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The ''Ligamentization'' Process in Anterior Cruciate Ligament Reconstruction: What Happens to the
Human Graft? A Systematic Review of the Literature
Steven Claes, Peter Verdonk, Ramses Forsyth and Johan Bellemans
Am J Sports Med 2011 39: 2476 originally published online April 22, 2011
DOI: 10.1177/0363546511402662
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*Address correspondence to Dr Steven Claes, Department of Orthopedic Surgery and Traumatology, University Hospitals Leuven Campus,
Pellenberg, Weligerveld 1, B-3212 Pellenberg, Belgium (e-mail:
steven.claes@uzleuven.be).
y
Department of Orthopedic Surgery and Traumatology, University
Hospitals Leuven, Belgium.
z
Department of Orthopedic Surgery and Traumatology, University
Hospital Ghent, Belgium.
2476
Downloaded from ajs.sagepub.com at UNIVERSITE LAVAL on July 7, 2014
METHODS
Search Strategy
We performed a systematic review of the literature to identify all studies concerning the biology of a successfully
reconstructed human ACL. The PubMed, MEDLINE,
EMBASE, and Cochrane Library databases were searched
from their earliest entry points to April 4, 2010, including
articles published online as Epub ahead of print. The
computerized search was performed using combinations
of the following search terms: anterior cruciate ligament
2477
Selection
Searches were limited to English-language studies examining the healing of the intra-articular portion of the tendon
graft based on biopsies of this graft in a living human.
Reports exclusively focusing on the biology of graft-tunnel
incorporation were excluded. Reports on the biology of synthetic grafts used in human ACL reconstruction were
excluded as well. In addition, each reference list from the
identified articles was manually checked to verify that relevant articles were not missed for the current review.
Data Extraction
Each study was evaluated for the following variables:
study type; method of ACL reconstruction; type and origin
of grafted tendon; number of ACLs biopsied; technique,
site, and size of the biopsy; study method and techniques
used to examine the samples; number of control biopsy
samples of native tendon or ligament; interval between
ACL reconstruction and biopsy; and proposed ligamentization time frames. Relevant data from each included study
were extracted and recorded on multiple worksheets.
RESULTS
Study Identification
The initial computerized search using the aforementioned
search terms identified around 300 potentially relevant
articles. Review of all available abstracts revealed 30
articles that were retrieved for further evaluation. These
manuscripts were studied in detail and the reference lists
were cross-checked by hand in order not to miss a relevant
report. After this procedure, 24 articles discussing the biology of the reconstructed ACL based on tissue biopsies of
living humans could be withheld. Subsequently, 2 articles
reporting on biopsies of a ruptured reconstructed ACL
were excluded from the review,7,33 as were 4 articles
reporting on a single case.11,23,28,46 Finally, 9 studies without control biopsies of either native tendon or ligament
were excluded,2,9,22,24,26,34,39-41 as well as 5 studies not providing a ligamentization timescale.8,20,27,44,45 Therefore, 4
studies were determined to be appropriate for systematic
2478 Claes et al
Studies excluded (n = 6)
Reason: biopsies from tendon-bone
interface of the graft
Studies concerning human ACL reconstruction
with biopsies of the intra-articular
portion of the graft (n = 24)
Studies excluded (n = 2)
Reason: biopsies of ruptured grafts
Figure 1. The Quality of Reporting of Meta-analyses (QUOROM) flow diagram, depicting the number of studies identified,
included, and excluded, as well as the reasons for exclusion.29
review.1,13,35,37 The Quality of Reporting of Meta-analyses
(QUOROM)29 flow diagram depicts the number of studies
identified, included, and excluded as well as the reasons
for exclusion (Figure 1).
Study Characteristics
Two studies were conducted in the United States,13,35 1
study was conducted in Europe,37 and another in Japan.1
The ACL reconstruction procedures were performed
between 1984 and 2008. The mean number of ACLs biopsied per study is 31 (range, 21-43), with a total of 124
ACL biopsies. With regard to graft origin, none of the
included studies reports on allografts. Two of the included
studies consider bonepatellar tendonbone (BPTB) grafts
exclusively,1,35 1 study considered hamstring grafts,37 and
Study Quality
Assessment of the methodologic quality of these studies
revealed that there were no randomized controlled trials
(level of evidence 1). Moreover, no prospective studies
could be retrieved, probably because of the invasive nature
2479
TABLE 1
Primary Study Characteristicsa
Rougraff et al (1993)35
Study quality
Level of evidence
Primary surgery:
ACL reconstruction
Graft origin
Graft type
Abe et al (1993)1
Falconiero et al (1998)13
Sanchez et al (2010)37
Autograft
BPTB
Autograft
BPTB
Autograft
Hamstrings
Surgical technique
Technique not
mentioned
Graft fixation
Open technique
(n = 11)
Arthroscopically assisted
(n = 10)
Not mentioned
Autograft
Hamstrings (n = 8)
BPTB (n = 35)
Arthroscopically
assisted
Surgeon
Return to sports
Single surgeon
Full competition
from 3-6 mo
Not mentioned
Full competition
from 10-12 mo
Multiple surgeons
Full competition from
when the operative
leg was fully
rehabilitated
Unrelated knee
problems
(n = 19)
Volunteers (n = 4)
3 wk6.5 y
n = 23
Basket forceps
Middle segment
either central
or superficial
1-3 mm 3 10-20 mm
Screw removal
New intra-articular
pathology
6 wk15 mo
n = 21
Basket forceps
Midzone superficial
layer of the core
3 mo10 y
n = 43
Not mentioned
Midportion of the graft,
1 superficial, 1 deep
3-5 mm3
Not mentioned
Native ACLs at
TKA (n =8)
Native patellar
tendons (n = 7)
No
Light microscopy
Electron microscopy
Hematoxylin/eosin
Native ACLs (n = 5)
Native hamstring
tendons (n = 2)
Yes, blinded
Light microscopy
Yes, blinded
Light microscopy
Hematoxylin/eosin
Vascularity
Cellularity, cellular
shape, cellular
arrangement
Collagen orientation
Vascularity
Cellularity
Hematoxylin/eosin
Alcian blue
Vascularity
Cellularity, nuclear
shape, and orientation
Crimp patterns
Fiber pattern
Presence of
glycosaminoglycans
Crimp
Secondary surgery:
Biopsy procedure
Indication
Interval
No. biopsied ACLs
Biopsy technique
Biopsy site
Independent examiner
Study method
Specimen staining
techniques
Quantitative histology
Ligamentization stages
Periodicity of crimp
Polarization
4
Not mentioned
Metaplasia
Arthroscopically
assisted
Addition of PRGF
(n = 22)
Femur: transcondylar
screw
Tibia: bone plug and
2 metal staples
Not mentioned
Not mentioned
Unrelated knee
problems (n = 17)
Cyclops (n = 20)
6-25 mo
n = 37
Basket forceps
Standardized with the
device under medial
femoral condyle
3 mm 3 5-10 mm
a
ACL, anterior cruciate ligament; BPTB, bonepatellar tendonbone; PRGF, preparation rich in growth factors; TKA, total knee
arthroplasty.
