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IN-VIVO, BILATERAL KNEE KINEMATICS IN GOATS WITH UNILATERAL ANTERIOR CRUCIATE LIGAMENT DEFICIENCY
By
ANA LUISA BASCUÑÁN
A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE
UNIVERSITY OF FLORIDA
2018
© 2018 Ana Luisa Bascuñán
To Jolene, Billie Jean, Lucy, Roxanne, Janie, Sally, Caroline, and Eileen
4
ACKNOWLEDGMENTS
I would like to thank my amazing family and friends for supporting me endlessly,
especially over the last three years as I completed this project. I would not have
accomplished a fraction of this without you.
I would also like to thank my mentors for this project – Dr. Stanley Kim, Dr.
Daniel Lewis, Dr. Scott Banks, and Dr. Adam Biedrzycki – who have guided and
encouraged me while continuously demonstrating kindness and patience throughout
this process. I admire each of them in their ability to maintain a sense of humor and in
their intellectual curiosity towards translational animal research.
Lastly, I would like to thank Mariajesus Soula, Kristina Millar, Catherine Monger,
and Debby Sundstrom for their tireless efforts in data collection, data analysis, and
manuscript preparation. Special thanks go to Cat for adopting our eight beautiful goats
and providing them a happy farm to live out the rest of their days after the project
concluded.
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TABLE OF CONTENTS page
ACKNOWLEDGMENTS ...................................................................................................... 4
LIST OF TABLES ................................................................................................................ 8
LIST OF FIGURES .............................................................................................................. 9
LIST OF ABBREVIATIONS ............................................................................................... 11
ABSTRACT ........................................................................................................................ 12
CHAPTER
1 LARGE ANIMAL TRANSLATIONAL MODELS FOR ANTERIOR CRUCIATE LIGAMENT RESEARCH ............................................................................................ 14
Introduction ................................................................................................................. 14 Anatomy ...................................................................................................................... 15
Human .................................................................................................................. 15 Canine .................................................................................................................. 16 Caprine ................................................................................................................. 17 Ovine .................................................................................................................... 18 Porcine.................................................................................................................. 19 Laprine .................................................................................................................. 20
Pathology .................................................................................................................... 21 Human .................................................................................................................. 21 Canine .................................................................................................................. 22 Caprine ................................................................................................................. 23 Ovine .................................................................................................................... 23 Porcine.................................................................................................................. 24 Laprine .................................................................................................................. 24
Biomechanics - Structural and Mechanical Properties .............................................. 25 Human .................................................................................................................. 25 Canine .................................................................................................................. 26 Caprine ................................................................................................................. 27 Ovine .................................................................................................................... 27 Porcine.................................................................................................................. 28 Laprine .................................................................................................................. 29
Biomechanics - Kinematics ........................................................................................ 30 Human .................................................................................................................. 31 Canine .................................................................................................................. 32 Caprine ................................................................................................................. 33 Ovine .................................................................................................................... 34 Porcine.................................................................................................................. 35 Laprine .................................................................................................................. 35
6
Conclusion................................................................................................................... 36 Figures and Tables ..................................................................................................... 37
2 IN-VIVO THREE-DIMENSIONAL KNEE KINEMATICS IN GOATS WITH ANTERIOR CRUCIATE LIGAMENT DEFICIENCY .................................................. 40
Introduction ................................................................................................................. 40 Materials and Methods ............................................................................................... 42
Procedures and Data Collection .......................................................................... 42 Tantalum bead placement ............................................................................. 42 Computed tomography .................................................................................. 43 Fluoroscopy ................................................................................................... 43 Force platform analysis ................................................................................. 44 Knee arthroscopy and ACL transection ........................................................ 44 Post-operative data collection ....................................................................... 45 End point criteria ............................................................................................ 45
Kinematic Data Processing .................................................................................. 45 Bone-model reconstruction ........................................................................... 45 2D to 3D registration ...................................................................................... 45 Calculation of joint kinematics ....................................................................... 46 Tibial plateau angle measurement ................................................................ 46
Statistical Analysis................................................................................................ 47 Results ........................................................................................................................ 48
Force Platform ...................................................................................................... 48 Kinematics ............................................................................................................ 48 Tibial Plateau Angle ............................................................................................. 50
Discussion ................................................................................................................... 50 Conclusions ................................................................................................................. 55 Figures ........................................................................................................................ 56
3 IN-VIVO THREE-DIMENSIONAL KNEE KINEMATICS OF THE UNAFFECTED KNEE IN GOATS WITH UNILATERAL ANTERIOR CRUCIATE LIGAMENT DEFICIENCY .............................................................................................................. 69
Introduction ................................................................................................................. 69 Materials and Methods ............................................................................................... 71
Procedures and Data Collection .......................................................................... 71 Tantalum bead placement ............................................................................. 71 Computed tomography .................................................................................. 71 Fluoroscopy ................................................................................................... 72 Force platform analysis ................................................................................. 72 Contralateral knee arthroscopy and ACL transection................................... 73 Post-operative data collection ....................................................................... 73 End point criteria ............................................................................................ 73
Kinematic Data Processing .................................................................................. 73 Bone-model reconstruction ........................................................................... 73 2D to 3D registration ...................................................................................... 73
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Calculation of joint kinematics ....................................................................... 74 Statistical Analysis................................................................................................ 74
Results ........................................................................................................................ 75 Force Platform ...................................................................................................... 75 Kinematics ............................................................................................................ 75
Discussion ................................................................................................................... 77 Conclusions ................................................................................................................. 81 Figures ........................................................................................................................ 82
4 SUMMARY .................................................................................................................. 94
LIST OF REFERENCES ................................................................................................... 96
BIOGRAPHICAL SKETCH ..............................................................................................108
8
LIST OF TABLES
Table page 1-1 Comparison of anatomic characteristics between humans and large animal
translational models ............................................................................................... 38
1-2 Comparison of pathologic characteristics between humans and large animal translational models ............................................................................................... 38
1-3 Comparison of biomechanical characteristics between humans and large animal translational models.................................................................................... 39
9
LIST OF FIGURES
Figure page 1-1 Cartesian coordinate system applied to the knee for analysis of kinematic
parameters. ............................................................................................................. 37
2-1 3D bone models of a goat limb (femur and tibia) with tantalum beads implanted. ............................................................................................................... 56
2-2 A- Lateral projection fluoroscopic image of the right knee of a goat during a treadmill walking gait. B- Shape matching: 3D bone models superimposed over fluoroscopic image ......................................................................................... 57
2-3 Body weight normalized mean peak vertical force (100*N/N) of the hind limbs during stance phase of a walking gait.. ................................................................. 58
2-4 Mean flexion angle throughout stance phase of gait before and after ACL transection. ............................................................................................................. 60
2-5 Mean flexion angle throughout swing phase of gait before and after ACL transection.. ............................................................................................................ 61
2-6 Mean anterior tibial translation in millimeters throughout stance phase of gait before and after ACL transection.. ......................................................................... 62
2-7 Mean anterior tibial translation in millimeters throughout swing phase of gait before and after ACL transection ........................................................................... 63
2-8 Mean axial rotation throughout stance phase of gait before and after ACL transection .............................................................................................................. 64
2-9 Mean axial rotation throughout swing phase of gait before and after ACL transection. ............................................................................................................. 65
2-10 Mean abduction angle throughout stance phase of gait before and after ACL transection.. ............................................................................................................ 66
2-11 Mean abduction angle throughout swing phase of gait before and after ACL transection. ............................................................................................................. 67
2-12 Measurement of tibial plateau angle from the computed tomographic scan of a goat hind limb. ..................................................................................................... 68
3-1 3D bone models of a goat limb (femur and tibia) with tantalum beads implanted.. .............................................................................................................. 82
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3-2 A- Lateral projection fluoroscopic image of the right knee of a goat during a treadmill walking gait. B- Shape matching: 3D bone models superimposed over fluoroscopic image. ........................................................................................ 83
3-3 Body weight normalized mean peak vertical force (100*N/N) of the hind limbs during stance phase of a walking gait.. ................................................................. 84
3-4 Mean flexion angle of the unaffected knee throughout stance phase of gait before and after contralateral ACL transection ...................................................... 86
3-5 Mean flexion angle of the unaffected knee throughout swing phase of gait before and after contralateral ACL transection...................................................... 87
3-6 Mean anterior tibial translation in millimeters of the unaffected knee throughout stance phase of gait before and after contralateral ACL transection .............................................................................................................. 88
3-7 Mean anterior tibial translation in millimeters of the unaffected knee throughout swing phase of gait before and after contralateral ACL transection. ............................................................................................................. 89
3-8 Mean axial rotation of the unaffected knee throughout stance phase of gait before and after contralateral ACL transection...................................................... 90
3-9 Mean axial rotation of the unaffected knee throughout swing phase of gait before and after contralateral ACL transection...................................................... 91
3-10 Mean abduction angle of the unaffected knee throughout stance phase of gait before and after contralateral ACL transection ............................................... 92
3-11 Mean abduction angle of the unaffected knee throughout swing phase of gait before and after contralateral ACL transection...................................................... 93
11
LIST OF ABBREVIATIONS
ACL Anterior cruciate ligament
ATT Anterior tibial translation
CT Computed tomography
3D
2D
Three-dimensional
Two-dimensional
12
Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Master of Science
IN-VIVO, BILATERAL KNEE KINEMATICS IN GOATS WITH UNILATERAL ANTERIOR CRUCIATE LIGAMENT DEFICIENCY
By
Ana Luisa Bascuñán
August 2018
Chair: Stanley Kim Major: Veterinary Medical Sciences
The goat is a popular translational animal model in ACL research, however the
normal and abnormal in-vivo kinematics associated with ACL transection have not been
previously described in this species. Three-dimensional knee kinematics were
determined before after unilateral ACL transection, in both the affected and the
unaffected knee of eight goats. Kinematics and force platform data were compared
between baseline and three post-operative time points to determine the effect of ACL
transection on the goat knee over time. Transient right hind limb lameness was noted in
all goats following ACL transection, but resolved by 6 weeks post ACL transection.
Increased extension of approximately 15 degrees was noted in both the affected and
unaffected knees by 3 months post ACL transection, in a bilaterally symmetric pattern.
Anterior tibial translation in the affected knee increased by approximately 4 mm after
ACL transection and persisted over the six month study period. No changes in axial
rotation or abduction angle developed in either knee. The results of these studies
demonstrate that ACL transection in the goat results in persistent kinematic alterations
in both the affected and unaffected knee, and yet the associated lameness appears to
resolve by 6 weeks following ACL transection. These kinematic changes should be
13
considered in future studies utilizing the goat as a translational animal model in ACL
research, as altered kinematics may affect outcome of ACL reconstruction or other
investigations into the goat ACL.
14
CHAPTER 1 LARGE ANIMAL TRANSLATIONAL MODELS FOR ANTERIOR CRUCIATE
LIGAMENT RESEARCH
Introduction
Large animal (non-rodent mammal) models are commonly used in translational
orthopedic research, as many experimental or invasive investigative methods are not
considered ethical or feasible in humans. There are several large animal species that
have been used to study the anterior cruciate ligament (ACL), and no species is
currently considered the gold standard as a translational model.(1) Each large animal
model has benefits and potential limitations, which should be carefully considered in
designing and interpreting results of individual studies. When selecting a large animal
translational model for ACL research, important considerations include anatomical
differences, the natural course of ACL pathology in that species, biomechanical
differences (particularly given the quadruped gait), as well as costs and societal
concerns. The purpose of this article is to review the current literature regarding
anatomy, pathology, and biomechanics for commonly utilized large animal models in
ACL research and to highlight advantages and disadvantages of each model within
these subjects. A brief review of human ACL characteristics is included for comparison.
This information may be useful in the selection process when designing future studies.
While terminology differences exist between animal models and humans (i.e. stifle joint
vs. knee), human terminology is used throughout this review for consistency in
comparison.
15
Anatomy
Anatomic similarity is an important consideration when selecting a large animal
model for ACL research, as even minor differences in anatomy may limit the value of
the study when translating findings to the human knee.
