53 WINTER 2018
Toxicity and Toxicokinetic Study of Subcutaneously
Administered RPh201 in Göttingen Minipigs page 3
Testing cognitive abilities over different life stages
in Göttingen Minipigs page 6
Obesity and diabetes result in pathological bone repair
around dental implants:
Demonstration in a Göttingen Minipigs models page 9
Using Göttingen Minipigs as model for peritoneal dialysis page 14
Vascular Access Buttons in Göttingen Minipigs page 15
Fifty Years with Göttingen Minipigs: Let’s Celebrate! page 18
Ellegaard Göttingen Minipigs Going Global page 19
Ellegaard Göttingen Minipigs Enters into a License
and Commercialization Agreement for Göttingen Minipigs
Research Models in Partnership with Exemplar Genetics page 19
Creating a stimulating and cooperative environment
for Göttingen Minipigs page 20
Invitation to join The 13th Minipig Research Forum
22-24 May 2019 in Vienna, Austria page 21
New scientific publications on Göttingen Minipigs page 22
can meet us
for clear results
The days are getting shorter and soon we will
be saying goodbye to 2018 and hello to a new
year. At Ellegaard Göttingen Minipigs, we will
especially remember 2018 for two important
landmark events: Approval of the Veterinary
Health Certificates for the export of Göttingen Minipigs
to both China and India! Read more about the availability
of Göttingen Minipigs in these new markets in this Newsletter.
We are getting ready to enter 2019 with the expectations of a
special year to come celebrating Fifty Years of Göttingen Minipigs
by, among other things, a roadshow of scientific events around
Europe as well as a few places in the USA and Asia. We reveal
more on the plans for our year of celebration at page 18, and I
recommend that you follow us on LinkedIn to stay updated on
venues and dates for the meetings and other exciting news.
Looking back at the old year, in my humble opinion, some highlights
at Ellegaard Göttingen Minipigs stood out: At the Minipig
Research Forum in Barcelona in May, the Ellegaard Göttingen
Minipigs Research Foundation announced a substantial grant
to a very promising and exciting scientific project entitled
“Speedgene targeted knock out of the PCSK-9 gene in Göttingen
Minipigs”; and in September, the GENISYST Project Steering
Group assembled for a successful two-day meeting in Denmark
including a visit to our location in Dalmose (see photo).
On 1 October 2018, we proudly turned 20 years of continued
and full AAALAC accreditation; a very important achievement
which emphasizes our passion and tireless engagement in the
welfare of our animals.
Finally, I am pleased to announce that early November 2018, Ellegaard
Göttingen Minipigs signed an agreement with Exemplar
Genetics to develop genetically modified animal models based
on our Göttingen Minipigs. Read more about this at page 19.
Further, during 2019, Ellegaard Göttingen Minipigs will offer
new services from our research barrier in Denmark; I look
forward to sharing more news with you on this in due course.
GENISYST Steering Group Meeting in Dalmose, Denmark. From left: Roy Forster
(Citoxlab France), Jaya Krishnan (Genome Biologics), Andy Makin (Citoxlab
Denmark), Jonathan Ward (Genome Biologics), Lars Friis Mikkelsen (Ellegaard
Göttingen Minipigs), Jens Ellegaard (Ellegaard Göttingen Minipigs), Marianne
Kronborg Bracken (Citoxlab Denmark), Peter Vestbjerg (Ellegaard Göttingen
Minipigs) and Henrik Duelund Pedersen (Ellegaard Göttingen Minipigs)
A warm thank you from all of us at Ellegaard Göttingen Minipigs
to customers and collaboration partners for working with us
during 2018 and also a big thank you for interesting talks, chats,
meetings and conferences around the world throughout 2018:
See you again next year, maybe at the MRF 2019 from 22-24
May in Vienna, Austria?
Happy Holidays and Happy Reading!
Lars Friis Mikkelsen, CEO
Ellegaard Göttingen Minipigs A/S
New Finance Manager
On 1 October 2018, we welcomed Klaus Kvist Rasmussen in
a new position as Finance Manager. Klaus holds a master’s
degree in economics from the University of Southern Denmark
and has previously worked for international consulting firms
such as PwC and Deloitte as well as for Novo Nordisk, where,
among other things, he advised on the optimization of financial
management and reporting. Since 2016, Klaus has worked as
an independent business consultant and added even more to
his extensive experience within his areas of financial
At Ellegaard Göttingen Minipigs, in addition
to being responsible for our financial
management, Klaus will no doubt play
an important role in the future develop-
ment and further internationalization
of our company. In his spare time, Klaus
is a passionate hunter and also enjoys
other outdoor activities.
Toxicity and Toxicokinetic Study of Subcutaneously
Administered RPh201 in Göttingen Minipigs . . . . . . . . . . 3
Testing cognitive abilities over different life stages
in Göttingen Minipigs . . . . . . . . . . . . . . . . . . . . . . . 6
Obesity and diabetes result in pathological bone repair
around dental implants: Demonstration in a Göttingen
Minipigs models . . . . . . . . . . . . . . . . . . . . . . . . . 9
Using Göttingen Minipigs as model for peritoneal dialysis . . 14
Vascular Access Buttons in Göttingen Minipigs . . . . . . . . 15
Fifty Years with Göttingen Minipigs: Let’s Celebrate! . . . . . 18
Ellegaard Göttingen Minipigs Going Global . . . . . . . . . . 19
Ellegaard Göttingen Minipigs Enters into a License and
Commercialization Agreement for Göttingen Minipigs
Research Models in Partnership with Exemplar Genetics . . . 19
Creating a stimulating and cooperative environment
for Göttingen Minipigs . . . . . . . . . . . . . . . . . . . . . 20
Invitation to join The 13th Minipig Research Forum
22-24 May 2019 in Vienna, Austria . . . . . . . . . . . . . . 21
New scientific publications on Göttingen Minipigs . . . . . . 22
Meeting Calendar 2019 . . . . . . . . . . . . . . . . . . . . . 24
Toxicity and Toxicokinetic Study
of Subcutaneously Administered RPh201
in Göttingen Minipigs
By Vanessa Ross 1 , Sydney Mukaratirwa 1 , Abraham Nyska 2 , Yuval Ramot 3 , Zadik Hazan 4 , Andre Lucassen 4 & Konstantin Adamsky 4
Envigo Ltd, Alconbury, Cambridgeshire, UK,
Timrat and Tel Aviv University, Tel Aviv Israel,
Hadadssah Hebrew University Medical Center, Jerusalem, Israel,
Regenera Pharma, Nes-Ziona, Israel
At Envigo, we ran a long-term (39 weeks) toxicity study in
Göttingen Minipigs in conjunction with Regenera Pharma. The
material investigated was an extract of mastic gum and such
extracts have traditionally been used as a dietary additive and
as a flavouring agent. These compounds are being developed
for a variety of clinical indications, which include treatment
of Crohn’s disease and the healing of peptic and dental ulcers.
RPh201 is an extract of mastic gum which has been formulated
and stabilised in a proprietary method, and is being developed
for a wide range of neurological indications.
32 male and 32 female Göttingen Minipigs were administered
subcutaneous injections of RPh201 (0, 3.1, 12.5. 50 mg/kg/occasion)
twice weekly for 39 weeks. The dose volumes were 0.062,
0.25 or 1 mL/kg/occasion respectively and the controls received
the vehicle at a dose volume of 1 mL/kg/occasion. There was a
26-week interim phase and a 6-week recovery period.
The protocol included routine clinical observations, hematology,
clinical chemistry, toxiciokinetics, blood evaluations, electroretinogram
and tonometry, electrocardiography, and macroscopic
and microscopic evaluations of selected organs.
Clinical observations (including ocular ERG and tonometry,
cardiac electrocardiography) and organ weights
There were no test article-related clinical signs or effects on
body weight or food consumption. During ophthalmic examination,
posterior suture line opacity was observed in the lens of
the eye of four animals. However, there was no effect on the
retina at electroretinogram examination and no ocular hypotension
or hypertension was evident. There were no effects on
Hematology investigations conducted in Week 26 of treatment
revealed slightly higher mean neutrophil counts observed in
both sexes receiving 12.5 or 50 mg/kg/occasion when compared
to controls. There was full recovery during the 6 week off-dose
period. In Week 39, a lower mean erythrocyte count and hemoglobin
concentration was observed in females receiving 50 mg/
kg/occasion in comparison with the controls. There was partial
recovery in both parameters following 6 weeks off-dose.
The rate of systemic exposure of minipigs to RPh201, measured
as the two components masticadienonic acid (MDA) and isomasticadienonic
acid (IMDA), was characterized by nonlinear,
subproportional, (dose dependent) kinetics over the dose range
from 3.1 to 50 mg/kg/day on Day 1 and during Week 13,
Week 26 and Week 39 of the 39 week subcutaneous toxicity
study. However, the extent of systemic exposure of minipigs
to MDA and IMDA was characterized by dose independent
(linear) kinetics over the same dose range and period. Systemic
exposure of minipigs to MDA was generally comparable to that
Clear oily liquid was found at the injection sites of all groups
at the 26 and 39-week sacrifice points, and was also observed
in controls and animals previously treated with 50 mg/kg/
occasion with a similar incidence in the 6-week recovery group.
