Biomaterials 27 (2006) 3379–3386

Deleterious tissue reaction to an alkylene bis(dilactoyl)-methacrylate

bone adhesive in long-term follow up after screw augmentation

in an ovine model

Lars Grossterlinden

a,b

, Arne Janssen

a,b

, Niels Schmitz

a,b

, Matthias Priemel

a,b

, Pia Pogoda

a,b

,

Michael Amling

a,b,

, Johannes M. Rueger

a,b

, Wolfgang Linhart

a,1

a

Department of Trauma, Hand and Reconstructive Surgery, University Medical Center Hamburg–Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

b

Experimental Trauma Surgery, Center for Biomechanics, University Medical Center Hamburg–Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany

Received 7 November 2005; accepted 31 January 2006

Available online 28 February 2006

Abstract

Biomaterials are designed to support orthopedic surgeons and once implanted they will help the body to heal itself. In this way one of

the most attractive substances are biomaterials that allow gluing of bone fragments and implant fixation. Although no bone adhesive is
established for practical use in clinical practice yet, there is evidence in vitro and in vivo that a new class of bone adhesives based on
alkylene bis(dilactoyl)-methacrylates may meet the requirements to bridge the gap between bench and bedside. The purpose of this
experimental study was to investigate the long-term biocompatibility as well as the integration in the remodeling process of a new
polymer of this group of substances that was used for both fragment adaptation and implant fixation in a large-scale animal model. In 24
sheep the lateral tibial condyle was osteotomized and refixed by three cortical screws. In 12 of them overdrilling the bone thread of one
screw was performed to simulate the poor mechanical properties of osteoporotic bone and the polymer was used in this setting for screw
augmentation, furthermore the osteotomy surface was covered with polymer before osteosynthesis to analyze the influence of the
material on bone healing. In the other 12 sheep that served as controls osteosynthesis was performed without a polymer. All animals were
permitted to walk immediately after surgery under full weight bearing conditions. Six animals of the polymer group and six animals of
the control group were analyzed after 6 weeks and 6 months, respectively. Bone healing and implant integration was evaluated by contact
X-rays, histology and histomorphometric quantification. After 6 weeks integrity of the healing bone in the polymer group was preserved
as compared to the controls, albeit signs of prolonged aseptic inflammation were observed in the polymer group, which is in line with
previous reports. In sharp contrast after 6 months, extensive tissue destruction was observed in all animals of the polymer group that was
attributed to a massive foreign body reaction at the histological level. These long-term results suggest that (i) short-term observation not
always allow valid conclusions regarding the biocompatibility of biomaterials, (ii) that biocompatibility might vary between species, and
(iii) that the polymer used in this setting, although previously attributed to be a good candidate for clinical use in patients, does not meet
the necessary criteria and tremendously interferes with the physiology of skeletal repair.
r

2006 Elsevier Ltd. All rights reserved.

Keywords: Osteoporosis

1. Introduction

The utilization of bone adhesives is an interesting

innovative technique to fix bone fragments and support
implant fixation above all in patients with reduced bone
stock like it is the case in osteopathies. Particularly the
deteriorated mechanical properties of osteoporotic bone
often prevents the secure anchorage of osteosynthesis
materials

[1,2]

. In addition the application of bone

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www.elsevier.com/locate/biomaterials

0142-9612/$ - see front matter r 2006 Elsevier Ltd. All rights reserved.
doi:

10.1016/j.biomaterials.2006.01.051

Corresponding author. Department of Trauma, Hand, and Recon-

structive Surgery, Center for Biomechanics, Experimental Trauma
Surgery and Skeletal Biology, University Medical Center Hamburg–Ep-
pendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Tel.: [phone]; fax. [phone].

E-mail address:

[e-mail] (M. Amling)

.

1

Current address: Department of Trauma and Hand Surgery, Uni-

versity Medical Center Du¨sseldorf, Moorenstrasse 5, 40225 Du¨sseldorf,
Germany

adhesives by gluing of fragments provides a more homo-
genous weight bearing distribution between the fragments
as compared to pinning where load is considerably
transferred by the pins. Therefore implant failure by
stress-overload due to high rigidity and stiffness of metallic
implants is reducible by the use of bone adhesives at least in
vitro

[3–5]

. Furthermore the application of bone adhesives

for filling of bone defects after trauma, especially in
fractures involving articular surfaces by replacement of
subchondral defects to avoid a secondary displacement
after surgery might be suitable. An ideal bone adhesive has
to meet several requirements before being used in clinical
practice. Firstly, it has to be biocompatible and should be
osteointegrated and degradable or rather replaced by bone
without the release of cytotoxic by-products and without
disturbing physiological fracture healing. Secondly, it
should fulfill the criteria of strong and flexible mechanical
properties with a sufficient period of effectiveness and the
sterilization of the material must be possible

[6,7]

.

