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Re: This is that study -- Comments on 5-year follow-up LARS study by Cerulli....
Posted By: Michael Frind
Date: Friday, 11 April 2008, at 12:12 p.m.
In Response To: This is that study (Kai)
Comments regarding the Cerulli et al. article
S.I.O.T. 2007; 33(suppl.1) : 8238-8242
ACL Reconstruction Using Artificial Ligament: Five Years Follow Up
This article was published by SIOT, the Italian Society of Orthopedics and Traumatology. From the information provided on their website (www.siot.it), it seems that they publish only in Italian, and so the PDF copy (converted to plain text) must have been translated privately. In any case, the translated article is replete with grammatical errors. But what concerns me more is that there no follow-up commentaries. Simply put, there are many deficiencies in the Cerulli et al. article.
Cerulli et al. considers the LARS synthetic ligament to be an ideal solution to torn ACLs, and they tout the rapid rehabilitation and absence of worries about donor-site morbidity or disease transmission. Unfortunately, this study has only a 5-year follow-up. And, only 25 patients were studied. The average patient age was 46 years, and it seems the patients were not tremendously active either.
It would have been appropriate for the study to give a summary table of details on patient histories (i.e. date of initial ACL-tearing incident, also any other knee-injury history not addressed by the exclusion criteria), activity levels (pre-injury, while ACL-deficient, and post-surgery), and general health (e.g. each patient's age, body mass, height). Such a summary table would have been more useful than the handful of means, maxima, and minima given in the study. Also desirable would have been tables and charts that clearly summarize the study findings, rather than placing the findings in the body text only. In other words, it would have been very helpful to have been able to follow each patient individually (e.g. identified by initials) through the study: age, activity level, physical attributes, ACL-injury chronicity (i.e. duration of ACL deficiency), pre-reconstruction knee stability, post-surgery knee stability, post-injury activities, test results, and so on.
Cerulli et al., in their conclusion, indicate that a LARS has a fatigue life of about 22 million cycles, which they equate to a decade of strenuous use. A 22-million-cycle life is more than I expected (I would have figured fatigue would be a problem earlier, especially given the disastrous experiences with synthetic ligaments in the 1980s), but much depends on how deeply the knee is flexed during activities, as well as the types of activities pursued. Nuances such as individual differences in muscle-activation patterns, physical stature, musculature (e.g. a 450-pound all-muscle football lineman versus a 150-pound basketball player), anatomy, neuromuscular "firmware", and biochemical/genetic variations could also play a major role in the demands a given person's body makes on a knee ligament (or surrogate ligament). Because an implanted synthetic LARS ligament is subjected to flexing but does not have the ability to regenerate cells as a natural ACL (or ligamentized autograft or allograft ACL) does, the fatigue concern is an extremely serious one.
Incidentally, the fatigue concern is still very much present even if the LARS product is used to "augment" an autograft or allograft ACL. The problem of strain-shielding, whereby a LARS product used for augmentation prevents the natural graft tissue from developing the parallel alignment of collagen tissues, has been well documented in studies on synthetic ligaments in the past. I will not delve into these concerns here, since the Cerulli article focuses specifically on using LARS as a sole ACL graft, hence as a drop-in replacement for a torn ACL.
So, we want to be certain that the LARS ligament does not fail inside the knee, since any such failure would mean frayed, nonbiodegrading synthetic fibres would be released into the joint. Also, serious damage to other structures (other ligaments, also meniscal damage and/or articular-cartilage damage via bone-bruising), merely as a result of the knee giving way, would occur. Both would increase the predilection towards premature osteoarthritis. So, allowing for an engineering-type factor of safety, then we could say that the life of a LARS is about 5-6-7 years. I wonder whether the doctor would recommend replacing the LARS ligament prophylactically, say at 6 years. Unfortunately, this would mean regular LARS-replacement surgeries (so, a lot of surgeries for a young patient, and still quite a few for an over-40 one), which means going through all the risks and hassles (including rehabilitation) each time. Ligament grafts should be installed with the intent of lasting the life of the patient...and this is especially important if the patient is young and active. (Even for people in their 40s, it is intrinsically appropriate for a ligament graft to carry the expectation of lifelong functionality, keeping in mind that human life expectancies are increasing. Many people live into their 90s now.)
I note that we already have autografts and allografts, which bring excellent success rates and are known to last the life of the patient. Any new surgical technique or grafting material should build on this solid record, or at least match it. It is very difficult to envision a synthetic material that remains in the knee indefinitely and that survives the tremendous demands (both the amount of flexing itself and the huge number of cycles) that can be expected over the remaining lifetime of an ACL-injury person. Since ACL injuries very often involve young and/or active people, it is logical to expect that the person would like to return to such a level of activity. This again points to the need to expect a high number of cyclical loadings on the LARS ligament. Here we see that, again, a factor of safety is appropriate.
