Instructional Course Lecture
The Need for Structural Allograft Biomechanical Guidelines Abstract Satoshi Kawaguchi, MD Robert A. Hart, MD
From Oregon Health & Science University, Portland, OR (Dr. Kawaguchi and Dr. Hart). Dr. Hart or an immediate family member has received royalties from DePuy and SeaSpine; is a member of a speakers’ bureau or has made paid presentations on behalf of DePuy and Medtronic; serves as a paid consultant to or is an employee of DePuy and Medtronic; has stock or stock options held in Spine Connect; has received research or institutional support from DePuy; and serves as a board member, owner, officer, or committee member of the American Academy of Orthopaedic Surgeons, American Orthopaedic Association, Cervical Spine Research Society, International Spine Study Group, Lumbar Spine Research Society, North American Spine Society, Oregon Association of Orthopaedic Surgeons, and Scoliosis Research Society. Neither Dr. Kawaguchi nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article. J Am Acad Orthop Surg 2015;23: 119-125 http://dx.doi.org/10.5435/ JAAOS-D-14-00263 Copyright 2015 by the American Academy of Orthopaedic Surgeons.
Because of their osteoconductive properties, structural bone allografts retain a theoretic advantage in biologic performance compared with artificial interbody fusion devices and endoprostheses. Present regulations have addressed the risks of disease transmission and tissue contamination, but comparatively few guidelines exist regarding donor eligibility and bone processing issues with a potential effect on the mechanical integrity of structural allograft bone. The lack of guidelines appears to have led to variation among allograft providers in terms of processing and donor screening regarding issues with recognized mechanical effects. Given the relative lack of data on which to base reasonable screening standards, we undertook basic biomechanical evaluation of one source of structural bone allograft, the femoral ring. Of our tested parameters, the minimum and maximum cortical wall thicknesses of femoral ring allograft were most strongly correlated with the axial compressive load to failure of the graft, suggesting that cortical wall thickness may be a useful screening tool for compressive resistance expected from fresh cortical bone allograft. Development of further biomechanical and clinical data to direct standard development appears warranted.
S
urgical implantation of structural allograft bone continues to increase despite advances in modern alternatives to allograft, including spine interbody fusion devices and peripheral joint endoprostheses. Although allograft bone historically has been prepared in bulk form with limited anatomic modifications, modern tissue processing includes preparations of amalgams of allograft bone tissue of specific shapes and sizes to suit specific surgical needs. Oversight of the allograft processing and delivery industry has been managed by the US FDA as well as through voluntary participation with the American Association of Tissue Banks (AATB). Guidelines for allograft bone products have primarily focused on
avoiding the transmission of neoplastic and infectious disease. Few guidelines exist regarding donor eligibility and bone processing methods with an emphasis on the mechanical integrity of structural allograft bone, thus raising concern for uniformity and reliability in the biomechanical performance of structural bone allografts. Here, we discuss our clinical experience and review American tissue bank practices with regard to screening donors and processing structural bone allograft. These issues are further evaluated with biomechanical data evaluating factors important to the mechanical performance of cortical femoral shaft allograft. Further efforts to assess the importance of these parameters on clinical outcomes, as well
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
119
The Need for Structural Allograft Biomechanical Guidelines
Figure 1
Increase in structural allograft bone transplant procedures performed in the United States per year from 1990 to 2004 (left y-axis) and the increase in tissue donors per year from 1994 to 2006 (right y-axis). (Adapted with permission from Jurgensmeier D, Hart R: Variability in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine [Phila Pa 1976] 2010;35[15]:E702-E707.)
as the development and adoption of biomechanical performance standards for structural allograft, may be warranted.
Structural Bone Allograft in Orthopaedic Surgery The use of structural bone allograft is a long-established surgical technique utilized for interbody spinal fusion1,2 as well as for reconstruction of defects of the long bones.3,4 Despite recent advances in modern alternatives to structural bone allografts, including prosthetic interbody devices for spinal fusion and larger endoprostheses for limb and pelvic reconstruction, structural bone allograft implantation has continually increased in the United States since the late 1990s5 (Figure 1). Compared with artificial interbody fusion devices and endoprostheses, structural bone allografts retain an advantage in biologic performance because of their osteoconductive
120
properties. Also, they are cost effective and provide easier radiologic assessment of bony fusion than do metal or plastic implants.6-8 However, the mechanical performance of structural bone allografts may be a disadvantage, made potentially worse by the negative effects of tissue processing and the less predictable effects of fatigue and postoperative remodeling on the strength of the graft. Although fracture of structural allografts following segmental grafting of various long bone defects has been well documented, with a reported incidence of 14% to 29% in recent literature,9-11 graft fracture following spinal fusion is a rare event.2 Incidence of graft fracture is reportedly zero to 2.7% following multilevel cervical corpectomy and fibular allograft fusion.12-15 Bone resorption resulting from creeping substitution16-18 and immune response17,19 has been implicated in some cases. Despite such low incidence of allograft bone fracture following spine surgery, we experienced two
consecutive cases within 3 months of delayed fractures of anterior fibular strut allografts following combined three-level cervical corpectomy and posterior instrumented fusion20 (Figures 2 and 3). These two patients’ allografts had been harvested from the same donor, a 69-year-old woman. The occurrence of this rare complication in two patients who shared the same donor suggested to us that the grafts may have been structurally inadequate for the intended clinical use. At the time, the tissue bank involved did not use donor age or osteoporosis as exclusion criteria for structural allograft donation. The occurrence of these fractures led us to question how allograft providers operate donor and tissue screening of structural allograft bone, especially with respect to variables that may influence mechanical strength of the graft.