Additional findings at the injection sites included skin thickening
(39-week sacrifice point), pale areas (26, 39-week and recovery
sacrifice points) and raised areas (week 26, week 39 and recovery
Clear oily liquid, enlargement and pale areas were seen at 26-
week, 39-week and 6-week recovery sacrifice points in various
lymph nodes (including axillary, inguinal, mandibular and mediastinal)
in animals treated with 50 mg/kg/occasion and in the
control group. Enlargement was also seen in one female animal
treated with 12.5 mg/kg/occasion and pale areas were also seen
in a male and female animal in this group.
Treatment-related findings were observed at injection sites
of animals from all sacrifice points, and included abscesses at
the 26 week and 39 week sacrifice and recovery phase and
recovering abscesses and an increase in fibrous tissue in the
39 week sacrifice and recovery phases. Abscesses graded as
moderate or marked were confined to animals receiving 50
mg/kg/occasion. Resolving abscesses were seen at the 39-
week sacrifice point in females receiving 50 mg/kg/occasion.
These were characterized by fibrous tissue, mineralization
and with few neutrophils present. At the 6 week recovery
sacrifice, the severity of the abscesses, resolving abscesses
and fibrosis was of a minimal or slight degree, which indicated
partial recovery from the findings seen at 26 and 39
Figure 1 legend:
A. Histopathological section of the subcutaneous injection site
in a Göttingen Minipig from the high-dose group (50 mg/
kg), main phase of the study. The tissue reaction consists of
chronic inflammation (asterisks). These findings were comparable
to the control group, and were considered as related
to the vehicle. In addition, abscesses (arrow) in the subcutis
(minimal grade) were seen, characterized by a cystic space
containing aggregates of neutrophils with a variable chronic
inflammatory component and a fibrous capsule of varying
B. Histopathological section of the subcutaneous injection
site in minipig from the high-dose group (50 mg/kg), main
phase of the study. The tissue reaction consists of chronic
inflammation (asterisks), and intermixed with empty spaces
reflecting the washed-out cotton-seed oil vehicle. Note the
abscess (arrows) in the subcutis (marked grade). This grade of
lesion is considered treatment related. H&E.
C. Histopathological section of the subcutaneous injection site
in a Göttingen Minipig from the high-dose group (50 mg/kg),
recovery phase of the study. Another example of a resolving
abscess. The tissue reaction is characterized by fibrous tissue
(arrow) and with only few neutrophils present (asterisk). H&E.
D. Histopathological section of the subcutaneous injection site
in a Göttingen Minipig from the high-dose group (50 mg/kg),
recovery phase of the study. Area of fibrosis (asterisks). The
increase in subcutaneous fibrosis was also seen in the 39-
week and 6-week recovery sacrifice, mainly in the high dose
Cystic spaces and chronic inflammation were seen at injection
sites of all treated groups and controls with the severity
generally correlating with the volume of vehicle administered.
The chronic inflammation was characterized by mononuclear
cells (lymphocytes and macrophages), foreign body giant cells,
fibrosis and occasional neutrophils. Incidence and severity of
the findings did not show signs of recovery after 6 weeks.
Cystic spaces and chronic inflammation were seen in the left
inguinal lymph node of all treated groups and controls at 26
week, 39 week and recovery phase with the severity generally
correlating with the volume of vehicle administered. Abscesses,
graded as minimal, were seen in the left inguinal lymph node
of a few animals killed at 26 weeks in all treated groups but
also in a female control killed after 39 weeks of treatment and
in the recovery group. They were also seen in other lymph
nodes in all three phases of this study that were examined
histopathologically due to being macroscopically abnormal.
Considering the overall incidence of abscesses in the left inguinal
lymph node and other lymph nodes in the study, this finding
was considered to be related to the vehicle. The incidence and
severity of the findings at the 6-week sacrifice point were
similar to the 39 week sacrifice point, therefore not showing
signs of recovery. Similar findings were also seen in the right
inguinal lymph node and in the axillary, mediastinal, medial
iliac, aortic and superficial inguinal lymph nodes when a macroscopic
abnormality was seen. Such abnormalities were present
most commonly in controls and animals receiving 50 mg/kg/
RPh201 was well tolerated for 39 weeks with no clinical or
dose-related signs observed and with no changes in body
weight, food consumption, electroretinography, intraocular
pressure, electrocardiography or blood chemistry and urinalysis
Treatment-related findings were seen at the injection sites and
included abscesses that correlated with a small increase in peripheral
neutrophil count. In animals given 50 mg/kg/occasion
abscesses graded above slight corresponded with macroscopically
thickened or raised areas (which contained either dark
fluid or green purulent material). The subcutaneous fibrosis
seen at the injection sites was considered secondary to chronic
inflammation and was again more pronounced in animals given
50 mg/kg/occasion and to a lesser extent in animals given
12.5 mg/kg/occasion. There was partial recovery from both
the abscess formation and fibrosis. Necrosis was not seen in
any of the injection sites, and bacterial colonies were not seen
in the abscesses. Therefore, these abscesses were concluded
to be sterile, and attributed to irritation from the presence
of the drug in a location with a relatively slow rate of absorption.
Under the conditions of this study, the No Observed Adverse
Effect Level (NOAEL) was considered to be 12.5 mg/kg/occasion,
after 39 weeks of administration followed by a 6-week recovery
period. RPh201 is a promising new and safe drug candidate for
the treatment of several neurological indications.
Figure 1E legend:
E. Histopathological section of the inguinal lymph-node (regional
to the injection site) in a Göttingen minipig from the
intermediate-dose group (12.5 mg/kg), main phase of the
study. The tissue reaction consists of chronic inflammation
(asterisks), and intermixed with empty spaces reflecting the
washed-out cotton-seed oil vehicle. These findings were
comparable to the control group, and were considered related
to the vehicle. In addition, abscesses (arrows) (minimal grade)
were seen, characterized by a cystic space containing aggregates
of neutrophils with a variable chronic inflammatory
component and a fibrous capsule of varying thickness. H&E.
Testing cognitive abilities over different
life stages in Göttingen Minipigs
By Caroline Clouard & Inonge Reimert
Wageningen University & Research, Department of Animal Sciences, Adaptation Physiology Group,
Wageningen, The Netherlands
The pig is a highly intelligent species and is, therefore, a good
animal model to investigate cognitive functions [1,2,3] . In the wild,
pigs have a mixed omnivorous diet, which requires high spatial
cognitive abilities to remember spatial location of food patches
 . This has also been shown by the plethora of pig studies
using spatial cognitive tasks such as the holeboard task [5,6,7,8,9,10] .
In these studies, however, pigs have been subjected to the
holeboard task during only one life stage, usually the juvenile or
pubertal life stage, and nothing is known about their cognitive
abilities in adulthood or the stability of their cognitive abilities
over life stages. It would therefore be interesting to determine
(1) whether pigs’ cognitive abilities are stable over time (i.e. from
juvenility to puberty to adulthood) and (2) whether pigs, which
are curious and novelty-seeking animals  , can be motivated
to perform the same task – which consists of a large number of
trials repeated over many testing days – multiple times throughout
life. To answer these research questions, we used Göttingen
Minipigs because their small size, even at the adult stage, makes
them very easy to handle and allows for longitudinal studies
in the same individuals, and because they have already been
tested in the holeboard task before [12,13,14] .
Animals and housing
In total, 8 female Göttingen Minipigs (Ellegaard, Denmark) were
subjected to the holeboard task during three consecutive life
stages: the juvenile stage (from 7 to 9 weeks of age), the pubertal
stage (from 17 to 20 weeks of age) and the adult stage (from
41 to 45 weeks of age). The animals were distributed over 3
consecutive batches, with a 2-week interval between batches.
In the first week after birth, piglets were kept with their sow
in individual farrowing pens (1.8 × 1.5 m). Pens had shredded
straw as bedding and contained a separate heated nest for the
piglets. From 1 week of age onwards, pigs were separated from
the sows and non-related pigs were housed in pairs in pens
(2.5 × 1 m) with shredded straw as bedding, and enriched with a
squeeze ball, a dog bed and 2 metallic chains per pen. Water was
available ad libitum and feed was given according to Ellegaard
All pigs were habituated to being handled by experimenters
and to the apple rewards (offered in a bucket in the home pen)
before the start of the holeboard task in the juvenile stage.
