The Need for Structural Allograft Biomechanical Guidelines

Satoshi Kawaguchi, MD Robert A. Hart, MD

Abstract Because of their osteoconductive properties, structural bone allografts retain a theoretic advantage in biologic performance compared with artiﬁ cial interbody fusion devices and endoprostheses. Current 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, a basic biomechanical evaluation was performed on one source of structural bone allograft, the femoral ring. Of the 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. Instr Course Lect 2015;64:87–93.

Surgical implantation of structural al- form with limited anatomic modifi - by the US FDA as well as through vol- lograft bone continues to increase de- cations, modern tissue processing in- untary participation with the American spite advances in modern alternatives cludes preparations of amalgams of Association of Tissue Banks (AATB). to allograft, including spine interbody allograft bone tissue of specifi c shapes Guidelines for allograft bone products fusion devices and peripheral joint en- and sizes to suit specifi c surgical needs. have primarily focused on avoiding doprostheses. Although allograft bone Oversight of the allograft processing the transmission of neoplastic and in- historically has been prepared in bulk and delivery industry has been managed fectious disease. Few guidelines exist regarding donor eligibility and bone Dr. Hart or an immediate family member has received royalties from DePuy and SeaSpine; is a member of a speakers’ processing methods with an emphasis 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 on the mechanical integrity of struc- from DePuy; and serves as a board member, owner, offi cer, or committee member of the American Academy of Orthopaedic tural allograft bone, thus raising con- Surgeons, the American Orthopaedic Association, the Cervical Spine Research Society, the International Spine Study cern for uniformity and reliability in the Group, the Lumbar Spine Research Society, the North American Spine Society, the Oregon Association of Orthopaedic Surgeons, and the Scoliosis Research Society. Neither Dr. Kawaguchi nor any immediate family member has received any- biomechanical performance of struc- thing of value from or has stock or stock options held in a commercial company or institution related directly or indirectly tural bone allografts. to the subject of this chapter.

spinal fusion is a rare event.2 The incidence of graft fracture is reportedly zero to 2.7% following multilevel cervical corpectomy and fi bular allograft fusion.12-15 Bone resorption resulting from creeping substitution16-18 and im- mune response17,19 has been implicated in some cases. Despite such low incidence of allograft bone fracture after spine surgery, this chapter’s authors experienced two consecutive cases within 3 months of delayed fractures of anterior fi bular strut allografts following combined three-level cervical corpectomy and posterior instrumented fusion20 (Fig- Figure 1 Graph showing the increase in structural allograft bone transplant procedures performed in the United States per year from 1990 to 2004 (left ures 2 and 3). The allografts used for y-axis) and the increase in tissue donors per year from 1994 to 2006 (right these patients had been harvested from y-axis). (Adapted with permission from Jurgensmeier D, Hart R: Variability the same donor, a 69-year-old woman. in tissue bank practices regarding donor and tissue screening of structural allograft bone. Spine [Phila Pa 1976] 2010;35[15]:E702-E707.) The occurrence of this rare complica- tion in two patients who shared the This chapter’s authors discuss their fusion and larger endoprostheses for same donor suggested that the grafts clinical experience and review Ameri- limb and pelvic reconstruction, struc- may have been structurally inadequate can tissue bank practices with regard to tural bone allograft implantation has for the intended clinical use. At the screening donors and processing struc- continually increased in the United time, the tissue bank involved did not tural bone allograft. These issues are States since the late 1990s5 (Figure 1). use donor age or osteoporosis as ex- further evaluated with biomechanical Compared with artifi cial interbody clusion criteria for structural allograft data evaluating factors important to fusion devices and endoprostheses, donation. The occurrence of these frac- the mechanical performance of cortical structural bone allografts retain an ad- tures led this chapter’s authors to ques- femoral shaft allograft. Further efforts vantage in biologic performance because tion how allograft providers operate to assess the importance of these pa- of their osteoconductive properties. donor and tissue screening of structural rameters on clinical outcomes, as well as Also, they are cost effective and provide allograft bone, especially with respect the development and adoption of bio- easier radiologic assessment of bony fu- to variables that may infl uence mechan- mechanical performance standards for sion than do metal or plastic implants.6-8 ical strength of the graft. structural allograft, may be warranted. However, the mechanical performance of structural bone allografts may be a Current Regulation of Structural Bone Allograft disadvantage, made potentially worse Allograft Bone Screening in Orthopaedic Surgery by the negative effects of tissue process- The FDA began regulatory oversight of The use of structural bone allograft is ing and the less predictable effects of the recovery and processing of human a long-established surgical technique fatigue and postoperative remodeling cadaver tissues in 1993, after reports used for interbody spinal fusion1,2 as on the strength of the graft. Although of serious disease transmission from well as for reconstruction of defects fracture of structural allografts follow- allograft tissues.21-23 Since then, reg- of the long bones.3,4 Despite recent ing segmental grafting of various long ulation of the human allograft supply advances in modern alternatives to bone defects has been well docu mented, with respect to infection control and structural bone allografts, including with a reported incidence of 14% to 29% disease transmission has continued to prosthetic interbody devices for spinal in recent literature,9-11 graft fracture after expand as additional pathogens have

