480862

0862Foot & Ankle InternationalRein et al

2013
FAIXXX10.1177/107110071348

Foot & Ankle International

Comparative Analysis of Inter- and

34(7) 1017­–1024
© The Author(s) 2013
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DOI: 10.1177/1071100713480862
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Nerve Endings in Ankle Ligaments:
A Cadaver Study

Susanne Rein, MD, PhD1, Uwe Hanisch, MD2, Hans Zwipp, MD, PhD1,
Armin Fieguth, MD, PhD3, Sophie Lwowski1, and Elisabet Hagert, MD, PhD4

Abstract
Background: The aim of this study was to analyze the inter-, intraligamentous, and side-related patterns of sensory nerve
endings in ankle ligaments.
Methods: A total of 140 ligaments from 10 cadaver feet were harvested. Lateral: calcaneofibular, anterior-, posterior
talofibular; sinus tarsi: lateral- (IERL), intermediate-, medial-roots inferior extensor retinaculum, talocalcaneal oblique and
canalis tarsi (CTL); medial: tibionavicular (TNL), tibiocalcaneal (TCL), superficial tibiotalar, anterior/posterior tibiotalar
portions; syndesmosis: anterior tibiofibular. Following immunohistochemical staining, the innervation and vascularity was
analyzed between ligaments of each anatomical complex, left/right feet, and within the 5 levels of each ligament.
Results: Significantly more free nerve endings were seen in all ligaments as compared to Ruffini, Pacini, Golgi-like, and
unclassifiable corpuscles (P ≤ .005). The IERL had significantly more free nerve endings and blood vessels than the CTL
(P ≤ .001). No significant differences were seen in the side-related distribution, except for Ruffini endings in right TCL
(P = .016) and unclassifiable corpuscles in left TNL (P = .008).The intraligamentous analysis in general revealed no significant
differences in mechanoreceptor distribution.
Conclusions: The IERL at the entrance of the sinus tarsi contained more free nerve endings and blood vessels, as
compared to the deeper situated CTL. Despite different biomechanical functions in the medial and lateral ligaments, the
interligamentous distribution of sensory nerve endings was equal.
Clinical Relevance: The intrinsic innervation patterns of the ankle ligaments provides an understanding of their innate
healing capacities following injury as well as the proprioception properties in postoperative rehabilitation.

Keywords: ankle, immunohistochemistry, ligaments, proprioception, sensory nerve endings

Several studies have investigated the innervation of human
ligaments in the knee,29 ankle,20,21,25 elbow,23 wrist,14,15,19
and finger2,3 joints, the spine,27 and the patellar tendon.4,5
The primary focus of these studies was sensory nerve end-
ings, so-called mechanoreceptors, which can be classified
morphologically via a designated shape.9,12 The different
types of sensory nerve endings are assigned different func-
tions. Ruffini endings, type I, are slowly adapting and low-
threshold receptors, which are responsible for the joint
position. In contrast, Pacini corpuscles, type II, are rapidly
adapting and low-threshold receptors, which react to joint
acceleration or deceleration. Golgi-like endings, type III,
are rapidly adapting and high-threshold receptors reacting
to extreme ranges of motion. Finally, free nerve endings,
type IV, function as nociceptors, responding to noxious or
inflammatory stimuli. Corpuscles, which cannot be classi-
fied as Ruffini, Pacini, Golgi-like endings, or free nerve
endings, are regarded as unclassifiable corpuscles.12 A
thorough analysis of the type and distribution of sensory
nerve endings in the ankle ligaments may therefore give
more insight into the proprioceptive function of these
ligaments.
Lateral ankle ligaments are often affected by ankle
sprains, which is the most common sports injury.6 Recurrent
ankle sprains can result in mechanical and/or functional
ankle instability. Functional ankle instability is defined as
1
University Hospital “Carl Gustav Carus,” Dresden, Germany
2
Hospital “Carl Thiem,” Cottbus, Germany
3
University Hospital of Hannover, Hannover, Germany
4
Karolinska Institutet, Hand & Foot Surgery Center, Stockholm, Sweden
Corresponding Author:
Susanne Rein, MD, PhD, University Hospital “Carl Gustav Carus,”
Department of Trauma and Reconstructive Surgery, Fetscherstr. 74,
01307 Dresden, Germany.
Email: susanne.rein@web.de