Also, with a synthetic ligament that requires regular replacements, problems such as osteopenia (softening of the bone, consequent to repeated graft removals and installation activities) will arise. And, of course, the costs of surgery each time would be considerable. I note that the cost of surgery is much greater than the cost of buying the ligament itself. (Incidentally, I think LARS is potentially suitable for certain salvage-type operations, for example if major tissue loss has occurred due to cancer, fire, or massive trauma. But the Cerulli et al. article focuses on ACL reconstruction in a sports-injury-type context, and my comments here reflect this.)
Also, Cerulli et al. do not discuss the missing-proprioception problem. A natural ACL contains tension-sensitive nerve endings, which serve to keep the brain apprised of goings-on in the knee. (Of course, other musculoskeletal structures contain such nerve endings too; in rehabilitation it is possible to train the brain to use these more to compensate for the missing information from the injured ACL; this falls under the rubric of surrogate proprioception.) However, Cerulli et al. do note that prompt rehabilitation (and with LARS, rehabilitation progress can be quicker than with tendon grafting, since there is no revascularization nor ligamentization to occur) is advantageous with regards to regaining surrogate proprioception as rapidly as possible.
The authors promise a wonderful future with a new synthetic ligament (under development) that will be bioactive: apparently tissue growth factors will be incorporated into the polyethylene terephthalate (the same polymer used in pop bottles and water bottles), and then natural tissue will grow on the plastic. I still see a lot of concerns. For example, when the plastic fatigues and fails, everything, including the grown-on tissue, must be ripped out. And, using such plastic would not subject any grown-on tissues to gradually increasing physiological stressing necessary for the development of the parallel-aligned collagen fibres that are the hallmark of true ligament tissue. What I would have hoped for is a synthetic ligament that serves as scaffolding on which a new ligament grows (exactly like today's autografts and allografts do), and that then gradually disappears as the nascent (and fully living) replacement ligament takes shape. (Such technology is already available in the form of bioabsorbable screws. However, ligamentous structures are much more challenging to engineer for because they must flex tremendously and frequently during their service. Therefore, much more research-and-development work is required before bioabsorbable ligament grafts become feasible.)
Actually, the whole Cerulli et al. article seems to have been written with the intent of promoting LARS, rather than evaluating it objectively. The authors, who should be focusing on reporting and discussing their findings, instead come across as feeling a need to justify their choice of LARS. I note, with regret, that I was unable to find the insight I set out to find in this article. In short, the article raises far more questions than it answers.
I also note that the article also seems rather sparse in terms of its references. A topic of this nature calls for an especially sizeable list of references from high-quality peer-reviewed medical journals.
All things considered, this study makes for interesting reading. But in terms of scientific rigour, it leaves something to be desired. Foremost among these is that the follow-up period is too short. Hopefully a 10-year (or longer) follow-up study on LARS will soon be made available. And, ideally it would involve active athletes, since what is called for is a study with a follow-up period that is either (a) substantially longer than the 22-million-cycle decade-of-strenuous-use benchmark that Cerulli et al. mention; or (b) long enough to encompass the longest time periods in which the LARS typically remains in the knee.
I note that no mention was made of a specific timeframe for LARS replacement. This means that no warning is given to patients that their LARS needs to be replaced on a set schedule, which could be either time-based (e.g. every 6 years for an athlete, every 10 years for a less-active person) or use-based (in which case some type of recordkeeping of knee use would be expected, analogous to recording the number of miles a car has been driven or airtime hours a helicopter airframe has flown). With these aspects in mind, perhaps a 15-year or longer follow-up study into LARS is needed.
I also corresponded with Sue Barber-Westin, a seasoned knee researcher known worldwide. She also noted that SIOT is not recognized by PubMed, and she is unsure of whether SIOT has a rigorous peer-review process (as AJSM, JBJS, KSSTA, AJARS, JB, CORR, and other such top-tier journals have).
With regards to the Cerulli et al. findings, Sue notes that the LARS graft restored normal anterior tibial translation (ATT) in only 40% (KT-2000 testing) of the knees, and normal coupled ATT and internal tibial rotation (pivot shift) in 24% of the knees. She notes that these results are not very impressive.
Sue also notes that the data regarding the activity level of the participants is confusing. She shares my concern about the dearth of information regarding activity levels, and she notes that the authors need to separate out the analysis of work and sports activities and make clear exactly what levels the patients were in before their injury and currently. She notes that the major motivation for using LARS is a quick return to activity. She notes that there needs to be a clear explanation for patients who were active (in knee-demanding activities) prior to surgery but who no longer pursue these activities afterwards.
Sue shares my concerns about the lack of scientific rigour in the study. The authors make a statement which I think reveals the questionable quality of the article even to the casual reader: "We can assure the patients that this new synthetic graft will never be responsible for synovitis and will provide knee stability". Sue noted that there have been so many problems with synthetic ligaments in general (short-term failure, long-term failure, complications such as synovitis) that such a statement comes across as unsupportable. And, as I noted earlier, a much longer term of study (e.g. 15 years or longer) would be needed in order for the authors to be suitably equipped to address the topic of long-term durability of LARS in the context of ACL reconstruction.
Michael Frind.
Knee Library http://factotem.org/library
Messages In This Thread
- LARS Study 2007 (views: 177) -- Becky Thomas -- Friday, 21 March 2008, at 10:49 a.m.
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