Ellegaard_Göttingen_Minipigs_Newsletter 53


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


where you

can meet us

in 2019

Clean pigs

for clear results

page 24



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.

Experimental design

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

electrocardiography parameters.

Clinical pathology

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

of IMDA.

Macroscopic observations

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

sacrifice points).

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.

Microscopic observations

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

thickness. H&E.

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

animals. H&E.

Vehicle-related findings

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

[4] . 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 [11] , 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.

Holeboard task

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 [5] ): 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).

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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International Journal of Comparative Psychology, 28.

2 Gieling, E.T., Nordquist, R.E., van der Staay, F.J. 2011. Assessing learning and memory in pigs. Animal Cognition, 14:151-173.

3 Kornum, B.R., Knudsen, G.M. 2011. Cognitive testing of pigs (Sus scrofa) in translational biobehavioral research. Neuroscience &

Biobehavioral Reviews, 35:437-451.

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.

Behavioural Brain Research, 205:303-306.

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

holeboard spatial discrimination task: the influence of environmental enrichment. Animal Cognition, 16:845–850.

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

Journal, 30:2466-2475.

10 Clouard, C., Le Bourgot, C., Respondek, F., Bolhuis, J.E., Gerrits, W.J. 2018. A milk formula containing maltodextrin, vs. lactose, as

main carbohydrate source, improves cognitive performance of piglets in a spatial task. Scientific Reports, 8:9433.

11 Wood-Gush, D.G.M., Vestergaard, K. 1991. The seeking of novelty and its relation to play. Animal Behaviour, 42:599-606.

12 Gieling, E., Wehkamp, W., Willigenburg, R., Nordquist, R.E., Ganderup, N.-C., et al. 2013. Performance of conventional pigs and

Göttingen miniature pigs in a spatial holeboard task: effects of the putative muscarinic cognition impairer Biperiden. Behavioral

and Brain Functions, 9:4.

13 Haagensen, A.M., Grand, N., Klastrup, S., Skytte, C., Sørensen, D.B. 2013. Spatial discrimination and visual discrimination: two

methods evaluating learning and memory in juvenile Göttingen minipigs. Behavioural Pharmacology, 24:172-179.

14 Haagensen, A.M., Klein, A.B., Ettrup, A., Matthews, L.R., Sørensen, D.B. 2013. Cognitive performance of Göttingen minipigs is affected

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 [1] , alveolar bone loss [2] and gum disease [3] ,

with adipose-derived pro-inflammatory cytokines thought to

be the common underlying basis for the degeneration in oral

health [4] . 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

[5] , having been shown to result in a higher incidence of

implant failure [6] . 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 [7] . 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)[8] . 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 [11] , 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 [12] , 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

implant material.

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 [13] . 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 [13] . 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

(Figure 2A-H).

Compromised animals demonstrate decreased bone healing

around implants

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

Surgical procedure

All surgeries were performed as previously described [14]. 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 [16] . 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 [15] .


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 [16] . 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 [17] .

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 [18] .

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 [19] . 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 [20] .


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2 Alabdulkarim M, Bissada N, Al-Zahrani M, Ficara A, Siegel B. Alveolar bone loss in obese subjects. J Int Acad Periodontol 2005;7:34–8.

3 Engebretson S, Chertog R, Nichols A, Hey-Hadavi J, Celenti R, Grbic J. Plasma levels of tumour necrosis factor-alpha in patients with

chronic periodontitis and type 2 diabetes. J Clin Periodontol 2007;34:18–24.

4 Di Benedetto A, Gigante I, Colucci S, Grano M. Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol


5 National Institutes of Health Consensus Development Conference statement on dental implants June 13-15, 1988. J Dent Educ


6 Marchand F, Raskin A, Dionnes-Hornes A, Barry T, Dubois N, Valéro R, et al. Dental implants and diabetes: conditions for success.

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12 Ionut V, Liu H, Mooradian V, Castro AVB, Kabir M, Stefanovski D, et al. Novel canine models of obese prediabetes and mild type 2

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20 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860–7.


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 [1] .

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

[1] . 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

ureteral stents.

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

the minipigs.

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

before use.

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

and scientifically.

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.

Pilot study

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

less attractive.

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

the activity.

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

same polarization.

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

original form.

Button implanted behind the ear

Main study

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

with alcohol.

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.


Group Housing

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,

second blocked,

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

vascular access.

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:

Let’s Celebrate!

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

Göttingen Minipigs.

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

Göttingen Minipigs.

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!


P. Glodek und B. Oldigs, 1981, Das Göttinger Miniaturschwein, p. 12:

1.3. Züchterische Entwicklung nach der Schnittentbindung in Relliehausen

1.3.1. Gewichtsentwicklung

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 ellegaard@minipigs.dk 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:





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

related complications.

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 krj@minipigs.dk



Invitation to join




• Toxicology

• 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



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.


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).

Visit www.minipigresearchforum.org

to get the booking form for rooms

at special conference rates at Novotel/Ibis.

Feedback from participants 2018:

My first MRF:


how friendly

and inclusive

all members were


the diversity

of topics and

numerous opportunities

to network

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


where you

can meet us

in 2018

page 28



Forum 2018

page 20

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

Clean pigs

for clear results

The next Newsletter delivered

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Our Newsletter is published three times a year. We welcome new and former subscribers

that we might have lost contact with during the GDPR process, and

ask you to sign up at https://minipigs.dk/contact-us/sign-up-for-our-newsletter/.

If you have suggestions for topics and/or authors, for a coming issue of the Newsletter,

please email the editor: Søs Pihl-Poulsen at spp@minipigs.dk.

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


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Fifty Years with Göttingen Minipigs

Europe and Asia

Ellegaard Göttingen Minipigs A/S

Sorø Landevej 302,

DK-4261 Dalmose,


Tel.: +45 5818 5818


North America

Marshall BioResources

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




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