend toward lower complication rates. Additionally, there was a decreased loss of correction observed postoperatively in the bioactive glass cohort. Notably, however, local autograft was used in all patients regardless of the patient’s primary treatment cohort. Violas et al. demonstrated that local autograft alone was effective in achieving sufficient fusion in patients with AIS, ultimately confounding the effect of bioactive glass shown by Ilharreborde et al.67,69 Similar to Ilharreborde et al., in 2009, Ameri et al. retrospectively compared the fusion efficacy of a bioactive glass–local autograft mixture in 20 AIS patients with a 90% fusion rate.70 No studies have evaluated the fusion efficacy of bioactive glass alone in the pediatric population; however, in the adult population, bioactive glass alone has shown poor fusion rates of 34%.66,71,72 Though there is still a paucity of information supporting the use of bioactive glasses in the pediatric population, the current studies support further research into the safety and efficacy of bioactive glasses in this population. Bioactive glass–local autograft mixtures may be of specific use in the pediatric population in instances in which there are insufficient quantities of autograft to result in arthrodesis.

Discussion

Spinal biologics have been described as the “future of spine surgery;” however, there is a dire need for critical evaluation of these agents in preclinical and clinical settings before they are applied universally to patients.73 An ideal biologic for spinal fusion would be one that retains osteoconductive, osteoinductive, and osteogenic properties that are comparable with those seen in autografts while avoiding the associated morbidity with autografts and their harvest. In an effort to improve fusion rates and assess the safety of various biologics within the pediatric population, the need for well-designed trials is crucial to the progression of the field. Following a review of listed clinical trials through the US National Library of Medicine website, we found that a majority of clinical trials studying pediatric spinal fusion were centered around pain management while none evaluated various biologics in this subpopulation.

As described in this review, there are a number of exciting biologics that have the potential to improve fusion outcomes while simultaneously reducing morbidity and costs associated with spinal fusion in children. At this time, autograft remains the gold-standard bone graft agent due to its superior fusion outcomes and complication rates compared with other bone graft substitutes and biologics.26,32 Allografts have shown excellent fusion rates with the use of modified surgical techniques and represent an autograft substitute with significant potential in the pediatric population.26,27,44,45 The use of BMP is controversial given its unknown safety profile and paucity of data regarding long-term outcomes; ultimately, caution is suggested at this time regarding BMP application in the general pediatric population.7,52,53,56 Furthermore, BMP may be of specific use in augmenting fusion rates in special populations or those with other factors resulting in poor osteogenic ability.45,52 DBM and bioactive glass have shown potential, but few studies have assessed their application in this population.8,54,67,70

Conclusions

As spinal fusion in children becomes increasingly prevalent and surgical technique improves, the need to improve fusion rates through the use of biologics will likely accelerate. While the reliable autograft is extremely efficacious in producing high fusion rates, the morbidity of the associated procedure is not ideal, specifically in this vulnerable population. There are a number of smaller studies that have examined the safety profiles of several bone graft substitutes, but no large-scale studies have been conducted to date. However, evidence has suggested the potential efficacy of these biologics, particularly when used in appropriate populations. As a result of the experimental nature of these substitutes, short-term and long-term risks must be discussed extensively with the patient’s caregivers. Prior to the widespread use of bone grafting substitutes in the pediatric population, the efficacy, side effect profile, dosing, and long-term safety data of these agents must be evaluated thoroughly. The increasing rates of bone graft substitute use in the pediatric population for spinal fusion despite the lack of this information indicates a pressing need for additional trials evaluating these biologics in this vulnerable population.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ampie, Letchuman. Acquisition of data: Letchuman. Analysis and interpretation of data: Ampie, Letchuman. Drafting the article: Ampie, Letchuman. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ampie.

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    • Export Citation
  • 39

    Samartzis D, Shen FH, Matthews DK, et al. Comparison of allograft to autograft in multilevel anterior cervical discectomy and fusion with rigid plate fixation. Spine J. 2003;3(6):451459.

    • Search Google Scholar
    • Export Citation
  • 40

    Zhang H, Yang L, Yang XG, et al. Demineralized bone matrix carriers and their clinical applications: an overview. Orthop Surg. 2019;11(5):725737.

