Regenerative surgical treatment of peri-implantosseous defects - a multicenter randomized prospective clinical study

Peri-implantitis is an infection of peri-implant tissues with subsequent bone
loss around an implant. If the condition is left untreated it often leads to
further loss of bone tissue, and eventually there is an imminent risk that the
entire implant is lost. In such cases, the jawbone must be regenerated before
it is possible to anchor a new implant. This takes a long time and is both
demanding and costly for the patient. If peri-implantitis is not treated
properly, there is also a risk that adjacent teeth and implants may be affected.
Peri-implantitis develops as a result of several factors such as oral pathogens
colonizing peri-implant pocket and tissues, host*s genetic susceptibility and
lifestyle factors. The microbial pathogens elicit an inflammatory response
that may progresses into a chronic situation.
The traditional method of treating peri-implantitis is cleaning around the
implant to attempt to remove the infection. However, experience shows that
peri-implantitis attacks usually continue despite this cleaning. There is
currently no established scientifically documented treatment strategy with a
certain outcome. A number of surgical techniques have been tested, but the
results have rarely produced lasting and predictable effects.
Nowadays, bone granules of a bovine origin are widely used within dentistry.
Yet, there is growing hesitation to use this xenotransplantation material.
Inert titanium granules may be a good alternative for alveolar bone
regeneration.
Tigran* porous titanium granules are irregularly shaped and porous granules
manufactured using commercially pure titanium. The granules are between 0.7 mm
and 1.0 mm. When they are mixed with the patient*s blood or with a saline
solution the granules attach to each other due to the capillary force. The
granules that have a porosity of about 80% and an osteoconductive surface
structure, imitate properties of human bone and create a scaffolding for bone
generation that stimulates osteoblast colonization and osseointegration. The
granules are non-resorbable and keep their volume during the operation and the
entire healing period which ensures mechanical stability and a desired
aesthetic result. This novel bone regeneration material has retained the
mechanical strength, permanent volume fill and the osteoconductivity of
titanium, while at the same time offer a porous architecture for optimal
cellular ingrowth, revascularization and bone in-growth.

Tigran Technologies has its origins in orthopedics. The first use of Tigran*s
porous titanium granules was in 1987*88, when they were used for the fixation
of hip prostheses (1, 2). The titanium granules were found to provide initial
mechanical stability, a scaffold for bone regeneration and ingrowth and
excellent long-term clinical results.
Animal experiments using a hemiarthroplasty model demonstrated bone ingrowth
through the porous granules and suggest the possibility of obtaining the
permanent prosthetic fixation by direct contact (osseointegration) between bone
and prosthesis (3, 4).
In a pilot study on depression fractures of the lateral tibial plateau, where
titanium granules were used to support the elevated articular surface, the
clinical and radiological results were excellent (5). The titanium granules
were found to offer several advantages compared with autograft bone and
commercially available bone substitutes. The most important: The granules are
not resorbed.

The first dental application with Tigran*s porous titanium granules was
performed in 1995, when the titanium granules were successfully used to enhance
bone regeneration following a ridge splitting in a case of a severely resorbed
maxillary dento-alveolar ridge and this allowed a cross arch bridge
installation (6). The titanium granules were also used successfully in cases
with large cystic cavities, which were removed, whereupon the bone voids were
filled with titanium granules * all patients recovered quickly with very good
results (7).
Many implant treatments today begin with bone regeneration treatment for both
functional and aesthetic reasons. Tigran porous titanium granules can be used
for bone regeneration in a number of application areas, such as
peri-implantitis, sinus lift and extraction cavities.

SINUS FLOOR AUGMENTATION
The first sinus floor augmentation with titanium granules was performed in 2003
with excellent clinical and radiological results (8). Later, sinus floor
augmentation with titanium granules was performed in sixteen patients,
comprising of 23 tooth implants that were followed for 1*3 years (9).
FURCATION DEFECTS
A randomized animal experiment has indicated that titanium granules can be
safely used as bone graft substitute in degree II molar furcation defects (10,
11)).
PERI-IMPLANTITIS
With Tigran titanium granules the affected implants (peri-implantitis) can
often be saved by bone regeneration around the implant and in this way
unnecessary intervention and major costs related to replacing the implant are
avoided.
The results of the pilot study were presented during the fall of 2008 and
clearly show that bone can be regenerated using porous titanium granules.
Tigran is first to through biopsies show that new bone grows in and around the
titanium granules and recreates bone tissue around the implant. Following bone
loss caused by peri-implantitis, parts of the implant surface becomes exposed
to inflammatory cells, microbes and organic contaminants. A human biopsy taken
12 months after treatment of a peri-implant osseous defect with titanium
granules showed well-integrated granules with bone ingrowth through the
porosities of the granules and re-osseointegration of the implant (12).
Improved osseous regeneration was seen in a series of animal experiments (13)
and improved osseous defect fill in a prospective randomized case control study
of 30 patients with peri-implant osseous defects (14). The present study is
similar to the previous study but has a multicentre approach. The titanium
granules are commercially available in the Netherlands (Solid Benelux BV,
Vreeland), and are used by dentists and oral surgeons.

We hypothesize that the patients treated with the titanium granules will
regenerate new bone around dental implants resulting in enhanced support of the
implants and therefore better implant endurance.