In the past different ways have been followed to create

bone adhesives with properties as described above. Poly-
methylmethacrylate (PMMA) or calcium phosphate bone
cements are two substances to increase the stability in
osteoporotic and pathological fractures

[8–10]

. The dis-

advantages of combined PMMA cement osteosynthesis are
the release of toxic monomers and the development of high
temperature during polymerization

[11,12]

. Furthermore

PMMA is not biodegradable and excludes a biological
bone healing and physiological biomechanical stability. In
cases of refractures or particularly if revision surgery is
necessary the removal of PMMA is complicated owing to
its stiff and rigid properties. Novel calcium phosphate bone
cements are bioresorbable and osteoconductive

[13–16]

and

are mainly used for filling of bone defects after trauma;
however unfortunately due to their limited mechanical
properties regarding low fracture strength, brittleness and
high susceptibility to fatigue failure

[17–19]

, they are

unsuitable for full load bearing situations.

Another approach is a new class of degradable polymers

[20,21]

. They have been developed on the basis of alkylene

bis(oligolactoyl)-methacrylates

[22]

. The mechanical prop-

erties are similar to PMMA, the pull-out strength of this
glue was in the range of PMMA augmented screws in vitro

[23,24]

. In vitro investigations of the degradation profile

demonstrated virtually a linear weight loss within 6
months, the in vitro biocompatibility tests showed promis-
ing results

[21]

. Most recently the bone adhesive was

described to exhibit good in vivo biocompatibility without
impairment of physiological fracture healing in a rabbit
model over a period of 84 days

[25]

. The present study was

undertaken to investigate the long-term biocompatibility,
particularly the influence on bone remodeling and bone
healing of alkylene bis(oligolactoyl)-methacrylate in a
ovine model using histological, histomorphometrical and
radiological methods, thereby transferring the in vivo
analysis from rodents to large scale animals and getting
the final step closer to clinical evaluation.

2. Materials and methods

2.1. Bone adhesive

The new injectable bone adhesive used in this study is based on alkylene

bis(dilactoyl)-methacrylate combined with a comonomer and acts as two-
component system

[20–22]

. The first one is an unpolymerized highly

viscous component. The second one contains a non-reactive oligomer
without reactive end groups and solubilized alkyl boron as radical donator
initiating polymerization process into highly branched, hydrolyzable
networks

[4,21,25]

. The monomer was synthesized out of ethylene glycol,

lactic acid and methacrylic acid. It consists of 1,2-ethylene glycol-oligo
lactic acid-dimethacrylate with 1 mass% methacrylic acid and 2 mass%
tert-butylperbenzoat. The polymer is applied by a two-component mixing
system. One chamber contains the polymer, the other one the initiator of
the polymerization. The chemical initiator for the polymer was
polyethylene glycol (400 g/mol) with 3 mass% 9-BBN (9-borabicyclo-
3,3,1-nonan). The polymer/initiator relation was 10:1, the mixed
components have pasty consistency, begins to harden after about 1 min
and reach complete setting after 24 h.

2.2. Study design

In the study, 24 mature female blackhead sheep weighing 50–90 kg were

used. Approval by an institutional review board of the state of Hamburg
was obtained (animal permit G8132/591-00.33). The surgical procedures
took place under aseptic conditions. After randomization of the animals
an osteotomy of the lateral tibial condyle was conducted. The fixation of
the lateral condyle was performed by three 3.5 mm fully threaded cortical
screws (Synthes Co., Bern, Switzerland) perpendicular to the fracture line.
Two screws were placed just below the joint margin. By overdrilling
(3.5 mm) the bone thread of the distal screw to the size of the outer
diameter of the screw thread we prepared the augmentation by the
polymer. This step should simulate the poor mechanical properties of
osteoporotic bone; that way 12 animals were prepared. The polymer was
injected on the osteotomia zone and for augmentation of the distal screw
before osteosynthesis. In 12 sheep osteosynthesis was performed without a
polymer and these animals were used as control group. Six animals from
the polymer group and 6 animals of the control group were sacrificed after
6 weeks and 6 months, respectively. Healing of the osteotomy and
degradation of the polymer was evaluated by radiological, morphological,
histological and histomorphometrical analysis.