    • Search Google Scholar
    • Export Citation
  • 41

    Koop SE, Winter RB, Lonstein JE. The surgical treatment of instability of the upper part of the cervical spine in children and adolescents. J Bone Joint Surg Am. 1984;66(3):403411.

    • Search Google Scholar
    • Export Citation
  • 42

    Stabler CL, Eismont FJ, Brown MD, et al. Failure of posterior cervical fusions using cadaveric bone graft in children. J Bone Joint Surg Am. 1985;67(3):371375.

    • Search Google Scholar
    • Export Citation
  • 43

    Hood B, Hamilton DK, Smith JS, et al. The use of allograft and recombinant human bone morphogenetic protein for instrumented atlantoaxial fusions. World Neurosurg. 2014;82(6):13691373.

    • Search Google Scholar
    • Export Citation
  • 44

    Groen JL, Peul WC, Pondaag W. Fusion rates support wired allograft combined with instrumented craniocervical fixation in the paediatric population. Acta Neurochir (Wien). 2020;162(5):985991.

    • Search Google Scholar
    • Export Citation
  • 45

    Murphy RF, Glotzbecker MP, Hresko MT, Hedequist D. Allograft bone use in pediatric subaxial cervical spine fusions. J Pediatr Orthop. 2017;37(2):e140e144.

    • Search Google Scholar
    • Export Citation
  • 46

    Urist MR. Bone: formation by autoinduction. Science. 1965;150(3698):893899.

  • 47

    Chao MT, Jiang S, Smith D, et al. Demineralized bone matrix and resorbable mesh bilaminate cranioplasty: a novel method for reconstruction of large-scale defects in the pediatric calvaria. Plast Reconstr Surg. 2009;123(3):976982.

    • Search Google Scholar
    • Export Citation
  • 48

    Cortes LE, Triana M, Vallejo F, et al. Adult proximal humerus locking plate for the treatment of a pediatric subtrochanteric femoral nonunion: a case report. J Orthop Trauma. 2011;25(7):e63e67.

    • Search Google Scholar
    • Export Citation
  • 49

    Dvoracek LA, Lee JY, Ayyash A, et al. Demineralized bone matrix and resorbable mesh bilaminate cranioplasty is ineffective for secondary reconstruction of large pediatric cranial defects. Plast Reconstr Surg. 2020;145(1):137e141e.

    • Search Google Scholar
    • Export Citation
  • 50

    Hass HJ, Krause H, Kroker S, et al. Bone formation using human demineralised bone matrix (Grafton) for the treatment of bone cysts in children. Eur J Pediatr Surg. 2007;17(1):4549.

    • Search Google Scholar
    • Export Citation
  • 51

    Subach BR, Haid RW, Rodts GE, Kaiser MG. Bone morphogenetic protein in spinal fusion: overview and clinical update. Neurosurg Focus. 2001;10(4):E3.

    • Search Google Scholar
    • Export Citation
  • 52

    Sayama C, Hadley C, Monaco GN, et al. The efficacy of routine use of recombinant human bone morphogenetic protein-2 in occipitocervical and atlantoaxial fusions of the pediatric spine: a minimum of 12 months’ follow-up with computed tomography. J Neurosurg Pediatr. 2015;16(1):1420.

    • Search Google Scholar
    • Export Citation
  • 53

    Dodwell E, Snyder B, Wright J. Off-label use of bone morphogenetic proteins in pediatric spinal arthrodesis. JAMA. 2012;308(14):14291432.

    • Search Google Scholar
    • Export Citation
  • 54

    Jain A, Kebaish KM, Sponseller PD. Factors associated with use of bone morphogenetic protein during pediatric spinal fusion surgery: an analysis of 4817 patients. J Bone Joint Surg Am. 2013;95(14):12651270.

    • Search Google Scholar
    • Export Citation
  • 55

    Kiely PD, Cunningham ME. Off-label rhBMP-2 use in pediatric spine deformity surgery. Letter. J Neurosurg Pediatr. 2015;15(5):545546.

  • 56

    Rocque BG, Kelly MP, Miller JH, et al. Bone morphogenetic protein-associated complications in pediatric spinal fusion in the early postoperative period: an analysis of 4658 patients and review of the literature. J Neurosurg Pediatr. 2014;14(6):635643.