Current Regulation of Allograft Bone Screening The FDA began regulatory oversight of the recovery and processing of human cadaver tissues in 1993, following reports of serious disease transmission from allograft tissues.21-23 Since then, regulation of the human allograft supply with respect to infection control and disease transmission has continued to expand as further pathogens have been identified and effective screening tests have been developed. In addition to the FDA oversight, the allograft tissue industry is selfregulated through voluntary membership in the AATB. The AATB was established in 1976 and currently has 100 member organizations, accounting for 90% of human allograft tissue used clinically in the United States. Current regulations have done much to address risks of disease transmission and tissue contamination. However, comparatively few guidelines exist
Journal of the American Academy of Orthopaedic Surgeons
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Satoshi Kawaguchi, MD, and Robert A. Hart, MD
regarding donor eligibility and bone processing issues with a potential effect on the mechanical integrity of structural allograft bone. Given this relative lack of guidelines from the FDA and the AATB, current practice with respect to these issues within the allograft industry has not been known.
Figure 2
Current Practices of Allograft Providers To assess current practices among allograft providers with regard to screening and processing and the structural assessment of allograft bones, we developed a questionnairebased survey.5 At the time of the survey, 45 AATB member tissue banks were involved to some degree in procuring or processing structural allograft bone. Of these, 16 organizations participated in tissue processing and the sale of allograft bone. Our questionnaire regarding tissue bank practices having potential impact on mechanical integrity of allograft bone was circulated to all 16 AATB-accredited tissue banks involved in processing structural allograft bone. Of the 16 AATB-accredited tissue banks, 14 responded to the questionnaire (Table 1). Forty-three percent of banks (6 of 14) reported no upper age restriction for structural allograft donors, or they accepted donors up to the age of 80 or 85 years, representing 15% of the total number of structural allograft bone donors (2,860 of 18,712) reported. The remaining eight banks reported upper age limits ranging from 55 to 75 years. Three banks reported differing age limits for male and female donors. The average upper age limits were 68.6 years for men and 66.8 for women. Eighty-six percent of banks (12 of 14) considered chronic steroid exposure to be an exclusion criterion, representing 86% of the total structural
A, Lateral view radiograph demonstrating apparent healing of the exterior graft at 6 months after surgery. B, Sagittal CT image of the cervical spine showing fracture of the allograft. (Adapted with permission from Jones J, Yoo J, Hart R: Delayed fracture of fibular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine [Phila Pa 1976] 31[17]: E595-E599, 200.)
allograft bone donors (15,912 of 18,712) reported. One hundred percent of banks (14 of 14) considered rheumatoid arthritis and ankylosing spondylitis to be exclusion criteria, representing 100% of total structural allograft bone donors (18,712 of 18,712) reported. Seven percent of banks (1 of 14) used a history of tobacco use or prior hysterectomy or oophorectomy for nonmalignant diagnosis to be exclusion criteria, representing 7% of total donors (1,400 of 18,712) reported. Fifty percent of banks (7 of 14) reported a prior diagnosis of osteoporosis to be an exclusion criterion, representing 55% of total donors (10,222 of 18,712) reported. Forty-three percent of banks (6 of 14) reported that history of prior use of diphosphonate medications was exclusionary, representing 62% of total donors (11,662 of 18,712) reported. Sixty-four percent of banks (9 of 14) reported using a minimum cortical wall thickness for structural
allograft prepared from long bones, representing 81% of the structural allograft bone supply (15,110 of 18,712). No bank reported using dual-energy x-ray absorptiometry (DEXA) scans as screening for potential donors or tissue. These findings indicate wide variation in tissue banks’ approaches to issues potentially affecting mechanical integrity of structural allograft bone. This contrasts with presumably consistent compliance with screening and processing requirements designed to avoid disease transmission and tissue contamination. Although those considerations must remain primary in ensuring safety of the allograft bone supply, issues of mechanical bone integrity would also seem to be important from the standpoint of quality control, given the increasing use of structural allograft in load-bearing applications. Biomechanical and clinical studies to determine which factors are most relevant to structural allograft mechanical
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
121
The Need for Structural Allograft Biomechanical Guidelines
Figure 3
A, Lateral radiograph demonstrating apparent healing of graft. B, Lateral radiograph of the cervical spine demonstrating fracture of the allograft and fracture of posterior instrumentation. C, Axial CT of the cervical spine demonstrating fracture of the allograft. (Adapted with permission from Jones J, Yoo J, Hart R: Delayed fracture of fibular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine [Phila Pa 1976] 31[17]:E595-E599, 200.)