Human
The human ACL is anatomically divided into distinct bundles - the number of
which varies between two and six depending on the report.(2-5) A recent, detailed
anatomical exploration divided the human ACL into three bundles - the anteromedial
(AM), intermediate (IM), and posterolateral (PL) - which are named for their tibial
insertions.(2) The femoral origin of the AM bundle extends to the rim of posterior
condylar cartilage and lies posterior to the origins of the IM and PL bundles.(2) The IM
and PL bundles share a similar femoral origin, which lies anterior to the AM bundle
origin and posterior to the intercondylar ridge.(2) The tibial insertion sites of the three
bundles follow their respective names, with the AM bundle inserting along the edge of
the medial tibial plateau articular cartilage and the IM and PL bundles inserting laterally
and posteriorly to the AM bundle.(2) The collective tibial insertion of the human ACL is
medial to, but not separated by, the anterior insertion of the lateral meniscus.(6)
Vascular supply to the human ACL is primarily derived from the middle genicular
artery, a branch of the popliteal artery.(7, 8) The infrapatellar ramifications of the inferior
genicular arteries provide a minor contribution to the vascularity of the distal ACL.(8)
Innervation of the human ACL is reported to arise from the posterior articular branch of
the sural nerve(7); however this observation is not consistent in all literature. Another
report identifies innervation to the ACL arising from the anterior articular branches of the
femoral, saphenous, and common fibular nerves.(9)
16
The topography of the tibial plateau in humans, particularly the slope of the
plateau in the sagittal plane, differs greatly from the quadruped tibial anatomy described
below. A recent, large scale, osteological study reported that the tibial plateau of the
human slopes posteriorly at an mean angle of 7 ± 4 degrees along the medial condyle
and 5 ± 4 degrees along the lateral condyle.(10) An earlier study reported the opposite
pattern, with a slope of 4 - 6 degrees along the medial condyle and 5 - 7 degrees along
the lateral condyle, varying by subject sex.(11) Another potentially significant anatomic
discrepancy is the concavity of the medial tibial condylar surface in humans, which is
not observed in any large animal models. Hashemi et al. (2008) measured a mean
depth of 3 mm in the medial tibial plateau and suggested that this may add additional
resistance to anterior tibial translation.(11) The mean medial to lateral width of the
human tibial plateau is 76 ± 5 mm.(12) This dimension will be used in a comparison of
overall knee size between the models.
Canine
The dog ACL is comprised of only two bundles - the smaller, AM bundle and the
larger, PL bundle.(13) The femoral origin of the canine ACL is fan shaped, and located
at the posteromedial edge of the lateral condyle.(6, 14) Tibial insertion of the dog ACL
lies along the medial slope of the intercondylar eminence, and is not separated by the
anterior attachment of the lateral meniscus.(6) While the dog differs from the human in
the number of bundles comprising the ACL, its similarity in tibial insertion offers an
advantage when considering reconstructive techniques, which often involve tunnel
placement at the tibial insertion site.
Vascular supply to the dog ACL arises from branches of the medial and lateral
genicular arteries, the popliteal artery, and from a branch of the descending genicular
17
artery that travels caudally.(14) Innervation is derived from the saphenous, common
fibular, and tibial nerves.(15)
Tibial plateau anatomy of the dog differs greatly from the human, as it is sloped
posteriorly with an average angle of 24 ± 4 degrees.(16) This anatomical difference is
associated with biomechanical consequences (discussed below), and is noted to some
degree in all of the large animal translational models. Sabanci et al. (2014) evaluated
the differential condylar slopes in the dog and reported a steeper slope in the lateral
compartment (26 ± 4 degrees) compared to the medial compartment (24 ± 3
degrees)(17). This pattern is similar to that reported by Hashemi et al. (2008) in the
human knee(11), however the magnitude of the slopes are markedly higher. The dog is
the second smallest species that is used as a large animal translational model, having a
tibial plateau width of 36 mm.(6)
Caprine
The caprine ACL is comprised of three distinct bundles: the AM, IM, and PL
bundles.(18) The femoral origins of the AM, IM, and PL bundles in the goat follow the
same pattern as that described in the human.(2) The tibial insertion of the goat ACL was
found in two separate studies to be split by the anterior horn of the lateral meniscus into
the AM and PL/IM bundles.(2, 18) A third study found that the lateral meniscus passed
posterior to the ACL insertion in the goat, suggesting that the goat has the most
anatomically similar tibial insertion to a human.(6)
A detailed description of the arterial supply to the goat hind limb has been
published, but circulation to the ACL was not specifically mentioned.(19) In that report,
the descending genicular artery gives off a branch which courses caudally at the level of
the tibial tuberosity, and is stated to supply the joint capsule at this level.(19) Innervation
18
of the ACL has not been specifically reported in this species. A study evaluating femoral
and sciatic nerve block in goats undergoing knee arthrotomy demonstrated improved
analgesia in goats that received the blocks vs. control animals, suggesting that
innervation to the knee arises from branches of one or both of these nerves.(20)
The mean tibial plateau angle in goats has not been specifically evaluated, but
was reported to be 20 degrees in the methods section of a study evaluating the
sensitivity of a transducer to measure forces in the goat ACL.(21) No methodology or
sample size was given with the reported tibial plateau angle, so it should be interpreted
with caution. The overall knee size in the goat is larger than that of the dog, and the
average tibial plateau width is 44 mm, approximately 60% that of a human knee.(6, 22)
Ovine
The ACL of the sheep is comprised of only two distinct bundles (AM and PL).(23)
The femoral origin of the ovine ACL is oval shaped and located at the posteromedial
edge of the lateral femoral condyle.(6, 23) The tibial insertions of the AM and PL
bundles are split by the intermeniscal ligament or the anterior insertion of the lateral
meniscus.(6, 23) The AM bundle of the sheep inserts at the medial aspect of the
intercondylar eminence and the PL bundle inserts on the lateral aspect of the medial
tibial spine, deep to the AM bundle.(6) The splitting of the ACL tibial insertion sites
differs from the human and raises question as to the correct placement of the tibial bone
tunnel in reconstructive techniques.
Vascular supply to the ovine ACL is derived from the middle genicular and
descending genicular arteries.(24) The ovine ACL is innervated by the posterior articular
nerve, a branch of the tibial nerve.(25)
19
The ovine tibial plateau angle is reported to be 20 ± 3 degrees, based on a
cadaveric assessment of 16 sheep.(23) The medial-lateral tibial plateau width in the
sheep measures a mean of 52 ± 2 mm, which is on average 68% that of the human.(12)
The sheep (with the same tibial plateau width as the pig) is the largest of the animal
models and therefore most similar to human in overall size.
Porcine
The pig ACL was originally reported as two distinct bundles (AM and PL), which
are separated on insertion by the anterior insertion of the lateral meniscus.(6, 26, 27) A
more recent anatomical evaluation identified the IM bundle in addition to the AM and PL
bundles in the pig.(2) The femoral origins of the AM, IM, and PL bundles in the pig
follow the same pattern as that described in the human.(2, 26) The insertion points of
the three ACL bundles in the pig are similar to that of the sheep since they have a split
insertion (2, 6), therefore raising the question as to correct tibial tunnel placement in
ACL reconstruction in the pig.
The vascular supply to the ACL has not been specifically reported in pigs, but the
pig has been used in an investigation of vascular response of the middle genicular
artery to exercise.(28) In that study the middle genicular artery was described as “a
major blood supplier to the knee joint”.(28) Similar to the vascular supply, innervation to
the porcine cruciate ligaments has not been specifically described. A recent study
evaluated the anatomic location and structural properties of porcine peripheral nerves
and concluded that the general nerve branching was consistent with that of the human
lower extremity.(29)
There are no published reports establishing the mean porcine tibial plateau
angle. A study by Cone et al. (2017) evaluated the angle between the porcine ACL and
20
the tibial plateau in growing pigs, demonstrating an increasing angle in the sagittal plane
throughout late adolescence.(30) The magnitude of this angle increase in pigs (30°) is
somewhat larger than is observed in human adolescents (20° increase), suggesting that
pigs may have a steeper tibial plateau angle than humans, similar to other
quadrupeds.(30, 31) The pig has a wide tibial plateau, similar to the sheep, with the
width being most similar to humans in overall size.(6) After normalization for tibial
plateau width, the porcine ACL was significantly longer than that of the human.(6) This
difference in ACL length was not observed in the sheep or other large animal models,
and may have undetermined biomechanical consequences.
Laprine
Distinct bundles of the ACL have not been identified in the rabbit.(6) The femoral
origin of the laprine ACL is located at the posteromedial border of the lateral femoral
condyle, as in the human and other quadrupeds.(6) The tibial insertion site is centered
on the tibial intercondylar eminences, posterior to the insertion of the anterior horn of
the lateral meniscus.(6) Because only one bundle is identified, one could argue that the
rabbit ACL is the least anatomically similar to the human of all the large animal models.
The rabbit ACL has been described as relatively poorly vascularized compared to
that of the human, with only a single artery, the middle geniculate, perforating the
anterior aspect of the ACL.(32) Another report confirms the primary blood supply as the
middle geniculate artery, and also stated that grossly visible vessels did not consistently
cover the entire ligament.(33) Innervation of the laprine ACL has not been specifically
reported.(34)
The tibial plateau is convex and posteriorly sloped in the rabbit, more
pronouncedly than in the human.(35) A recent evaluation of tibial growth alteration in
21
the rabbit demonstrated the average tibial plateau angle in the control limb to be 24 ± 5
degrees along the medial aspect and 28 ± 3 degrees along the lateral aspect.(36) The
rabbit tibial plateau width is also the smallest of the large animal models, measuring an
average of just 17 mm.(6)
Pathology
ACL pathology occurs naturally in humans and in select large animal models.
Mechanism of ACL injury is an important consideration when evaluating literature and
its translational value to the human knee. In the majority of large animal studies, the
ACL is transected surgically. The resultant pathology in these studies may or may not
translate directly to the human knee, as the joint environment preceding and following
naturally occurring ACL pathology is likely to differ from that following surgical ACL
transection. Another important consideration is how readily degenerative joint disease
develops as a consequence of ACL transection in these animals, as this will affect
outcome measures when evaluating the success of surgical procedures and other
treatment techniques.
Human
Naturally occurring ACL injury is common in humans, with acute, non-contact
traumatic injury being the most common mechanism of injury.(37) The incidence of ACL
injury in a sample of 7,769 sports-related knee injuries was 1,580 or 20%.(38) Chronic
ACL injury is associated with an increased risk of meniscal injury.(39) The long-term
(10-20 year) risk of developing osteoarthritis secondary to ACL injury (with or without
surgical stabilization) in the human patient is 50%.(39) This finding is not reflective of
the large animal translational models, which tend to develop degenerative changes
more reliably than the human.
22
Canine
In contrast to other translational animal models, naturally occurring ACL
pathology is a common clinical condition that affects the dog. A small percentage of
dogs experience ACL injury secondary to an acute, traumatic event, whereas the
majority of ACL disease in dogs involves chronic degeneration.(15, 40) Dogs are
believed to have both biomechanical and biological factors that predispose or subject
animals to ACL rupture.(40) Potential biomechanical risk factors include the slope of the
tibial plateau predisposing to increased shear force, femoral torsion, imbalance of
muscular forces, hypermobile menisci, and joint incongruity.(40-42) Potential biological
risk factors include genetic predisposition, immune-mediated or infectious inflammatory
disease, and hormonal and metabolic causes, including those induced by early
spay/neuter.(40) It is unknown whether abnormal biomechanics or abnormal biology (or
both) is responsible for the high prevalence of naturally occurring ACL pathology in the
dog, but it is a striking difference between the dog and the other large animal models
and therefore an important consideration. ACL research performed in the dog is
inevitably confounded by the abnormal biomechanics and/or biology that the native ACL
is subjected to in this species.
Canine ACL deficiency is a well-established model of evoking degenerative joint
disease (Pond Nuki model), as degenerative changes reliably appear in this species
within weeks of ACL transection.(43) Inflammatory cells, degradation enzymes, and
anti-collagen antibodies have been demonstrated in the knee in various studies of ACL
deficiency in the dog.(40) The reliable course of degenerative joint disease in the dog
can be considered either a benefit or a limitation of this animal model, and degeneration
progresses much more rapidly than in the human.
23
Caprine
Naturally occurring ACL pathology is an uncommon clinical problem in the goat.
Interestingly, the development of degenerative joint disease following ACL transection
has been reported to be inconsistent in this species.(44-47) In a study by Jackson et al.
(1999), compensatory changes in other structural stabilizers of the stifle occurred with
chronic ACL deficiency.(44) An increase in the cross-sectional area and volume of the
posterior horn of the medial meniscus, as well as thickening of the joint capsule and
capsule attachments was observed 8 months after ACL transection.(44) Degenerative
changes on gross examination of the stifle were limited to the medial femoral
condyle.(44) In a study of degenerative changes in skeletally immature goats following
ACL transection, macroscopic medial meniscal lesions and articular cartilage softening
was first noted at 6 months post-ACL transection.(45) This is in contrast to a similar
study performed in young goats, which demonstrated no degenerative changes at 8
months post-ACL transection despite persistent stifle instability.(46) In a fourth study
focusing on ACL reconstruction, lameness resolved within 6 weeks but degenerative
changes affecting 20-40% of the surfaces of the patellar and femoral sulcus developed
after 3 months in a control group which did not undergo ACL reconstruction.(47) Goats
may be a preferred animal model over dogs for evaluating the outcome of various
reconstruction techniques, since the goat appears to develop osteoarthritis more slowly
than the dog and the graft material may be exposed a less hostile environment than in
the dog.
Ovine
Naturally occurring ACL pathology is an uncommon clinical problem in sheep.
Osteoarthritis is thought to develop relatively slowly in sheep with experimental ligament
24
transection.(48) In a prospective study of ACL transection followed by immediate
reconstruction of the native ACL, by 20 weeks the operated sheep had significantly
higher cartilage damage and osteophytosis scores compared to non-operated control
animals.(49) Similar to goats, the sheep can be considered one of the large animal
models to develop degenerative joint disease more slowly than other species.