Principle and apparatus
The holeboard arena (3 × 3 m; Figure 1) had black, wooden,
80-cm-high walls and 4 entrances with guillotine doors that
could be operated from the southwest corner of the arena with
a system of ropes and pulleys. The arena was surrounded by
a corridor for the pig to access the 4 entrances, a waiting area
containing a jute bag and some toys in the southeast corner of
the room and an area for the observers on the southwest corner
of the room. In the arena, 16 grey metallic buckets (juvenile stage,
Ø10.5 cm – H10 cm; pubertal and adult stage, Ø12 cm – H12 cm)
were screwed to the floor in a 4 × 4 matrix (Figure 2). During the
task, 4 of the buckets were baited with a piece of apple (juvenile
stage ~ 12 × 12 × 12 mm; pubertal and adult stage ~ 12 × 12 ×
20-40 mm) according to 1 out of 4 different configurations. To
prevent the use of visual cues to find the rewards, the rewards
were hidden under a thin layer of shredded straw. All buckets
also had a perforated false bottom under which fresh pieces of
apple were placed at the start of the day to also prevent the use
of odour cues to locate the baited buckets. Pigs were deprived
from feed overnight during the whole period of holeboard testing.
Before the start of the holeboard test, the juvenile piglets were
gradually habituated to the experimenters, the buckets and
rewards, the corridor leading to the test room, the test room
and the task in sessions of 10-15 min per day. At the end of this
8-day habituation period, piglets liked/ate the rewards, showed
no extreme stress responses (high-pitched vocalizations, standing
alert, escape attempts) when alone in the holeboard arena,
and performed the task (i.e. looking into the buckets).
Figure 1. Lay out of the holeboard arena.
Figure 2. From left to right, a pig in the holeboard arena in the juvenile, pubertal and adult stage, respectively.
After the habituation was completed, testing started with acquisition
In the juvenile stage, piglets were individually subjected to 2
massed trials (i.e.performed a few minutes apart) per day on 14
consecutive working days, i.e. 28 acquisition trials. Each testing
day, both piglets from a pen were brought to the test room.
While one piglet was being tested, its pen mate was kept in the
waiting area. The test pig was led to the starting box (at the
south door) or released into the corridor where it could walk
freely to the correct entrance door, which was then opened. Two
different entrances were used on a testing day (i.e. 1 entrance
per trial), to prevent piglets from developing a fixed pattern of
visits that would reduce the working memory (WM) load. A trial
started when the piglet had its 4 legs in the holeboard arena
and ended when the piglet found all 4 rewards or after 180 s.
Every time the piglet visited a baited bucket for the first time,
a clicker sound was produced to facilitate learning. If the piglet
completed the task (i.e. found the 4 rewards in fewer than 180
s), the exit (south) door was opened, the piglet was congratulated
(“good job!”, “well done!”), and received half of a white
grape. If the piglet did not complete the task within the 180 s,
a police siren sound was produced for 1-2 s; the piglet was not
congratulated and did not receive a reward. After the trial, the
piglet was led back into the waiting area, and the other piglet
was tested. After the 2 piglets per pen had been tested twice,
they were brought back to their home pen and allowed to eat.
For the acquisition phase, 4 different configurations of baited
buckets were used in total (the 4 configurations were rotated
versions of the one shown in Figure 1). Each piglet was tested on
a fixed configuration throughout the acquisition phase, with the
configuration of baited buckets differing between the 2 piglets
in each pen and balanced over all piglets. Testing order within
and between pens was changed daily.
In the pubertal stage, the pigs were individually subjected to
2 massed trials per day on 12 consecutive working days, i.e.
24 re-acquisition trials. Pigs were tested according to the same
procedures and with the same configurations as in the juvenile
stage. However, after the re-acquisition phase was completed,
the pigs were also individually subjected to 16 reversal trials,
with 2 massed trials per day on 8 consecutive working days. The
procedures were the same as in the re-acquisition phase, but the
pigs were assigned to another, mirrored, configuration of baited
buckets. In the reversal phase, the pigs’ cognitive flexibility can
be assessed, i.e. how well pigs learn a new configuration.
In the adult stage, the number of trials and the procedures were
completely similar to those used in the pubertal stage. In the
re-acquisition phase, piglets were, however, tested with the
same configurations as those used in the reversal phase of the
pubertal stage, but in the reversal phase, 4 new configurations,
with completely different patterns, were used.
During each trial, all visits and revisits to all buckets, latencies
to all bucket visits, trial duration, and the total number of
defecations, urinations, high-pitched vocalizations and escape
attempts were scored using The Observer XT 10 software
(Noldus Information Technology, Wageningen, The Netherlands).
From these parameters, the following variables were calculated
a posteriori according to van der Staay et al. (2012  ): working
memory scores, reference memory scores, trial duration, inter-visit-interval
and total number of visits.
Results and Conclusions
Göttingen Minipigs seemed to be able to perform the task equally
in each life stage, as shown by the consistent average working
and reference memory scores over the 3 life stages (Figure 3).
Working and reference
memory scores of the
pigs in the different life
stages and test phases.
Figure 4. Trial duration, inter-visit-interval and total number of visits of the pigs in the different life stages and test phases.
It is worth noting, however, that in the juvenile stage only 1 of
8 piglets managed to complete finding the 4 rewards in all 28
trials, and that 4 of 8 piglets failed more than 50% of the trials.
In the pubertal and adult stages, all 8 pigs completed 100% of
the 24 acquisition and 16 reversal trials (except 1 pig which
failed 1 trial in the pubertal stage). Furthermore, in the juvenile
stage, piglets took more time to finish the trial and had longer
inter-visit-intervals, but did not visit more buckets than in the
other stages (Figure 4). These data suggest that the juvenile
piglets were less focussed and/or less motivated for the task,
i.e. explored the arena more or were more distracted in between
2 bucket visits, compared to the older pigs. It is also possible
that the juvenile piglets were performing worse as they were
less trained, but that is less likely as there were no differences
between the pubertal and the more trained adult pigs. These
findings may also explain why many piglets failed to find the 4
rewards before the end of the 180-s trial in the juvenile phase.
In conclusion, while juvenile Göttingen Minipigs appear to show
lower attention/motivation for the task, cognitive performance
and motivation for the task remained high and stable in the
pubertal and adult stages, even after many days of testing.
Moreover, in each life stage the pigs did not show any clear
stress responses such as escape attempts and high-pitched
vocalizations anymore after several days of testing.
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3 Kornum, B.R., Knudsen, G.M. 2011. Cognitive testing of pigs (Sus scrofa) in translational biobehavioral research. Neuroscience &
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4 Nawroth, C, Langbein J, Puppe B. 2018. Swine cognition. In: Vonk, J and Shackelford, TK (eds), Encyclopedia of Animal Cognition
and Behavior. Springer International Publishing AG.
5 van der Staay, F.J., Gieling, E.T., Pinzón, N.E., Nordquist, R.E., Ohl, F. 2012. The appetitively motivated “cognitive” holeboard: a family
of complex spatial discrimination tasks for assessing learning and memory. Neuroscience & Biobehavioral Reviews, 36:379-403.
6 Arts, J.W., van der Staay, F.J., Ekkel, E.D. 2009. Working and reference memory of pigs in the spatial holeboard discrimination task.
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7 Antonides, A., Schoonderwoerd, A.C., Nordquist, R.E., van der Staay, F.J. 2015. Very low birth weight piglets show improved
cognitive performance in the spatial cognitive holeboard task. Frontiers in Behavioral Neuroscience, 9:43.
8 Bolhuis, J.E., Oostindjer, M., Hoeks, C.W., de Haas, et al. 2013. Working and reference memory of pigs (Sus scrofa domesticus) in a
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9 Clouard, C., Kemp, B., Val-Laillet, D., Gerrits, W.J., Bartels, A.C., et al. 2016. Prenatal, but not early postnatal, exposure to a Western
diet improves spatial memory of pigs later in life and is paired with changes in maternal prepartum blood lipid levels. The FASEB
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by diet in a spatial hole-board discrimination test. PLoS One, 8:e79429.
Obesity and diabetes result in pathological
bone repair around dental implants:
Demonstration in a Göttingen Minipigs models
Rebecca Sandgren 1 & Benjamin E. Pippenger 2
Biomedical Center, Lunds University, Lund, Sweden
Institut Straumann, Preclinical & Translational Research, Basel, Switzerland
The number of obese and diabetic patients in need of medical
treatment, especially for the oral cavity, is growing steadily.
Obesity (metabolic syndrome) and, by extension, type 2 diabetes
mellitus are known risk factors for oral diseases including
periodontal disease  , alveolar bone loss  and gum disease  ,
with adipose-derived pro-inflammatory cytokines thought to
be the common underlying basis for the degeneration in oral
health  . Not only do obesity and diabetes often result in oral
health deterioration, but these same systemic diseases can also
be considered contraindications for dental implantation procedures
 , having been shown to result in a higher incidence of
implant failure  . While the treatment of obesity and diabetes
aims to avoid the development of oral health complications, the
risk of severe periodontal disease remains 3-4 times higher in
these patients  . Therefore, novel dental materials and/or material
surface treatments are needed that can reliably perform in
compromised patients, but their development is hindered by a
lack of clinically relevant obese/diabetic animal models.