Table 1 Tissue Banks’ Response to Survey Questions Regarding Donor Exclusion Criteria for Structural Bone Allograft
Criterion Age limit Chronic steroid exposure Rheumatoid arthritis/ankylosing spondylitis Tobacco use Hysterectomy/oophorectomy Diagnosis of osteoporosis History of osteoporosis medication
No. of Tissue Banks Employing Parameter in Screening Structural Bone Allograft Donors (%)
No. of Structural Allograft Bone Donors Affected (%)
8/14 (57) 12/14 (86) 14/14 (100)
15,852/18,712 (85) 15,912/18,712 (85) 18,712/18,712 (100)
1/14 (7) 1/14 (7) 7/14 (50) 6/14 (43)
1,400/18,712 (7) 1,400/18,712 (7) 10,222/18,712 (55) 11,662/18,712 (62)
Adapted with permission from Jurgensmeier D, Hart R: Variability in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine (Phila Pa 1976) 2010;35(15):E702-E707.
properties and clinical success seem warranted to determine whether further standards for donor and tissue acceptance are appropriate. Given the relative lack of data on which to base reasonable screening standards, we undertook basic biomechanical evaluation of one source of structural bone allograft.
122
Biomechanical Performance of Femoral Ring Allograft To determine which factors most strongly affect the mechanical strength of structural allograft bone, multiple donor and graft variables were assessed for their impact on compressive load
resistance of femoral ring allograft.24 Fresh-frozen human femurs from 34 cadaver donors were each sectioned into ten 20-mm thick specimens. Bone mineral density (BMD), as measured by DEXA scans of the proximal femur; donor age; and graft dimensions were recorded for each specimen. We ultimately tested a total
Journal of the American Academy of Orthopaedic Surgeons
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Satoshi Kawaguchi, MD, and Robert A. Hart, MD
Figure 4
Scatter plots indicating the compressive load to failure as function of bone mineral density (A), sex-specific age (B), minimum (C) and maximum (D) cortical wall thicknesses, and minimum (E) and maximum (F) outer ring diameters. (Adapted with permission from Hart RA, Daniels AH, Bahney T, Tesar J, Sales JR, Bay B: Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. J Orthop Res 2011;29 [12]:1840-1845.)
of 327 specimens under quasi-static axial compression. Linear regression models assessed load to failure as a function of BMD, sex-specific donor age, minimum/maximum cortical wall
thickness, and minimum/maximum outer ring diameter. As shown in Figure 4, correlations between minimum and maximum cortical wall thickness and load to
failure were statistically significant (r = 0.73, P , 0.001, and r = 0.74, P , 0.001, respectively). BMD showed a weaker negative correlation with load to failure (r = 20.11,
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
123
The Need for Structural Allograft Biomechanical Guidelines
Table 2 Load Threshold Statistics for the Sample Population (327) Specimens 3.4 kN Load Multipliera 1· 2· 3· 4· 5· 10· 20·
Load Threshold (kN)
Predicted Min Wall Thickness (mm)
Number of Samples Above Threshold (%)
3.4 6.8 10.2 13.6 17.0 34.0 68.0
1.38 1.87 2.40 2.93 3.46 6.09 11.35
306/327 (93.6) 302/327 (92.4) 281/327 (85.9) 268/327 (82.0) 229/327 (70.0) 43/327 (13.1) 0/327 (0.0)
a Load multiplier = multiples of expected physiologic load of 3.4 kN. Seventy percent of harvested specimens resisted five times this expected load. Adapted with permission from Hart RA, Daniels AH, Bahney T, Tesar J, Sales JR, Bay B: Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. J Orthop Res 2011;29(12):1840-1845.
P = 0.05). Correlations between load to failure and minimum and maximum outer ring diameter and age (r = 0.06, P = 0.31) were not significant. Of the tested parameters, the minimum and maximum cortical wall thicknesses of femoral ring allograft were the most strongly correlated with the axial compressive load to failure of the graft. These findings suggest that cortical wall thickness may be a useful screening tool for compressive resistance expected from fresh cortical bone allograft. It is important to note that remodeling and fatigue during healing may further reduce the strength of an allograft spacer. Thus, an ideal interbody device should withstand a substantially higher force level than the anticipated clinical load at the time of implantation. Knowing the appropriate maximum load to failure potentially affects suitability of the implant. For example, while 70% of specimens supported up to five times estimated clinical loading, only 13% of specimens supported 10 times these expected loads (Table 2). We extended these results with a further nonlinear analysis of the predictive strength of the various parameters.25 This analysis showed that BMD and age are so weakly
124
correlated with strength that they may be safely excluded from consideration as a screening parameter for allograft bone strength. It is critical to acknowledge that optimizing load to failure of femoral ring allografts may not optimize their clinical performance. For example, thicker-walled grafts might limit space available for osteogenic material within the ring with a concomitant negative impact on fusion rates. Alternatively, a thicker wall may limit slight subsidence of the graft into vertebral end plates, again with a potential negative impact on fusion rates. Further efforts to determine the importance of various parameters on clinical outcomes would represent the benchmark for data. In the meantime, however, the basic biomechanical data described above are useful to consider as an initial basis for rational screening approaches to potential allograft bone donation.
for structural allograft bone are currently in place. As a result of this lack of standardization, practices among tissue processors and suppliers remain variable within the United States. Development of further biomechanical and clinical data to direct standard development appears warranted. In the meantime, surgeons should discuss with their allograft providers their individual approach to these issues.
References Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 7 is a level I study. References 1-4, 6, 8-17, 19, and 21 are level III studies. References 20 and 23 are level IV studies. References printed in bold type are those published within the past 5 years. 1. Buttermann GR, Glazer PA, Bradford DS: The use of bone allografts in the spine. Clin Orthop Relat Res 1996;324:75-85. 2. Singh K, DeWald CJ, Hammerberg KW, DeWald RL: Long structural allografts in the treatment of anterior spinal column defects. Clin Orthop Relat Res 2002;394: 121-129. 3. Mankin HJ, Fogelson FS, Thrasher AZ, Jaffer F: Massive resection and allograft transplantation in the treatment of malignant bone tumors. N Engl J Med 1976;294(23):1247-1255. 4. Muscolo DL, Ayerza MA, AponteTinao LA: Massive allograft use in orthopedic oncology. Orthop Clin North Am 2006;37(1):65-74. 5. Jurgensmeier D, Hart R: Variability in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine (Phila Pa 1976) 2010;35(15): E702-E707.
Conclusions and Summary
6. Kleinstueck FS, Hu SS, Bradford DS: Use of allograft femoral rings for spinal deformity in adults. Clin Orthop Relat Res 2002;394: 84-91.
Use of structural allograft bone in spine fusion and other orthopaedic surgical applications continues to increase. Unlike artificial implants, no biomechanical performance standards
7. McKenna PJ, Freeman BJ, Mulholland RC, Grevitt MP, Webb JK, Mehdian SH: A prospective, randomised controlled trial of femoral ring allograft versus a titanium cage in circumferential lumbar spinal fusion with minimum 2-year clinical results. Eur Spine J 2005;14(8):727-737.
Journal of the American Academy of Orthopaedic Surgeons
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Satoshi Kawaguchi, MD, and Robert A. Hart, MD 8. Miller LE, Block JE: Safety and effectiveness of bone allografts in anterior cervical discectomy and fusion surgery. Spine (Phila Pa 1976) 2011;36(24): 2045-2050. 9. Aponte-Tinao LA, Ayerza MA, Muscolo DL, Farfalli GL: Should fractures in massive intercalary bone allografts of the lower limb be treated with ORIF or with a new allograft? Clin Orthop Relat Res 2014;May 3:e-Pub ahead of print 10. Bus MP, Dijkstra PD, van de Sande MA, et al: Intercalary allograft reconstructions following resection of primary bone tumors: A nationwide multicenter study. J Bone Joint Surg Am 2014;96(4):e26. 11. Frisoni T, Cevolani L, Giorgini A, Dozza B, Donati DM: Factors affecting outcome of massive intercalary bone allografts in the treatment of tumours of the femur. J Bone Joint Surg Br 2012;94(6):836-841. 12. Grossman W, Peppelman WC, Baum JA, Kraus DR: The use of freeze-dried fibular allograft in anterior cervical fusion. Spine (Phila Pa 1976) 1992;17(5): 565-569. 13. Macdonald RL, Fehlings MG, Tator CH, et al: Multilevel anterior cervical corpectomy and fibular allograft fusion for
cervical myelopathy. J Neurosurg 1997;86 (6):990-997. 14. Martin GJ Jr, Haid RW Jr, MacMillan M, Rodts GE Jr, Berkman R: Anterior cervical discectomy with freeze-dried fibula allograft: Overview of 317 cases and literature review. Spine (Phila Pa 1976) 1999;24(9):852-858. 15. Mayr MT, Subach BR, Comey CH, Rodts GE, Haid RW Jr: Cervical spinal stenosis: Outcome after anterior corpectomy, allograft reconstruction, and instrumentation. J Neurosurg 2002;96 (1, suppl):10-16.
20. Jones J, Yoo J, Hart R: Delayed fracture of fibular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine (Phila Pa 1976) 2006;31(17): E595-E599. 21. Mroz TE, Joyce MJ, Lieberman IH, Steinmetz MP, Benzel EC, Wang JC: The use of allograft bone in spine surgery: Is it safe? Spine J 2009;9(4):303-308. 22. Mroz TE, Joyce MJ, Steinmetz MP, Lieberman IH, Wang JC: Musculoskeletal allograft risks and recalls in the United States. J Am Acad Orthop Surg 2008;16 (10):559-565.
16. Enneking WF, Campanacci DA: Retrieved human allografts: A clinicopathological study. J Bone Joint Surg Am 2001;83(7): 971-986.
23. Simonds RJ, Holmberg SD, Hurwitz RL, et al: Transmission of human immunodeficiency virus type 1 from a seronegative organ and tissue donor. N Engl J Med 1992;326(11):726-732.
17. Goldberg VM, Stevenson S: Natural history of autografts and allografts. Clin Orthop Relat Res 1987;225:7-16.
24.
Hart RA, Daniels AH, Bahney T, Tesar J, Sales JR, Bay B: Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. J Orthop Res 2011;29(12): 1840-1845.
25.
Krishnamoorthy B, Bay BK, Hart R: Bone mineral density and donor age are not predictive of femoral ring allograft bone mechanical strength. J Orthop Res 2014;32 (10):1271-1276.
18. Wheeler DL, Enneking WF: Allograft bone decreases in strength in vivo over time. Clin Orthop Relat Res 2005;435: 36-42. 19. Stevenson S, Shaffer JW, Goldberg VM: The humoral response to vascular and nonvascular allografts of bone. Clin Orthop Relat Res 1996;326:86-95.