Porcine
Naturally occurring ACL pathology is an uncommon clinical problem in pigs. The
pig appears to be a popular model for the study of gene expression in osteoarthritis
following ACL transection, with fewer reports on the development of macroscopic
disease.(50-52) Macroscopically, there is one study which suggests that pigs are slow
to develop degenerative change within the menisci, with no visible signs of meniscal
degeneration on magnetic resonance imaging 26 weeks following ACL transection.(53)
A study of cartilage degeneration, however, noted gross cartilage irregularity as early as
4 weeks following ACL transection, which was also detected on magnetic resonance
imaging.(54) Although this finding suggests that pigs are one of the faster large animal
models to develop degenerative joint disease following ACL transection, magnetic
resonance imaging is particularly sensitive at detecting joint pathology. Additional
studies are needed to elucidate the course of macroscopic degenerative joint disease in
the pig.
Laprine
Naturally occurring ACL pathology is not commonly reported in the rabbit,
although a retrospective review of laprine radiographs revealed that 21% of non-clinical
rabbits had radiographic evidence of osteoarthritis in the knee.(55) This suggests that
there could be a population of rabbits with subclinical ACL or other knee injury.
25
Following unilateral ACL transection in the rabbit, degenerative changes were noted to
primarily affect the femoral condylar cartilage four weeks after ACL transection.(56) In
another report of unilateral ACL transection in the rabbit, gross morphological changes
including synovial hyperplasia, capsular thickening, and bucket handle medial meniscal
tears were observed in all operated knees at six weeks post-operatively.(57)
Biomechanics - Structural and Mechanical Properties
Beyond the physical division of the ACL into separate anatomical bundles, it is
generally accepted that each bundle serves different functions within the knee.
Biomechanical evaluations performed in several species have established that
individual bundles are differentially taut as the knee flexes across the arc of motion.
Additionally, tensile properties of the native ACL have been established in the large
animal models discussed. These characteristics should be considered when selecting a
large animal model for translational ACL studies, as the forces acting on the ACL would
ideally be similar to those experienced in the human knee.
Human
Functional studies of the human ACL have shown that the AM bundle is taut in
flexion and the PL bundle is taut in extension.(3, 58) The IM bundle, while anatomically
distinct, has not been shown to have a major biomechanical contribution to knee
stability.(3) The distance between the center of the femoral origin and tibial insertion of
the ACL was shown to be isometric during passive flexion and extension in cadaveric
specimens.(59)
The mean ultimate load and stiffness of the femur-ACL-tibia complex in human
specimens aged 22-35 years was 2,160 ± 157 N and 242 ± 28 N/mm, respectively.(60)
Mean ultimate stress, which takes into account the cross-sectional area of the ACL, was
26
36 ± 2 MPa in the human femur-ACL-tibia complex.(61) Tensile properties of the human
ACL have been shown to decrease with increasing age.(60)
Canine
The AM bundle of the canine ACL is taut in both flexion and extension, whereas
the PL bundle is only taut in extension.(13) This pattern differs from that of the human,
indicating an increased dependence on the AM bundle for stability throughout range of
motion in the canine knee.
Butler et al. (1983) examined tensile properties of the native, intact ACL in a
study evaluating ACL reconstruction in dogs. Mean ultimate load at failure of the native
ACL ranged from 1264 - 2091 N, depending on the time point after contralateral ACL
reconstruction.(62) Mean ultimate stress ranged from 128 - 159 MPa, depending on
post-operative time point.(62) Mean stiffness ranged from 260 - 417 N/mm in the native
ACL, again varying by time point.(62) These findings were confirmed in a second
evaluation of canine ACL tensile properties, which reported similar mean ultimate load
(1867 ± 324 N) and stiffness (201 ± 41 N/mm) of the native ACL.(63) The similarity in
mean ultimate load and stiffness between the dog and the human ACL is interesting
given that the dog is much smaller than the human. This is reflected in the markedly
higher mean ultimate stress of the dog ACL relative to the human ACL, as cross-
sectional area is taken into account in this metric. The differential in size and strength
suggests that the canine ACL is under relatively more stress than the human ACL
throughout normal activity. This may offer a comparative advantage of the dog over the
other large animal models in that evaluation of tensile properties in ACL reconstruction
can be easily translated from the dog to the human.
27
Caprine
In a study of caprine ACL biomechanics reported by Tischer et al. (2009), the AM
bundle carried the majority of the load, except at 30 degrees flexion, when the PL band
shared in load transfer. These findings led Tischer et al. to conclude that the functions
of the goat ACL are similar to that of the human, in which the PL bundle is taut in
extension and the AM bundle is taut in flexion, however stability of the goat knee is
purportedly more dependent on the AM bundle than the human knee.(64) The IM
bundle in the goat was found to play only a minor role in limiting anterior tibial
translation and rotation compared to the AM and PL bundles, similar to that reported in
the human knee.(64)
Zantop et al. (2008) established tensile properties of the caprine ACL. Mean
ultimate load (462 ± 20 N), stiffness (48 ± 11 N/mm), and stress (15 ± 2 N/mm2) of the
intact goat ACL(65) are markedly less than that reported in humans and dogs(60-63).
The underlying reason for the relatively low tensile strength of the goat ACL compared
to the human is unknown and is worthy of further research.
Ovine
Zhao et al. (2015) evaluated the crimp pattern of the ovine ACL at various
flexion/extension angles as a means of assessing contribution of each bundle to stability
of the knee. Based on a loss of crimp pattern, the AM bundle was found to be most
active during stance phase when the knee is extended and the PL bundle was found to
be least active during stance.(66) A portion of the AM bundle remained active in all
positions, whereas the PL bundle appeared to be active in the maximal extension and
flexion positions.(66) The conclusion was that the PL bundle provides stability during
motion in other planes, such as internal-external rotation, although this kinematic
28
parameter was not specifically evaluated.(66) The finding that the AM bundle is active in
all positions suggests a similarity between sheep, dogs, and goats, where an increased
dependence on the AM bundle is noted compared to humans.
In an evaluation of in situ forces on the ACL during anterior tibial load application,
both the magnitude and direction of force in the sheep ACL was significantly different
than that of the human ACL.(27) The sheep ACL carried less force at both 50N and
100N compared to the human ACL, and the force direction tended to propagate more
posteriorly in the sheep.(27) It was postulated in that report that these differences were
due to the anatomical variations between humans and sheep, including the division of
insertion of the AM and PL bundles.(27) It is important to note, however, that this
division is present in other animal models (notably the pig), which have more similar in
situ force patterns to human knees.
Mean ultimate load to failure ranged from 1200 - 2580 N in a study evaluating
tensile properties of the ovine femur-ACL-tibia complex, including both interstitial
failures and avulsion failures.(67) In the same study, mean ultimate stress ranged from
60 - 123 MPa, which is markedly higher than that of the human ACL, and more similar
to the dog.(61, 62, 67) Mean ACL stiffness has not been reported in this species.
Porcine
An early study stated that the PL bundle of the porcine ACL was found to be taut
in both flexion and extension, whereas the AM bundle was found to be taut only in
extension.(26) This pattern was not supported by a more recent investigation by Kato et
al. (2010), which demonstrated that the porcine AM bundle carried the majority of in situ
forces at all flexion angles.(68) That study concluded that the AM and PL bundles of the
29
porcine ACL have similar roles to those bundles in the human knee, and that the IM
bundle has a relatively minor contribution to knee stability.(68)
The pig was found to be most similar to humans (compared to goat and sheep) in
magnitude and direction of in situ ACL forces when an anterior tibial load was
applied.(27) Mean ultimate load of the intact porcine ACL in a femur-ACL-tibia complex
has been reported as 1266 ± 250 N(69) and 770 ± 105 N(70) in two different studies.
Stiffness of the native ACL in the pig was reported to be 94 ± 16 N/mm.(70) Mean
ultimate stress in the pig femur–anterior cruciate ligament–tibia complex was reported to
be 32 ± 16 MPa in a separate study.(71) The mean ultimate load and stiffness values
are markedly less than the reported tensile properties in the human, however the mean
ultimate stress is more similar, suggesting that, when corrected for the smaller size of
the pig ACL, it is similar in strength to the human ACL.
Laprine
Anatomically the rabbit ACL is described as a single bundle(6), therefore
descriptions of differential function dependent on knee flexion angle are not found in this
species. In a cadaveric evaluation of the rabbit knee during hopping, the posterior
cruciate and lateral collateral ligaments were found to be the primary stabilizers of the
knee, while the ACL sustained only minimal loads during early stance phase.(72) This
finding suggests that the rabbit does not depend on the ACL for stability in the same
manner as a human or the other commonly studied quadrupeds.
Consistent with its small size, the reported mean ultimate load (approximately
350 N) and stiffness (approximately 150 N/mm) in the rabbit ACL(73) is much less than
that of the human ACL. The mean ultimate load was found to be independent of knee
flexion angle when tested along the ligament’s axis, whereas stiffness was found to be
30
significantly increased at 90 degrees of flexion compared to 0 degrees.(73) Mean
ultimate stress of the rabbit ACL was 69 ± 7 MPa(74), which is markedly higher than
that of the human ACL.(61) This suggests that the rabbit ACL experiences increased
load during normal activity than the human ACL, which could be ascribed to differences
in gait (hopping vs. walking) and knee rotational range of motion (increased rotational
range in the rabbit, see below).(75)
Biomechanics - Kinematics
A joint coordinate system to calculate three dimensional, in vivo kinematics of the
knee was described by Grood and Suntay (1983). Motion of the knee is described in six
degrees of freedom: flexion/extension, abduction/adduction, internal/external tibial
rotation, medial/lateral translation, anterior/posterior translation, and proximal/distal
translation.(76) A Cartesian coordinate system (Figure 1), which allows precise,
quantitative measurements of kinematic parameters, has been applied to humans and
the large animal models to evaluate kinematic changes following ACL injury or
transection. The femoral and tibial origin points, which are used for calculation of
translations and rotations, are based on the mechanical axis of the bone(76), as well as
relevant anatomical landmarks such as the origin/insertion points of the ACL(77).
An important distinction exists between measurements of passive laxity that
quantify knee motion in a sedated or anesthetized animal or cadaveric tissues vs.
measurements of dynamic, functional stability of the joint obtained in an awake, weight-
bearing animal.(78) ACL injury or transection almost always results in increased knee
laxity; however, the subject may be able to dynamically stabilize their knee by
alterations in the degree of weight-bearing and regional muscle activity.(78) In the
31
following section, tests of laxity and analyses of dynamic motion are reviewed, and care
should be taken in comparing them directly.
Human
The ACL was determined to be the primary restraint against anterior tibial
translation (ATT) in the cadaveric human knees, providing an average of 86% of the
total resisting force at 5 mm of ATT.(79) A study by Girgis et al (1975) reported an
average increase in ATT from 7 mm to 13 mm following ACL transection in cadaveric
specimens.(80) The effect of ACL deficiency on rotational stability has been evaluated
with varying results. Girgis et al. (1975) reported an average increase in external tibial
rotation of 12 degrees and internal tibial rotation of 8 degrees with the knee positioned
in extension following ACL transection.(80) A conflicting report by Lane et al. (1994)
demonstrated a much smaller effect of ACL transection with the knee positioned in
extension, with average increases of just 4 degrees internal rotation and 1 degree
external rotation.(81)
Some studies report the tibia in ACL deficient knees remaining more externally
rotated during activities such as walking and platform climbing.(82, 83) The proposed
mechanism of this compensatory kinematic change was that external tibial rotation will
unload of the ACL, which may avoid instability associated with ACL deficiency.(83) This
is in contrast to a study by Defrate et al. (2006), which assessed knee kinematics during
a lunging motion which demonstrated increased internal tibial rotation at low flexion
angles, as well as increased anterior (3 mm) and medial (1 mm) tibial translation.(84) In
a more recent study by Chen et al. (2012), ACL deficiency resulted in increased anterior
tibial translation of 3 ± 5 mm in the ACL deficient knees vs. 0 ± 3 mm in the intact
knees, as well as increased flexion during stance phase of gait while patients walked on
32
a treadmill.(85) Increased flexion is not universally reported in ACL deficient knees, with
many studies reporting increased extension of the knee during stance phase.(86-88)
This kinematic adaptation is thought to reduce activity in the quadriceps muscles
(termed quadriceps avoidance gait), which must counteract a flexion moment at the
knee during weight bearing.(86)
Canine
There is a wide range of reported increases in ATT following ACL transection in
the dog, making it difficult to draw conclusions as to the similarity in magnitude of ATT
to the human knee. Arnoczky et al. (1977) reported an increase in ATT following ACL
transection from 0 mm to 2 - 10 mm, with the amount of translation being dependent on
knee flexion angle.(13) Another study of anterior-posterior stability in canine cadaveric
limbs demonstrated an increase in ATT from 2 mm to 5 mm following ACL
transection.(89) This laxity increased to as much as 7 mm when the joint capsule was
removed from the ACL transected specimens.(89) A more recent cadaveric evaluation
demonstrated that ATT increased from 7 mm to 22 mm following ACL transection.(90)
Rotational laxity in the dog knee was altered following ACL transection, with internal
tibial rotation increased by as much as 15 degrees in extension and 26 degrees in
flexion.(13, 90) Neither study reported an increase in external tibial rotation, as is
reported in the human knee.(13, 90)
Knee kinematics in normal, intact ACL dogs during routine activity were
established in a recent study by Kim et al. (2015). The canine knee with an intact ACL
has a typical biphasic flexion-extension curve and very little anterior-posterior translation
of 1 to 3 mm, depending upon activity type. Internal tibial rotation was generally
33
associated with flexion angle, and axial rotational range of motion was greater when
dogs were trotting compared to walking.(91)
Kinematic patterns during activity are significantly altered in dogs with naturally
occurring ACL deficiency.(77, 92-95) Anterior tibial translation in dogs with ACL
deficiency measured 9.7 mm at mid-stance, and increased internal tibial rotation
throughout stance phase was noted compared to ACL-intact knees.(95) The duration of
stance phase and angular excursions are decreased in ACL deficient limbs compared to
limbs with an intact ACL.(94) An increased duration of double limb support was
observed for the first 18 weeks following experimental ACL transection.(94) In one study
assessing motion before and 12 weeks after ACL transection in the dog, motion was
significantly altered in all six degrees of freedom in the ACL deficient knees.(77) In a
follow-up study that measured dogs serially for 2 years after ACL transection, peak
anterior tibial translation initially increased by 10 mm and this alteration did not change
over time.(93) Dogs with ACL deficiency maintain their knees in increased flexion(92,
95), which differs from studies in humans demonstrating increased knee extension
(quadriceps avoidance gait).(86-88)
Caprine
A study evaluating selective ACL bundle transection in goats estimated the
contribution of each bundle to anterior-posterior stability of the knee.(64) Transection of
the AM bundle resulted in increased ATT by 2 mm at 60 and 90 degrees of flexion.