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1018 Foot & Ankle International 34(7)

the patient’s subjective feeling that the ankle is giving way, Table 1. The Dissected Ligaments.
in other words, the “sense” of instability of the ankle, espe-
Anatomical Complex Abbreviation Ligament
cially when walking or running on uneven ground.8 Freeman
et al8 hypothesized that functional instability is caused by a Syndesmosis ATiFL Anterior tibiofibular ligament
Lateral ATFL Anterior talofibular ligament
proprioceptive deficit resulting from partial deafferentation
CFL Calcaneofibular ligament
due to damage of sensory nerve endings in the joint. In con- PTFL Posterior talofibular ligament
trast, mechanical instability involves an anatomical abnor- Medial
mality such as disruption of a ligament.26  Superficial TNL Tibionavicular ligament
The ligamentous stability of the ankle joint is based on 4 TCL Tibiocalcaneal ligament
complexes: the distal tibiofibular syndesmosis, the lateral STTL Superficial tibiotalar ligament
and medial complexes, as well as the sinus tarsi ligaments.  Deep ATTL Anterior tibiotalar ligament
PTTL Posterior tibiotalar ligament
Previous studies have investigated the lateral and medial
Sinus tarsi IERL Inferior extensor retinaculum,
ankle ligaments only using the gold chloride technique.20,21 lateral root
However, gold chloride impregnates not only nerve tissue IERI Inferior extensor retinaculum,
but also elastic fibers in blood vessels and reticular fibers, intermediate root
thus providing nonspecific imaging of neural elements in IERM Inferior extensor retinaculum,
medial root
tissue.11,18,30 Recently, sensory nerve endings have been
TCOL Talocalcaneal oblique ligament;
analyzed in wrist ligaments with a combination of the fol- synonym: cervical ligament
lowing immunohistochemical markers: the glial cell S-100 CTL Canalis tarsi ligament;
protein, the low-affinity neurotrophic receptor p75, and the synonym: interosseous
protein gene product 9.5.13-15 These 3 antibodies allow a talocalcaneal ligament
precise differentiation of the sensory nerve endings due to
selective delineation of specific neural and perineural struc-
tures in sensory nerve endings. A complete immunohisto- the ligaments of the sinus tarsi were exposed. Ligaments
chemical analysis with comparison of the innervation were defined according to the description of Zwipp,32
patterns in medial, lateral, and sinus tarsi ligaments as well Pankovich and Shivaram,22 and Schmidt.28 The dissected
as the ATiFL of the distal tibiofibular syndesmosis has pre- ligaments and their abbreviations are illustrated in Table 1.
viously not been published, nor has an exact analysis of the All 140 ligaments were completely dissected from their
intraligamentous distribution of sensory nerve endings insertion into bone.
within each ligament been described.
The purpose of this study was to describe the sensory
nerve endings around the ankle in terms of comparing the Immunohistochemistry
pattern and types of mechanoreceptors between the liga- The 140 harvested ligaments were immediately fixed in 4%
ments in the lateral, sinus tarsi, and medial complexes, as formaldehyde, then paraffin-sectioned into 4 µm-thick sec-
well as within each investigated ligament of the ankle joint tions before being mounted on glass slides. All ligaments
using designated immunohistochemical markers. were cut at 5 levels, with a 50-µm cutting interval between
each level. Standard immunohistochemical protocol was
followed,13,15 and a combination of antibody staining was
Materials and Methods performed to validate our findings of sensory nerve endings
Cadaver Specimens in the ankle ligaments. Briefly, 3 primary antibodies were
used: anti–nerve growth factor receptor p75 (p75; working
All protocols in this study were approved by the local ethics dilution: 1:200; code N-3908; Sigma, Saint Louis, MO),
committee review board. A total of 10 feet from 5 subjects (2 anti–Protein Gene Product 9.5 (PGP 9.5; working dilution
women and 3 men) with a mean age of 57±20 years (range, 1:500; code: 7863-0504; AbD Serotec, Düsseldorf,
36 to 86 years) were included in this study. In all, 5 left and Germany), and anti-S100 (S100; working dilution 1:500;
5 right feet were analyzed. The cadavers were refrigerated code Z 0311; DakoCytomation, Glostrup, Denmark). The
(4°C) pending ligament harvest, and the mean time between p75 antibody specifically reacts with the low-affinity neu-
death and harvest was 3.6±2.4 days (range, 1 to 7 days). All rotrophic receptor, which binds nerve growth factor and all
feet were assessed macroscopically and showed no signs of other neurotrophins, including brain-derived neurotrophic
ligament injury or structural abnormality. factor, neurotrophin-3 and -4. The antibody against PGP 9.5
is a panneuronal marker reacting with PGP 9.5 in all mam-
malian species tested, including humans. The antibody
Ligament Specimens against S100 specifically stains the S100 protein, including
A lateral and medial semicircular skin incision was made in the Schwann cells of the peripheral nervous system. The
over the ankle. The lateral and medial ligaments as well as 1A4 antibody (sm-actin; working dilution 1:750; code M