2480 Claes et al
Biopsy Procedure
Mostly, the ACL biopsies were performed during secondlook arthroscopy at the time of hardware removal or
when addressing new unrelated knee injury such as meniscal tears or chondral lesions. Some subjects volunteered to
undergo a second-look arthroscopy for the sole purpose of
biopsy. In 1 paper,37 more than half of biopsy specimens
were obtained during an arthroscopy performed for ACLrelated symptoms (cyclops lesion), thus possibly compromising the representability of the specimens in this series.
Most authors used a standard 2.5-mm or 3-mm basket
forceps to perform the biopsy. With this technique, a superficial specimen of the reconstructed ACL could be obtained.
However, the spatial terminology of the biopsy zone differs
among these authors: . . .middle segment, either central or
superficial,35 . . .superficial layer of the core,1 or by positioning the forceps directly under the femoral condyle
thus enabling the forceps to reach the same area of the
graft at any time in all patients.37 Although 3 of 4
included reports mention the use of a comparable biopsy
device, the mean biopsy sample size between reports
ranged from 3 to 5 cubic millimeters to 1 to 3 3 10 to
20 mm. Although some of the included papers mention concerns regarding the potential deleterious effects of the
biopsy on graft integrity, such effects have not been witnessed during follow-up by any of these reports. However,
none of the studies have provided direct evidence of biopsy
site healing.
2481
Animals
38
Maturation
Early Remodeling
Humans
Early
Remodeling
Early
Maturation
Remodeling
Early
13
Maturation
Remodeling
Remodeling
12
Maturation
Early
Quiescent
15
37
Maturation
18
21
24
30
36
48
Figure 2. Differing ligamentization time frames in human grafts compared with a recent review of animal reports.38
animal models as described in a recent overview by Scheffler et al38 are shown as well.
The ligamentization end point is defined as the time
point from which no further changes are witnessed in the
remodeled grafts. Falconiero et al13 found no significant
differences in the histologic aspect of their 12-month grafts
compared with controls, concluding that ligamentization
occurs over a 12 month period with peak maturity evident
at 1 year. Rougraff et al,35 on the other hand, still
observed areas of degeneration, neovascularity, and hypercellularity until 3 years after reconstruction. From that
time on, these authors describe the grafts as quiescent
and similar to ACL controls. Abe et al1 state that the graft
is still undergoing the process of remodeling at 1 year after
surgery; however, these authors did not study grafts older
than 15 months. According to Sanchez et al,37 the grafts
reach maturity at around 2 years after surgery.
DISCUSSION
Much of the current knowledge on the biologic phenomena
occurring in the healing ACL graft have been derived
from numerous animal studies. To date, the literature has
been fueled by fairly large amounts of data from ACL reconstructed dogs, goats, sheep, rabbits, and monkeys. However,
no ideal animal ACL model has been developed so far, as is
reflected in this wide variety of studied animal species.
Moreover, when comparing the large amounts of animal
data with the scarce human biopsy studies, important differences have been revealed.38 For example, the timeline
of biologic graft changes between animals and humans
appears to be substantially different, with a much slower
remodeling activity in human grafts compared with animals
(Figure 2). On the other hand, some in vivo animal reports
found that the graft undergoes an early phase of vast necrosis occurring in the center of the graft,3,6 while this necrosis
was barely seen in human biopsy specimens. The same
important differences have been shown in nonbiopsy studies
using gadolinium- enhanced MRI. Howell et al21 could not
detect any revascularization except for the periligamentous
2482 Claes et al
whether it had undergone degeneration and became acellular over time. Clearly, a better understanding of the graft
biology in human ACL reconstruction will depend on the
possibility to obtain core biopsy samples of these grafts.
Accordingly, probably the key finding of this systematic
review is that although ACL reconstruction is performed
as a routine surgical procedure all around the world, the
underlying ligamentization process is still poorly understood in the human knee. Further human studies are
needed to understand normal graft healing after ACL
reconstruction.
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