Transection of the PL bundle resulted in increased ATT by 1 mm at 30 degrees of
flexion. Transection of the IM bundle alone resulted in no change in ATT at any flexion
angle. Transection of all three bundles resulted in a much more pronounced increase in
ATT of 14 mm.(64) Another study of goat ACL biomechanics found a similar increase in
34
ATT of 16 mm at 60 degrees flexion following ACL transection in cadaveric goat
limbs.(65) Following complete ACL transection, internal tibial rotation increased by 8
degrees in the goat(64), a magnitude which is similar to the ACL deficient human knee.
In the previously mentioned study by Jackson et al., ex-vivo kinematic analysis in
goats demonstrated reduced anterior tibial translation from 8 mm at time zero post
transection to 5 mm at 8 months post-ACL transection.(44) Oster et al. (1992)
demonstrated significant increases in ATT, up to 11 mm, varus/valgus rotation, and
internal tibial rotation following ACL transection in an in vitro model.(22) Dynamic, in-
vivo kinematic analysis has not been reported in this species.
Ovine
Radford et al. (1994) measured anterior-posterior laxity following ACL transection
in the sheep. Prior to ACL transection, 1 mm of ATT was measured.(96) Following ACL
transection, ATT ranged from 5 to 9 mm, with greater ATT noted at 30 degrees
compared to 90 degrees of knee flexion.(96) Interestingly, no significant change in
rotational laxity was demonstrated following ACL transection in this study.(96) While this
observation may be a result of small sample size and type II statistical error, this finding
may suggest that sheep are not dependent on the integrity of the ACL for rotational
stability of the knee. If this was the case, this would be considered a notable difference
between the sheep, humans, and the other large animal models.
Detailed, in vivo kinematic patterns in walking and trotting sheep have been
described for the normal, intact ACL knee and following experimental ligamentous
injury.(48, 97, 98) Under normal conditions, average ATT in sheep was 2 mm.(97) Two
weeks following transection of the ACL and medial collateral ligament, the knees were
flexed to a greater degree at hoof strike (9 ± 3 degrees of increased flexion) and the
35
tibiae were anteriorly displaced (5 mm ± 1 mm) at mid-stance.(48) By 20 weeks post
surgery, the flexion normalized but ATT of 6 mm ± 2 mm persisted.(48)
Porcine
Pigs, like dogs and goats, appear to depend more heavily on the ACL for
anterior-posterior stability than the human. In the previously mentioned cadaveric study
by Kato et al. (2010), ATT increased from approximately 4 mm to approximately 15 mm
after complete ACL transection.(68) These results corroborate observations in an earlier
study by Zaffagnini et al. (2000), which demonstrated an increase in ATT from 4 mm in
pigs with intact knees up to 16 mm following ACL transection.(99) ACL transection also
resulted in 4 - 20 degrees of increased laxity in internal-external rotation in the pig
knee.(99) Zaffagnini et al. (2000) suggested, based on their findings in pigs, that
evaluation of internal-external rotational laxity, in combination with anterior-posterior
translational laxity, might be helpful in determining ACL status in the human.(99)
Reports of dynamic, in-vivo kinematic evaluation of the porcine knee could not be found,
which is surprising given the popularity of this species as a model in ACL research.
Laprine
Anterior tibial translation was measured in anesthetized rabbits before and after
ACL transection, and again 3 months after ACL reconstruction.(100) With the ACL
intact, a mean of 3 - 4 mm of ATT was measured at both 30 and 90 degrees of knee
flexion.(100) Following ACL transection, ATT increased to a mean of 6 - 8 mm, with
increased ATT at 30 degrees compared to 90 degrees of knee flexion.(100) Three
months following ACL reconstruction, ATT decreased to a mean of 4 - 6 mm, with
improved stability noted in double bundle vs. single bundle reconstruction
technique.(100) The magnitude of ATT increase in the rabbit with ACL deficiency is
36
relatively small compared to the human. This is probably related to the notable size
difference between the two species or may suggest that the rabbit does not rely on the
ACL for anterior-posterior stability of the knee.
Milne et al. (2001) reported the rotational laxity of the intact rabbit knee. A
maximum internal-external rotational range of motion of 75 degrees was reported, with
up to 50 degrees of internal rotation and 25 degrees of external rotation.(75) This is
somewhat larger in magnitude than the human knee, which is reported to have a
maximum degree of rotation of 42 degrees when assessed in the loaded state.(81) This
difference should be considered if selecting the rabbit for ACL reconstruction, as
protheses or graft material would be exposed to increased rotational range. The effect
of ACL transection on rotational laxity has not been reported in this species.
An evaluation of normal hopping in healthy rabbits revealed two distinct landing
patterns that occurred within animals in multiple trials - in the frontal plane, rabbits land
with either a neutral or a valgus pattern.(101) An in-vivo evaluation of rabbit knee
kinematics before and after ACL transection and partial medial meniscectomy
demonstrated a small, but significant, increase in ATT of 2 mm at 4 weeks. This
increase in ATT was no longer observed by 12 weeks post surgery.(102) A significant
decrease in range of knee flexion from 39 degrees pre-operatively to 32 degrees post-
operatively was noted in the first month after surgery.(102) The tibiae tended to remain
more externally rotated in all phases of the gait cycle after ACL transection and partial
medial meniscectomy in this study.(102)
Conclusion
Validated large animal translational models are an essential component for
advancing the treatment of ACL injuries in humans. None of the current large animal
37
models are a perfect representation of the human ACL, and each model has benefits
and limitations specific to that species. The information provided in this article is
intended to guide future researchers in selecting large animal models most appropriate
for their research goals. Additionally, this review has highlighted areas where further
research is needed to improve interpretation and application of current large animal
translational models.
Figures and Tables
Figure 1-1. Cartesian coordinate system applied to the knee for analysis of kinematic
parameters.
38
Table 1-1. Comparison of anatomic characteristics between humans and large animal translational models
Human Dog Goat Sheep Pig Rabbit
Number of ACL bundles
Three (2)
Two (13)
Three (18)
Two (23)
Three (2)
One (6)
ACL tibial insertion pattern
Not split (2)
Not split (2)
Split (2, 18)/ Not split (6)
Split (6, 23)
Split (2, 6)
Not split (6)
Tibial plateau angle (degrees)
7 ± 4 (10)
24 ± 4 (16)
20 (21)
20 ± 3 (23)
Not reported
24 ± 5 (36)
Medial-lateral tibial plateau width (mm)
76 ± 5 (12)
36 (6),+
44 (6),+
52 ± 2 (12)
52 (6),+
17 (6),+
+extrapolated from tibial index data reported by Proffen et al. 2012
Table 1-2. Comparison of pathologic characteristics between humans and large animal translational models
Human Dog Goat Sheep Pig Rabbit
Naturally occurring pathology
Common (37)
Common (40)
Uncommon Uncommon Uncommon Maybe (sub-clinical) (55)
Time to develop-ment of DJD
10 to 20 years (39)
Weeks to months (43)
6-8 months (44, 45)
5 months (49)
4-6 weeks (54)
4-6 weeks (56, 57)
39
Table 1-3. Comparison of biomechanical characteristics between humans and large animal translational models
Human Dog Goat Sheep Pig Rabbit
AM bundle taut
Flexion (3, 58)
Flexion + Extension (13)
Flexion + Extension (64)
Flexion (66)
Flexion (68)
Not reported
PL bundle taut
Extension (3, 58)
Extension (13)
Extension (64)
Not reported
Extension (68)
Not reported
Mean ultimate load (N)
2160 ± 157 (60)
1867 ± 324 (63)
462 ± 20 (65)
1200 - 2580 (67)
1266 ± 250 (69)
350 (73)
Mean ultimate stiffness (N/mm)
242 ± 28 (60)
201 ± 41 (63)
48 ± 11 (65)
Not reported
94 ± 16 (70)
150 (73)
Mean ultimate stress (MPa)
36 ± 2 (61)
128 - 159 (62)
15 ± 2 (65)
60 – 123 (67)
32 ± 16 (71)
69 ± 7 (74)
Youngs modulus (MPa)
278 – 447 (61)
479 – 623 (62)
Not reported
180 – 234 (67)
148 ± 62 (71)
727 ± 67 (74)
Anterior-posterior laxity (mm) ACL intact
7 (80)
0 - 7 (13, 89, 90, 103)
2.5 (64)
1 (96)
4 (68)
3 - 4 (100)
Anterior-posterior laxity (mm) ACL deficient
13 (80)
5 - 22 (89, 90)
16 (64)
5 - 9 (96)
15 (68)
6 - 8 (100)
Anterior tibial translation (mm) ACL intact
0 (85) 1 – 3 (91) Not reported
2 (97) Not reported
3 (102)
Anterior tibial translation (mm) ACL deficient
3 (85) 10 (93, 95)
Not reported
5 – 6 (48) Not reported
5 (102)
40
CHAPTER 2 IN-VIVO THREE-DIMENSIONAL KNEE KINEMATICS IN GOATS WITH ANTERIOR
CRUCIATE LIGAMENT DEFICIENCY
Introduction
Injury to the anterior cruciate ligament (ACL) occurs frequently and can have
profound clinical consequences in human patients(39). Acute, non-contact, traumatic
ACL rupture is the one of the most common athletic injuries in humans.(37, 38) While
the ACL is a primary restraint against excessive anterior tibial translation(79), the laxity
caused by injury to the ACL does not uniformly result in instability that necessitates
restoration of ACL function.(78) A large cohort study assessing 100 consecutive
patients with acute ACL injury that were randomly assigned to be treated either
surgically or conservatively found that after 15 years both groups scored similarly in
activity and pain scales.(104) Furthermore, only half of the patients developed
radiographic evidence of osteoarthritis, independent of treatment group.(104)
Considering abnormal mechanics are thought to initiate and accelerate OA, these
findings conflict with kinematic studies demonstrating subluxation of greater than 6 mm
occurring in ACL-deficient knees during walking.(85) Bates et al. (2015) reviewed an
expansive body of research investigating the biomechanics of ACL deficiency and
reconstructive techniques, and concluded that complete restoration of normal
kinematics following ACL reconstruction remains elusive.(105)
Large animal (non-rodent mammal) models are commonly used in translational
orthopedic research, as many experimental or invasive investigative methods are not
considered ethical or feasible in humans. Goats are among the commonly chosen large
animal models in studies of ACL biomechanics and reconstruction.(47, 64, 65, 106,
107) Comparative anatomic studies have demonstrated a high degree of similarity
41
between the human and goat knee.(2, 6, 18) While the goat is an accepted translational
model for ACL research, the reported deleterious effects of ACL transection on joint
homeostasis in this species are inconsistent. Despite goats having appreciable passive
laxity after ACL transection, lameness in ACL transected goat does not persist and
development of radiographic abnormalities attributed to osteoarthritis has not been
consistently observed.(45-47) Interpretation of these findings is hindered because there
is a lack of understanding regarding the abnormal in-vivo joint motion occurring in goats
with ACL deficiency.