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Rein et al 1019

*
600

500 §
400
Number (n) Free nerve
300 endings
Blood
200 vessels

100

IERM
IERI
ATiFL

ATFL

ATTL
TNL

IERL
PTFL

STTL

PTTL
CFL

TCL

CTL
TCOL
Syn- Lateral Medial Sinus tarsi
desmosis

Figure 1. Distribution of free nerve endings and blood vessels. Means with standard deviations for the free nerve endings and blood
vessels are demonstrated for each ligament. The IERL (*) had significantly more free nerve endings (P < .0001) and blood vessels (P =
.001) than the CTL. In addition, the IERI (§) had significantly more blood vessels than the CTL (P = .005).
ATiFL = anterior tibiofibular ligament of the distal tibiofibular syndesmosis; ATFL = anterior talofibular ligament; ATTL = anterior tibiotalar ligament;
CFL = calcaneofibular ligament; CTL = canalis tarsi ligament; IERI = intermediate root of the inferior extensor retinaculum; IERL = lateral root of the in-
ferior extensor retinaculum; IERM = medial root of the inferior extensor retinaculum; PTFL = posterior talofibular ligament; PTTL = posterior tibiotalar
ligament; STTL = superficial tibiotalar ligament; TCL = tibiocalcaneal ligament; TCOL = talocalcaneal oblique ligament; TNL = tibionavicular ligament.

0851; DakoCytomation, Glostrup, Denmark) was also used
to analyze blood vessels due to immunoreactivity (IR) of
smooth muscles in their wall.
Morphological Analysis and Cell Counting
Histological examination of the stained tissue sections was
performed using a Leica light microscope (Leitz DMRBE,
Wetzlar, Germany) with a Leica camera (Leica DC 300,
Leica Microsystems CMS GmbH, Heerbrugg, Switzerland).
Hematoxylin-eosin (H&E) and Elastica van Gieson
(EvG) stains were used for determination of tissue morphol-
ogy, and all ligaments were evaluated to exclude signs of
ligament lesion before starting the mechanoreceptor analy-
sis. Mechanoreceptors were analyzed according to the clas-
sification of Freeman and Wyke, modified by Hagert.9,12
Ruffini, Pacini, Golgi-like, and free nerve endings as well as
unclassifiable corpuscles were counted in the S100, p75, and
PGP 9.5 stains in all 5 levels with respect to total cell count/
section at an original magnification of 400x. A standard 10 ×
10 grid was used for determination of mechanoreceptor size.
Blood vessels were counted at 2 representative levels in the
sm-actin stain. All specimens were blinded for cell counts.
Statistical Analysis
The first purpose of this study was to examine the inter-
ligamentous distribution of mechanoreceptors in each
anatomical complex. The ATFL, PTFL, and CFL were
compared in the lateral complex. The ligaments of the
sinus tarsi, namely, the IERL, IERM, IERI, TCOL, and
CTL were compared to each other. Finally, the 5 different
portions of the deltoid ligament from the medial complex
were compared.
The Kolmogorov–Smirnov test was performed to inves-
tigate data distribution. Since all groups were found to not
have normal distribution, the statistical analysis was per-
formed using the Kruskal–Wallis test followed by Mann–
Whitney with post hoc Bonferroni adjustments. The final
significance for the analysis of the lateral ligaments was
P = .017 (3 ligaments with 3 statistical tests). The final sig-
nificance for the sinus tarsi ligaments and the deltoid liga-
ments was P = .005 (5 ligaments with 10 tests,
respectively).
The second purpose was to compare the total number
and types of mechanoreceptors within each ligament. This
was performed with a Friedman test followed by a Wilcoxon
test with post hoc Bonferroni adjustment with a final sig-
nificance of P = .005 (10 tests, 5 sensory nerve endings).
The third purpose was to compare the right- and left-side
distribution of the mechanoreceptors of each ligament,
using a Mann–Whitney test with post hoc Bonferroni
adjustments.
The fourth purpose was to analyze the intraligamentous
distribution of sensory nerve endings in each ligament
between the 5 levels studied. The Friedman test followed by

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1020 Foot & Ankle International 34(7)

the Wilcoxon with post hoc Bonferroni adjustments was

used, with a final significance of P = .005 (10 tests of sig-
nificance between the 5 levels at the Bonferroni
adjustment).