Göttingen Minipig models have long been used in translational
research, surgical models, and procedural training (particularly
in the dental field). Their specificity for experimental studies has
excluded them from low-fat producing, selective breeding programs
and their normal adult weight remains within a manageable
range ( ~ 40 kg) . Additionally, obese/metabolic syndrome
Göttingen Minipig models have already been developed through
a high energy feeding diet for periods up to 3 months [9,10] .
While these Minipigs become extremely obese, their adult body
weight rarely exceeds 80-90 kg, demonstrating that even in
an obese condition, this animal model remains manageable for
the experimentator. A type 2-like diabetes can also be induced
in Göttingen Minipigs by administration of Streptozotocin, a
chemical agent which damages the insulin-producing beta-cells
of the pancreas  , demonstrating the potential to model a com-
Figure 1: Physical and critical organ
weight gain upon obesity induction
followed by stabilization following
diet control. A) Animal weight profiles
throughout the duration of the experiment
(47 weeks) demonstrating rapid
weight gain for cafeteria diet animals
(labeled obese and diabetic) in the first
phase followed by weight stabilization
in the remainder of the experiment.
STZ: beginning of Streptozotocin
administration. B) Heart (left and right
ventricles weighed separately) and
lung weights at 47 weeks (sacrifice)
demonstrating higher average weights
for critically affected organs in obese
and diabetic animals. C) Liver, spleen
and kidney wet weights at 47 weeks
(time of sacrifice).
promised patient condition using an obese/diabetic Göttingen
Minipig. However, while stable metabolic syndrome/diabetes
animal models exist in the dog  , no stable pathological changes
have yet been reported for the Göttingen Minipig. Finally, it is
unknown what consequence/s such an optimized model would
have on dental implant materials.
In the present pilot study, we aimed to: 1) demonstrate the proof
of principal of the induction of both stable metabolic syndrome
and diabetes in a Göttingen Minipig animal model and 2) validate
both of these disease-optimized Göttingen Minipig models
for the testing of dental materials. Evidence of stable metabolic
syndrome and type 2 diabetes induction is demonstrated
through blood analysis, tissue histology and weight progression
monitoring. We then implanted bone level dental implants into
the mandibles of these compromised animal models to determine
whether the induction of one or both systemic diseases
affects the osseointegration and short term performance of the
Materials and Methods
Establishment of obese & diabetic Minipig models
All experimentation was conducted in the Magneten building
for Surgical Research, Lund University, Lund-Malmö, Sweden
(ethical approval number M-206-11 Malmö-Lunds djurförsöks
etiska nämnd). A total of nine female Göttingen Minipigs
(Ellegaard, Dalmose, Denmark) of 18 months of age (33-38 kg
in weight) were used for this study. Minipigs were split into 3
groups: 1) control (normal diet) (n = 3), 2) obese (cafeteria diet)
(n = 3) and 3) diabetic (cafeteria diet + Streptozotocin) (n = 3).
The animals were fed twice a day with either a combination
of Minipig Expanded Standard Diet (SDS Special Diets Services,
UK) and a custom made RDS Control Diet (control group) or RDS
Cafeteria Diet (Research Diet Services , NL) (obese and diabetic
groups), as previously described  . For the Minipig diets, we
split the timing of the different diets into 3 phases: conversion,
growing and maintenance phases. To induce obesity, Minipigs
(n = 6; groups 2 and 3) were gradually introduced to the cafete-
Figure 2: Blood and plasma marker profiles demonstrate effective induction of metabolic syndrome and a diabetic phenotype. A) Blood glucose levels following STZ
administration. Glucose levels are particularly elevated in diabetic animals but obese animal levels are comparable to control. B) Blood ketone levels are elevated in
the diabetic group. Obese and control groups remain at basal levels. C-F) Average plasma levels of Tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), Cortisol
and Insulin taken at the time of implantation and termination. Plasma levels of all proteins demonstrated the same overall trend in that the obese group had the
highest levels of all the groups (except for TNF-α-highest in the diabetic group). * = p ≤ 0.05. G) Insulin staining and H) quantification after 47 weeks. Data represent
means ± SD.
ia diet over a period of 4 weeks (25% decrease in normal diet
on a weekly basis and restricted feeding to 2 x 500 g/day;
conversion phase), after which time they remained at 100%
cafeteria diet for 8 months and were allowed to feed ad libitum
(growth phase). Once obese and diabetic group animals reached
the desired body weight (roughly doubling in weight), the cafeteria
diet was then halved with control diet to maintain the
animals at the desired weight (maintenance phase). Control animals
were fed standard diet and water throughout the duration
of the experiment. A type 2 diabetic state in the pigs was then
induced by slow injection (over a period of 1 minute; through
the ear vein catheter) of filter-sterilized β-cell cytotoxin Streptozotocin
solution (STZ, Enzo Life Sciences, Raamsdonksveer,
the Netherlands) (20 mg/kg in 0.1 mol/l Na-citrate, pH 4.5) on
two consecutive days after overnight fasting, as previously
described  . STZ-injected swine were given free access to food
during the day time and after the second STZ injection, during
day and night. At the end of each of the first 2 days of STZ
treatment, 25 g glucose was fed to offset insulin release from
β-cells, thereby preventing hypoglycemia.
other groups (Figure 1B). Liver and kidney weights increased
from control to diabetic, with obese group weights being intermediate.
However, the liver seemed to be the most effected
of the two organs with a marked increase of weight the more
compromised the animal became. Spleens decreased in weight
with the severity of the compromised condition (Figure 1C).
Blood analysis corroborated macroscopic evidence that obese
animals were indeed suffering from metabolic syndrome
with evidence of inflammation and stress, and that STZ induced
animals were suffering a mild form of type 2 diabetes
Compromised animals demonstrate decreased bone healing
Experimental bone chamber and removal torque implants were
placed into the 3 animal model groups and animals were allowed
to heal for 12 weeks. Maximum torque-out is commonly used
as an indirect measure of the osseointegration around a dental
All surgeries were performed as previously described . Briefly,
teeth (P1, P2, P3 and M1) were extracted bilaterally from the
mandibles of 6 Minipigs. Custom designed 4.2 x 6 mm implants
(bone chamber and removal torque experimental implants,
Titanium-SLA, Straumann, Switzerland) were placed bilaterally
in transverse orientation and the soft tissue was closed.
Implant and tissue analytic procedures
Removal torque and histology
Immediately after sacrifice, mandibles were collected for either
removal torque measurements or histological analysis. Mandibles
were excised and the left and right halves separated. Right
hemi-mandible implants (side with Torque-out implants) were
then subjected to biomechanical removal torque measurements
according to a previously established method  . Oral hard and
soft tissue for histological slide preparation was performed
and histomorphometric measurements were calculated (Bone
area to toal area – BATA and bone to implant contact – BIC), as
previously described  .
Induction of stable metabolic syndrome
and mild type 2 diabetes
Animal weights from both the cafeteria diet groups (obese and
diabetic) continued to climb beyond that of the control group,
which plateaued at 45 kilograms at 14 weeks after the beginning
of the study and remaining at this weight for the duration
of the study. By week 27 (STZ administration for diabetic group),
obese and diabetic groups had almost tripled in weight, having
gained an average of 37 kg and 44 kg, respectively (both groups
completely tripled in weight by week 35). Diluting the cafeteria
diet 50% with control diet combined with STZ administration had
the overall effect of weight stabilization on the diabetic group
(Figure 1A). Organ wet weights demonstrated the obese group
having heavier left ventricle and right ventricle wet weights
than both the control and diabetic groups (Figure 1B). Lung
wet weights for the diabetic group were higher than for both
Figure 3: Biomechanical and histomorphometric measurements. A) Maximum
torque-out values for implants at time of sacrifice. Lower torque-out vales
demonstrate that the osseointegration of implants in obese and diabetic
animals is significantly less than in the control group. Furthermore, there are
no significant differences between obese and diabetic groups. B) Histomorphometric
analysis of tissue/implant sections. BATA corresponds to the new bone
area per total area within a defined region of interest (ROI), here defined as the
total area from the defect border to the implant surface. BIC corresponds to
the total bone to implant contact and is expressed as a percentage of the bone
physically attached to the implant surface as compared to the total implant
surface. Histological evidence supports the biomechanical measurements and
demonstrates the significantly less new bone formation around dental implants
is obese and diabetic groups as compared to the control group. * = p ≤ 0.05; **
= p ≤ 0.01; *** = p ≤ 0.001; ns = not significant.
implant, with higher values demonstrating a higher degree
of osseointegration. While the control group reached average
levels of approximately 260 Ncm, both metabolic syndrome and
diabetic groups had much lower average values (90 Ncm and 60
Ncm, respectively). Importantly, not only did the compromised
groups measure removal torque values that were significantly
less than the control group, but the metabolic syndrome group
values were not statistically different from those of the diabetic
group (Figure 3A).
