Hybrid Vigor (?)

If two lives join, there is oft a scar.

We may not like it, but orthopaedic sports medicine specialists have confronted the fact that anterior cruciate ligament (ACL) reconstruction is not as successful as we once believed. Many athletes don’t return to their sport after surgery. When they do, their performance doesn’t always measure up to the preinjury level. Even apparently successful results may not be permanent: after reconstruction, an athlete’s risk of sustaining another ACL injury, whether to their other ACL or their graft, is greater than that of their peers. A reinjury of a reconstructed ACL is a particularly painful event for the patient and surgeon alike. Considerable clinical research has consequently been aimed at identifying and mitigating the causes of such failures. Patient anatomy, biomechanics, age, and activity level as well as graft choice, source, and size have all been implicated.

In 2012, Magnussen and colleagues ¹⁸ published the results of their investigation into the possible association of ACL revision surgery with graft size and patient age, sex, and body mass index. Their findings were clearly expressed in the title of their article: “Graft Size and Patient Age Are Predictors of Early Revision After Anterior Cruciate Ligament Reconstruction With Hamstring Autograft.” After a mean 14 months of follow-up, the authors reported that 18 of 256 patients had undergone revision surgery. Looking at patient age, they noted that 17 of these revisions were among the 119 patients younger than 20 years, compared with only 1 of the 137 older patients. Looking at graft size, they noted that 8 (13.6%) of 59 patients whose grafts were ≤7 mm in diameter had undergone revision surgery, compared with 9 (6.5%) of 139 patients whose graft diameter was 7.5 or 8 mm and 1 (1.7%) of 58 patients whose graft diameter was larger than 8 mm. The combination of youth and thin hamstring tendons was a double whammy: 16 of the 18 revisions occurred in patients younger than 20 years with grafts that were ≤8 mm, yielding a revision rate of 16.4% among the 97 patients in this category.

Since that publication, several other studies have documented associations between small-diameter hamstring ACL autografts and undesirable surgical outcomes. In collaboration with Magnussen and colleagues, ¹⁸ Mariscalco et al ²² reported in 2013 that increasing graft diameter correlated with better Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) subjective functional knee score as well as a lower risk of graft rupture. Large database studies from the Swedish National Knee Ligament Register and the Kaiser Permanente ACLR Registry have also supported the association between small hamstring grafts and an increased risk of reinjury. The Swedish study ²⁶ reported that every 0.5-mm increase in graft diameter between 7.0 and 10.0 mm was associated with a 0.86 times lower likelihood of revision surgery, while the Kaiser Permanente study’s ²⁷ strikingly similar conclusion was that every 0.5-mm increase in graft diameter from 7.0 to 9.0 mm was associated with a 0.82 times lower likelihood of revision.

How should a surgeon respond when faced with a small-diameter hamstring graft? An obvious solution might be to select an alternative graft source, such as the quadriceps tendon. However, this is a less attractive option if the patient’s hamstring tendons have already been harvested. Creating a hybrid graft by augmenting the native hamstring tendon with allograft tissue has been a commonly proposed solution. In horticulture, breeding different plant varieties together is often said to increase the fitness of the offspring, a phenomenon known as hybrid vigor. In horticultural parlance, fitness does not refer to enhanced appearance or flavor but an improved ability to survive and reproduce. While we don’t expect hybrid ACL grafts to reproduce, we would like them to survive better than their nonaugmented counterparts.

Studies investigating the survival of hybrid ACL hamstring grafts have reported mixed results. Simple logic suggests that adding tissue to a given graft will increase its tensile strength and ultimately its chance of survival. However, ACL grafts are not inert; once implanted, they undergo a biologic remodeling process. This introduces an element of uncertainty into the outcome, because ACL allografts have been observed to mature more slowly than autografts.^2,9,17,23

In a 2017 study by Jacobs et al, ¹⁰ hybrid grafts performed in the manner that simple biomechanics might have predicted. These surgeons routinely used patellar tendon autografts for ACL reconstruction, but chose hamstring tendons for skeletally immature patients or those whom they anticipated might have difficulty with their postoperative rehabilitation. In response to the publication of studies linking hamstring graft failure to their diameter, the authors began routinely augmenting their hamstring autografts with semitendinosus allografts. They compared the retear rate among 46 hamstring autografts, whose diameter averaged 7.8 mm, with that of 42 hybrid grafts averaging 9.9 mm in diameter. By 47 months after surgery, 28% of the hamstring autografts had failed, whereas by 31 months postoperatively, 12% of the hybrid grafts had failed. While acknowledging that the differing length of follow-up may have affected their findings, the authors proposed that their specific technique of enveloping the allograft inside the autograft may have resulted in better performance of the hybrids.

Other studies have contrasted with these results. Burrus et al ⁵ compared pure hamstring ACL autografts with autograft-allograft hybrids in a 2015 report. Although the choice was left to surgeon discretion, their practice was generally to hybridize autografts smaller than 7.5 mm. When comparing matched groups, they reported that 13.8% of hybrid grafts had failed and that an additional 27.6% appeared partially ruptured on magnetic resonance imaging or at second-look arthroscopic surgery, in contrast with only 3.4% of autografts that failed and 3.4% that partially ruptured. In addition, the IKDC subjective knee score of the patients with hybrid grafts (71.3) was significantly lower than that of the patients who received pure autografts (85.7).