2.3. Surgical procedures

All animals were starved for a minimum of 12 h before surgery.

Antibiotic preparation was given once to each animal in a perioperative
way as single shot 1 g cefazolin (Elzogram

s

, Lilly, GieXen, Germany). The

animals were premedicated with 0.01 mg/kg xylazine (Rompun

s

, Bayer,

Leverkusen, Germany). The anaesthesia was applied by 0.03 ml/kg
Carbostesin 0,5%

s

(AstraZeneca, Zug, Switzerland) for a spinal block

and Isofluran

s

(Baxter, Volketswil, Switzerland) via a cuffed endotracheal

tube on a semi-closed circle anaesthesia system. The surgical site was
shaved and desinfected by Cutasept

s

(Bode, Hamburg, Germany). An

anterolateral approach was used to expose the lateral proximal tibia. We
osteotomized the lateral condyle under continuous saline cooling and
fractured the dorsal cortex with a sharp osteotome to take care of the
popliteal artery. We imitated that way a simple condylar split fracture
(

Fig. 1

). For the polymer group approximately 5 ml of the adhesive was

applied into the osteotomy gap, following by the reduction of the lateral
condyle and temporary fixation with standard reduction forceps within the
hardening time of the polymer of 1 min. After an additional period of
5 min the fixation of the lateral condyle was performed by three 3.5 mm
fully threaded cortical screws (Synthes Co., Bern, Switzerland) perpendi-
cular to the fracture line. Two screws were placed just below the joint
margin after 2.5 mm drilling of the bone thread. By overdrilling (3.5 mm)

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L. Grossterlinden et al. / Biomaterials 27 (2006) 3379–3386

3380

the bone thread of the distal screw to the size of the outer diameter of the
screw thread we prepared the augmentation by the polymer. The hole for
the distal screw was filled with 1.5 ml of the adhesive and then the screws
were placed immediately. In the control group the osteosynthesis was
performed without a polymer. Wounds were sutured in multiple layers.
Standard X-rays were taken postoperatively and animals were observed
during the first 2 h of the recovering time continuously. Postoperative
analgesia consisted of 50 mg/kg metamizol i.v. (Novaminsulfon-ratio-
pharm

s

, Ratiopharm, Ulm, Germany) for 8–10 days.

2.4. Follow-up and sacrifices

In all cases the animals were permitted to walk immediately after

surgery. Body temperature, body weight and general conditions were
examined until completed wound healing. After 6 weeks and 6 months
animals were sacrificed by i.v. injection of 20 ml T61

s

(Hoechst AG,

Frankfurt, Germany). To assess dynamic histomorphometric changes by
fluorochrome bone label 20 mg/kg calcein (Sigma C-0875, Sigma–Aldrich,
St. Louis, Missouri, USA) was injected subcutaneously 10 and 2 days
before sacrifices. Standard X-rays were taken post mortem. The knee joint
was dissected out (from the distal femoral shaft to the proximal tibial
shaft) and the soft tissues removed. Biopsies were taken from the
parenchyma of lung, liver and spleen and from the lymphatic nodes of the
popliteal fossa, of the groin and para-iliac nodes and para-aortic nodes.

2.5. Histological and radiological evaluation

In the post mortem survey contact radiographs in two planes were

taken at 60 kV (Faxitron, Phillips, Germany). Bone samples and biopsies
were fixed in 3.7% PBS-buffered formaldehyde for 18 h at 4 1C. Biopsies
of all soft tissues were embedded in paraffin and evaluation was performed
on 5 mm H&E-stained sections. After removal of the screws the proximal
tibia was cut into 4-mm-thick and 30-mm-long slices in a sagittal plane
and contact radiographs were performed (Faxitron, Phillips, Germany).
After dehydration, the undecalcified bone specimens were embedded in
methylmethacrylate that does not react with polylactides. The embedded
specimens were sectioned parallel to the longitudinal axis of the screw
holes perpendicular to the osteotomy zone using a rotation microtome
(Cut 4060E, MicroTech, Munich, Germany). The thickness of the slices
was 5 mm. Sections were stained with toluidine blue and evaluated using a
Zeiss microscope (Axio Scope II, Carl Zeiss, Jena, Germany)