Histomorphometric analysis on bone chamber implants confirmed
the trend seen in the biomechanical removal torque
experiment. Two different histomorphometric parameters were
measured: bone area to implant area (BATA) and bone to implant
contact (BIC). The control group, for both BATA and BIC
measurements, had significantly higher values than both of the
compromised groups (BATA- control: 40%, obese: 25%, diabetic:
25%; BIC- control: 45%, obese: 22%, diabetic: 18%). Importantly,
there was no significant difference between the compromised
groups for both BATA and BIC measurements (Figure 3B). These
measurements were also evident by visual examination of the
histological slides, especially in terms of BIC, in that the new
bone growth around the implant is less than compared to both
compromised groups (Figure 4).
This study, using an animal model considered physiologically
similar to that of humans, demonstrates that bone remodeling
is indeed severely affected in obese individuals. Not only was
the bone regeneration around implants placed into bone defects
less pronounced in obese animals as compared to control, but
the biomechanical stability of the newly formed bone seems
to be less mature, as demonstrated by mechanical torque out
measurements. In line with Doucette et al., the inflammatory
factor TNF-α was also found to be only slightly affected by the
induction of an obese phenotype. However, previous studies
have shown that an alternative inflammatory factor (C-reactive
protein (CRP)) is particularly increased in obese humans and
suggests a source of infection or inflammation is more common
among obese subjects than in nonobese subjects  . This study
also measured CRP levels and found significantly higher levels
of CRP in obese animals, suggesting Minipig models do indeed
mirror the pathological events associated with metabolic syndrome
found in humans.
We demonstrate that after induction of obesity, the animal
weight can indeed be stabilized without reversing the disease
process itself. Interestingly, this suggests that Minipigs manifest
a similar disease process to humans in that the deleterious
clinical effects of obesity in human subjects are reversible upon
concerted weight loss, not weight stabilization  .
Biomechanical analysis of implant osseointegration (torqueout)
showed significant differences between the control and
compromised groups. This further demonstrated that implant
osseointegration, and therefore secondary stability, is greatly
affected by the animals’ compromised state. Based on the
present data, it appears that implant osseointegration is equally
compromised in obese and diabetic animals. This corresponds to
recent work in humans demonstrating that bone mineral density
is already reduced in metabolic syndrome adolescents  .
Here, we demonstrate it is possible to induce a mild state of
diabetes (with detectable glucose metabolism deficiency) using
a dose (twice 20 mg/kg STZ) previously reported to have no metabolic
effect of Göttingen Minipigs. However, we first induced
metabolic syndrome in the animals before STZ administration,
contrary to previous studies that administered STZ on healthy
Figure 4: Histological sections demonstrating the differences between the study groups in terms of new bone formation surrounding implants. Top row = Hematoxylin
and eosin stained sections; bottom row = Region of interest defined for BATA calculations. New bone is clearly distinguished from existing bone by color (new bone
= slightly darker pink) and morphology (new bone = higher percentage of trabeculae; less mature).
individuals. It appears that healthy individuals are resistant to
low doses of STZ, whereas metabolic syndrome animals are not,
further highlighting that a compromised state is present already
in obese animals. While this remains a pilot study, these data
also suggest that the aberrant bone remodeling previously
reported in type 2 diabetic individuals could have its origins in
obesity rather than diabetes. In line with this, the aberrant bone
remodeling may be related to the pro-inflammatory status present
during metabolic diseases, with severe pro-inflammation
at diabetes and more mild pro-inflammation at pre-diabetes or
metabolic syndrome. In the present study, the minipigs were fed
a cafeteria diet containing substantial amounts of hydrogenated
oils, consisting of trans-fatty acids which are known to induce
chronic inflammation  . It may well be that the aberrant bone
remodeling in obese pigs is amplified by using dietary trans fatty
acids, thereby creating a more severe state of pro-inflammation
at obesity. The increase of inflammatory factors also shown to
be increased in human obese patients shows that the systematic
inflammation present in this animal model more closely resembles
that of the human disease state  .
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Using Göttingen Minipigs as model
for peritoneal dialysis
Anette Blak Gross & Andrew Makin, Citoxlab Denmark, Ejby, Denmark
Peritoneal dialysis is a commonly used treatment in human
patients with severe renal and other diseases. Extended use
of peritoneal dialysis including new peritoneal dialysis formulations
in the pharmaceutical industry requires appropriate
animal models in order to meet the regulatory requirements for
approval of products.
Selection of the correct or most appropriate model depends
on similarities between animals and humans in terms of both
physiology and anatomy. To a degree the relative size of the
animal model can be important. Similar transport properties of
solute and water across the peritoneal membrane in humans
and animals have been important factors in choosing the right
animal model  .
Rats, rabbits, and genetically modified mice have been used as
experimental models, but also larger animals such as pigs dogs,
sheep, or even kangaroos have been used [1,2,3] .
The use of each animal model offers advantages and disadvantages
 . Rodents are cheap and readily available, but the small
size also complicates catheter insertion and increases the risk
of complications. In addition, the size of the parietal peritoneum
and ratio of peritoneal surface area is different from that of
humans and larger animals. Pigs and other large animal models
also offer the advantage that large volumes of dialysate solution
and human size catheters may be used.
Pigs are an attractive model for peritoneal dialysis due to
similarities in the anatomy and physiology of several of the
abdominal organs and not least the similar size to humans.
In addition, pigs are widely used as a model for many other
procedures involving abdominal tissues and organs (for instance
renal transplantation, intrarenal surgery, artificial bladders and
At Citoxlab we have developed an excellent model for peritoneal
dialysis products in the Göttingen Minipig.
The minipigs we have used have been around 4 to 5 months old
and with a weight of ca 10 kg at study initiation. Under general
anaesthesia intraperitoneal catheters are placed and tunnelled
subcutaneously to the neck skin. Dosing is performed once
daily for 10-20 minutes using injection pumps while the animals
are walking freely in their pen unaffected by the dosing as the
catheters are sufficiently long to ensure normal behaviour of
After some time, typically a few hours, the dialysate (infused
formulation included) can be collected by drainage of the
catheters in conscious animals (typically 75%-100% of infused
formulation can be retrieved). Drainage is preferably achieved
by gravity, and suction only used if necessary. Suitable toxicokinetic/clinical
chemistry/hematology parameters can be
measured in the dialysate after retrieval.
Formulations for intraperitoneal dosing should obviously be
sterile, isotonic, non-irritating and heated to body temperature
Surgery and handling of catheters are only performed by
dedicated, trained personnel using aseptic procedures at all
time. Care should be taken to ensure that the placement of
the catheter does not compromise the organs and tissues in the
abdomen; irritation could lead to inflammation and peritonitis.
To assist in this, the catheter end is curled, and placement is as
far away from the omentum as possible.
Using these methods, we have successfully achieved dosing
daily for up to 10 days.
When performed correctly, intraperitoneal catheters are very
well tolerated and the Göttingen Minipig is considered a suitable
model for peritoneal dialysis products.
1. Animal models in peritoneal dialysis, Olga Nikitidou,Vasiliki
I. Peppa,Konstantinos Leivaditis, Theodoros Eleftheriadis,Sotirios,
G. Zarogiannis, and Vassilios Liakopoulos, Front Physiol.
2015; 6: 244.
2. Swine as Models in Biomedical Research and Toxicology
Testing, M. M Swindle, A. Makin, A. J. Herron, Veterinary
Pathology, 2012: 49 (2): 344.
3. Pawlaczyk K., Baum E., Schwermer K., Hoppe K., Lindholm B.,
Breborowicz A. (2015). Animal models of peritoneal dialysis:
thirty years of our own experience. Biomed. Res. Int. 2015:
Article ID 261813.
Vascular Access Buttons in Göttingen Minipigs
Adrian Zeltner, Ellegaard Göttingen Minipigs, Dalmose, Denmark
Infusion and serial blood sampling are often important technical
aspects of an experimental design. Superficial vessels in the
minipig are few and frequently accessing them is a challenge.
Although minipigs have a convenient size for handling, restraint
and venipuncture can be stressful and affect blood parameters.
Therefore, when experiments require infusion or frequent blood
sampling, catheterization is often the best option, both ethically
The implantation of Vascular Access ports and Seldinger Catheters
is described and published in various variations. Ellegaard
already supplies Minipigs with pre-implanted systems of that
type. To add another option when choosing the optimal study
design, we tested the Rat Vascular Access Button (VAB) in
Göttingen Minipigs. The button allows up to three catheters to
be connected and opens the possibility to sample and dose via
separate catheters in one device. In contrast to a VAP this device
allows for pain free access as it is percutaneously implanted.