    • Search Google Scholar
    • Export Citation
  • 57

    Sayama C, Willsey M, Chintagumpala M, et al. Routine use of recombinant human bone morphogenetic protein-2 in posterior fusions of the pediatric spine and incidence of cancer. J Neurosurg Pediatr. 2015;16(1):413.

    • Search Google Scholar
    • Export Citation
  • 58

    Liu FY, Yang DL, Huang WZ, et al. Risk factors for dysphagia after anterior cervical spine surgery: a meta-analysis. Medicine (Baltimore). 2017;96(10):e6267.

    • Search Google Scholar
    • Export Citation
  • 59

    Cohen LL, Yang BW, O’Neill NP, et al. Use of recombinant human bone morphogenetic protein for revision cervical spine fusion in children with Down syndrome: a case series. J Neurosurg Pediatr. 2020;25(5):535539.

    • Search Google Scholar
    • Export Citation
  • 60

    Abd-El-Barr MM, Cox JB, Antonucci MU, et al. Recombinant human bone morphogenetic protein-2 as an adjunct for spine fusion in a pediatric population. Pediatr Neurosurg. 2011;47(4):266271.

    • Search Google Scholar
    • Export Citation
  • 61

    Fahim DK, Whitehead WE, Curry DJ, et al. Routine use of recombinant human bone morphogenetic protein-2 in posterior fusions of the pediatric spine: safety profile and efficacy in the early postoperative period. Neurosurgery. 2010;67(5):11951204.

    • Search Google Scholar
    • Export Citation
  • 62

    Lindley TE, Dahdaleh NS, Menezes AH, Abode-Iyamah KO. Complications associated with recombinant human bone morphogenetic protein use in pediatric craniocervical arthrodesis. J Neurosurg Pediatr. 2011;7(5):468474.

    • Search Google Scholar
    • Export Citation
  • 63

    Huang M, Briceño V, Lam SK, et al. Survey of the effectiveness of internet information on patient education for bone morphogenetic protein. World Neurosurg. 2016;87:613618.

    • Search Google Scholar
    • Export Citation
  • 64

    Stiel N, Hissnauer TN, Rupprecht M, et al. Evaluation of complications associated with off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in pediatric orthopaedics. J Mater Sci Mater Med. 2016;27(12):184.

    • Search Google Scholar
    • Export Citation
  • 65

    Molinari RW, Kerr C, Kerr D. Bone morphogenetic protein in pediatric spine fusion surgery. J Spine Surg. 2016;2(1):912.

  • 66

    Cottrill E, Pennington Z, Lankipalle N, et al. The effect of bioactive glasses on spinal fusion: A cross-disciplinary systematic review and meta-analysis of the preclinical and clinical data. J Clin Neurosci. 2020;78:3446.

    • Search Google Scholar
    • Export Citation
  • 67

    Ilharreborde B, Morel E, Fitoussi F, et al. Bioactive glass as a bone substitute for spinal fusion in adolescent idiopathic scoliosis: a comparative study with iliac crest autograft. J Pediatr Orthop. 2008;28(3):347351.

    • Search Google Scholar
    • Export Citation
  • 68

    Vrouwenvelder WC, Groot CG, de Groot K. Histological and biochemical evaluation of osteoblasts cultured on bioactive glass, hydroxylapatite, titanium alloy, and stainless steel. J Biomed Mater Res. 1993;27(4):465475.

    • Search Google Scholar
    • Export Citation
  • 69

    Violas P, Chapuis M, Bracq H. Local autograft bone in the surgical management of adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2004;29(2):189192.

    • Search Google Scholar
    • Export Citation
  • 70

    Ameri E, Behtash H, Mobini B, et al. Bioactive glass versus autogenous iliac crest bone graft in adolescent idiopathic scoliosis surgery. Acta Med Iran. 2009;47(1):4145.

    • Search Google Scholar
    • Export Citation
  • 71

    Acharya NK, Kumar RJ, Varma HK, Menon VK. Hydroxyapatite-bioactive glass ceramic composite as stand-alone graft substitute for posterolateral fusion of lumbar spine: a prospective, matched, and controlled study. J Spinal Disord Tech. 2008;21(2):106111.

    • Search Google Scholar
    • Export Citation
  • 72

    Frantzén J, Rantakokko J, Aro HT, et al. Instrumented spondylodesis in degenerative spondylolisthesis with bioactive glass and autologous bone: a prospective 11-year follow-up. J Spinal Disord Tech. 2011;24(7):455461.