[26]

. For

assessment of dynamic histomorphometric parameters 12 mm thick,
unstained sections were mounted in Fluoromount (Electron Microscopy
Sciences, Fort Washington, PA) to permit evaluation by fluorescent
microscopy. For quantitative analysis of new bone formation of the
osteotomy gap the distance between the lamellar bone of both sides of the
gap in three sections of each sample 1.5 cm below the articular surface
after 6 weeks and 6 months was measured on toluidine blue-stained

sections using the osteomeasure histomorphometry system. The quanti-
tative analysis of new bone formation of the bone thread of the distal
screw in the toluidine blue-stained sections was performed by measure-
ment of the diameter of the screw thread limited by the surrounding
lamellar bone 5 mm from each side of the osteotomy gap. Statistical
analysis comparing osteotomy gap and bone thread of the distal screw was
done by Student’s t-test (SPSS for Windows 11.5

s

, SPSS Software

GmbH, Munich, Germany). Significant differences were considered by p-
values

o0.05.

3. Results

All sheep recovered during the postoperative period.

There was no case of local tissue infection. The intrao-
perative application of the polymer was uneventful and
perifocal indurated polymer was easily removed. The
postoperative standard radiographs in two planes demon-
strated a sufficient reduction of the osteotomized lateral
condyle in all animals. Secondary loss of reduction was
detected over the whole study time in none of the animals.
There was no liver or splenic enlargement. The histological
survey of lung, liver and spleen and of the lymphatic nodes
was without pathological findings in all groups. More
specifically there was no difference in the number of
activated lymphatic follicles between the polymer group
and the control group.

3.1. Six weeks group

There was regular bone healing in all animals of the

control group 6 weeks after operation. The contact
radiographs demonstrated a satisfactory reduction of the
laterale condyle in all animals. The sections stained with
toluidine blue showed a physiological bone remodeling
after 6 weeks in all specimens of the control group. The
fluorescent microscopy of these specimens presented the
typical double-calcein contour of the bone formation
immediate to the osteotomia zone and regular bone
formation was observed adjacent to the distal screw holes
after 6 weeks in the control group. In between the screw
channel and the newly formed bone a small layer of
connective tissue was found (

Figs. 2(A)–(C)

). In the

ARTICLE IN PRESS

Fig. 1. Macroscopic view of the proximal tibia. The pointed line marks the area of the osteotomy of the lateral tibial condyle to imitate a simple condylar
split fracture (A). Representative postoperative radiographs in two planes of the knee joint 6 weeks after surgery demonstrating sufficient reduction of the
osteotomized lateral condyle (B).

L. Grossterlinden et al. / Biomaterials 27 (2006) 3379–3386

3381

polymer group after 6 weeks the contact radiographs
demonstrated a good reduction of the lateral condyle in all
animals and physiological bone remodeling in the former
osteotomia zone was observed in all sections. The adhesive
did not represent an obstacle for cellular migration and
proceeding of osseous repair via connective tissue, hyaline
cartilage to ossifying cartilage and woven bone. The
polymer group demonstrated a mosaic picture of osteoid

formation, connective tissue and cartilage very similar to
the control group (

Figs. 2(A) and (D)

). In the fluorescent

microscopy the surrounding bone of the osteotomia zone
in polymer group demonstrated a regularly ordered
calcein-labeling (

Fig. 2E

). Analogous to the osteotomia

zone the distal screw channel of the polymer group
presented a beginning of bony restoration with physiolo-
gical osteogenesis. The soft tissue layer was thicker as

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Fig. 2. Histological sections of the control and polymer group 6 weeks after surgery: left column—control group; right column—polymer group (original
magnification 40 ). Light micrographs of toluidine blue sections show regular bone healing in osteotomia zone of the control group (A). Fluorescence
microscopy presents typical double-calcein labels indicating bone formation immediate to the osteotomia zone (B). Star in (C) points a typical small layer
of connective tissue surrounding the screw holes. In the polymer group the osteotomia zone was similar to the control group with a mosaic picture of
osteoid, connective tissue and cartilage (D) and fluoroscopy confirms regular bone formation (E). The screw channel of the polymer group also shows the
initiation of bony restoration (F).