Sophisticated methods using fluoroscopy have been developed to accurately
characterize in-vivo joint kinematics in three dimensions. Fluoroscopy can be used to
record skeletal motion in live subjects during a wide array of activities; precise three-
dimensional joint kinematics can then be ascertained by matching digital bone models
or fiduciary markers to the fluoroscopic images. In-vivo fluoroscopic analysis of the
human knee is frequently utilized to better comprehend normal and abnormal ACL
biomechanics, as well as to compare and refine ACL reconstructive techniques and
total knee replacement designs.(82, 84, 108) Recently, our group described the in-vivo
fluoroscopic analysis of the dog knee, establishing normal knee kinematics during
various daily activities for this species.(91) Detailed characteristics of ACL
biomechanics have been shaped from the results of fluoroscopic analysis in dogs with
experimental ACL transection and naturally occurring ACL deficiency.(95, 109) The aim
of this investigation was to quantify the in-vivo, three-dimensional kinematics of caprine
knees before and after ACL transection. Knowledge of normal and abnormal knee
kinematics in this species would improve the understanding of the goat as a model for
42
studying ACL injury, and be useful in objectively assessing surgical and non-surgical
treatment of ACL deficiency in future research.
Materials and Methods
The protocol for this study was reviewed and approved by the institution’s animal
care and use committee. Eight adult, female goats were acquired from a local source
and subjected to the standard isolation and serum testing for Coxiella burnetii. Goats
were trained to walk on a treadmill during daily training sessions for 4 weeks prior to any
data collection.
Procedures and Data Collection
Tantalum bead placement
The goats underwent general anesthesia for tantalum bead implantation.
Anesthetic protocol varied slightly at the discretion of the attending anesthesiologist.
Typical pre-medications included butorphanol (0.1 mg/kg) and diazepam (0.2 mg/kg)
administered intravenously, followed by ketamine (2 mg/kg) and propofol (2-4 mg/kg)
intravenously to effect for induction. Anesthesia was maintained with inhaled isoflurane
in all goats. Medical-grade, 1.6 mm tantalum beads (X-Medics, Frederiksberg,
Denmark) were percutaneously implanted (6 in each bone) into the cortex of the distal
femur and proximal tibia of each limb. These beads were placed as fiduciary markers
for the 2D-3D image registration process. The bead placement protocol was as follows:
a small (5 mm) skin incision was made over the intended placement site. A cannulated
bone marrow biopsy needle (Jamshidi, 11-gauge x 6 inches, BD, Vernon Hills, IL.) with
trocar was inserted through the soft tissues to the level of the bone and held securely in
place. The trocar was removed to allow access to the bone through the cannulated
needle. A 1.57 mm diameter Kirschner wire was advanced through the cannulated
43
needle and a 2 mm deep hole was drilled into the cortex. The Kirschner wire was
removed and a single tantalum bead was introduced into the bone through the
cannulated needle. The trocar was initially inserted to ensure that the bead was secured
in the hole drilled in the cortical bone. The trocar was then removed and a small amount
of sterile bone wax inserted into the cannulated needle. The trocar was replaced to
apply the wax over the bead to help secure the position of the bead.
Computed tomography
Computed tomographic scans were acquired (Toshiba Prime 160 Multidetector
Row CT, Toshiba America Medical Systems, Tustin, CA) during the same anesthetic
event for tantalum bead placement. Data volume acquisitions were performed using
standard resolution algorithms (pitch factor = 0.638; helical pitch = 65; kVp = 120; mAs
= 262). For all goats, a data volume extending from the cranial aspect of the wings of
the ilium to the mid aspect of the metatarsi were performed. Transverse image
reconstructions of the ilium through the metatarsi were performed using bone and soft
tissue algorithms with 2-3 mm slice thicknesses, and sagittal and dorsal plane images
were reformatted using the data set with 1 mm slice thickness. The goats were
recovered from anesthesia and allowed to recover for 2 weeks until incisions were
healed. Analgesia was provided in the form of oral Banamine (1.0 mg/kg) for three days
post bead implantation.
Fluoroscopy
Horizontal-beam lateral projection fluoroscopic images of the knees were
acquired as each goat was walked on a treadmill at a comfortable walking velocity of
2.4 mph. Three separate trials of 3 to 5 gait cycles per trial were acquired for each goat.
Video recordings (Cannon VIXIA HF G10, Melville, NY.) were obtained of the hind limbs
44
to determine time at hoof-strike and hoof-off, which was used to delineate stance and
swing phases of gait. At the beginning of each trial, a metallic wand was waved in front
of the fluoroscopic detector. The low point of the wand wave was synchronized between
the video and the fluoroscopic images during data analysis. Images were acquired with
a pulse width of 1 ms, at 30 frames per second. The typical fluoroscope settings were
76 - 106 kV and 50 - 63 mA, with adjustments according to goat body size.
Force platform analysis
The goats were familiarized with the surroundings and practiced walking across
the force platform (force platform model #OR6-6-1000, Advanced Mechanical
Technology Inc., Newton, MA) at a velocity of 1.0 m/s; acceleration of +0.5 m/s2. The
goats were walked without tension on the leash during the force platform evaluations.
The handler walked the goat across the force plate system to gather the required data
for a series of five valid trails on each side. Data for both fore- and hindlimbs were
acquired. Peak vertical force (PVF), determined as a percentage of body weight, is
reported.
Knee arthroscopy and ACL transection
Three to ten weeks following bead implantation and two to four weeks after
baseline fluoroscopy and force platform data collection, the right knee of each goat was
examined via a cranial, parapatellar arthroscopic approach during general anesthesia.
The knees were graded for macroscopic evidence pathology, including degree of OA
according to the Outerbridge classification system.(110) The right ACL was then
completely transected under arthroscopic guidance using a #15 scalpel blade. An
arthroscopic shaver (Arthrex 3.8mm Sabre tooth) was used to debride the transected
ligamentous stumps. The skin incisions were closed in routine fashion and the goats
45
were allowed to recover for 2 weeks with three days of oral Banamine (1.0 mg/kg) for
analgesia.
Post-operative data collection
Imaging and force plating were repeated as described above at the intervals of 2
weeks, 3 months, and 6 months after ACL transection.
End point criteria
The goats were closely monitored throughout the study period for signs of pain,
lameness, or other illness. End point criteria included pain that could not be adequately
controlled, moderate to severe lameness persisting beyond a 2 month period after ACL
transection, or other illness that could not be remedied through the standards of care
similar to that of a client owned goat. At the end of the 6 month study period, the goats
were adopted with informed consent and knowledge of prior procedures and conditions.
Kinematic Data Processing
Bone-model reconstruction
The DICOM files of the CT scan were transferred to a personal computer and
segmented with segmentation software. The generated contours were imported into
reverse engineering software (ITK-SNAP, http://www.itksnap.org) to create a 3D surface
mesh of the bones (Figure 2-1). The locations of anatomical landmarks for the femur
and tibia were interactively identified on the bone models and a coordinate system for
the femur and tibia was created as previously described (Geomagic Inc, Research
Triangle Park, NC).(77)
2D to 3D registration
A silhouette of the 3D bone models were superimposed over the corresponding
bone on each lateral-projection fluoroscopic image using an open source 3D shape
46
matching software (JointTrack, University of Florida:
http://sourceforge.net/projects/jointtrack/). The femur and tibia models were manually
translated and rotated until the tantalum beads of each bone’s projected silhouette
aligned with the tantalum beads in the bones on lateral projection fluoroscopic images,
thereby recreating the positions of the femur and tibia (Figure 2-2). These techniques
have been shown to be highly accurate, to within 0.38 mm for translation and to within
0.42 degrees for rotational measurements.(111)
Calculation of joint kinematics
The relative alignment between the femur and tibia in 6 degrees of freedom–
flexion/extension internal/external axial rotation, adduction/abduction, anterior/posterior
translation, medial/lateral translation, and proximal-distal translation - was calculated
from the bone model orientation obtained from the shape-matching software using a
custom written computer program.(76) The center of the origin and insertion of the ACL
defined the origin of the femoral and tibial coordinate systems for determining
translations. Rotations were defined in degrees; translations were defined in mm. Mean
anterior tibial translation was zeroed to the mean value at beginning of stance phase at
baseline for all post ACL transection time points. Previous studies do not recommend
measuring out of plane (medial/lateral) translation using these methods(108, 112), and
proximal/distal translation has nominal clinical relevance in this model, therefore these
data were not included in this report.
Tibial plateau angle measurement
Tibial plateau angle was measured from the CT scan in the sagittal plane as
previously described for dogs using lateral projection radiographs.(16) A sagittal slice
centered over the medial tibial condyle was selected for measurement of each tibia
47
using a picture archiving and communication system (Merge PACS; IBM Watson
Health, Chicago, IL.). The Cobb angle tool was utilized for tibial plateau angle
measurement. The tibial long axis was defined as a line intersecting the center of the
talus and the medial intercondylar eminence. A proximal tibial joint line was defined as a
line passing through the cranial and caudal margins of the medial tibial condyle. The
tibial plateau angle was defined as the angle formed between a line perpendicular to the
tibial long axis and the tibial joint line (Figure 2-12).
Statistical Analysis
The gait cycle timing was normalized to permit averaging across multiple cycles
and between goats, despite variations in gait velocity and stride length. Each gait cycle
was divided into its swing and stance components using slow motion videography
synchronized to the fluoroscopic images. Each phase of gait was then statistically
analyzed and graphed in 5% intervals. An average curve for each kinematic parameter
for each goat was created from the 3 trials acquired at each session. These average
curves were combined to create group averages for the baseline (intact ACL) and post-
ACL transection (2 weeks, 3 months, and 6 months) time points.
To determine the temporal effect of ACL transection, the kinematic parameters at
each of the gait cycle intervals were compared between time points using a two-way
repeated measures ANOVA with a post hoc pairwise comparison using the Tukey
Honestly Significant Difference test. A two-way repeated measures ANOVA with a post
hoc pairwise comparison using the Tukey Honestly Significant Difference test was also
used to determine the difference in peak vertical force during stance phase of a walking
gait at each time point. To determine the difference in peak vertical force between the
affected (right) and unaffected (left) hind limbs within each time point, a paired, two-
48
tailed t-test was performed, with p<0.025 considered significant after a Bonferroni
correction for multiple comparisons.
Results
Force Platform
Transient, mild right hind limb lameness was visible in all goats after ACL
transection for 3 to 6 weeks. A significant reduction in peak vertical force to 73% of
baseline value was noted in the affected limb at 2 weeks post ACL transection (Figure
2-3). Peak vertical force in the affected limb was also significantly lower 2 weeks post
ACL transection than at 6 months post ACL transection (Figure 2-3). A significant
difference in peak vertical force between the right hind limb (ACL transected) and left
hind limb (normal) was noted at 2 weeks post ACL transection (p = 0.003) but was no
longer present at the later time points (Figure 2-3).
Kinematics
Mean flexion angle during stance phase ranged from 49.0 – 69.0 degrees at
baseline. (Figure 2-4). In early stance phase (hoof strike) the knees at baseline were
moderately extended at 49.0 degrees. The knees at baseline then flexed by
approximately 18 degrees through mid-stance before extending by approximately 8
degrees to hoof-off. Knees were more extended during the last 35% of stance phase by
a mean of 9.2 and 10.4 degrees at 3 and 6 months post ACL transection, respectively,
when compared to baseline. Mean flexion angle was not different from baseline at any
point during stance phase at the 2 weeks post ACL transection time point. For the
majority of stance phase, the knees were more extended by a mean of 10.3 and 10.7
degrees at 3 and 6 months post ACL transection, respectively, compared to 2 weeks
post ACL transection. (Figure 2-4)
49
Mean flexion angle during swing phase ranged from 55.3 – 81.8 degrees at
baseline (Figure 2-5). The knees at baseline flexed by approximately 26 degrees
through mid-swing before extending by approximately 26 degrees in preparation for
hoof strike. The knees were more extended for the first 45% of swing phase by a mean
of 15.0 and 15.3 degrees at 3 and 6 months post ACL transection, respectively,
compared to baseline. The knees were more extended in early and late swing phase by
a mean of 11.5 and 12.2 degrees at 3 and 6 months post ACL transection, respectively,
compared to 2 weeks post ACL transection. (Figure 2-5)
Mean anterior tibial translation during stance phase was up to 1.55 mm prior to
ACL transection (Figure 2-6). Following ACL transection, mean anterior tibial translation
during stance phase was as high as 7.0 mm. Mean anterior tibial translation was
increased during the majority of stance phase at 2 weeks, 3 months, and 6 months post
ACL transection compared to baseline, with mean increases of 3.1 ± 0.8 mm, 4.3 ± 0.6
mm, and 5.5 ± 0.5 mm, respectively. (Figure 2-6)
Mean anterior tibial translation during swing phase was up to 2.7 mm prior to
ACL transection (Figure 2-7). Following ACL transection, mean anterior tibial translation
during swing phase was as high as 6.1 mm. Mean anterior tibial translation was
increased in early and late swing phase at 3 and 6 months post ACL transection
compared to baseline, with mean increases of 2.9 ± 0.6 mm and 3.4 ± 0.7 mm,
respectively. Mean anterior tibial translation at 2 weeks post ACL transection was only
greater than baseline at hoof-off. (Figure 2-7)
In stance phase prior to ACL transection (baseline), the tibia was maintained in
external rotation relative to the femur, with a range of 8.2 – 15.4 degrees of mean
50
external rotation (Figure 2-8). Following ACL transection, there were no significant
changes in mean axial rotation during stance phase at any time point. (Figure 2-8)
In swing phase prior to ACL transection, the tibia remained externally rotated but
to a lesser degree than in stance phase, with a range of 3.3 – 9.5 degrees of mean
external rotation. There were no differences in mean axial rotation during swing phase
following ACL transection at any time point. (Figure 2-9)
A small degree of adduction was noted throughout stance (range 5.0 – 7.5
degrees) and swing (range 4.6 – 6.7 degrees) phase at all time points. There were no
differences in mean abduction/adduction angle following ACL transection. (Figures 2-10
and 2-11)
Tibial Plateau Angle
Mean tibial plateau angle was 24.5 ± 2.6 degrees (range 20 – 28 degrees).