Results
Interligamentous Distribution and
Mechanoreceptor Types
The analysis between the sinus tarsi ligaments showed that
the IERL had significantly more free nerve endings
(96±46.7) than the CTL (27.6±13.3; P ≤ .0001; Figure 1).
In addition, the IERL (391.9±211.56; P = .001) and the
IERI (218.8±56.6; P = .005) had significantly more blood
vessels (Figure 2) than the CTL (151.3±59.7; Figure 1).
Aside from this, no significant differences were noted in the
number of mechanoreceptors between the ligaments of
each complex (see Figures 2-4).
Significantly more free nerve endings than Ruffini
(Figure 3), Pacini (Figure 4), Golgi-like (Figure 5), and
unclassifiable corpuscles were seen in all investigated liga-
ments (P ≤ .005, respectively).

Right- and Left-Side Distribution

No significant differences were seen for all sensory nerve
endings for the ATiFL (see Figure 1) and all ligaments of
the lateral and sinus tarsi complex. Right feet (0.8±0.24) of
the TCL had significantly more Ruffini endings than left
feet (0.12±0.27; P = .016). Significantly more unclassifi-
able corpuscles of the TNL were counted in left feet
(0.37±0.12) as compared to right feet (0.04±0.9; P = .008).

Intraligamentous Distribution
No significant differences of Ruffini endings, Pacini cor-
puscles, Golgi-like endings, free nerve endings, or unclas-
sifiable corpuscles were observed between all levels in each
ligament, except for the free nerve endings between the
superficial level 1 (71.9±37.7) and the deeper located level
4 (128.6±60.7) in the PTFL (P ≤ .005).
Discussion
The distinct pattern of mechanoreceptor populations within
the ligament is likely to reflect the innate functions of these
ligaments. Interestingly, despite known differences in the
biomechanical functions of the medial and lateral ankle
ligaments,33 we found no significant differences in the den-
sity or distribution of mechanoreceptors within these com-
plexes, nor in the interligamentous distribution of nerve
endings. Studies of joint capsules have shown that regions
of high load generally have a greater density of innervation.10
Figure 2. Blood vessels. An artery from an anterior
tibiofibular ligament, as stained with H&E (a), EvG (b), and with
immunoreactivity (IR) for sm-actin (c). The black-stained elastic
fibers of the internal elastic membrane (arrow in b) and the
external elastic membrane (arrowheads in b) are clearly visible.
The smooth muscle in the wall of the vessel is IR for sm-actin
(arrow in c), whereas the accompanying vessels (arrowheads in
c) are also IR for sm-actin. Original magnification ×200.
Since the ATFL is exposed to a high risk of injury,16,26,33 one
may have anticipated a richer innervation of sensory nerve
endings as compared to the CFL or PTFL.
In fact, our results are in contrast to previous gold chlo-
ride investigations of mechanoreceptors in ankle liga-
ments.20,21 Michelson and Hutchins20 found significantly

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Rein et al 1021

Figure 3. Ruffini ending. A Ruffini corpuscle in an intermediate root of the inferior extensor retinaculum in the sinus tarsi as stained
for H&E (a), S100 (b), p75 (c), and PGP 9.5 (d). Note the specific IR of the dendritic terminal nerve endings (b, c, d) and thin, at times
partial, encapsulation (arrowhead) of the corpuscle (c). The central axon (arrow) of the corpuscle is clearly visualized by showing
specific S100 IR (b) and PGP 9.5 IR (d). No IR of the central axon is seen in the p75 staining (c). Due to its characteristic dendritic
nerve endings, the Ruffini corpuscle is also unspecifically stained and visible in the H&E staining (a). Original magnification ×400.

fewer Pacini corpuscles and Golgi-like endings in the CFL
compared to the PTFL, whereas Moraes et al21 found a
greater prevalence of Pacini corpuscles as compared to
Ruffini and Golgi-like endings in the ATFL, PFTL, and
CFL. An explanation for these differences may be that gold
chloride stains not only nerve tissue but also elastic fibers in
blood vessels and reticular fibers, thus providing nonspe-
cific imaging of neural elements in tissue.11,18,30 The pri-
mary difference between our study and those published
previously is that we used a combination of immunohisto-
chemical markers to target specific mechanoreceptor struc-
tures, as well as performed the total analysis on a large
number of sections at 5 different levels in each ligament.
We propose that our analysis offers a greater distinction of
both receptor type and frequency.
The IERL at the entrance of the sinus tarsi was richly
innervated with free nerve endings, as compared to the
deeper situated CTL. This is in accordance with a previous
study where abundant free nerve endings and mechanore-
ceptors were found in fatty and synovial membranes of lat-
eral sinus tarsi tissue in patients with sinus tarsi syndrome.1
Based on this, it may be assumed that the pain of sinus tarsi
syndrome mainly originates at its entrance. Furthermore,
studies have shown that patients with functional ankle insta-
bility and pain near the sinus tarsi have a prolonged peroneal
reaction time (PRT). After injection of lidocaine into the
sinus tarsi, the PRT significantly shortened in these patients,
whereas the PRT in healthy controls remained unchanged.17
This indicates a proprioceptive role of the sensory nerve
endings at the sinus tarsi in regulating the activities of
gamma motor neurons of the peroneal muscles, which in
turn may cause the symptoms of functional ankle instability
and prolonged PRT.17 Interestingly, the presence of mecha-
noreceptors and nerve structures also varied between human
wrist ligaments, investigated with the immunohistochemical
markers of S100, p75, and PGP 9.5.13 The dorsal intercarpal,