L. Grossterlinden et al. / Biomaterials 27 (2006) 3379–3386

3382

compared to the control group, but in a comprehensible
way due to the fact that the distal bone thread in the
polymer group was overdrilled to the size of the outer
diameter of the screw thread (

Fig. 2F

). Histological

sections did show adverse signs of polymer degradation
in the polymer group. Mononuclear macrophages and
multinucleated giant cells occurred in both study groups,
although more prevalent in the polymer group, where
polymer was surrounded by connective tissues and multi-
nucleated giant cells (

Fig. 3

).

There was no significant difference of the screw thread

diameters between the control and polymer group after 6
weeks as assessed by histomorphometry (

Fig. 4

). There was

also no significant difference ðp ¼ 0:082Þ between the study

groups regarding the distance in between the lamellar bone
of both sides of the osteotomy gap 6 weeks after surgical
procedure (

Fig. 5

).

3.2. Six months group

After 6 months there were deleterious tissue reactions

with dramatic signs of osteolysis and necrotic bone both
macroscopically as well as in the contact radiographs of the
polymer group (

Fig. 6

). In contrast the osteotomia zone of

the control group was totally replaced by new bone and the
implants were securely fixed in the bone at the same time.
The histological sections of the control group presented
with regular bone formation (

Fig. 7A

). The interface of the

screw holes to the adjacent bone in the control group
showed regular new bone as assessed by toluidine blue-
stained sections (

Fig. 7B

). In sharp contrast the osteotomia

zone of the polymer group was completely filled with
connective tissue without any signs of bone healing. There
was massive polymer debris that was surrounded by
connective tissue, polynucleated giant cells and macro-
phages (

Fig. 7C

). The same histological features, including

fibrous tissue, polymer debris and activated macrophages
were observed at the interface of the screw holes (

Fig. 7D

).

Histomorphometry

revealed

significant

differences

ð

p

o0:01Þ regarding the screw thread diameters and the

distance in between the lamellar bone of both sides of the
osteotomy gap between the control vs. polymer group after
6 months (

Figs. 4 and 5

).

4. Discussion

In the present study alkylene bis(dilactoyl)-methacrylate

exhibited initially good in vivo biocompatibility without
impairment of physiological bone healing in accordance
with a previous study

[25]

. However in the long-term

survey of this study deleterious tissue reaction were found
in all experimental animals uncovering the bioincompatible
nature of this polymer. The aim of the current study was to
investigate the long-term biocompatibility, particularly the

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Fig. 3. Toluidine blue sections of the polymer group 6 weeks after surgery. The polymer was still preserved and surrounded by connective tissues (A)
(original magnification 60 ). Multinucleated giant cells surrounding the polymer debris (B). Polymer particles are indicated by red stars, the arrows
indicate multinucleated giant cells (original magnification 100 ).

0

2

4

6

8

10

12

14

16

6 weeks

6 months

diameter (mm)

control

polymer

Fig. 4. Quantification and statistical evaluation of the diameters (mm) of
the distal screw thread measured as the diameter of the screw thread
limited by the surrounding lamellar bone 5 mm from each side of the
osteotomy gap using a stereomicroscope (Axio Scope II, Carl Zeiss, Jena,
Germany). While there were no significant differences in the screw thread
diameter between the control and polymer group after 6 weeks, the
situation changed with time and after 6 months significant differences (**:
p

o0.01) between the control and polymer group were observed.

L. Grossterlinden et al. / Biomaterials 27 (2006) 3379–3386

3383

influence on bone remodeling and bone healing of this
polymer. Secondary displacement is a well-known compli-
cation after utilization of bone adhesives

[6]

. Therefore we

perform a proper osteosynthesis by three cortical screws to
avoid secondary displacement in all study groups. By doing
that comparable anatomical settings are guaranteed
especially in the region of the osteotomy gap to gain valid
histological results. The additional simulation of the poor
mechanical properties of reduced bone stock like it is
observed in patients with osteoporosis was achieved in the
present model by overdrilling the bone thread of the distal
screw. Thereby it was possible to prove sufficient adhesive
effect of the new polymer. Sacrifices of the animals after 6
weeks and 6 months enabled analysis of bone healing,
degradation of the polymer and the evaluation of its long-
term biocompatibility. And indeed polymer application did
not cause any local or systemic infection in the study

groups. After 6 weeks there was no significant difference in
bone remodeling and healing between the polymer and
control group. At this early stage the bone adhesive did not
represent an obstacle for physiological bone healing and
initiation of bone formation. One reason for this good
short-term biocompatibility might be the low polymeriza-
tion temperature of 40 1C