    • Search Google Scholar
    • Export Citation
  • 73

    An HS, Phillips FM. Editorial. Are spine biologics the future in spinal surgery? Spine J. 2005;5(6)(suppl):207S208S.

Contributor Notes

Correspondence Leonel Ampie: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. leonel.ampie@nih.gov.

INCLUDE WHEN CITING DOI: 10.3171/2021.3.FOCUS2148.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • View in gallery

    Properties of biologics for pediatric spinal fusion. Representative illustrations of top vertebra (A), intervertebral space containing structural biomaterial (B), bottom vertebra (C), and rigid internal fixation structure (D).

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    Haque A, Price AV, Sklar FH, et al. Screw fixation of the upper cervical spine in the pediatric population. Clinical article. J Neurosurg Pediatr. 2009;3(6):529533.

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    Reintjes SL, Amankwah EK, Rodriguez LF, et al. Allograft versus autograft for pediatric posterior cervical and occipito-cervical fusion: a systematic review of factors affecting fusion rates. J Neurosurg Pediatr. 2016;17(2):187202.

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    Iyer RR, Tuite GF, Meoded A, et al. A modified technique for occipitocervical fusion using compressed iliac crest allograft results in a high rate of fusion in the pediatric population. World Neurosurg. 2017;107:342350.

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    Sawin PD, Traynelis VC, Menezes AH. A comparative analysis of fusion rates and donor-site morbidity for autogeneic rib and iliac crest bone grafts in posterior cervical fusions. J Neurosurg. 1998;88(2):255265.

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    Sheha ED, Meredith DS, Shifflett GD, et al. Postoperative pain following posterior iliac crest bone graft harvesting in spine surgery: a prospective, randomized trial. Spine J. 2018;18(6):986992.

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  • 31

    Zhang YH, Shen L, Shao J, et al. Structural allograft versus autograft for instrumented atlantoaxial fusions in pediatric patients: radiologic and clinical outcomes in series of 32 patients. World Neurosurg. 2017;105:549556.

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  • 32

    Skaggs DL, Samuelson MA, Hale JM, et al. Complications of posterior iliac crest bone grafting in spine surgery in children. Spine (Phila Pa 1976). 2000;25(18):24002402.

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    Gupta A, Kukkar N, Sharif K, et al. Bone graft substitutes for spine fusion: a brief review. World J Orthop. 2015;6(6):449456.

  • 34

    Tuchman A, Brodke DS, Youssef JA, et al. Autograft versus allograft for cervical spinal fusion: a systematic review. Global Spine J. 2017;7(1):5970.

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  • 35

    Gross RH. The use of bone grafts and bone graft substitutes in pediatric orthopaedics: an overview. J Pediatr Orthop. 2012;32(1):100105.

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  • 36

    Ehrler DM, Vaccaro AR. The use of allograft bone in lumbar spine surgery. Clin Orthop Relat Res. 2000;(371):3845.

  • 37

    Malloy KM, Hilibrand AS. Autograft versus allograft in degenerative cervical disease. Clin Orthop Relat Res. 2002;(394):2738.

  • 38

    Samartzis D, Shen FH, Goldberg EJ, An HS. Is autograft the gold standard in achieving radiographic fusion in one-level anterior cervical discectomy and fusion with rigid anterior plate fixation? Spine (Phila Pa 1976). 2005;30(15):17561761.

    • Search Google Scholar
    • Export Citation
  • 39

    Samartzis D, Shen FH, Matthews DK, et al. Comparison of allograft to autograft in multilevel anterior cervical discectomy and fusion with rigid plate fixation. Spine J. 2003;3(6):451459.

    • Search Google Scholar
    • Export Citation
  • 40

    Zhang H, Yang L, Yang XG, et al. Demineralized bone matrix carriers and their clinical applications: an overview. Orthop Surg. 2019;11(5):725737.

    • Search Google Scholar
    • Export Citation
  • 41

    Koop SE, Winter RB, Lonstein JE. The surgical treatment of instability of the upper part of the cervical spine in children and adolescents. J Bone Joint Surg Am. 1984;66(3):403411.

    • Search Google Scholar
    • Export Citation
  • 42

    Stabler CL, Eismont FJ, Brown MD, et al. Failure of posterior cervical fusions using cadaveric bone graft in children. J Bone Joint Surg Am. 1985;67(3):371375.