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1022 Foot & Ankle International 34(7)

Figure 4. Pacini corpuscle. A Pacini corpuscle in the tibiocalcaneal portion of the deltoid ligament as seen in (a) H&E staining, (b) with
S100, (c) with p75, as well as (d) with PGP 9.5 IR. The central axon (arrow) of the afferent nerve is clearly delineated with S100 (b).
Note the characteristic multilamellar capsule (arrowhead) with strong p75 IR in the inner and outer lamellae (c) and PGP 9.5 IR in the
inner lamellae (arrowhead in d). Due to unspecific staining of its characteristic onion-layered capsule, the Pacini corpuscle is also visible
in the H&E staining (a). Original magnification ×400.

the dorsal radiocarpal, and the scapholunate interosseous
ligaments are richly innervated, but the lunotriquetral inter-
osseous ligament is almost without innervation. However, a
semiquantitative estimation of the innervation was used in
this study.13 The authors concluded that the difference in
innervation between the ligaments might reflect differential
function, whereas ligaments without innervation might act
as structures of passive restraint, and ligaments with rich
innervation may provide proprioceptive information.13
Furthermore, mechanoreceptors were distributed evenly
throughout human annular and transverse medial ligaments
at the elbow. Increased density toward the origin and distal
insertions has been observed in the radial, posterior, and
anterior medial elbow ligaments. However, gold chloride
impregnation was used in this study.23
We also chose to investigate the potential differences in
innervation patterns between left and right feet, as previous
studies have indicated side-related differences in ankle pro-
prioceptive qualities.24 A meta-analysis of clinical balance
studies after unilateral ankle sprain has shown that balance
is bilaterally impaired after an acute lateral ankle sprain, but
not seen in patients with chronic ankle instability.31
Wikstrom et al31 suggested that centrally mediated changes
in individuals with chronic ankle instability are responsible
for the adaptation of postural control and balance between
chronic unstable and contralateral unaffected ankle joints.
This proposal is in agreement with a study on rabbits where
an injury of the knee medial collateral ligament resulted in
biomechanical changes on the collagen fibril diameter of
the contralateral uninjured medial collateral ligament,7 indi-
cating that systemic factors, such as neural transmitters or
hormonal changes, may have trophic functions.7 Our mor-
phological analysis of side-related differences was not able
to deduct an innate difference in the innervation pattern
between right and left feet, supporting the notion that bilat-
eral proprioceptive defects may be central rather than
peripheral. In addition, when examining the intraligamen-
tous distribution of innervation in ankle ligaments, it
became apparent that they had a consistent distribution of
sensory nerve endings among the 5 different investigated
levels, which is in accordance with other authors,20 indicat-
ing that even within a ligament, the innervation pattern is
stable and consistent. Similarly, no histological differences
in the pattern of free nerve endings were observed between
the ventral, middle, and dorsal parts of human lumbar liga-
ments, using S100 immunohistochemistry.27

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Rein et al 1023

Figure 5. Golgi-like ending. A Golgi-like corpuscle in the superficial tibiotalar portion of the deltoid ligament is shown as stained
for H&E (a), S100 (b), p75 (c), and PGP 9.5 (d) IR. An afferent nerve fascicle (arrow) courses to the center of the corpuscle. Smaller
corpuscles within the Golgi-like corpuscle are seen, each of them containing terminal nerve endings (arrowheads in b, c, d). Original
magnification ×100.

Acknowledgments Grant: MedDrive 33, Medical Faculty of the Technical University,

The authors thank the following individuals for their contributions
to this article: Ursula Range for statistical support, Suzanne
Manthey for histological preparation Thomas Albrecht for photo-
graphical work as well as Reinhold Krentscher and Hans-Dieter
Tröger for logistical support.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
Dresden, Germany.
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