[21]

that obviously did not result

in local thermal necrosis of adjacent tissue; in contrast
PMMA is known to temperatures of approximately 80 1C

[11]

which have been shown to be responsible for necrosis

of the surrounding tissue

[12,27,28]

. These findings are

completely in line with a previous study by Heiss and
coworkers who reported that alkylene bis(oligolactoyl)-
methacrylates exhibited good in vivo biocompatibility in a
rabbit model after 84 days of implantation. The authors
further reported that the adhesive did not interfere with
physiological fracture healing and no necrotic areas were
found

[25]

. Degradation behavior of the polymer was

explained by hydrolysis of ester bindings of the hardened
glue and cellular degradation by phagocytosis mediated by
macrophages and multinucleated giant cells

[12,21,29,30]

.

While these short-term results seemingly supported the

promising results previously reported in the rabbit model

[25]

the long-term proved the opposite. After a period of 6

months there was a deleterious tissue reaction in the former
osteotomy gap of the polymer group. Both areas were the
polymer was used, the osteotomy gap and the augmented
screw holes, respectively, presented with massive aseptic
inflammation. Numerous foreign body giant cells were
found in close proximity to fragmented remnants of the
polymer. It has been previously shown that some polymers,
especially polyglycolactides, can cause inflammatory for-
eign body reaction and focal osteolysis in patients. The
latter have been attributed to an uncontrolled degradation
of the respective polymer and the release of acidic by-
products. Furthermore there have also been reports of
subcutaneous swelling observed in patients as late as 3
years postoperatively, which might be related to the highly
crystalline debris formed upon degradation of polylactides,
osteolysis and a potential for toxicity due to local decrease
in the pH around the polymer

[31–34]

.

ARTICLE IN PRESS

Fig. 6. Proximal tibia of the animals in the polymer group 6 months after surgery presented with dramatic signs of osteolysis and necrosis both
macroscopically (A) and radiographically (B).

0

2

4

6

8

10

12

14

16

6 weeks

6 months

osteotomy gap (mm)

control

polymer

Fig. 5. Quantification and statistical evaluation of the osteotomy gap
measured as the distance between the lamellar bone of both sides of the
gap in three sections of each sample 1.5 cm below the articular surface
after 6 weeks and 6 months, respectively, using a stereomicroscope (Axio
Scope II, Carl Zeiss, Jena, Germany). No significant differences ðp ¼
0:082Þ between the study groups after 6 weeks. After 6 months significant
differences (**: p

o0.01) between the control and the polymer group.

L. Grossterlinden et al. / Biomaterials 27 (2006) 3379–3386

3384

However despite promising results regarding the short-

term biocompatibility, the long-term biocompatibility of the
polymer in this survey was rather poor. This is in line with
the very recent report on the same adhesive by Dr. Ignatius
and coworker, who describe that the pullout force of screws
augmented with the new polymer was significantly reduced
in comparison to PMMA augmented and non-augmented
screws, respectively

[35]

. Indeed this decreased pullout force

that was observed in the 12 sheep used by the Ulm group
has been attributed to an inflammatory reaction at the tissue
level similar to the one described in our present study.

5. Conclusion

Taken together, these long-term results suggest that (i)

short-term observation not always allow valid conclusions
regarding the biocompatibility of biomaterials, (ii) that
biocompatibility might vary between species, and (iii) that
the polymer used in this setting, although previously been

attributed to be a good candidate for clinical use in
patients, does not meet the necessary criteria and
tremendously interferes with the physiology of skeletal
repair. Thus, further material development has to be done
to fill the gap between bench and bedside towards the
clinical application of a bone adhesive for improvement of
fracture treatment in orthopedic and trauma surgery.

Acknowledgements

The authors thank Olga Winter and Cordula Mueldner

for excellent technical assistance. This experimental study
was supported by BMBF (German Ministry of Education
and Research; Grant no.: 03N4013).

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ARTICLE IN PRESS

Fig. 7. Toluidine blue sections of the control and polymer group 6 months after surgery (original magnification 60 ). In the specimens from the control
group lamellar bone was found in the region of the former osteotomia (A) as well as in the interface to the screws (B). In contrast within the polymer group
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any signs of bone healing and without any bone formation. Red stars indicate polymer remnants that are surrounded by connective tissue and
macrophages.

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