The device is designed for rats, but we wanted to find out if such
a button can be used in a minipig and whether a decent patency
period can be achieved. Furthermore, it was of interest whether
group housing is an option.
As with all catheters, clotting, biofilm and fibrin build up are
the main factors affecting patency. Therefore, we also tested
different vessels and different types of catheters in the pilot
study to see if there is a significant difference.
Four Minipigs at around 15 kg were implanted with a three port
VAB. Each Minipig had three catheters implanted:
1. In the left carotid artery; two Minipigs in cranial direction and
in two in caudal direction. A 3fr PU catheter, with a bead at 3
cm was inserted to that length and fixed with a purse string
suture and tissue glue.
2. In the left internal Jugular vein. This vessel runs alongside
the carotid artery. It was ligated and a 3fr PU catheter, with
two lateral perfusion holes, at 3 cm and 2 mm apart was
inserted to a length of 7-8 cm, so the tip was in the vena
3. In the right internal jugular vein. A 3fr PU catheter, was
inserted in the same manner as in the other vein.
After implantation the Minipigs were left to recover for a week
after which regular patency testing started.
The VABs were accessed once a week for two months and any
difficulties were recorded. In week 2 typical catheter related
incidences were observed with the arterial and perfusion holes
catheters. Some were blocked early, others could be revived by
The standard catheters (3) performed best, with only tree rinsing
incidents in two pigs after week 6. All were still patent in week 8
when the study was concluded.
The Vascular Access Button is small device with one, two or
three ports in the same button. It is available in one size only,
catheters have a size of 3fr but are available in different designs
and lengths. Here, we used catheters with rounded tips, beads
and in some cases added prefusion holes just proximal of the
tip. The ports have a small septum which can be penetrated with
an adapter that fits to any syringe with luer. The smallest inside
diameter of the system is 27 g and is in the adapter.
The ports and the part of the button that is exposed is protected
by an aluminum cap that is fixed with a magnet.
All parts are available from Instech Laboratories, Inc. USA.
Group housing study
In the pilot study we had some issues in the group after recovery.
One of the Minipigs was not as social anymore after
recovery and was bothering the others. At the time we decided
to single house them, so the study did not get compromised.
As we did not want to give up altogether in trying to group
house Minipigs with VABs we designed a small study where we
could test the group housing situation. We hypothesized that
the pen mates will go after the VAB because it is sticking out
and has a strong color. The idea was to camouflage the bright
red cap of the button and/or add some bitter taste to it, so it is
Rat Vascular Access Button with three ports ready to be implanted.
Four male Minipigs of around 20 kg, that were group housed
previously, were implanted with single port Buttons, without the
catheter. Some of the caps were painted in a color closer to pig
skin, others were covered with bitter nail polish. After they were
all fully recovered we grouped them again, observed and filmed
There was certainly a lot of activity, typical male pig behavior
and it carried on for several hours before they calmed down a
bit. We did not observe any dedicated attacks on the VAB, nor
any interest in them. Some of the caps did fall off during the
observation period, but after analyzing the videos it was clear
that it was due to random movements or normal interaction
between the animals. We also realized that in some occasions
the cap flew off and we concluded it was because of the two
magnets in the button with different polarization. When the cap
is twisted far enough the cap is repelled by the magnet of the
To avoid this situation, we modified the single port buttons to
avoid the twisting of the cap for the main study and decided to
go ahead and group house the Minipigs.
There seemed to be no real difference between the original and
the “camouflaged” caps, therefore we decided to use them in the
Button implanted behind the ear
Apart from a larger number we also wanted to test if this system
could be used in a toxicology setting and what the chances are
to have it patent throughout a 13 week period. A further aim
was to evaluate if it is an advantage to have two catheters in
respect to obtaining a longer patency. An obvious advantage
of having two catheters is that one can be used for dosing, the
other for sampling.
We chose 8 kg minipigs and planned to run the study for 3
months. Four groups of four Minipigs:
Male, one catheter in left external jugular vein.
Female, one catheter in left external jugular vein.
Male, two catheters in left external jugular vein, tip 2 cm apart.
Female, two catheters in left external jugular vein, tip 2 cm
Group housing, testing of VAB once a week commencing one
week after surgery. Necropsy with macroscopic pathology at the
end of study or after complete loss of patency.
Behind the ear, where the skin is thinnest, a dorsal-ventral skin
incision of around 4 cm is made and a pocket is formed by blunt
dissection so the lower part the button can be placed in it. Then,
after an incision in the jugular grove the external jugular vein
is exposed by blunt dissection, ligated cranially and one or two
catheters inserted to a length where the tip is placed in the
cranial vena cava, just cranially of the right atrium. If there are
two catheters, this position is for the longer one, the other is
2-3 cm more cranial. The catheters are tied to the vessel and
tunneled to the pocket behind the ear. Now they can be cut to
length and connected to the VAB. After testing functionality, the
button is placed in the pocket and the skin fitted into the collar
of the button. The incision is closed tightly and after making
sure the catheters are not kinked the jugular site is closed in
three layers. After final testing and locking the cap is placed on
the button and the Minipig left to recover.
Taking a blood sample
Sampling, saline and lock solution syringes have been prepared
and fitted with the adapter in an aseptic manner. The Minipigs
placed in the sling, the cap removed, and the ports disinfected
The sampling syringe is pushed in the port and the plunger
pulled back. If blood was flowing, around 1 ml was drawn, the
catheter flushed immediately with saline, and locked with 0.4 ml
Taurolock under positive pressure.
If it was not possible to draw blood in the first attempt the
Minipig was repositioned slightly and retested. I that did not
help it was flushed with saline and then retested again.
Locking under positive pressure with this device describes the
procedure where the adapter is slowly redrawn from the septum
of the port while continuously pushing the plunger of the
syringe. This ensures that the pressure in the system is always
larger than the blood pressure and no blood enters the lumen
of the catheter. All rinsing and locking should be done like that.
Soon after the groups were established in their pens, the caps
started falling off randomly. The modification of the VAB was
not enough to prevent it. We removed some of the most prone
animals from the group and single housed them as we were
concerned about cleanness and systemic infections if the caps
were off. At the same time, we talked to the manufacturer and
ordered caps with two magnets to have stronger adhesion and
avoid twisting. Even with two magnets we were not completely
successful and added a screw to the cap which did not solve the
problem entirely either. At the end we resigned and left the caps
off permanently. This was not quite as hygienic as we wished,
but it did not seem to be an issue at the end. We had one pair
in each group throughout the study and whether there was a
cap or not the Minipigs did not interfere with each other’s VAB.
We have no explanation why in the pilot study the caps stayed
on for the entire two months but fell off in the main study.
Biological Compatibility and Patency
A total of 24 Göttingen Minipigs were implanted with Buttons.
No Complications were observed in the first two studies. The
incisions in the neck and at the site of the button healed well
and no signs of infection was observed. The Dracon collar of the
button was grown in the subcutaneous tissue to seal the exit site
completely. In the main study some infections around the button
appeared in 6 cases (25%) four weeks post-surgery. In four of
them recovered after treatment with antibiotics but two animals
(8%) were euthanized, as infection did not clear and the button
was rejected by the tissue.
No systemic infections were observed
Blood sampling performed by one person with Minipig in a sling
Accessing the ports was easy and painless and with the Minipig
in a hammock it could be performed by one person only.
In the main Study there were a total of 24 catheters in 16 pigs.
All catheters worked fine initially, but some typical catheter
related issues appeared along the way
Patency main study:
After one month: 23/24 patent 1 never worked properly
After two months: 16/24 patent 1 never worked properly,
2 infected VAB,
4 in 2 animals blocked
After three months: 10/24 patent as above and rest blocked.
Conclusion and discussion
The amount of infection in the main study, relatively late after
surgery, might be because of a small change in procedure. In
some cases, the Dracon cuff was placed in the subcutaneous fat
rather than below the fat layer. That might have slowed down
the ingrowing process and made it more prone to infections.
It can be concluded that Rat Vascular Access ButtonsTM can
successfully be implanted in Minipigs and provide long term
Because of the small diameters in the system flow speed is reduced
to a certain degree compared with larger bore catheters.
Typical catheter related issues are to be expected like: temporary
blockage, rinsing before patency is restored and fibrin build
up around catheter. This is no different to other systems. Proper
training and experience with catheter handling will give better
results and it is possible that patency could be improved if the
system was accessed and rinsed in a higher frequency. Testing
this hypothesis was not a the goal of this study.
The buttons can accommodate 1-3 catheters which gives to
opportunity to infuse and sample trough the same unit without
cross-contamination. It might be possible to use the VAB when
cannulating other vessels, like portal vein or bile duct, but this
has not been tested yet.
