Factors Associated with Increased Allograft Failure Rate in Anterior Cruciate Ligament Reconstruction

Keywords

ACL, allograft, failure, processing, reconstruction

Acknowledgments

I would to thank my KPACLRR colleagues Gregory B. Maletis, MD; Tadashi T. Funahashi, MD; Jason Chen, MA; and Rebecca Love, MPH, RN, for their invaluable collaboration on our research, and the many Kaiser Permanente orthopaedic surgeons who contribute to the KPACLRR every year.

Acknowledgments

Introduction

Allograft tissue is a common graft choice for anterior cruciate ligament reconstruction (ACLR). A 2013 survey conducted by the American Orthopaedic Society of Sports Medicine found that allograft was selected in 27% of those cases, with use trending higher in patients 40 years and older. Surgeons were more likely to use allograft for primary ACLR because of decreased donor site morbidity, decreased postoperative pain, improved cosmesis, and decreased surgical time. Concerns voiced regarding allograft use for primary ACLR included a younger patient, graft failure rates reported in the literature, patient intent to return to high anterior cruciate ligament (ACL)-demanding activity, graft incorporation rate, disease transmission, personal experience with graft failure, and cost.

Numerous studies, despite their small sample size, have suggested slower revascularization, inferior biologic properties, increased postoperative laxity, and decreased clinical outcome scores associated with the use of allograft tissue in ACLR when compared with autograft. The explanations for these findings have been multifactorial and remain incompletely understood, but are believed to be due to a combination of graft characteristics and patient attributes. Multiple studies from the Kaiser Permanente ACL Reconstruction Registry (KPACLRR) have provided descriptive and outcome data on ACLR from a large community-based sample. Of the 21,926 ACLRs in the KPACLRR registered between 2005 and 2013, 41% were performed with allograft. KPACLRR studies ranging from approximately 9800–16,200 patients have revealed that allografts have lower overall graft survival versus autografts, a 3.02 times higher risk of aseptic revision than bone–patellar tendon–bone (BPTB) autografts specifically, and are also a risk factor for nonrevision reoperations after ACLR. Most recently, in the largest such cohort ever, a 2015 KPACLRR study on 5968 allograft primary ACLR cases found that graft irradiation over 1.8 Mrad, BioCleanse graft processing, younger patients, male patients, and BPTB allograft are all associated with a higher risk of aseptic failure and subsequent revision surgery after primary allograft ACLR ( Fig. 117.1 ). This study will be discussed in further detail and serve as a benchmark comparison for additional research done on the topic.

Graft Processing

The goal of allograft processing remains to sterilize tissue to a minimum sterility assurance level of 10 ⁻³, as mandated by the Food and Drug Administration for implanted biologic medical devices, without compromising mechanical properties or biologic potential. While oversight exists from the American Association of Tissue Banks, there remains no established gold standard for tissue processing, which can include a combination of hydrogen peroxide, high temperature, chemical washes, gamma irradiation, supercritical CO ₂, antibiotics, fresh-frozen preservation, freeze-drying preservation, cryopreservation, proprietary techniques, and other methods, each with uncertain impact on the resultant biologic and mechanical properties of the tissue.

Proprietary Techniques

BioCleanse is a proprietary technique that sterilizes tissue through vacuum and pressure, followed by chemical sterilants and finally germicide removal. The 2015 KPACLRR study of 5968 primary allograft ACLR cases included 367 processed with BioCleanse. After adjusting for patient age, gender, and body mass index (BMI), this subset of patients was found to have a 2.45 times higher risk of revision when compared with other methods of graft processing. These findings were in contrast with a smaller subset of 43 patients undergoing isolated ACLR with BioCleanse-processed BPTB allografts, which found no difference in functional outcome at 2-year follow-up compared with aseptically processed grafts. Numerous time-zero biomechanical studies have demonstrated that allografts sterilized by the BioCleanse technique do not demonstrate any obvious significant compromise in mechanical integrity, as measured by ultimate failure stress and creep. In 2012 tibialis anterior allografts sterilized by BioCleanse were found to have higher stiffness compared with irradiated grafts, the clinical impact of which is unknown. Considering the general validation of BioCleanse processing at time zero, the higher observed clinical failure rate may be explained by the postoperative behavior of the graft during the process of ligamentization. One laboratory study revealed zero osteoinductivity for bone treated with BioCleanse in comparison with 43% osteoinductivity found with Allowash and 100% osteoinductivity with a third processing method involving nonionic detergents, hydrogen peroxide, and denatured ethanol. It is presently unknown if soft-tissue processed with BioCleanse similarly experiences decreased biologic activity, resulting in altered graft incorporation and remodeling postoperatively, with clinical failure and aseptic revision in select instances. Further study is warranted.

Irradiation

Irradiation is effective in sterilizing allograft tissue prior to implantation; however, concerns persist regarding deleterious effects the process may have on graft integrity in a dose-dependent fashion, and whether this decrease in strength correlates with higher clinical failure rates. One study tested BPTB allograft specimens sterilized with 2.5 or 3.4 Mrad of high-dose irradiation, finding both groups to have lower stiffness, lower failure load, and higher creep in comparison with nonirradiated controls. A similar study examined the effect of low-dose irradiation on BPTB allografts, finding that 1.0–1.2 Mrad irradiation decreased stiffness by 20% but had no significant effect on load to failure, suggesting these low-dose levels may not create clinically significant changes. Ultimately the question of what the specific Mrad threshold is for safe allograft sterilization remains to be answered.