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
125
The Need for Structural Allograft Biomechanical Guidelines Abstract Satoshi Kawaguchi, MD Robert A. Hart, MD
From Oregon Health & Science University, Portland, OR (Dr. Kawaguchi and Dr. Hart). Dr. Hart or an immediate family member has received royalties from DePuy and SeaSpine; is a member of a speakers’ bureau or has made paid presentations on behalf of DePuy and Medtronic; serves as a paid consultant to or is an employee of DePuy and Medtronic; has stock or stock options held in Spine Connect; has received research or institutional support from DePuy; and serves as a board member, owner, officer, or committee member of the American Academy of Orthopaedic Surgeons, American Orthopaedic Association, Cervical Spine Research Society, International Spine Study Group, Lumbar Spine Research Society, North American Spine Society, Oregon Association of Orthopaedic Surgeons, and Scoliosis Research Society. Neither Dr. Kawaguchi nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article. J Am Acad Orthop Surg 2015;23: 119-125 http://dx.doi.org/10.5435/ JAAOS-D-14-00263 Copyright 2015 by the American Academy of Orthopaedic Surgeons.
Because of their osteoconductive properties, structural bone allografts retain a theoretic advantage in biologic performance compared with artificial interbody fusion devices and endoprostheses. Present regulations have addressed the risks of disease transmission and tissue contamination, but comparatively few guidelines exist regarding donor eligibility and bone processing issues with a potential effect on the mechanical integrity of structural allograft bone. The lack of guidelines appears to have led to variation among allograft providers in terms of processing and donor screening regarding issues with recognized mechanical effects. Given the relative lack of data on which to base reasonable screening standards, we undertook basic biomechanical evaluation of one source of structural bone allograft, the femoral ring. Of our tested parameters, the minimum and maximum cortical wall thicknesses of femoral ring allograft were most strongly correlated with the axial compressive load to failure of the graft, suggesting that cortical wall thickness may be a useful screening tool for compressive resistance expected from fresh cortical bone allograft. Development of further biomechanical and clinical data to direct standard development appears warranted.
S
urgical implantation of structural allograft bone continues to increase despite advances in modern alternatives to allograft, including spine interbody fusion devices and peripheral joint endoprostheses. Although allograft bone historically has been prepared in bulk form with limited anatomic modifications, modern tissue processing includes preparations of amalgams of allograft bone tissue of specific shapes and sizes to suit specific surgical needs. Oversight of the allograft processing and delivery industry has been managed by the US FDA as well as through voluntary participation with the American Association of Tissue Banks (AATB). Guidelines for allograft bone products have primarily focused on
avoiding the transmission of neoplastic and infectious disease. Few guidelines exist regarding donor eligibility and bone processing methods with an emphasis on the mechanical integrity of structural allograft bone, thus raising concern for uniformity and reliability in the biomechanical performance of structural bone allografts. Here, we discuss our clinical experience and review American tissue bank practices with regard to screening donors and processing structural bone allograft. These issues are further evaluated with biomechanical data evaluating factors important to the mechanical performance of cortical femoral shaft allograft. Further efforts to assess the importance of these parameters on clinical outcomes, as well
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
119
The Need for Structural Allograft Biomechanical Guidelines
Figure 1
Increase in structural allograft bone transplant procedures performed in the United States per year from 1990 to 2004 (left y-axis) and the increase in tissue donors per year from 1994 to 2006 (right y-axis). (Adapted with permission from Jurgensmeier D, Hart R: Variability in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine [Phila Pa 1976] 2010;35[15]:E702-E707.)
as the development and adoption of biomechanical performance standards for structural allograft, may be warranted.
Structural Bone Allograft in Orthopaedic Surgery The use of structural bone allograft is a long-established surgical technique utilized for interbody spinal fusion1,2 as well as for reconstruction of defects of the long bones.3,4 Despite recent advances in modern alternatives to structural bone allografts, including prosthetic interbody devices for spinal fusion and larger endoprostheses for limb and pelvic reconstruction, structural bone allograft implantation has continually increased in the United States since the late 1990s5 (Figure 1). Compared with artificial interbody fusion devices and endoprostheses, structural bone allografts retain an advantage in biologic performance because of their osteoconductive
120
properties. Also, they are cost effective and provide easier radiologic assessment of bony fusion than do metal or plastic implants.6-8 However, the mechanical performance of structural bone allografts may be a disadvantage, made potentially worse by the negative effects of tissue processing and the less predictable effects of fatigue and postoperative remodeling on the strength of the graft. Although fracture of structural allografts following segmental grafting of various long bone defects has been well documented, with a reported incidence of 14% to 29% in recent literature,9-11 graft fracture following spinal fusion is a rare event.2 Incidence of graft fracture is reportedly zero to 2.7% following multilevel cervical corpectomy and fibular allograft fusion.12-15 Bone resorption resulting from creeping substitution16-18 and immune response17,19 has been implicated in some cases. Despite such low incidence of allograft bone fracture following spine surgery, we experienced two
consecutive cases within 3 months of delayed fractures of anterior fibular strut allografts following combined three-level cervical corpectomy and posterior instrumented fusion20 (Figures 2 and 3). These two patients’ allografts had been harvested from the same donor, a 69-year-old woman. The occurrence of this rare complication in two patients who shared the same donor suggested to us that the grafts may have been structurally inadequate for the intended clinical use. At the time, the tissue bank involved did not use donor age or osteoporosis as exclusion criteria for structural allograft donation. The occurrence of these fractures led us to question how allograft providers operate donor and tissue screening of structural allograft bone, especially with respect to variables that may influence mechanical strength of the graft.