Discussion
The objective of this study was to quantify kinematic patterns induced by ACL
transection in goats, and to determine how the kinematics changed over a 6 month
period. Following ACL transection in the goat, lameness was transient and resolved
without intervention, despite persistent kinematic abnormalities including increased
knee extension and approximately 3 - 4 mm of anterior tibial translation. Interestingly,
these kinematic abnormalities not only persisted throughout the study period but
worsened over time despite resolution of lameness.
Following ACL transection, knees tended to be more extended than at baseline,
with the exception of the 2 weeks post ACL transection time point, in which increased
flexion was noted during stance phase. Increased flexion during stance phase in the
acute post-operative period may be associated with surgical pain or may represent an
51
early adaptation to an unstable joint. Increased flexion at the knee while walking has
been demonstrated in people in the first 3 months of acute ACL injury.(113) Over time,
however, increased extension developed in the goats. Quadriceps avoidance is a
mechanism by which humans with ACL injury may adapt to the instability (primarily
anterior tibial translation) induced by the pull of the quadriceps muscle group.(86)
Quadriceps contraction is necessary to counteract an external knee flexion moment
(induced by weight bearing) to maintain equilibrium at the knee.(86, 87) Humans with
chronic ACL injury can have decreased flexion at the knee during mid-stance, and it is
proposed that this is a kinematic adaption to avoid quadriceps contraction and resultant
anterior tibial translation.(86, 87) The quadriceps avoidance adaptation in humans was
most pronounced during a walking gait, compared to jogging and stair decent.(86) By 3
and 6 months post ACL transection, the goats in this study demonstrated increased
knee extension in both stance and swing phase compared to baseline, suggesting that
quadriceps avoidance may be a component of chronic adaptation to ACL deficiency in
this species. Other human studies have sought to interpret kinematic changes with
muscle activation using electromyography. These studies demonstrate that while
decreased knee flexion is observed in ACL injured patients, the quadriceps muscle
group is not actually contracting to a lesser degree.(114, 115) In fact in one report,
quadriceps muscle activity was consistently higher in the ACL-deficient patients
compared to controls.(115) Instead, a co-contraction pattern of the hamstrings group in
these patients was proposed to directly oppose the quadriceps muscle contraction,
therefore preventing anterior tibial translation.(114) Electromyographic measurements in
52
goats with ACL transection would allow interpretation of the reported kinematic changes
with respect to alterations in muscle group activity, but was not performed in our study.
An increase of approximately 3 - 4 mm of mean anterior tibial subluxation
occurred throughout stance phase and in early and late swing phase in ACL transected
goats. The magnitude of increased anterior tibial translation (3 mm) is similar in humans
with ACL deficiency(85), however the timing of anterior tibial translation appears to differ
between humans and goats. Anterior tibial translation in humans with an intact ACL
occurs primarily in terminal swing phase, as the knee extends in preparation for heel
strike, and at heel strike when the knee becomes loaded in extension and is subjected
to shearing force.(86, 116) Electromyographic activity in humans with ACL deficiency
shows increased hamstring muscle group activity at heel strike to counter the force of
the quadriceps pulling the knee into drawer.(115) Andriacchi et al. (2005) demonstrated
decreased magnitude of anterior tibial translation at heel strike in patients with ACL
deficiency compared to ACL intact knees.(116) It was suggested that this reduced
translation resulted from kinematic alterations (primarily in axial rotation) during terminal
swing phase, when physiologic anterior tibial translation normally occurs.(116) This
finding was not observed in a kinematic evaluation by Chen et al. (2012), which
demonstrated no significant difference in anterior tibial translation between ACL
deficient and ACL intact knees at heel strike, but noted increased anterior tibial
translation of approximately 3 mm in late stance phase.(85) The persistence of
increased anterior tibial translation throughout stance phase and in early and late swing
phase in the goat, while similar in overall magnitude to that in humans, suggests that
53
this species does not develop compensatory stabilization techniques equivalent to
humans within the first 6 months after ACL transection.
One proposed explanation for the observed duration of anterior tibial translation
in the goat relates to differences in topography of the proximal tibia, specifically the tibial
plateau angle or slope. The slope of the human tibial plateau is on average 7
degrees.(10) A steeper slope is thought to promote anterior tibial subluxation during
weight bearing, as the femoral condyles are more likely to slip posteriorly on an angled
surface. One report on ACL force measurement found that the tibial plateau in the goat
slopes posteriorly at approximately 20 degrees, but no description of methodology or
sample size was given.(21) In the current study, the mean tibial plateau angle of the
goats was 24.5 degrees, although this was based on just 16 limbs.
Stability in axial rotation is another important function of the ACL. The “screw
home” mechanism describes internal tibial rotation during swing phase (knee flexion)
and external tibial rotation during stance phase (knee extension).(117) Kinematic
studies in humans with ACL deficiency have identified increased internal tibial rotation
associated with extension of the knee during various exercises including walking,
squatting, and lunging, demonstrating a loss of the normal screw home mechanism in
some subjects.(84, 113, 116, 118) In the normal goat knee, external tibial rotation
decreased with knee flexion, which is consistent with the screw home mechanism
described in humans. Interestingly this pattern was maintained after ACL transection,
with no disturbances to axial rotation during the gait cycle in ACL-transected knees.
This finding represents a biomechanical difference between goats and humans with
ACL deficiency, in that axial rotation is disrupted in humans but not in the goat. In
54
humans, preferential activation of the vastus lateralis muscle can prevent internal tibial
rotation after ACL injury.(115) Whether similar compensatory mechanisms involving
changes to muscle activation occur in goats is unknown.
ACL transection in the goat resulted in transient hind limb lameness, with
complete resolution by 3 months post ACL transection. This finding is consistent with
previous studies, which demonstrate that lameness does not persist following ACL
transection in goats, and that radiographic evidence of degenerative joint disease does
not develop as readily as in other animal models such as dogs.(46, 47) The transient
nature of this lameness is interesting given that the kinematic abnormalities of ACL
transection persisted beyond the resolution of lameness. In humans with ACL injury, a
subset of patients have been identified as ‘copers’.(114) Copers are able to resume all
preinjury activities without requiring surgical intervention. Furthermore, kinematic
studies reveal that copers have improved stability of the knee compared to non-copers,
despite the presence of ACL deficiency.(114, 118) In the current study goats do not
appear to be coping with ACL transection in the traditional sense, as their lameness
improved despite persistent (even worsening) instability of the knee. One proposed
explanation for the resolution of lameness in this species relates to the nature of the
goat as a prey animal, in which demonstration of lameness confers a survival
disadvantage. A study by Gentle (2001) found that chickens could be distracted from
demonstrating lameness related to a painful intra-articular injection by placing them in
an unfamiliar environment or in a cage with unfamiliar conspecifics.(119) Therefore it is
possible that the goats’ attention was shifted away from the perception of pain during
data collection events, which took place out of their normal housing environment.
55
Subjectively, lameness was not appreciated in the goats beyond 6 weeks post ACL
transection even within their normal housing environment, but this cannot be objectively
confirmed. Further supporting the prey animal theory, similar findings were reported in a
sheep study, where lameness was not visually detected following ACL and medial
collateral ligament transection.(48) Alternatively, the resolution of lameness in the goat
may be explained by the relatively low magnitude of anterior tibial translation (3 – 4 mm)
in that the degree of instability may be small enough to overcome once surgical pain
and inflammation have resolved.
Limitations of this study include a relatively short study period of 6 months post
ACL transection. It is unknown whether the documented kinematic changes in goats
would have persisted or resolved with time. Kinematic data was collected with single-
plane fluoroscopy, which has been shown to be less accurate for out-of-plane
translations than dual-plane fluoroscopic systems.(108, 112) Because of this, we were
not able to evaluate medial/lateral translations in this study, which have been shown to
change after ACL injury in humans.(84) Familiarity and comfort with the treadmill and
fluoroscopy unit may have improved in the goats over the study period, which may have
influenced the kinematic data over time. Furthermore, treadmill gait has been shown to
differ mildly from over ground gait in other species(120, 121).
Conclusions
In-vivo kinematics of the goat knee before and after ACL transection demonstrate
some similarity to the human knee. Following ACL transection, lameness was transient
and resolved without intervention, despite persistent kinematic abnormalities including
increased knee extension and approximately 4 mm of anterior tibial translation. These
findings suggest that the goat is suitable for translational research of ACL
56
biomechanics, as the kinematic consequences of ACL transection are closely
representative of what has been observed in humans with ACL deficiency.
Figures
Figure 2-1. 3D bone models of a goat limb (femur and tibia) with tantalum beads
implanted. Bone sections with beads implanted are cut away for fluoroscopic shape matching purposes.
57
Figure 2-2. A- Lateral projection fluoroscopic image of the right knee of a goat during a
treadmill walking gait. B- Shape matching: three-dimensional bone models are superimposed over the lateral projection fluoroscopic image of the right goat knee.
58
Figure 2-3. Body weight normalized mean peak vertical force (100*N/N) of the hind
limbs during stance phase of a walking gait. Significant differences were found in the right hind limb when comparing baseline and 2 weeks post ACL transection (*), and between 2 weeks and 6 months post ACL transection (^). A significant difference was also noted between the right and left hind limb at 2 weeks post ACL transection (X).
*^x
10
20
30
40
50
60
70
80
Baseline 2 weeks post op 3 months post op 6 months post op
Mean Peak Vertical Force (100*N/N)in the Hind Limbs
Right hind limb Left hind limb
59
Key for Figures 2-4 through 2-11:
A 2 weeks post ACL transection vs. Baseline
B 3 months post ACL transection vs. Baseline
C 2 weeks post ACL transection vs. 3 months post ACL transection
D 6 months post ACL transection vs. Baseline
E 2 weeks post ACL transection vs. 6 months post ACL transection
F 6 months post ACL transection vs. 3 months post ACL transection
60
Figure 2-4. Mean flexion angle throughout stance phase of gait before and after ACL
transection. Significant differences are denoted by a letter corresponding to the provided key.
CE
CE
CE
CE
CE
CE
CE
CE
CE
CE
CE
CE
CDE
CDE
BDE
BDE
BDE
BDE
CDE
BCDE
BCDE
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100% Stance Phase
Mean Flexion Angle (degrees) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
61
Figure 2-5. Mean flexion angle throughout swing phase of gait before and after ACL
transection. Significant differences are denoted by a letter corresponding to the provided key.
BCDE
BCDE
BCDE
BCDE
BCD
BD
BD
BD
BD
BE E C
E
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100% Swing Phase
Mean Flexion Angle (degrees) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
62
Figure 2-6. Mean anterior tibial translation in millimeters throughout stance phase of gait
before and after ACL transection. Significant differences are denoted by a letter corresponding to the provided key.
BCDE
BCDE
BCDE
ABDE
ABDE
ABD
ABD
ABD
ABDE
ABDE
ABD
ABD
ABD
ABD
ABD
ABD
ABD
ABD
ABD
ABD
ABD
-2.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
0 10 20 30 40 50 60 70 80 90 100
% Stance Phase
Mean Anterior Tibial Translation (mm) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
63
Figure 2-7. Mean anterior tibial translation in millimeters throughout swing phase of gait
before and after ACL transection. Significant differences are denoted by a letter corresponding to the provided key.
ABDE
BDE
BDE B
D D DDE
DE
DE
DE
BDE
BDE
-2.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
0 10 20 30 40 50 60 70 80 90 100
% Swing Phase
Mean Anterior Tibial Translation (mm) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
64
Figure 2-8. Mean axial rotation throughout stance phase of gait before and after ACL
transection. Positive y-values represent internal rotation and negative y-values represent external rotation. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Stance Phase
Mean Internal (+)/External (-) Axial Rotation (degrees) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
65
Figure 2-9. Mean axial rotation throughout swing phase of gait before and after ACL
transection. Positive y-values represent internal rotation and negative y-values represent external rotation. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Swing Phase
Mean Internal (+)/External (-) Axial Rotation (degrees) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
66
Figure 2-10. Mean abduction angle throughout stance phase of gait before and after
ACL transection. Positive y-values represent abduction and negative y-values represent adduction. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Stance Phase
Mean Abduction (+)/Adduction (-) (degrees) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
67
Figure 2-11. Mean abduction angle throughout swing phase of gait before and after ACL
transection. Positive y-values represent abduction and negative y-values represent adduction. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Swing Phase
Mean Abduction (+)/Adduction (-) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
68
Figure 2-12. Measurement of tibial plateau angle from the computed tomographic scan
of a goat hind limb.