1. Bjursten LM, Bruce L, Urban RM, Alffram P-A, Bruce I, Andersson GBJ.
Implantation of the femoral stem into a bed of titanium granules using
vibration provides long term clinical stability. Transactions Society for
Biomaterials 1999;25:472.
2. Alffram P-A, Bruce L, Bjursten LM, Urban RM, Andersson GBJ. Implantation of
the femoral stem into a bed of titanium granules using vibration. A pilot study
of a new method for prosthetic fixation in five patients followed for up to 15
years. Ups J Med Sci 2007;112(2):183*9.
3. Turner TM, Urban RM, Jacobs JJ, Berzins A, Hall DJ, Lawrence-Smith AM,
Bjursten LM, Bruce L, Bruce I, Alffram P, Andersson GBJ. Fixation of a femoral
hip stem by vibration into porous titanium granules in a canine model.
Transactions Orthopaedic Research Society 2000;25:532.
4. Turner TM, Urban RM, Hall DJ, Andersson GBJ. Bone ingrowth through porous
titanium granulate around a femoral stem. Histological assessment in a
six-month canine hemiarthroplasty model. Ups J Med Sci 2007;112(2): 191*7.
5. Jónsson B, Mjöberg B. Surgical treatment of depression fractures of the
lateral tibial plateau using porous titanium granules. Ups J Med Sci
2009;114(1):52*4.
6. Holmberg L, Forsgren L, Kristerson L. Porous titanium granules for implant
stability and bone regeneration * a case followed for 12 years. Ups J Med Sci
2008;113(2):217*20.
7. Magistri A, Botticelli L, Romitelli AM, De Luca P, Evangelisti N, Guadagno
I. Trattamento delle grandi cavità cistiche con biomateriali. ChirOrale
2006;2(2):16*9.
8. Bystedt H. Natix used as osteoconductive material for sinus floor
augmentation. Three years follow-up. Case report. Swedish Dental Journal
2007;31(4):193.
9. Bystedt H, Rasmusson L. Porous titanium granules used as osteoconductive
material for sinus floor augmentation: a clinical pilot study. Clin Implant
Dent Relat Res 2009;11(2):101*5.
10. Wohlfahrt JC, Rönold HJ, Aass AM, Heijl L, Lyngstadaas SP. Porous titanium
granules in furcation defects * an animal experimental study. Presented at the
44th Meeting of the International Association for Dental Research, September 9*
12, 2009, Munich, Germany.
11. Sabetrasekh R, Tiainen H, Lyngstadaas SP, Reseland J, Haugen H. A novel
ultra-porous titanium dioxide ceramic with excellent biocompatibility. J
Biomater Appl 2010 (Epub ahead of print).
12. Wohlfahrt JC, Aass AM, Rønold HJ, Lyngstadaas SP. Titanium granules for
treating peri-implantitis * clinical study with human histology. Presented at
the 17th Annual Meeting of the European Association for Osseointegration,
September 18*20, 2008, Warsaw, Poland.
13. Wohlfahrt JC, Monjo M, Rønold HJ, Aass AM, Ellingsen JE, Lyngstadaas SP.
Porous titanium granules promote bone healing and growth in rabbit tibia
peri-implant osseous defects. Clin Oral Implants Res 2010;21(2):165*73.
14. Wohlfahrt JC. Porous titanium granules in the surgical treatment of
peri-implant osseous defects * a randomized clinical study. Presented at the
6th Congress of the European Federation of Periodontology, June 4*6, 2009,
Stockholm, Sweden.

Project description:
A controlled randomized multicentre prospective clinical trial of 12 months
duration at 5 centres. To evaluate and compare appliance of porous titanium
granules (PTG) during surgical treatment of peri-implant osseous defects of
implants with sham (flap operation without appliance of PTG).

Primary Objective
To evaluate if appliance of porous titanium granules (PTG Tigran Technologies
AB) during surgical treatment of peri-implant osseous defects:
a) gives significantly enhanced defect fill and
b) limit the progression of the decease after 12 months in comparison to sham.

Secondary Objectives
* To evaluate clinical parameters (Pocket probing depth (PPD), BoP, PUS )
* To evaluate subclinical parameters (radiographic defect resolution)
* To evaluate microbial composion of the peri-implant sulcus before and after
treatment
* To evaluate interaction between the host (fibroblasts) and pathogens
(especially P. gingivalis) in peri-implantitis, and further to study
susceptibility to peri-implantitis on cellular level. Fibroblasts will be
stimulated with P. gingivalis, but also with other commensal oral
microorganisms (defined later), and cytokine-response to these cells will be
defined.
* To evaluate soft parameters such as patients subjective satisfaction.
* Aesthetics

Controlled randomized multicentre prospective clinical trial of 12 months
duration at 5 centres. To evaluate and compare appliance of porous titanium
granules (PTG) during surgical treatment of peri-implant osseous defects of non
submerged implants with sham (treatment without appliance of PTG).

In each centre 6 test patients will be treated during the flap operation with
debridement and porous titanium granules, and 6 control patients will be
treated during the flap operation only with debridement (sham).

Each patient will be treated with a ordinary flap operation for
peri-implantitis but the test patients will be treated during the flap
operation also with porous titanium granules.
During flap surgery tissue material will removed (waste) and otherwise throuwn
away. Now we would like keep this material and grow fibroblasts in vitro from
this material.
Using a sterile paper point, additional subgingival bacterial samples (standard
protocol, non-invasive ) for microbiological diagnostics will be taken 6 and 12
months after surgery.
The risks associated with taking part in this clinical study are no greater
than with ordinary flap surgery. As with ordinary flap operation, there may be
some bleeding, pain and swelling for the first few days after the procedure.
There is a risk that the implant anyhow will come loose as may happen after
ordinary flap operation as well. If this happens the loose implant and the
granules will be removed through further surgery.
There is also a risk that the titanium granules will not anchor sufficiently.
If this happens the granules will be removed and ordinary flap operation will
take place.