Current Regulation of Allograft Bone Screening The FDA began regulatory oversight of the recovery and processing of human cadaver tissues in 1993, following reports of serious disease transmission from allograft tissues.21-23 Since then, regulation of the human allograft supply with respect to infection control and disease transmission has continued to expand as further pathogens have been identified and effective screening tests have been developed. In addition to the FDA oversight, the allograft tissue industry is selfregulated through voluntary membership in the AATB. The AATB was established in 1976 and currently has 100 member organizations, accounting for 90% of human allograft tissue used clinically in the United States. Current regulations have done much to address risks of disease transmission and tissue contamination. However, comparatively few guidelines exist
Journal of the American Academy of Orthopaedic Surgeons
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Satoshi Kawaguchi, MD, and Robert A. Hart, MD
regarding donor eligibility and bone processing issues with a potential effect on the mechanical integrity of structural allograft bone. Given this relative lack of guidelines from the FDA and the AATB, current practice with respect to these issues within the allograft industry has not been known.
Figure 2
Current Practices of Allograft Providers To assess current practices among allograft providers with regard to screening and processing and the structural assessment of allograft bones, we developed a questionnairebased survey.5 At the time of the survey, 45 AATB member tissue banks were involved to some degree in procuring or processing structural allograft bone. Of these, 16 organizations participated in tissue processing and the sale of allograft bone. Our questionnaire regarding tissue bank practices having potential impact on mechanical integrity of allograft bone was circulated to all 16 AATB-accredited tissue banks involved in processing structural allograft bone. Of the 16 AATB-accredited tissue banks, 14 responded to the questionnaire (Table 1). Forty-three percent of banks (6 of 14) reported no upper age restriction for structural allograft donors, or they accepted donors up to the age of 80 or 85 years, representing 15% of the total number of structural allograft bone donors (2,860 of 18,712) reported. The remaining eight banks reported upper age limits ranging from 55 to 75 years. Three banks reported differing age limits for male and female donors. The average upper age limits were 68.6 years for men and 66.8 for women. Eighty-six percent of banks (12 of 14) considered chronic steroid exposure to be an exclusion criterion, representing 86% of the total structural
A, Lateral view radiograph demonstrating apparent healing of the exterior graft at 6 months after surgery. B, Sagittal CT image of the cervical spine showing fracture of the allograft. (Adapted with permission from Jones J, Yoo J, Hart R: Delayed fracture of fibular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine [Phila Pa 1976] 31[17]: E595-E599, 200.)
allograft bone donors (15,912 of 18,712) reported. One hundred percent of banks (14 of 14) considered rheumatoid arthritis and ankylosing spondylitis to be exclusion criteria, representing 100% of total structural allograft bone donors (18,712 of 18,712) reported. Seven percent of banks (1 of 14) used a history of tobacco use or prior hysterectomy or oophorectomy for nonmalignant diagnosis to be exclusion criteria, representing 7% of total donors (1,400 of 18,712) reported. Fifty percent of banks (7 of 14) reported a prior diagnosis of osteoporosis to be an exclusion criterion, representing 55% of total donors (10,222 of 18,712) reported. Forty-three percent of banks (6 of 14) reported that history of prior use of diphosphonate medications was exclusionary, representing 62% of total donors (11,662 of 18,712) reported. Sixty-four percent of banks (9 of 14) reported using a minimum cortical wall thickness for structural
allograft prepared from long bones, representing 81% of the structural allograft bone supply (15,110 of 18,712). No bank reported using dual-energy x-ray absorptiometry (DEXA) scans as screening for potential donors or tissue. These findings indicate wide variation in tissue banks’ approaches to issues potentially affecting mechanical integrity of structural allograft bone. This contrasts with presumably consistent compliance with screening and processing requirements designed to avoid disease transmission and tissue contamination. Although those considerations must remain primary in ensuring safety of the allograft bone supply, issues of mechanical bone integrity would also seem to be important from the standpoint of quality control, given the increasing use of structural allograft in load-bearing applications. Biomechanical and clinical studies to determine which factors are most relevant to structural allograft mechanical
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
121
The Need for Structural Allograft Biomechanical Guidelines
Figure 3
A, Lateral radiograph demonstrating apparent healing of graft. B, Lateral radiograph of the cervical spine demonstrating fracture of the allograft and fracture of posterior instrumentation. C, Axial CT of the cervical spine demonstrating fracture of the allograft. (Adapted with permission from Jones J, Yoo J, Hart R: Delayed fracture of fibular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine [Phila Pa 1976] 31[17]:E595-E599, 200.)