69
CHAPTER 3 IN-VIVO THREE-DIMENSIONAL KNEE KINEMATICS OF THE UNAFFECTED KNEE
IN GOATS WITH UNILATERAL ANTERIOR CRUCIATE LIGAMENT DEFICIENCY
Introduction
Anterior cruciate ligament (ACL) rupture is the most common ligamentous injury
in humans.(122) The ACL functions as the primary restraint against anterior tibial
translation, internal tibial rotation, and hyperextension of the knee. Advancing medical
and surgical management for patients with ACL injury is a major area of research
interest.(123-127) Understanding the biomechanical and pathologic consequences of
anterior cruciate ligament deficiency in the affected limb is an important component of
these management advances.(126, 128, 129)
While the biomechanical abnormalities of ACL deficiency have been well
described in both in-vivo and in-vitro studies, fewer studies have assessed the
compensatory kinematic changes in the unaffected limb after unilateral ACL injury.
Furthermore, kinematic studies of the unaffected knee often evaluate ACL
reconstructed patients(130, 131), which may not be representative of unaffected knee
kinematics in patients with ACL deficiency without surgical intervention. A study
evaluating patients with unilateral ACL deficiency reported increased extension in the
knee in both the affected and unaffected limbs compared to control (bilateral ACL-intact)
knees.(86) Hofbauer et al. (2014) found that 12 months post ACL reconstruction, the
unaffected knee was more extended with increased external tibial rotation compared to
similar measurements at 5 months.(130) A recent kinematic evaluation of both ACL
reconstructed and non-reconstructed knees as well as the unaffected limb during a
drop-jump activity reported increased extension at the knee and hip in both groups
compared to controls.(88)
70
In both human and veterinary literature, the unaffected limb is used as the normal
control for comparison within the subject.(95, 107, 132-135) However little is known
about the compensatory kinematic changes in the unaffected knee that develop in
comparison to the pre-injured state. Kinematic changes in the unaffected knee after
unilateral ACL injury may be a limiting factor if the unaffected limb is being used as a
normal control.
Large animal (non-rodent mammal) models are commonly used in translational
orthopedic research, as many experimental or invasive investigative methods are not
considered ethical or feasible in humans.(136) Goats are among the commonly chosen
among the large animal models in studies of ACL biomechanics and reconstruction.(47,
64, 65, 106, 107) Comparative anatomic studies have demonstrated a high degree of
similarity between the human and goat knee.(2, 6, 18)
The purpose of this investigation was to establish in-vivo three-dimensional
kinematic patterns of the unaffected knee before and after unilateral transection of the
ACL in the goat using fluoroscopy. In-vivo fluoroscopic analysis of the human knee is
frequently utilized to better comprehend normal and abnormal ACL biomechanics, as
well as to compare and refine ACL reconstructive techniques and total knee
replacement designs.(82, 84, 108) Characterization of the compensatory kinematic
changes of the unaffected knee will help determine the limitations of using the
unaffected limb as a normal control. Additionally, establishing the kinematic changes in
the unaffected knee may reveal adaptive strategies for managing unilateral knee
instability in the goat.
71
Materials and Methods
The protocol for this study was reviewed and approved by the institution’s animal
care and use committee. This investigation was a part of an in-vivo kinematic evaluation
caprine ACL deficiency; the kinematics of the affected limb are described in Chapter 2.
Eight adult, female goats were acquired from a local source and subjected to the
standard isolation and serum testing for Coxiella burnetii. Goats were trained to walk on
a treadmill during daily training sessions for 4 weeks prior to any data collection. All
methods for this study were identical to those described in Chapter 2, except that the
unaffected knee was evaluated rather than the affected knee.
Procedures and Data Collection
Tantalum bead placement
Tantalum beads were percutaneously implanted into the unaffected limb as
described in Chapter 2. Briefly, medical-grade, 1.6 mm tantalum beads were placed into
the cortex of the distal femur and proximal tibia through a small (5 mm) skin incision
using a cannulated bone marrow biopsy needle (Jamshidi, 11-gauge x 6 inches, BD,
Vernon Hills, IL.).
Computed tomography
Computed tomographic scans were acquired of the unaffected limb as described
in Chapter 2. Briefly, a data volume extending from the cranial aspect of the wing of the
ilium to the mid-metatarsal region was performed. Transverse image reconstructions of
the ilium through the metatarsi were performed using bone and soft tissue algorithms
with 2-3 mm slice thicknesses, and sagittal and dorsal plane images were reformatted
using the data set with 1 mm slice thickness.
72
Fluoroscopy
Horizontal-beam lateral projection fluoroscopic images of the unaffected knee
were acquired as each goat was walked on a treadmill at a comfortable walking velocity
of 2.4 mph. Three separate trials of 3 to 5 gait cycles per trial were acquired for each
goat. Video recordings (Cannon VIXIA HF G10, Melville, NY.) were obtained of the hind
limbs to determine time at hoof-strike and hoof-off, which was used to delineate stance
and swing phases of gait. At the beginning of each trial, a metallic wand was waved in
front of the fluoroscopic detector. The low point of the wand wave was synchronized
between the video and the fluoroscopic images during data analysis. Images were
acquired with a pulse width of 1 ms, at 30 frames per second. The typical fluoroscope
settings were 76 - 106 kV and 50 - 63 mA, with adjustments according to goat body
size.
Force platform analysis
The goats were familiarized with the surroundings and practiced walking across
the force platform (force platform model #OR6-6-1000, Advanced Mechanical
Technology Inc., Newton, MA) at a velocity of 1.0 m/s; acceleration of +0.5 m/s2. The
goats were walked without tension on the leash during the force platform evaluations.
The handler walked the goat across the force plate system to gather the required data
for a series of five valid trails on each side. Data for both fore- and hindlimbs were
acquired. Peak vertical force (PVF), determined as a percentage of body weight, is
reported.
73
Contralateral knee arthroscopy and ACL transection
Two to four weeks following bead implantation, the right knee of each goat was
examined via a cranial, parapatellar arthroscopic approach during general anesthesia.
The right ACL was then completely transected as described in Chapter 2.
Post-operative data collection
Imaging and force plating were repeated in the unaffected limb as described
above at the intervals of 2 weeks, 3 months, and 6 months after ACL transection.
End point criteria
The goats were closely monitored throughout the study period for signs of pain,
lameness, or other illness. End point criteria is further described in Chapter 2.
Kinematic Data Processing
Bone-model reconstruction
The DICOM files of the CT scan were transferred to a personal computer and
segmented with segmentation software. The generated contours were imported into
reverse engineering software (ITK-SNAP, http://www.itksnap.org) to create a 3D surface
mesh of the bones (Figure 3-1). The locations of anatomical landmarks for the
unaffected femur and tibia were interactively identified on the bone models and a
coordinate system for the femur and tibia was created as previously described
(Geomagic Inc, Research Triangle Park, NC).(77)
2D to 3D registration
A silhouette of the 3D bone models of the unaffected limb were superimposed
over the corresponding bone on each lateral-projection fluoroscopic image using an
open source 3D shape-matching software (JointTrack, University of Florida:
http://sourceforge.net/projects/jointtrack/). The femur and tibia models were manually
74
translated and rotated until the tantalum beads of each bone’s projected silhouette
aligned with the tantalum beads in the bones on lateral projection fluoroscopic images,
thereby recreating the positions of the femur and tibia (figure 3-2). These techniques
have been shown to be accurate to within 0.38 mm for translation and to within 0.42
degrees for rotational measurements.(111)
Calculation of joint kinematics
Joint kinematics of the unaffected knee were calculated as described in Chapter
2. Briefly, the relative alignment between the femur and the tibia was calculated in 6
degrees of freedom using a custom written computer program.(76) Rotations were
defined in degrees; translations were defined in mm. Mean anterior tibial translation was
zeroed to the mean value at beginning of stance phase at baseline for all post ACL
transection time points.
Statistical Analysis
The gait cycle timing was normalized to permit averaging across multiple cycles
and between goats, despite variations in gait velocity and stride length. Each gait cycle
was divided into its swing and stance components using slow motion videography
synchronized to the fluoroscopic images. Each phase of gait was then statistically
analyzed and graphed in 5% intervals. An average curve for each kinematic parameter
for each goat was created from the 3 trials acquired at each session. These average
curves were combined to create group averages for the baseline (intact contralateral
ACL) and post-contralateral ACL transection (2 weeks, 3 months, and 6 months) time
points.
To determine the temporal effect of ACL transection, the kinematic parameters at
each of the gait cycle intervals were compared between time points using a two-way
75
repeated measures ANOVA with a post hoc pairwise comparison using the Tukey
Honestly Significant Difference test. A two-way repeated measures ANOVA with a post
hoc pairwise comparison using the Tukey Honestly Significant Difference test was also
used to determine the difference in peak vertical force during stance phase of a walking
gait at each time point. To determine the difference in peak vertical force between the
affected (right) and unaffected (left) hind limbs within each time point, a paired, two-
tailed t-test was performed, with p<0.025 considered significant after a Bonferroni
correction for multiple comparisons.
Results
Force Platform
There were no significant differences in peak vertical force in the unaffected limb
at any time point when compared to baseline measurements (range 43.2 – 50.6%;
Figure 3-3). A significant difference in peak vertical force between the affected (right)
and unaffected (left) hind limb was noted at 2 weeks post ACL transection (p = 0.003)
but was no longer present at the later time points (Figure 3-3).
Kinematics
Mean flexion angle of the unaffected limb throughout stance phase prior to
contralateral ACL transection ranged from 51.2 to 67.1 degrees (Figure 3-4). At 2 weeks
post ACL transection, there were no significant differences during stance phase in mean
flexion angle of the unaffected limb (range 48.4 – 63.1 degrees) compared to baseline
values. At 3 and 6 months post ACL transection, the unaffected knees were more
extended by a mean of 12 degrees and 14.3 degrees, respectively, at the end of stance
phase compared to baseline values. (Figure 3-4)
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Mean flexion angle of the unaffected limb during swing phase prior to
contralateral ACL transection ranged from 60.2 to 82.2 degrees (Figure 3-5). At 2 weeks
post contralateral ACL transection, there were no significant differences in mean flexion
angle of the unaffected limb compared to baseline values during swing phase (range
55.3 – 80.5 degrees). At 3 months and 6 months post contralateral ACL transection, the
knees were more extended by a mean of 15 degrees and 14.8 degrees, respectively, at
the beginning of swing phase compared to baseline values. (Figure 3-5)
Mean anterior tibial translation (ATT) of -0.3 to 1.1 mm was noted in the
unaffected limb during stance phase across all time points, with no significant difference
before and after contralateral ACL transection (Figure 3-6). During swing phase, mean
ATT ranged from -0.5 to 2.2 mm across all time points, with no significant differences
before and after contralateral ACL transection (Figure 3-7).
The tibia was maintained in external rotation in the unaffected limb during stance
phase, with mean external tibial rotation measuring 10.2 to 12.9 degrees prior to
contralateral ACL transection (Figure 3-8). Following ACL transection in the
contralateral limb, there was no significant difference in mean tibial rotation at any time
point compared to baseline (range 7.7 – 16.0 degrees of mean external tibial rotation
across all time points). Similarly, during swing phase before transection, the tibia was
externally rotated (range 3.3 – 11.9 degrees of mean external tibial rotation) with no
significant difference following ACL transection (range 3.2 – 12.6 degrees) (Figure 3-9).
A small degree of adduction was noted throughout stance (range 3.1 – 5.1
degrees) and swing (range 1.7 – 4.0 degrees) phase at all time points. There were no
77
differences in mean abduction/adduction angle following ACL transection. (Figures 3-10
and 3-11)
Discussion
The purpose of this study was to describe the kinematic changes that develop in
the unaffected knee following unilateral ACL transection in the goat. While most
kinematic parameters were unchanged, increased extension in the unaffected knee was
demonstrated at the end of stance phase and the beginning of swing phase at 3 and 6
months following unilateral ACL transection. No significant changes were noted in
anterior tibial translation, internal/external rotation, abduction/adduction, or peak vertical
force in the unaffected limb.
Increased extension was shown to develop in the unaffected knee of goats by 3
months following contralateral ACL transection. Several human studies have also
identified development of increased extension in the unaffected knee following unilateral
ACL injury (+/- reconstruction). Berchuck et al. (1990) noted increased extension of the
knee in the unaffected limb in patients with ACL deficiency compared to control
subjects, although the duration of injury was not reported. Hofbauer et al. (2014)
reported a mean increase of 3.2 degrees of extension in the unaffected knee 12 months
after ACL reconstruction compared to the same knee 7 months earlier.(130) They
proposed that this change was a bilateral kinetic response that allows for compensation
of the ACL-intact knee for deficits in the ACL reconstructed knee, and suggested that
future kinematic studies focus not only on the injured knee but also the unaffected
knee.(130) Hebert-Losier et al. (2018) also identified increased extension in the
unaffected knee of people with ACL injury (+/- reconstruction) compared to control
subjects during a drop-jump activity.(88) Comparing these results to our findings should
78
be made with caution, as different species (human vs. goat) and different activities
(hopping/jumping vs. treadmill walking) were evaluated. Furthermore, ACL
reconstruction could affect the kinematic changes that develop in the unaffected limb
and was not performed in the goats in this study. Whether comparing findings in goats
to humans or within the species, increased extension in the unaffected limb before and
after hoof-off should be considered in any future ACL studies in goats that use the
contralateral limb as a normal control.