    • Search Google Scholar
    • Export Citation
  • 43

    Hood B, Hamilton DK, Smith JS, et al. The use of allograft and recombinant human bone morphogenetic protein for instrumented atlantoaxial fusions. World Neurosurg. 2014;82(6):13691373.

    • Search Google Scholar
    • Export Citation
  • 44

    Groen JL, Peul WC, Pondaag W. Fusion rates support wired allograft combined with instrumented craniocervical fixation in the paediatric population. Acta Neurochir (Wien). 2020;162(5):985991.

    • Search Google Scholar
    • Export Citation
  • 45

    Murphy RF, Glotzbecker MP, Hresko MT, Hedequist D. Allograft bone use in pediatric subaxial cervical spine fusions. J Pediatr Orthop. 2017;37(2):e140e144.

    • Search Google Scholar
    • Export Citation
  • 46

    Urist MR. Bone: formation by autoinduction. Science. 1965;150(3698):893899.

  • 47

    Chao MT, Jiang S, Smith D, et al. Demineralized bone matrix and resorbable mesh bilaminate cranioplasty: a novel method for reconstruction of large-scale defects in the pediatric calvaria. Plast Reconstr Surg. 2009;123(3):976982.

    • Search Google Scholar
    • Export Citation
  • 48

    Cortes LE, Triana M, Vallejo F, et al. Adult proximal humerus locking plate for the treatment of a pediatric subtrochanteric femoral nonunion: a case report. J Orthop Trauma. 2011;25(7):e63e67.

    • Search Google Scholar
    • Export Citation
  • 49

    Dvoracek LA, Lee JY, Ayyash A, et al. Demineralized bone matrix and resorbable mesh bilaminate cranioplasty is ineffective for secondary reconstruction of large pediatric cranial defects. Plast Reconstr Surg. 2020;145(1):137e141e.

    • Search Google Scholar
    • Export Citation
  • 50

    Hass HJ, Krause H, Kroker S, et al. Bone formation using human demineralised bone matrix (Grafton) for the treatment of bone cysts in children. Eur J Pediatr Surg. 2007;17(1):4549.

    • Search Google Scholar
    • Export Citation
  • 51

    Subach BR, Haid RW, Rodts GE, Kaiser MG. Bone morphogenetic protein in spinal fusion: overview and clinical update. Neurosurg Focus. 2001;10(4):E3.

    • Search Google Scholar
    • Export Citation
  • 52

    Sayama C, Hadley C, Monaco GN, et al. The efficacy of routine use of recombinant human bone morphogenetic protein-2 in occipitocervical and atlantoaxial fusions of the pediatric spine: a minimum of 12 months’ follow-up with computed tomography. J Neurosurg Pediatr. 2015;16(1):1420.

    • Search Google Scholar
    • Export Citation
  • 53

    Dodwell E, Snyder B, Wright J. Off-label use of bone morphogenetic proteins in pediatric spinal arthrodesis. JAMA. 2012;308(14):14291432.

    • Search Google Scholar
    • Export Citation
  • 54

    Jain A, Kebaish KM, Sponseller PD. Factors associated with use of bone morphogenetic protein during pediatric spinal fusion surgery: an analysis of 4817 patients. J Bone Joint Surg Am. 2013;95(14):12651270.

    • Search Google Scholar
    • Export Citation
  • 55

    Kiely PD, Cunningham ME. Off-label rhBMP-2 use in pediatric spine deformity surgery. Letter. J Neurosurg Pediatr. 2015;15(5):545546.

  • 56

    Rocque BG, Kelly MP, Miller JH, et al. Bone morphogenetic protein-associated complications in pediatric spinal fusion in the early postoperative period: an analysis of 4658 patients and review of the literature. J Neurosurg Pediatr. 2014;14(6):635643.

    • Search Google Scholar
    • Export Citation
  • 57

    Sayama C, Willsey M, Chintagumpala M, et al. Routine use of recombinant human bone morphogenetic protein-2 in posterior fusions of the pediatric spine and incidence of cancer. J Neurosurg Pediatr. 2015;16(1):413.