been identiﬁ ed and effective screening AATB. The AATB was established in Current regulations have done much tests have been developed. 1976 and currently has 100 member to address risks of disease transmission In addition to the FDA oversight, the organizations, accounting for 90% of and tissue contamination. However, allograft tissue industry is self-regulated human allograft tissue used clinically comparatively few guidelines exist re- through voluntary membership in the in the United States. garding 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.

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, a questionnaire-based survey was developed by this chapter’s authors.5 Figure 2 A, Lateral radiograph demonstrating apparent healing of the At the time of the survey, 45 AATB exterior graft at 6 months after surgery. B, Sagittal CT image of the cervical member tissue banks were involved to spine showing fracture of the allograft. (Adapted with permission from Jones some degree in procuring or process- J, Yoo J, Hart R: Delayed fracture of ﬁ bular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine [Phila Pa 1976] 31[17]: ing structural allograft bone. Of these, E595-E599.) 16 organizations participated in tissue

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 ﬁ bular strut allograft following multilevel anterior cervical spine corpectomy and fusion. Spine [Phila Pa 1976] 31[17]:E595-E599.)

Table 1 Tissue Banks’ Response to Survey Questions Regarding Donor Exclusion Criteria for Structural Bone Allograft

No. of Tissue Banks Using Param- eter in Screening Structural Bone No. of Structural Allograft Bone Criterion Allograft Donors (%) Donors Affected (%) Age limit 8/14 (57) 15,852/18,712 (85) Chronic steroid exposure 12/14 (86) 15,912/18,712 (85) Rheumatoid arthritis/ankylosing spondylitis 14/14 (100) 18,712/18,712 (100) Tobacco use 1/14 (7) 1,400/18,712 (7) Hysterectomy/oophorectomy 1/14 (7) 1,400/18,712 (7) Diagnosis of osteoporosis 7/14 (50) 10,222/18,712 (55) History of osteoporosis medication 6/14 (43) 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. processing and the sale of allograft ankylosing spondylitis to be exclusion integrity of structural allograft bone. bone. The questionnaire regarding criteria, representing 100% of total This contrasts with presumably con- tissue bank practices having a poten- structural allograft bone donors (18,712 sistent compliance with screening and tial effect on mechanical integrity of of 18,712) reported. Seven percent of processing requirements designed to allograft bone was circulated to all 16 banks (1 of 14) used a history of tobacco avoid disease transmission and tissue AATB-accredited tissue banks involved use or prior hysterectomy or oophorec- contamination. Although those consid- in processing structural allograft bone. tomy for nonmalignant diagnosis to be erations must remain primary in ensur- Of the 16 AATB-accredited tissue exclusion criteria, representing 7% of ing safety of the allograft bone supply, banks, 14 responded to the question- total donors (1,400 of 18,712) reported. issues of mechanical bone integrity naire (Table 1). Forty-three percent Fifty percent of banks (7 of 14) reported would also seem to be important from of banks (6 of 14) reported no upper a prior diagnosis of osteoporosis to be the standpoint of quality control, given age restriction for structural allograft an exclusion criterion, representing 55% the increasing use of structural allograft donors, or they accepted donors up to of total donors (10,222 of 18,712) re- in load-bearing applications. the age of 80 or 85 years, representing ported. Forty-three percent of banks Biomechanical and clinical studies 15% of the total number of structural (6 of 14) reported that history of prior to determine which factors are most allograft bone donors (2,860 of 18,712) use of diphosphonate medications was relevant to structural allograft mechan- reported. The remaining eight banks exclusionary, representing 62% of total ical properties and clinical success seem reported upper age limits ranging from donors (11,662 of 18,712) reported. warranted to determine whether further 55 to 75 years. Three banks reported Sixty-four percent of banks (9 of 14) standards for donor and tissue accep- differing age limits for male and female reported using a minimum cortical wall tance are appropriate. Given the relative donors. The average upper age limits thickness for structural allograft pre- lack of data on which to base reasonable were 68.6 years for men and 66.8 for pared from long bones, representing screening standards, a basic biomechan- women. 81% of the structural allograft bone ical evaluation of one source of struc- Eighty-six percent of banks (12 of supply (15,110 of 18,712). No bank re- tural bone allograft was undertaken. 14) considered chronic steroid exposure ported using dual-energy x-ray absorp- to be an exclusion criterion, represent- tiometry (DEXA) scans as screening Biomechanical Performance ing 86% of the total structural allograft for potential donors or tissue. of Femoral Ring Allograft bone donors (15,912 of 18,712) reported. These ﬁ ndings indicate wide vari- To determine which factors most One hundred percent of banks (14 of ation in tissue banks’ approaches to strongly affect the mechanical strength 14) considered rheumatoid arthritis and issues potentially affecting mechanical of structural allograft bone, multiple