Table 1 Tissue Banks’ Response to Survey Questions Regarding Donor Exclusion Criteria for Structural Bone Allograft
Criterion Age limit Chronic steroid exposure Rheumatoid arthritis/ankylosing spondylitis Tobacco use Hysterectomy/oophorectomy Diagnosis of osteoporosis History of osteoporosis medication
No. of Tissue Banks Employing Parameter in Screening Structural Bone Allograft Donors (%)
No. of Structural Allograft Bone Donors Affected (%)
8/14 (57) 12/14 (86) 14/14 (100)
15,852/18,712 (85) 15,912/18,712 (85) 18,712/18,712 (100)
1/14 (7) 1/14 (7) 7/14 (50) 6/14 (43)
1,400/18,712 (7) 1,400/18,712 (7) 10,222/18,712 (55) 11,662/18,712 (62)
Adapted with permission from Jurgensmeier D, Hart R: Variability in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine (Phila Pa 1976) 2010;35(15):E702-E707.
properties and clinical success seem warranted to determine whether further standards for donor and tissue acceptance are appropriate. Given the relative lack of data on which to base reasonable screening standards, we undertook basic biomechanical evaluation of one source of structural bone allograft.
122
Biomechanical Performance of Femoral Ring Allograft To determine which factors most strongly affect the mechanical strength of structural allograft bone, multiple donor and graft variables were assessed for their impact on compressive load
resistance of femoral ring allograft.24 Fresh-frozen human femurs from 34 cadaver donors were each sectioned into ten 20-mm thick specimens. Bone mineral density (BMD), as measured by DEXA scans of the proximal femur; donor age; and graft dimensions were recorded for each specimen. We ultimately tested a total
Journal of the American Academy of Orthopaedic Surgeons
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Satoshi Kawaguchi, MD, and Robert A. Hart, MD
Figure 4
Scatter plots indicating the compressive load to failure as function of bone mineral density (A), sex-specific age (B), minimum (C) and maximum (D) cortical wall thicknesses, and minimum (E) and maximum (F) outer ring diameters. (Adapted with permission from Hart RA, Daniels AH, Bahney T, Tesar J, Sales JR, Bay B: Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. J Orthop Res 2011;29 [12]:1840-1845.)
of 327 specimens under quasi-static axial compression. Linear regression models assessed load to failure as a function of BMD, sex-specific donor age, minimum/maximum cortical wall
thickness, and minimum/maximum outer ring diameter. As shown in Figure 4, correlations between minimum and maximum cortical wall thickness and load to
failure were statistically significant (r = 0.73, P , 0.001, and r = 0.74, P , 0.001, respectively). BMD showed a weaker negative correlation with load to failure (r = 20.11,
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
123
The Need for Structural Allograft Biomechanical Guidelines
Table 2 Load Threshold Statistics for the Sample Population (327) Specimens 3.4 kN Load Multipliera 1· 2· 3· 4· 5· 10· 20·
Load Threshold (kN)
Predicted Min Wall Thickness (mm)
Number of Samples Above Threshold (%)
3.4 6.8 10.2 13.6 17.0 34.0 68.0
1.38 1.87 2.40 2.93 3.46 6.09 11.35
306/327 (93.6) 302/327 (92.4) 281/327 (85.9) 268/327 (82.0) 229/327 (70.0) 43/327 (13.1) 0/327 (0.0)
a Load multiplier = multiples of expected physiologic load of 3.4 kN. Seventy percent of harvested specimens resisted five times this expected load. Adapted with permission from Hart RA, Daniels AH, Bahney T, Tesar J, Sales JR, Bay B: Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. J Orthop Res 2011;29(12):1840-1845.
P = 0.05). Correlations between load to failure and minimum and maximum outer ring diameter and age (r = 0.06, P = 0.31) were not significant. Of the tested parameters, the minimum and maximum cortical wall thicknesses of femoral ring allograft were the most strongly correlated with the axial compressive load to failure of the graft. These findings suggest that cortical wall thickness may be a useful screening tool for compressive resistance expected from fresh cortical bone allograft. It is important to note that remodeling and fatigue during healing may further reduce the strength of an allograft spacer. Thus, an ideal interbody device should withstand a substantially higher force level than the anticipated clinical load at the time of implantation. Knowing the appropriate maximum load to failure potentially affects suitability of the implant. For example, while 70% of specimens supported up to five times estimated clinical loading, only 13% of specimens supported 10 times these expected loads (Table 2). We extended these results with a further nonlinear analysis of the predictive strength of the various parameters.25 This analysis showed that BMD and age are so weakly
124
correlated with strength that they may be safely excluded from consideration as a screening parameter for allograft bone strength. It is critical to acknowledge that optimizing load to failure of femoral ring allografts may not optimize their clinical performance. For example, thicker-walled grafts might limit space available for osteogenic material within the ring with a concomitant negative impact on fusion rates. Alternatively, a thicker wall may limit slight subsidence of the graft into vertebral end plates, again with a potential negative impact on fusion rates. Further efforts to determine the importance of various parameters on clinical outcomes would represent the benchmark for data. In the meantime, however, the basic biomechanical data described above are useful to consider as an initial basis for rational screening approaches to potential allograft bone donation.
for structural allograft bone are currently in place. As a result of this lack of standardization, practices among tissue processors and suppliers remain variable within the United States. Development of further biomechanical and clinical data to direct standard development appears warranted. In the meantime, surgeons should discuss with their allograft providers their individual approach to these issues.
References Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 7 is a level I study. References 1-4, 6, 8-17, 19, and 21 are level III studies. References 20 and 23 are level IV studies. References printed in bold type are those published within the past 5 years. 1. Buttermann GR, Glazer PA, Bradford DS: The use of bone allografts in the spine. Clin Orthop Relat Res 1996;324:75-85. 2. Singh K, DeWald CJ, Hammerberg KW, DeWald RL: Long structural allografts in the treatment of anterior spinal column defects. Clin Orthop Relat Res 2002;394: 121-129. 3. Mankin HJ, Fogelson FS, Thrasher AZ, Jaffer F: Massive resection and allograft transplantation in the treatment of malignant bone tumors. N Engl J Med 1976;294(23):1247-1255. 4. Muscolo DL, Ayerza MA, AponteTinao LA: Massive allograft use in orthopedic oncology. Orthop Clin North Am 2006;37(1):65-74. 5. Jurgensmeier D, Hart R: Variability in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine (Phila Pa 1976) 2010;35(15): E702-E707.
Conclusions and Summary
6. Kleinstueck FS, Hu SS, Bradford DS: Use of allograft femoral rings for spinal deformity in adults. Clin Orthop Relat Res 2002;394: 84-91.
Use of structural allograft bone in spine fusion and other orthopaedic surgical applications continues to increase. Unlike artificial implants, no biomechanical performance standards
7. McKenna PJ, Freeman BJ, Mulholland RC, Grevitt MP, Webb JK, Mehdian SH: A prospective, randomised controlled trial of femoral ring allograft versus a titanium cage in circumferential lumbar spinal fusion with minimum 2-year clinical results. Eur Spine J 2005;14(8):727-737.
Journal of the American Academy of Orthopaedic Surgeons
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Satoshi Kawaguchi, MD, and Robert A. Hart, MD 8. Miller LE, Block JE: Safety and effectiveness of bone allografts in anterior cervical discectomy and fusion surgery. Spine (Phila Pa 1976) 2011;36(24): 2045-2050. 9. Aponte-Tinao LA, Ayerza MA, Muscolo DL, Farfalli GL: Should fractures in massive intercalary bone allografts of the lower limb be treated with ORIF or with a new allograft? Clin Orthop Relat Res 2014;May 3:e-Pub ahead of print 10. Bus MP, Dijkstra PD, van de Sande MA, et al: Intercalary allograft reconstructions following resection of primary bone tumors: A nationwide multicenter study. J Bone Joint Surg Am 2014;96(4):e26. 11. Frisoni T, Cevolani L, Giorgini A, Dozza B, Donati DM: Factors affecting outcome of massive intercalary bone allografts in the treatment of tumours of the femur. J Bone Joint Surg Br 2012;94(6):836-841. 12. Grossman W, Peppelman WC, Baum JA, Kraus DR: The use of freeze-dried fibular allograft in anterior cervical fusion. Spine (Phila Pa 1976) 1992;17(5): 565-569. 13. Macdonald RL, Fehlings MG, Tator CH, et al: Multilevel anterior cervical corpectomy and fibular allograft fusion for
cervical myelopathy. J Neurosurg 1997;86 (6):990-997. 14. Martin GJ Jr, Haid RW Jr, MacMillan M, Rodts GE Jr, Berkman R: Anterior cervical discectomy with freeze-dried fibula allograft: Overview of 317 cases and literature review. Spine (Phila Pa 1976) 1999;24(9):852-858. 15. Mayr MT, Subach BR, Comey CH, Rodts GE, Haid RW Jr: Cervical spinal stenosis: Outcome after anterior corpectomy, allograft reconstruction, and instrumentation. J Neurosurg 2002;96 (1, suppl):10-16.
20. Jones J, Yoo J, Hart R: Delayed fracture of fibular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine (Phila Pa 1976) 2006;31(17): E595-E599. 21. Mroz TE, Joyce MJ, Lieberman IH, Steinmetz MP, Benzel EC, Wang JC: The use of allograft bone in spine surgery: Is it safe? Spine J 2009;9(4):303-308. 22. Mroz TE, Joyce MJ, Steinmetz MP, Lieberman IH, Wang JC: Musculoskeletal allograft risks and recalls in the United States. J Am Acad Orthop Surg 2008;16 (10):559-565.
16. Enneking WF, Campanacci DA: Retrieved human allografts: A clinicopathological study. J Bone Joint Surg Am 2001;83(7): 971-986.
23. Simonds RJ, Holmberg SD, Hurwitz RL, et al: Transmission of human immunodeficiency virus type 1 from a seronegative organ and tissue donor. N Engl J Med 1992;326(11):726-732.
17. Goldberg VM, Stevenson S: Natural history of autografts and allografts. Clin Orthop Relat Res 1987;225:7-16.
24.
Hart RA, Daniels AH, Bahney T, Tesar J, Sales JR, Bay B: Relationship of donor variables and graft dimension on biomechanical performance of femoral ring allograft. J Orthop Res 2011;29(12): 1840-1845.
25.
Krishnamoorthy B, Bay BK, Hart R: Bone mineral density and donor age are not predictive of femoral ring allograft bone mechanical strength. J Orthop Res 2014;32 (10):1271-1276.
18. Wheeler DL, Enneking WF: Allograft bone decreases in strength in vivo over time. Clin Orthop Relat Res 2005;435: 36-42. 19. Stevenson S, Shaffer JW, Goldberg VM: The humoral response to vascular and nonvascular allografts of bone. Clin Orthop Relat Res 1996;326:86-95.
February 2015, Vol 23, No 2
Copyright ª the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
125