    • Search Google Scholar
    • Export Citation
  • 58

    Liu FY, Yang DL, Huang WZ, et al. Risk factors for dysphagia after anterior cervical spine surgery: a meta-analysis. Medicine (Baltimore). 2017;96(10):e6267.

    • Search Google Scholar
    • Export Citation
  • 59

    Cohen LL, Yang BW, O’Neill NP, et al. Use of recombinant human bone morphogenetic protein for revision cervical spine fusion in children with Down syndrome: a case series. J Neurosurg Pediatr. 2020;25(5):535539.

    • Search Google Scholar
    • Export Citation
  • 60

    Abd-El-Barr MM, Cox JB, Antonucci MU, et al. Recombinant human bone morphogenetic protein-2 as an adjunct for spine fusion in a pediatric population. Pediatr Neurosurg. 2011;47(4):266271.

    • Search Google Scholar
    • Export Citation
  • 61

    Fahim DK, Whitehead WE, Curry DJ, et al. Routine use of recombinant human bone morphogenetic protein-2 in posterior fusions of the pediatric spine: safety profile and efficacy in the early postoperative period. Neurosurgery. 2010;67(5):11951204.

    • Search Google Scholar
    • Export Citation
  • 62

    Lindley TE, Dahdaleh NS, Menezes AH, Abode-Iyamah KO. Complications associated with recombinant human bone morphogenetic protein use in pediatric craniocervical arthrodesis. J Neurosurg Pediatr. 2011;7(5):468474.

    • Search Google Scholar
    • Export Citation
  • 63

    Huang M, Briceño V, Lam SK, et al. Survey of the effectiveness of internet information on patient education for bone morphogenetic protein. World Neurosurg. 2016;87:613618.

    • Search Google Scholar
    • Export Citation
  • 64

    Stiel N, Hissnauer TN, Rupprecht M, et al. Evaluation of complications associated with off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in pediatric orthopaedics. J Mater Sci Mater Med. 2016;27(12):184.

    • Search Google Scholar
    • Export Citation
  • 65

    Molinari RW, Kerr C, Kerr D. Bone morphogenetic protein in pediatric spine fusion surgery. J Spine Surg. 2016;2(1):912.

  • 66

    Cottrill E, Pennington Z, Lankipalle N, et al. The effect of bioactive glasses on spinal fusion: A cross-disciplinary systematic review and meta-analysis of the preclinical and clinical data. J Clin Neurosci. 2020;78:3446.

    • Search Google Scholar
    • Export Citation
  • 67

    Ilharreborde B, Morel E, Fitoussi F, et al. Bioactive glass as a bone substitute for spinal fusion in adolescent idiopathic scoliosis: a comparative study with iliac crest autograft. J Pediatr Orthop. 2008;28(3):347351.

    • Search Google Scholar
    • Export Citation
  • 68

    Vrouwenvelder WC, Groot CG, de Groot K. Histological and biochemical evaluation of osteoblasts cultured on bioactive glass, hydroxylapatite, titanium alloy, and stainless steel. J Biomed Mater Res. 1993;27(4):465475.

    • Search Google Scholar
    • Export Citation
  • 69

    Violas P, Chapuis M, Bracq H. Local autograft bone in the surgical management of adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2004;29(2):189192.

    • Search Google Scholar
    • Export Citation
  • 70

    Ameri E, Behtash H, Mobini B, et al. Bioactive glass versus autogenous iliac crest bone graft in adolescent idiopathic scoliosis surgery. Acta Med Iran. 2009;47(1):4145.

    • Search Google Scholar
    • Export Citation
  • 71

    Acharya NK, Kumar RJ, Varma HK, Menon VK. Hydroxyapatite-bioactive glass ceramic composite as stand-alone graft substitute for posterolateral fusion of lumbar spine: a prospective, matched, and controlled study. J Spinal Disord Tech. 2008;21(2):106111.

    • Search Google Scholar
    • Export Citation
  • 72

    Frantzén J, Rantakokko J, Aro HT, et al. Instrumented spondylodesis in degenerative spondylolisthesis with bioactive glass and autologous bone: a prospective 11-year follow-up. J Spinal Disord Tech. 2011;24(7):455461.

    • Search Google Scholar
    • Export Citation
  • 73

    An HS, Phillips FM. Editorial. Are spine biologics the future in spinal surgery? Spine J. 2005;5(6)(suppl):207S208S.

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