In 2017, Pennock and colleagues ²⁴ reported their findings in 50 teenage patients whose hamstring autografts had measured less than 7 mm. According to surgeon preference, 26 of the grafts were augmented with semitendinosus or tibialis anterior allografts, while 24 were implanted without augmentation. The mean diameter was 8.9 mm for the hybrid grafts, compared with 6.4 mm for the nonaugmented grafts. Nevertheless, after 3 years, 6 of 20 (30%) of the hybrid grafts had failed, compared with 1 of 20 (5%) of the autografts. Because 5 of the 6 hybrid failures occurred in the first 12 postoperative months, the authors hypothesized that slower graft incorporation might have been responsible. Recalling that previous studies had reported higher failure rates with ACL allografts compared with autografts,^4,8,21 the authors stated, “Therefore, it appears that when ‘hybrid’ constructs are used combining autograft and allograft tissue, the graft behaves more like an allograft.”^24(p337)

Still other studies on this topic have reported a variety of outcomes. In 2 groups of 27 patients that averaged 20 years of age, Darnley et al ⁶ found no significant differences in outcomes or survival between hamstring autografts and hybrids, but they noted that the 11% higher failure rate in hybrids would be clinically important if borne out in a study with greater statistical power. In a similarly sized comparative investigation of patients whose mean age was 32 years, Wang et al ²⁹ reported inferior subjective outcome scores and 11% more failures in the hybrid group, although again, this apparent difference in failure rates was not statistically significant. In contrast, among patients averaging 27 to 28 years of age in whom hamstring grafts smaller than 8 mm were routinely hybridized, Leo et al ¹⁶ reported neither statistically nor clinically significant differences in outcome scores or failure rates. Kraeutler et al ¹¹ reviewed a group of older patients, comparing hamstring autografts with hybrid grafts that had been planned preoperatively; patients whose grafts were hybridized to augment their size were specifically excluded. These authors actually reported better outcome scores and a nonsignificant trend toward a lower failure rate in the patients who received hybrids. In 2018, after completing a systematic review that included many of the studies already discussed, Abouljoud et al ¹ could not conclude that hybridization results in higher failure rates compared with pure hamstring autografts.

An article in June’s The American Journal of Sports Medicine added one more piece of evidence to the conflicted literature on hybrid hamstring ACL reconstruction, specifically in the high-risk group of children and adolescents. ²⁵ In this retrospective study, Perkins and colleagues ²⁵ examined the results of ACL reconstruction in young patients who had 1 of 3 graft types implanted: 4-strand autogenous hamstring tendon, 5-strand autogenous hamstring tendon, or 6-strand hybrid graft. The graft types were not randomly assigned. In the early portion of the study period, the authors augmented their standard 4-strand hamstring autograft with a semitendinosus or tibialis posterior allograft if the autograft was less than 7.5 mm in diameter. As some reports of inferior performance of hybrid grafts began to emerge, they switched to augmenting the graft by tripling the native semitendinosus whenever possible.^12,14,15 The 4-strand autografts averaged 8.3 mm in diameter, and the 5-strand autografts averaged 8.9 mm; the hybrids averaged 6.8 mm before and 9.2 mm after the addition of the allografts.

After a mean 24 to 26 months, 14% of the grafts had failed. The unadjusted failure rates for the 3 graft types were not significantly different: 14% for the 4-strand grafts, 12% for the 5-strand grafts, and 20% for the hybrids. When the authors further analyzed their data by adjusting for patient age and graft size, the patients with hybrid grafts had 2.6 (95% CI, 1.02-6.50) times the odds of failure, compared with those who had received a 4-strand autograft. On the other hand, the odds of failure in those who had received a 5-strand autograft were not significantly different from those who had received a 4-strand autograft (odds ratio, 1.2 [95% CI, 0.5-2.7]).

Does it make sense to adjust the analysis for graft size? After all, a patient whose 4-strand graft measures 6.8 mm doesn’t have the option of a larger 4-strand autograft. However, the 5-strand autograft may often be a possible alternative. These results suggest that in the authors’ hands, tripling the native semitendinosus tendon was preferable to adding an allograft as a strategy for augmenting a small 4-strand construct.

So, do ACL grafts exhibit “hybrid vigor”? Does hybridizing a small hamstring autograft with allograft tissue increase its chance of survival? Or does it actually augment the risk of failure? The answer may seem to depend upon which study you last read. As usual, the devil may lurk in the details, and the truth is hard to ferret out. Not all allografts are the same. Graft sterilization and preservation methods have been linked to the chance of survival,^3,7,13,19,28 so differences in allograft preparation may be responsible for some of this confusion. Youth, and its accompanying high activity level, has been shown to increase the risk of ACL graft failure,^20,30,31 so the young age of the participants in some studies may have been a contributing factor to the failure rate. The precise method used to combine the 2 components of the hybrid, the nature of the postoperative rehabilitation program, and the timing of eventual return to sport are additional factors that might influence graft survival. Future studies will hopefully help us sort through these factors. In the meantime, caution in the use of hybrid grafts seems warranted, especially in young patients.

The study by Perkins and colleagues ²⁵ reminds us that there are other available options besides allograft hybridization when a surgeon wishes to enlarge a small-diameter hamstring graft. Their results suggest that increasing the number of native hamstring tendon strands, when feasible, is a promising option.^12,14,15,25 Augmentation with additional autogenous tissue, whether ipsilateral or contralateral, remains a possibility for cases in which that technique doesn’t seem reasonable. These options appear particularly relevant for patients who may already be at an increased risk of failure, owing to their youth or activity level. If a hamstring hybrid is chosen, the surgeon may wish to opt for minimal allograft processing and adjust the rehabilitation program to account for the possibility of slower graft maturation. Of course, if the situation is recognized before the hamstring tendons have been harvested, an alternative graft may be selected, obviating the entire dilemma.