Figure 4 Scatterplots indicating the compressive load to failure as function of bone mineral density (A), sex-speciﬁ c age (B), minimum (C) and maximum (D) cortical wall thicknesses, and minimum (E) and maximum (F) outer ring diam- eters. (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.) donor and graft variables were assessed into ten 20-mm thick specimens. Bone 327 specimens was ultimately tested for their effect on compressive load mineral density (BMD), as measured by under quasi-static axial compression. resistance of femoral ring allograft.24 DEXA scans of the proximal femur; Linear regression models assessed Fresh-frozen human femurs from donor age; and graft dimensions were load to failure as a function of BMD, 34 cadaver donors were each sectioned recorded for each specimen. A total of sex-speci ﬁ c donor age, minimum/

Table 2 Load Threshold Statistics for the Sample Population (327) Specimens

Load Threshold Predicted Minimum Wall Thickness Number of Samples Above Threshold 3.4 kN Load Multipliera (kN) (mm) (%) 1× 3.4 1.38 306/327 (93.6) 2× 6.8 1.87 302/327 (92.4) 3× 10.2 2.40 281/327 (85.9) 4× 13.6 2.93 268/327 (82.0) 5× 17.0 3.46 229/327 (70.0) 10× 34.0 6.09 43/327 (13.1) 20× 68.0 11.35 0/327 (0.0)

aLoad multiplier = multiples of expected physiologic load of 3.4 kN. Seventy percent of harvested specimens resisted fi ve 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. maximum cortical wall thickness, potentially affects suitability of the im- basic biomechanical data described in and minimum/maximum outer ring plant. For example, although 70% of the this chapter are useful to consider as diameter. specimens supported up to fi ve times an initial basis for rational screening As shown in Figure 4, correlations estimated clinical loading, only 13% of approaches to potential allograft bone between minimum and maximum cor- the specimens supported 10 times these donation. tical wall thickness and load to failure expected loads (Table 2). were statistically signifi cant (r = 0.73, These results were extended with Summary P < 0.001, and r = 0.74, P < 0.001, a further nonlinear analysis of the Use of structural allograft bone in spine respectively). BMD showed a weaker predictive strength of the various pa- fusion and other orthopaedic surgical negative correlation with load to failure rameters.25 This analysis showed that applications continues to increase. (r = −0.11, P = 0.05). Correlations be- BMD and age are so weakly correlated Unlike artifi cial implants, no biome- tween load to failure and minimum and with strength that they may be safely chanical performance standards for maximum outer ring diameter and age ex cluded from consideration as a structural allograft bone are currently (r = 0.06, P = 0.31) were not signifi cant. screening parameter for allograft bone in place. As a result of this lack of stan- Of the tested parameters, the minimum strength. dardization, practices among tissue pro- and maximum cortical wall thick nesses It is critical to acknowledge that cessors and suppliers remain variable of femoral ring allograft were the most optimizing load to failure of femoral within the United States. Development strongly correlated with the axial com- ring allografts may not optimize their of further biomechanical and clinical pressive load to failure of the graft. clinical performance. For example, data to direct standard development These fi ndings suggest that cortical wall thicker-walled grafts might limit space appears warranted. In the meantime, thickness may be a useful screening tool available for osteogenic material within surgeons should discuss with their al- for compressive resistance expected the ring with a concomitant negative lograft providers their individual ap- from fresh cortical bone allograft. It is effect on fusion rates. Alternatively, proach to these issues. important to note that remodeling and a thicker wall may limit slight subsi- fatigue during healing may further re- dence of the graft into vertebral end References duce the strength of an allograft spacer. plates, again with a potential negative 1. Buttermann GR, Glazer PA, Brad- Thus, an ideal interbody device should effect on fusion rates. Further efforts ford DS: The use of bone allografts in the spine. Clin Orthop Relat Res withstand a substantially higher force to determine the importance of vari- 1996;324:75-85. level than the anticipated clinical load at ous parameters on clinical outcomes 2. Singh K, DeWald CJ, Hammerberg the time of implantation. Knowing the would represent the benchmark for KW, DeWald RL: Long structural appropriate maximum load to failure data. In the meantime, however, the allografts in the treatment of anterior

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