Minipigs with pre-implanted VAB, VAP or Seldinger catheters
are available from Ellegaard Göttingen Minipigs or you can learn
to implant them by joining one of our courses in Denmark.
Minipig in pen after surgery
For further information please contact Adrian Zeltner:
Fifty Years with Göttingen Minipigs:
During the 1960’s, the Georg-August-University in Göttingen,
Germany, worked on the creation of a small pig model and in
1969, they managed to establish the first barrier-bred population
of Göttingen Minipigs at the University’s experimental farm
in Relliehausen, Germany.
In 1992, Ellegaard Göttingen Minipigs entered into a licensing
agreement with the University, giving the exclusive world-wide
right to breed and sell Göttingen Minipigs to Ellegaard Göttingen
Minipigs, and the first colony of barrier-bred, microbiologically
and genetically defined Göttingen Minipigs was established
through Caesarean section at Ellegaard Göttingen Minipigs in
Denmark. Since then, Ellegaard Göttingen Minipigs has extended
its operations and sublicensed the breeding of Göttingen Minipigs
to Marshall BioResources, the US, and OYC, Japan.
During the coming year we will host several scientific events
as a roadshow around the world to celebrate Fifty Years with
The roadshow events will take place at several locations in
Europe, as well as a number of locations in the US and Asia,
respectively, together with our global partners. The events
will feature speakers and topics for discussion of interest
to researchers and users of Göttingen Minipigs, including an
outlook on future needs and the further development of
Roadshow events being planned
The roadshow events are currently in the planning phase, and
invitations with venue, dates and final program will be published
at our website and LinkedIn during 2019.
We look forward to welcoming you to join us celebrating the
first Fifty Years with Göttingen Minipigs!
THE BIRTH OF THE FIRST COLONY OF GÖTTINGEN MINIPIGS:
P. Glodek und B. Oldigs, 1981, Das Göttinger Miniaturschwein, p. 12:
1.3. Züchterische Entwicklung nach der Schnittentbindung in Relliehausen
Der Erfolg der Selektion auf geringeres Wachstum und adultes Körpergewicht ist in
starkem Maße vom Gesundheitszustand in den Zuchtpopulationen abhängig, da genetische
Fortschritte nicht mit umweltbedingten Kümmerern erzielt werden können. Die unzureichenden
Stallverhältnisse in der Friedländer Anlage führten mit sinkendem Gewicht der Tiere zu
erhöhten Kümmererfrequenzen, so daß beschlossen wurde, das gesamte Zuchtprogramm
über Hysterektomie und künstliche Aufzucht der schnittentbundenen Ferkel in eine neue
geschlossene SPF-Anlage auf dem Versuchsgut Relliehausen zu überführen, die 1969 mit
Unterstützung der Stiftung Volkswagenwerk errichtet werden konnte.
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Fifty Years with Göttingen Minipigs
Ellegaard Göttingen Minipigs Going Global
Göttingen Minipigs are now available in all major R&D markets, including China and India!
At Ellegaard Göttingen Minipigs, we are truly pleased to be able
now also to supply local pharmaceutical companies, contract
research organizations and research institutions in both China
and India with Göttingen Minipigs for their biomedical research
and studies. Thus, we can comply with the great interest and
demand for our high-quality minipig model which comes
well-characterized and with lots of background data as well as
has a very well-defined health and genetic background.
Please contact us via email@example.com if you are interested
in learning more about our supply of Göttingen Minipigs to
China and India. Our expert colleagues are also always ready to
support you scientifically and/or technically.
Head of Business Development, Peter Vestbjerg and CEO, Lars
Friis Mikkelsen attended the Society of Toxicology Pathology-India
(SPS-I) conference in Hyderabad, India, in October 2018 to
present and talk about Göttingen Minipigs to the Indian research
Lars Friis Mikkelsen, CEO at the MoU signing ceremony at the Royal Danish
Embassy in Beijing, China with Li Genping, Beijing Administration Office of
Laboratory Animal (BAOLA), attended by the Danish Minister for Environment
and Food, Jakob Ellemann-Jensen, and the Ambassador of Denmark to China,
A. Carsten Damsgaard. Photo: Royal Danish Embassy Beijing, September 2018
The participants of STP-I conference 26-28 October 2018, Hyderabad, India. Photo: Glenmark Pharmaceuticals Limited, November 2018
Do you spot Peter and Lars in the picture...?
Ellegaard Göttingen Minipigs Enters into
a License and Commercialization Agreement for Göttingen Minipigs
Research Models in Partnership with Exemplar Genetics
Late November 2018, Ellegaard Göttingen Minipigs A/S announced the signing of a license and commercialization agreement
with Exemplar Genetics to develop and commercialize genetically modified Göttingen Minipigs models of human disease on
a target-by-target basis.
“Adding Göttingen Minipig genetics to our offerings will allow us to better serve our customer needs,” said John R. Swart,
President of Exemplar Genetics. “We are very excited to partner with Ellegaard Göttingen Minipigs in providing models to the
research community that we believe will translate well to the clinic.”
Lars Friis Mikkelsen, CEO, added: “At Ellegaard Göttingen Minipigs, we are looking forward to working with Exemplar in providing
genetically modified animal models based on our high-quality and well-defined Göttingen Minipigs. We, too, are very
excited to launch this new partnership supporting the development and commercializing of transgenic Göttingen Minipigs.”
Read the full press release here:
CREATING A STIMULATING AND COOPERATIVE ENVIRONMENT
FOR GÖTTINGEN MINIPIGS
Kirsten Rosenmay Jacobsen & Lars Friis Mikkelsen, Ellegaard Göttingen Minipigs A/S, Denmark
When developing behavioral management and husbandry procedures for laboratory minipigs, it is important to recognize that minipigs are highly intelligent
animals with a unique perspective about their environment. This intelligence might cause a challenge to the provision of a stimulating and appropriate environment.
The poster gives examples on how to stimulate natural behaviors providing species specific and appropriate environmental enrichment. Daily socialization
and positive human interaction is furthermore an important part of creating a stimulating and cooperative environment for minipigs.
The recommendations described in the poster are based on years of in-house observation and experience from breeding, housing, and socializing several
thousand Göttingen Minipigs in a barrier breeding environment.
Göttingen Minipigs (GM) are curious and friendly animals. As conventional
swine, GM possess a great explorative and investigative
motivation, and they will spend much of their awake time rooting
and exploring the surroundings. The active behavior is highly related
to feeding and the time afterwards.
Floor feeding facilitates the natural rotting process. Furthermore,
floor feeding allows easy access to the diet and ability to feed at
the same time.
Natural products such as straw prompt and stimulate natural behaviors
such as rooting, manipulation and exploration, and can be
used in a variety of ways to maintain novelty and remaining interest.
The use of straw hacks increase the time engaged in these behaviors.
Furthermore long fibered hay placed in racks increases
nesting behavior the day before farrowing for pregnant sows.
GM are socialized from birth and intensively after weaning. However
GM can be socialized at any time in life, with a combination
of treats and positive experiences with humans.
GM should be housed in social groups due to a strong social disposition.
The hierarchy within the group is typically stable and agonistic
behavior is mainly related to changes in group composition.
The success of mixing new animals can be enhanced by appropriate
enrichment, a neutral area, reducing the olfactory stimulation
by alternative smells, the use of nanny-sows for young females
Homemade devices such as ice cubes with or without flavor are a
good supplement to engage minipigs in short term active behaviors.
The cubes must be adapted to the size of the animals e.g
small ice cubes for weaning animals, and large for adult animals.
Many types of commercial enrichment devices can be used to
stimulate GM. Items that stimulate multiple behaviors are more
likely to engage the minipigs for a longer time. E.g. toys that dispense
food items. Currently we are testing Porcichew enrichment
device (ERFS, UK) that besides manipulation and biting also stimulates
olfaction, as it comes with various smells. To add a little extra
comfort especially during shedding, we are currently also testing
the Scratch-n-All pads (Scratchnall, USA).
Furthermore, GM can easily be trained to engage in study or husbandry
related procedures. They respond very well to the Positive
Reinforcement training technique, and most food items can be
used as rewards. However, new flavours might need a little habituation
time. In general, GM have a strong preference of sucrose
and they reject bitter things. Various aromas can be used to camouflage
an unwanted taste e.g. a special diet or medicine for voluntary
GM will naturally divide their pen into three zones: a sleeping area,
a eating/active area and a elimination area. Any of these areas
need be modified to match the individual needs e.g. piglets and
newly weaned pigs need additional heat and shelter in the sleeping
area to avoid hypothermia and to give them a feeling of protection
and cover. Sexually mature animals that are very active
during heat benefit from pen dividers to give small hiding areas,
and farrowing sows need a calm environment to reduce farrowing
Dedicated play pens can be implemented to minipigs of any age to
stimulate play and active behavior. Furthermore, these pens can
be used during mixing of animals to reduce the amount of
Locomotion and exploration can be stimulated simply be letting
the pigs out of the pens. Everything will potentially be manipulated
! A water hose, empty buckets, old rubber boots etc. will be
used for play.