Multiple outcome studies have revealed that primary ACLR with high-dose irradiated allografts have a higher risk of clinical failure when compared with autografts. Failure rates as high as 34% have been observed after 2.5 Mrad high-dose irradiated grafts were used for BPTB ACLR in a study of 99 patients, compared with 8.8% in the nonirradiated allograft group and 6.1% in the autograft group at mean 31-month follow-up. Likewise, a study on 98 patients after hamstring tendon (HT) ACLR found 86% of patients in the autograft group and only 32% in the 2.5 Mrad high-dose irradiated allograft group had a side-to-side difference of less than 3 mm at mean 42-month follow-up. Similarly, when comparing 2.5 Mrad high-dose irradiated and nonirradiated HT allograft for ACLR, 84% of the patients in the nonirradiated allograft group compared with only 32% in the irradiated allograft group had side-to-side differences of less than 3 mm according to KT-2000, also suggesting irradiation may have a deleterious effect on the implanted allograft tissue. Furthermore, a review of 90 ACLR patients with Achilles tendon allograft at minimum 6-month follow-up found 2% of the nonirradiated group had catastrophic failure, in contrast with 33% of the 2–2.5 Mrad high-dose irradiated group.

Although irradiated allografts were found to perform similarly to autografts and nonirradiated allografts in 1-year follow-up after ACLR in one study of 238 patients, a meta-analysis of 21 ACLR publications with 415 irradiated (<2.5 Mrad) and 1038 nonirradiated allografts found that knees with even low-dose irradiated allografts had increased postoperative laxity and a higher proportion of revision surgery compared with nonirradiated grafts. The aforementioned 2015 KPACLRR study found that using allograft sterilized with specifically over 1.8 Mrad of irradiation ( n = 1146) carries a 1.64 times increased risk of aseptic failure and subsequent revision surgery, as opposed to no increased risk when irradiation of less than 1.8 Mrad is used ( n = 4822). In totality, multiple ACLR outcome studies suggest a negative impact on graft performance when irradiation above 1.8 Mrad is used, and a less clear effect when lower dose irradiation is used, with possible confounding variables such as graft type, patient age, surgical technique, graft fixation, and postoperative rehabilitation clouding the issue. Given the implications for clinical failure and reoperation, surgeons should be aware of the precise gamma irradiation dosage used for their allografts, as there is a lack of industry standardization.

Graft Type

In the 2015 KPACLRR study, BPTB allograft ( n = 1029) was found to have a higher risk of failure (HR = 1.79) when compared with soft-tissue allograft ( n = 3751). The explanation for this is unclear, but may result from the structural difference between the graft types. The two bone blocks attached to the patellar tendon of the BPTB graft may undergo changes in mechanical properties or biologic behavior, secondary to processing techniques, that could contribute to the higher observed failure rate. It is known that with increased exposure time to hydrogen peroxide during allograft bone processing, for example, a linear decrease in osteoinductivity occurs. Likewise, in both static and fatigue testing, terminal high-dose gamma irradiation has been found to lessen the mechanical strength of allograft bone, and has been shown to reduce its osteoinductive potential as well. This potential decreased mechanical strength and osteoinductive behavior of the BPTB bone blocks may result in suboptimal postoperative graft incorporation. One meta-analysis of 5182 patients found a threefold increase in revision rate with allograft BPTB ACLR in comparison with autograft BPTB. Further study on BPTB allograft and its associated risk factors for failure is warranted.

Graft Donor Age

It has been hypothesized that higher donor age for allograft may increase the risk of subsequent revision surgery, due to lower inherent tissue quality from patients in their later years. In 1991 a biomechanical laboratory study on 27 pairs of human cadaver knees found that graft stiffness, ultimate load, and energy absorbed were found to decrease significantly with specimen age, most notably in the 60- to 97-year-old group, suggesting allografts from this donor population should be implanted with caution. A later evaluation of the biomechanical properties of BPTB allografts from donors aged 18–55 years showed no difference among the age groups for load at failure, stiffness, or elongation, suggesting donor age below 55 years is not a factor at time zero. This was supported by a study that concluded donor age up to 65 years did not significantly affect initial failure load, stiffness, or displacement at failure of tibialis anterior allografts treated with 1.46–1.80 Mrad of gamma irradiation terminal sterilization. In 2014, a controlled laboratory study examining 550 allograft posterior tibialis tendons revealed decreased ultimate tensile strength in patients over 50 years old, although the magnitude of these changes was small in relation to the strength of the native ACL and felt to be clinically insignificant for ACLR. In a retrospective clinical study of 75 patients at mean 2-year follow-up after BPTB allograft ACLR, donor age ranged from 14 to 65 years and as a continuous variable was not found to have an effect on postoperative Lysholm or Tegner scores. Consistent with these published reports, the 2015 KPACLRR allograft study found that donor age did not significantly affect revision risk after primary allograft ACLR, including grafts over 60 years of age ( n = 892), suggesting surgeons can potentially be comfortable when implanting tissue from this donor age group if necessary due to the limited availability of younger specimens.

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