CONTENTS:

Ø INTRODUCTION

Ø HISTORY OF OSSEOINTEGRATION

Ø DEFINITIONS AND OTHER TERMINOLOGIES

Ø MECHANISM OF OSSEOINTEGRATION

· INFLAMMATORY PHASE

· PROLIFERATIVE PHASE

· MATURATIVE PHASE

Ø FACTORS RESPONSIBLE FOR OSSEOINTEGRATION

· MATERIAL BIOCOMPATIBILITY

· IMPLANT DESIGN: MACRO STRUCTURE

· IMPLANT SURFACE: MICRO STRUCTURE

· STATE OF HOST BED

· SURGICAL CONSIDERATIONS

· LOADING CONDITIONS

Ø CLINICAL EVALUATION OF OSSEOINTEGRATION

Ø SCOPE OF OSSEOINTEGRATION

Ø CONCLUSION

Ø REFERENCES

INTRODUCTION :

Since tooth loss from disease and trauma has always been a feature of mankind’s existence, it is not surprising that the history of tooth replacement is a long one. Evidence from ancient civilizations shows that attempts were made to replace missing teeth by banding artificial tooth replacements to remaining teeth with metal many centuries ago. For the mechanism of attachment, clinicians have long sought an analog for periodontal ligament. Experiments were made to develop a fibrous attachment that could serve the same purpose as the periodontal ligament but all in vain. The periodontal ligament in a specialized structure which serves not only as an efficient attachment mechanism but also as a shock absorber and sensory organ, so it was impossible to reproduce.

HISTORY OF OSSEOINTEGRATION :

Implants may indeed be anchored in bone by means of surrounding sheath of connective tissue, but in general this has not shown the degree of organization and specialization that would allow it to pass as a substitute for the periodontal ligament. In most cases, loading leads to gradual widening of fibrous tissue layer and loosening of implant, with consequent implant failure. In contrast to periodontal ligament, a fibrous tissue sheath is a poorly differentiated layer of scar tissue.

Dr. Per Ingvar Branemark, an anatomist is credited as the person who has coined the term “osseointegration”. Branemark along with his team was working in the laboratory of the vital microscopy (1952), laboratory of experimental Biology, University of Goteberg Sweden, (1960), Institute of Applied biotechnology, Goteberg (1978). The main study of his group was to understand the mechanism of bone healing and bone response to the thermal, mechanical, chemical injuries by using vital microscopy.

Vital microscopy, is a type of the miniature microscope, which is introduced in to the living organisms. E.g. Rabbit in their study the titanium (Ti) chambers were used for placing the vital microscope into the rabbit’s fibula. After the studying of the bone biomechanics in one animal, the team used to recover the vital microscope and place it into the other animal model. While recovering Branemark observed that the Ti chambers were firmly adherent to the bone. By this observation they concluded that the titanium was firmly integrated to the bone and later they used Ti screws and Ti bars for reconstruction of the long bones and mandibles of the dogs.

After ensuring the favourable bone response to the Ti, the team tried to replace the teeth for the dogs. The Ti implants also showed good response for the mucosa and skin penetrating implants. The implants, which used for replacement of the teeth in the dogs showed good integration upto 10 years and the implants could bear the load of upto 100 Kgs without failure at the bone-implant interface. By observing this property the integration between the bone and Ti screws was termed as “osseointegration”.

The Ti vital microscopic chambers were used to analyze microcirculation in the healthy and diabetic human volunteers without any signs of inflammation around the Ti chamber. In 1965, first human edentulous patient was treated by using the Ti screws (implants) by reconstruction of resorbed edentulous arches using autologus tibial bone grafts.

The salient features of Branemark and his team’s work

Ø About more than 50 designs of Ti screws (Implants) were tested and used.

Ø The surgical protocol followed was : two stage surgery, which was proved beneficial.

Ø Minimal trauma during the surgery results in bone regeneration rather than bone repair at the implant site.

Ø Non-contaminated implants (sterile and clean implants) proved good integration.

Ø Prosthesis and abutments were screw attached for more technical flexibility.

Ø There were more mechanical failures at the interface rather than biological failures.

In the longitudinal study of the Ti implants from 1965 to 1974 showed a success rate of 99% in mandibles and 89% in maxilla.

In the mean time Schroeder et al. (1970), the members of the international team for development of oral implants (I.T.I) studied the Ti plasma sprayed Cp Ti cylindrical implants in Monkey models and achieved the firm integration between the implant and the tissues. In their study the bone was joined to implant by fine bridges of fibrous tissue. They termed this union as functional ankylosis.

DEFINITION AND OTHER TERMINOLOGIES :

Osseointegration :

Branemark defined it “as a direct contact between the bone and metallic implants, without interposed soft tissues layers” (1969).

Later it is modified “as a direct structural and functional connection between ordered, living bone and the surface of a load carrying implant” (1977). [Structurally oriented definition]

American Academy of Implant Dentistry (1986):

Contact established without interposition of non-bone tissue between normal remodeled bone and an implant entailing a sustained transfer and distribution of load from implant to and within the bone tissue.