In our associated study of the affected knee in goats, increased extension
occurred in late stance and early swing phase at 3 and 6 months post ACL transection,
in a pattern similar to that observed in the unaffected knee in the current study. The
presence of bilaterally symmetric kinematic change, and specifically increased knee
extension, has been reported in human studies.(86, 88) Berchuck et al. (1990) noted
that patients with unilateral ACL deficiency tended to walk with a bilaterally symmetrical
gait, such that increased extension in the affected knee corresponded to increased
extension of the unaffected knee compared to control subjects.(86) Bilateral increases
in knee extension were also noted in a recent study of chronic (non-reconstructed) ACL
deficiency performing a drop-jump activity.(88) In a separate study evaluating a drop-
jump task, significant kinematic differences were noted between chronic ACL
reconstructed knees and control knees, but no differences were noted between chronic
ACL reconstructed knees and the uninjured knee within the same patient, suggesting
that long-term bilateral adaptations occur with unilateral ACL rupture, despite
reconstruction.(137) Relating back to the discussion of prey species and resolution of
lameness in goats from the previous chapter, it is possible that the development of
79
bilaterally symmetric kinematic changes confers a survival advantage to prey animals
by allowing the overall gait to appear more uniform. The mechanism of bilateral
kinematic adaptation to unilateral disease has not been clearly defined, but it is an
interesting finding that appears to be preserved across both humans and goats and
warrants future investigation.
The kinematic changes in the unaffected limb developed over 3-6 months in the
goat, with no significant differences noted in the acute post-operative period. It is
unknown if the observed changes in knee extension would have resolved or persisted
beyond the 6 month study period. Given that compensatory adaptations appear to
develop over time in the unaffected knee in both humans(88, 137) and goats, this may
have implications regarding timing of surgical intervention in humans with acute ACL
injury. For instance, it is unknown whether early stabilization may prevent bilateral
compensatory abnormalities from occurring. Herbert-Losier et al. (2018) evaluated
patients that had undergone ACL reconstruction on average 3.5 years post ACL injury
(range 0 – 8 years) and found kinematic changes in both the affected and unaffected
knee during a drop-jump activity.(88) To the author’s knowledge, there are no reports
evaluating long-term kinematic changes in only patients that underwent ACL
reconstruction during the acute period.
Although no significant changes in axial rotation were observed in the unaffected
knee in the goat, disturbances in axial rotation have been identified in the unaffected
knee in humans with contralateral ACL reconstruction.(130, 131) Hofbauer et al. (2014)
noted increased external tibial rotation to develop over time in the unaffected knee
during single-leg hopping, while opposite changes (increased flexion and internal tibial
80
rotation) were identified in the ACL reconstructed knee.(130) It is possible that a change
in axial rotation was developing in the goats - at 6 months post contralateral ACL
transection, the unaffected knee was held in more external tibial rotation during swing
phase (Figure 8), although the difference was not statistically significant compared to
other time points. In contrast, an evaluation of patients during walking and stair climbing
2-3 years post ACL reconstruction and demonstrated increased internal tibial rotation of
the unaffected limb during stair ascent and descent when compared to the ACL
reconstructed knee and to healthy controls.(131) The results of these studies suggest
that disturbances in axial rotation may develop in the unaffected limb after ACL
injury/reconstruction during certain activities, but the results are inconsistent across
studies and warrant more focused assessments to determine true patterns of
compensatory change.
When using the unaffected knee as a normal control in biomechanical studies of
ACL injury, it is assumed that the unaffected knee functions normally without
derangement secondary to the contralateral injury. Given the relatively minor changes
to kinematics observed over time, the unaffected limb may serve as a suitable control in
this species, although increased extension of the knee during the transition between
stance and swing phase should be considered in evaluating kinematic outcomes.
Extrapolation of these findings to humans and other large animal translational models
should be assumed with much caution, since kinematic changes with ACL deficiency
appear have variations across species.(48, 93, 95, 101, 102)
Limitations of this study include a relatively short study period of 6 months post
ACL transection. Aforementioned studies demonstrated kinematic changes in the
81
unaffected limb well beyond 6 months post injury(88, 130, 131), and it is unknown
whether the documented kinematic changes in goats would have persisted or resolved
with time. Kinematic data was collected with single-plane fluoroscopy, which has been
shown to be less accurate for out-of-plane translations than dual-plane fluoroscopic
systems.(108, 112) Because of this, we were not able to evaluate medial/lateral
translations in this study. Given the lack of changes in other kinematic parameters such
as anterior tibial translation and abduction/adduction, the authors believe it is unlikely
that medial/lateral translation would have changed significantly over time in the
unaffected limb. Familiarity and comfort with the treadmill and fluoroscopy unit may
have improved in the goats over the study period, which may have influenced the
kinematic data over time. Furthermore, treadmill gait has been shown to differ mildly
from over ground gait in other species(120, 121), so these data must be interpreted in
light of the studied activity.
Conclusions
The results of this study demonstrate that increased extension of the knee
develops in the unaffected limb following contralateral ACL transection in the goat. The
increased extension in the unaffected knee mirrored the changes in extension observed
in the affected knee in the previous chapter. The development of bilaterally symmetric
kinematic alteration following unilateral ACL transection in the goat may be of benefit in
a prey species as it would allow for the appearance of a uniform gait. Because the
kinematic changes are relatively mild, use of the unaffected limb as an internal control
for each subject may be valid in the goat, obviating the need for enrollment of normal,
ACL intact animals. Future studies of kinematic changes in unaffected limbs of humans
and other translational animal models may be warranted.
82
Figures
Figure 3-1. 3D bone models of a goat limb (femur and tibia) with tantalum beads
implanted. Bone sections with beads implanted are cut away for fluoroscopic shape matching purposes.
83
Figure 3-2. A- Lateral projection fluoroscopic image of the right knee of a goat during a
treadmill walking gait. B- Shape matching: three-dimensional bone models are superimposed over the lateral projection fluoroscopic image of the right goat knee.
84
Figure 3-3. Body weight normalized mean peak vertical force (100*N/N) of the hind
limbs during stance phase of a walking gait. Significant differences were found in the right hind limb when comparing baseline and 2 weeks post ACL transection (*), and between 2 weeks and 6 months post ACL transection (^). A significant difference was also noted between the right and left hind limb at 2 weeks post ACL transection (X).
*^x
10
20
30
40
50
60
70
80
Baseline 2 weeks post op 3 months post op 6 months post op
Mean Peak Vertical Force (100*N/N)in the Hind Limbs
Right hind limb Left hind limb
85
Key for Figures 3-4 through 3-11:
A 2 weeks post ACL transection vs. Baseline
B 3 months post ACL transection vs. Baseline
C 2 weeks post ACL transection vs. 3 months post ACL transection
D 6 months post ACL transection vs. Baseline
E 2 weeks post ACL transection vs. 6 months post ACL transection
F 6 months post ACL transection vs. 3 months post ACL transection
86
Figure 3-4. Mean flexion angle of the unaffected knee throughout stance phase of gait
before and after contralateral ACL transection. Significant differences are denoted by a letter corresponding to the provided key.
D DBDD
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100% Stance Phase
Mean Flexion Angle (degrees) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
87
Figure 3-5. Mean flexion angle of the unaffected knee throughout swing phase of gait
before and after contralateral ACL transection. Significant differences are denoted by a letter corresponding to the provided key.
BD
BD
BD
BD
BD
BD
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100% Swing Phase
Mean Flexion Angle (degrees) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
88
Figure 3-6. Mean anterior tibial translation in millimeters of the unaffected knee
throughout stance phase of gait before and after contralateral ACL transection. No significant differences were found between time points.
-4.00
-2.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
0 10 20 30 40 50 60 70 80 90 100
% Stance Phase
Mean Anterior Tibial Translation (mm) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
89
Figure 3-7. Mean anterior tibial translation in millimeters of the unaffected knee
throughout swing phase of gait before and after contralateral ACL transection. No significant differences were found between time points.
-4.00
-2.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
0 10 20 30 40 50 60 70 80 90 100
% Swing Phase
Mean Anterior Tibial Translation (mm) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
90
Figure 3-8. Mean axial rotation of the unaffected knee throughout stance phase of gait
before and after contralateral ACL transection. Positive y-values represent internal rotation and negative y-values represent external rotation. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Stance Phase
Mean Internal (+)/External (-) Axial Rotation (degrees) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
91
Figure 3-9. Mean axial rotation of the unaffected knee throughout swing phase of gait
before and after contralateral ACL transection. Positive y-values represent internal rotation and negative y-values represent external rotation. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Swing Phase
Mean Internal (+)/External (-) Axial Rotation (degrees) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
92
Figure 3-10. Mean abduction angle of the unaffected knee throughout stance phase of
gait before and after contralateral ACL transection. Positive y-values represent abduction and negative y-values represent adduction. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Stance Phase
Mean Abduction (+)/Adduction (-) (degrees) During Stance Phase
Baseline 2 weeks post op 3 months post op 6 months post op
93
Figure 3-11. Mean abduction angle of the unaffected knee throughout swing phase of
gait before and after contralateral ACL transection. Positive y-values represent abduction and negative y-values represent adduction. No significant differences were found between time points.
-25
-20
-15
-10
-5
0
5
0 10 20 30 40 50 60 70 80 90 100
% Swing Phase
Mean Abduction (+)/Adduction (-) (degrees) During Swing Phase
Baseline 2 weeks post op 3 months post op 6 months post op
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CHAPTER 4 SUMMARY
Large animal models are frequently used in translational research of ACL
anatomy, pathology, and biomechanics. Chapter 1 provided a review of commonly
chosen translational large animal models (dog, goat, sheep, pig, and rabbit) in ACL
research, and highlighted the similarities and differences of each species compared to
the human ACL. This collated information will be valuable in guiding future researchers
in their selection of an appropriate animal model, based on the particular aspect of ACL
research they are aiming to evaluate. Chapter 1 also demonstrated important gaps in
the literature within each animal model and will provide direction for further study of the
large animal models to ensure that interpretation of findings in large animal ACL
research and their application to human medicine is appropriate.
An example of a gap in the literature noted in Chapter 1 was the understanding
of in-vivo kinematic consequences of ACL deficiency in the goat. The goat is a
commonly used translational animal model for ACL reconstruction(47, 64, 65, 106, 107),
yet little is known about kinematics of the goat knee. In Chapter 2, we demonstrated
that ACL transection results in persistent kinematic abnormalities in the goat knee,
characterized by increased anterior tibial translation (mean 3 – 4 mm) and increased
extension of the knee (mean 10 – 15 degrees) compared to baseline values.
Interestingly, despite persistent kinematic alterations, goats appear to resolve their
lameness by 3 months after unilateral ACL transection. The underlying mechanism of
the resolution of lameness despite persistent instability remains unknown.
In Chapter 3, we explored the development of kinematic changes in the
unaffected knee following unilateral ACL transection in the goats. The unaffected knee
95
is often used as an internal control within each patient, under the assumption that
kinematic alterations do not occur as compensation for instability in the affected knee.
This assumption does not appear to be valid in many human studies, which
demonstrate increased knee extension and disturbances in axial rotation in patients with
chronic ACL injury (+/- reconstruction) compared to control subjects.(86, 88, 130, 131)
In Chapter 3 we demonstrated that the goats developed increased knee extension
(mean 12 – 15 degrees) in the unaffected knee in late stance and early swing phase by
3 months post contralateral ACL transection. This finding may represent a bilateral
kinematic compensatory mechanism, given that increased knee extension was also
demonstrated in the affected limb in Chapter 2.
The results of these studies help to further define the goat as a large animal
translational model for ACL research by filling an important gap in the literature for this
species. Description of the in-vivo kinematic changes that develop over time in both the
ACL transected and the unaffected knee will provide comparative researchers with
valuable data for evaluating future studies of ACL reconstruction and assessing
outcomes in the goat.
96
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BIOGRAPHICAL SKETCH
Ana Luisa Bascuñán was born and raised in northern Colorado. She attended
the Barrett Honors College at Arizona State University for her undergraduate studies,
originally registering as a pre-medical student. In her second year at Arizona State
University she enrolled in an animal behavior course, which helped her recognize that
she wished to pursue veterinary rather than human medicine. After completing her
undergraduate studies, she moved back to Colorado and worked as a veterinary
technician for one year before enrolling in the College of Veterinary Medicine and
Biological Sciences at Colorado State University. During her time as a veterinary
technician Ana developed a love for small animal surgery and pursued this interest from
day one of veterinary school. After graduating as a Doctor of Veterinary Medicine in
2014, Ana completed a Rotating Internship in Small Animal Medicine and Surgery
through the Veterinary Medical Teaching Hospital at Texas A&M University. She was
then accepted into a Small Animal Surgical Residency at the University of Florida Small
Animal Hospital. Ana completed her Master of Science in Veterinary Medical Sciences
degree in 2018 as a component of her residency training. Her surgical and research
interests include microsurgical techniques, minimally invasive surgery, and
cardiovascular surgery.
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