The positive relationship with humans must be maintained by continuous
positive interaction with humans. The minipigs are not as
forgiving as dogs. The relationship starts at the arrival of the minipigs.
During the acclimation period, the minipigs can be further
socialized and adapted to the new environment—both from a microbiological
and behavioral perspective. Habituation to new routines
and potential training of procedures can start a few days
after. Proper socialization, habituation and training results in calm
animals and reduces stress—both for the animals and for the staff
working with then. Both aspects are important in order to ensure
optimal welfare of the animals and to gain valid study results
when using GM in experimental research.
For more information, contact Kirsten Rosenmay Jacobsen at firstname.lastname@example.org
Invitation to join
THE 13TH MINIPIG RESEARCH FORUM
22-24 MAY 2019 IN VIENNA, AUSTRIA
MAIN SCIENTIFIC TOPICS:
• Animal training & welfare
• Better understanding of the Göttingen Minipig
• Transgenic models
• Immune system
• Species selection in regulatory toxicology
• Designing regulatory toxicology studies
• Identifying disease model gaps
The program also features poster presentations and time for networking with minipig users from all around
the world. We accept posters now with technical (e.g. tips & tricks) and/or scientific (including data)
content. View the poster guidelines at www.minipigresearchforum.org and send your poster as pdf to
ONLINE CONFERENCE REGISTRATION OPENS MID-DECEMBER 2018: FEE € 350
Including: 5 scientific sessions, 1 workshop of choice, get-together evening (Wednesday), social event with
dinner (Thursday), lunches, coffee breaks and conference material.
The full program with speakers will be ready during February/March 2019.
START YOUR PLANNING NOW
Duration: 22 May 2019 at 14:00 hrs. CEST to
24 May 2019 at 13:00 hrs. CEST
Venue: Novotel Wien Hauptbahnhof
(15 min. from Vienna Airport by direct train)
Accommodation is also available at Ibis Wien
Hauptbahnhof (situated next to the venue hotel).
to get the booking form for rooms
at special conference rates at Novotel/Ibis.
Feedback from participants 2018:
My first MRF:
all members were
of topics and
The MRF is a non-profit organization with more than 500 members worldwide
working with minipigs in industry, academia and regulatory bodies.
Participation in the annual MRF conference requires membership (free of charge).
Read more and apply for membership at www.minipigresearchforum.org
New scientific publications
on Göttingen Minipigs
Ellegaard Göttingen Minipigs gives high priority to collaborative projects that aim to better characterize
and validate Göttingen Minipigs as a translational animal model and which facilitate and refine the use of
Göttingen Minipigs in research projects and safety testing. Please contact us if you have an idea for such
a collaborative project. Below is a list of a few recent articles on Göttingen Minipigs.
• Gauthier BE, Penard L, Bordier NF, Briffaux JJ, Ruty BM. Specificities of the Skin Morphology in
Juvenile Minipigs. Toxicol Pathol. 2018 Oct 22. [Epub ahead of print]
• Carbonero F, Mayta-Apaza AC, Yu JZ, et al. A comparative analysis of gut microbiota disturbances in
the Gottingen minipig and rhesus macaque models of acute radiation syndrome following bioequivalent
radiation exposures. Radiat Environ Biophys. 2018 Nov;57(4):419-426.
• Christoffersen B, Straarup EM, Lykkegaard K, et al. FGF21 decreases food intake and body weight in
obese Göttingen minipigs. Diabetes Obes Metab. 2018 Oct 17. [Epub ahead of print]
• Inomata K, Tajima K, Yagi H, et al. A Pre-Clinical Large Animal Model of Sustained Liver Injury and
Regeneration Stimulus. Sci Rep. 2018 Oct 9;8(1):14987.
• Fiebig U, Fischer K, Bähr A, et al. Porcine endogenous retroviruses: Quantification of the copy number
in cell lines, pig breeds, and organs. Xenotransplantation. 2018 Jul;25(4):e12445.
• Andreasen LJ, Krog S, Ludvigsen TP, et al. Dietary normalization from a fat, fructose and cholesterol-rich
diet to chow limits the amount of myocardial collagen in a Göttingen Minipig model of obesity.
Nutr Metab (Lond). 2018 Sep 25;15:64.
• Ronnander P, Simon L, Spilgies H, Koch A. Modelling the in-vitro dissolution and release of sumatriptan
succinate from polyvinylpyrrolidone-based microneedles. Eur J Pharm Sci. 2018 Dec 1;125:54-63.
• Lingner M, Seidling R, Lehmann LJ, et al. Osseointegrative effect of rhBMP-2 covalently bound on
a titan-plasma-spray-surface after modification with chromosulfuric acid in a large animal bone
gap-healing model with the Göttingen minipig. J Orthop Surg Res. 2018 Aug 30;13(1):219.
• Mahan B, Moynier F, Jørgensen AL, et al. Examining the homeostatic distribution of metals and Zn
isotopes in Göttingen minipigs. Metallomics. 2018 Sep 19;10(9):1264-1281.
• Bech J, Glud AN, Sangill R, et al. The porcine corticospinal decussation: A combined neuronal
tracing and tractography study. Brain Res Bull. 2018 Sep;142:253-262.
• Measey TJ, Pouliot M, Wierzbicki W, et al. Expanded Characterization of a Hemi-Body Shielded Göttingen
Minipig Model of Radiation-induced Gastrointestinal Injury Incorporating Oral Dosing Procedures.
Health Phys. 2018 Jan;114(1):32-42.
• Meier K, Qerama E, Ettrup KS, et al. Segmental innervation of the Göttingen minipig hind body. An
electrophysiological study. J Anat. 2018 Oct;233(4):411-420.
• Lillethorup TP, Glud AN, Landeck N, et al. In vivo quantification of glial activation in minipigs overexpressing
human α-synuclein. Synapse. 2018 Dec;72(12):e22060.
• Kenchegowda D, Legesse B, Hritzo B, et al. Selective Insulin-like Growth Factor Resistance Associated
with Heart Hemorrhages and Poor Prognosis in a Novel Preclinical Model of the Hematopoietic Acute
Radiation Syndrome. Radiat Res. 2018 Aug;190(2):164-175.
• Figueiredo C, Carvalho-Oliveira M, Chen-Wacker C, et al. Immunoengineering of the vascular endothelium
to silence MHC expression during normothermic ex vivo lung perfusion. Hum Gene Ther. 2018
Sep 27. [Epub ahead of print]
52 AUTUMN 2018
Towards 3Rs: Multiplex protein profiling
from minipig, cyno, dog and rat samples,
to get the most out of preclinical safety
studies page 3
Experience with mixed groups of intact
female and castrated male Göttingen Minipigs
can meet us
for pharmacokinetic studies in drug discovery research
– summary of behavioral observations and collected
back-ground data page 6
Anti-cancer drug development: Comparison of toxicity
in Göttingen Minipigs and mouse page 10
Body surface area measurement in Göttingen Minipigs
using a computed tomography scanner page 14
The Göttingen Minipig for the study of buccal and sublingual
products page 17
Update from Oriental Yeast Co., Ltd., Japan page 24
Update from WOOJUNGBIO, Korea page 25
Update from Marshall BioResources North America page 26
New scientific publications on the Göttingen Minipig page 27
Join the CONFIRM Initiative page 28
for clear results
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If you have suggestions for topics and/or authors, for a coming issue of the Newsletter,
please email the editor: Søs Pihl-Poulsen at email@example.com.
Meeting Calendar 2019
Name Date Location
SOT Annual Meeting & ToxExpo 10-14 March Baltimore, MA, USA
Janssen Juvenile Toxicity Symposium 25-26 April Beerse, Belgium
Minipig Research Forum 22-24 May Vienna, Austria
FELASA 10-13 June Prague, Czech Republic
TALAS 24-28 June Bangkok, Thailand
EUROTOX 8-11 September Helsinki, Finland
SPS 22-25 September Barcelona, Spain
AFSTAL 2-4 October La Rochelle, France
ACT 17-20 November Phoenix, AZ, USA
CALAS TBA TBA, China
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Fifty Years with Göttingen Minipigs
Europe and Asia
Ellegaard Göttingen Minipigs A/S
Sorø Landevej 302,
Tel.: +45 5818 5818
North Rose, NY 14516, USA
Tel.: +1 315 587 2295
Fax: +1 315 587 2109
Japan & Taiwan
Oriental Yeast Co. Ltd.
3-6-10, Azusawa, Itabashi-ku
Tokyo, 174-8505, Japan
Tel.: +81 3 3968 1192
Fax: +81 3 3968 4863
B-3F, 145 Gwanggyo-ro,
Yeongtong-gu, Suwon, Korea
Tel.: +82 31 888 9369
Fax: +82 31 888 9368