Meffert et al. (1987) Subdivided into

Adaptive Osseointegration: Osseous tissue approximating the surface of the implant without apparent soft tissue interface at light microscopic level.

Biointegration: Is a direct biochemical bone surface attachment confirmed at electron microscopic level.

Zarb and T. Albrektsson (1991): It is a process whereby clinically asymptomatic rigid fixation of alloplastic materials is achieved and maintained, in bone during functional loading.

Schroeder et al (1970’s): Coined the term “Functional Ankylosis”.

Osseointegration

Fibro integration

Concept of Bony Anohorage Branemark (1969)

Concept of soft tissue anchorage

Linkow (1970), James (1975), Weiss (1986)

MECHANISM OF OSSEOINTEGRATION :

After the surgical placement of implants into endosteal location, the traumatized bone around these implants begins the process of wound healing. As mentioned previously, it can be separated into the inflammatory phase, the proliferative phase, and the maturation phase. This is summarized in Table along with some of the specific aspects of bone healing during these stages.

Phase	Timing	Specific Occurrence
1. Inflammatory phase	Day 1 – 10	· Adsorption of plasma proteins. Platelet aggregation & activation. Clotting cascade activation. Cytokine release. · Non-specific cellular inflammatory response. · Specific cellular inflammatory response. Macrophage mediated inflammation.
2. Proliferative phase	Day 3 – 42	· Neovascularization. · Differentiation, proliferation and activation of cells. · Production of immature connective tissue matrix.
3. Maturation phase	After day 28	· Remodeling of the immature Bone matrix with coupled resorption and deposition of bone. · Bone remodeling in response to implant loading. · Physiological bone recession.

MUCOPERIOSTEAL HEALING :

Implants are placed into their endosteal position through incisions in the mucoperiosteum. They can be placed using a one stage technique, in which the endosteal and transmucosal portions of he implant are allowed to heal as a single unit, or a two staged technique, in which the endosteal component is placed initially followed some time later by the placement of the transmucosal portion after a period of healing. Healing of the mucoperiosteal complex around implants is of paramount importance for the longevity of prosthetic reconstructions. An understanding of the biologic processes involved in generalized wound repair and how soft tissue wounds heal around implant fixtures is vital information for appropriate management of implant patients. As in the previous section on bone healing, there are also three phases of wound healing in soft tissue wounds: inflammatory, proliferative and maturation phases. In addition, there is also significant overlap between these phases as they pertain to mucoperiosteal wound healing.

IMPLANT TISSUE INTERFACE :

Ø It consists of implant and bone interface.

Ø Implant and connective tissue interface.

Ø Implant and epithelium interface.

Implant and bone interface :

On observing the implant and bone interface at the light microscopic level (100X) it shows that close adaptation of the regularly organized bone next to the Ti implants.

Scanning electron microscopic study of the interface shows that parallel alignment of the lamellae of haversian system of the bone next to the Ti implants. No connective tissue or dead space was observed at the interface. Ultra microscopic study of the interface (500 to 1000X) shows that presence of amorphous coat of glycoproteins on the implants to which the collagen fibers are arranged at right angles and are partly embedded into the glycoprotein layer.

Mechanism of attachment :

As a general rule cells do not bind directly to the foreign materials. The cells binds to each other or any other foreign materials by a layer of extracellular macro molecules (glycoproteins).

The glycoprotein layer in between the cells or in between the tissues will be at a thickness of 10 to 20 nm (100 to 200 A⁰).

At the interface the glycoprotein layer of normal thickness (10-20 nm) is adsorbed on the implant surface within the help of adhesive macromolecules like Fibronectin, Laminin, Epibiolin, Epinectin, Vitronectin (serum spreading factor), Osteopontin, thrombospodin and others. At the molecular level the macromolecules contains Tri-peptides made up of Arginin-glycin-Aspertic acid (RGD). The cells like fibroblasts and other connective tissue cells contain binding elements called as “integrins”. The integrins recognizes the RGDs and bind to them.

The macromolecules are adherent more firmly to the metallic oxide layer on the Ti implants. The mode of attachment between the oxide layer and the macromolecules may be of covalent bonds, ionic bonds or van-der-walls bonding.

Implant connective tissue interface :

The connective tissue above the bone attaches to the implant surface in the similar manner as that of the implant bone interface. The supra crestal connective tissue fibers will be arranged parallel to the surface of the implant. Because of this type of the attachment the interface between the connective tissue and implant is not as strong as that of the connective tissue and tooth interface. But the implant connective tissue interface is strong enough to withstand the occlusal forces and microbial invasions.

Implant epithelial interface :

The implant epithelial interface is considered as Biologic seal by many authors. At this interface the glycoprotein layer is adherent to the implant surface to which hemidesomosomes are attached. The hemidesmosomes connect the interface to the plasma membrane of the epithelial cells. Because of this attachment the implant epithelial interface is almost similar to the junctional epithelium. For the endosseous implants the sulcus depth varies from 3 to 4mm.

Factors of importance to ensure a reliable bone anchorage of an

implanted device :

In most cases whenever an implant is inserted in bone, healing will dependent on the conditions like adequate cells, nutrition to these cells and adequate stimuli for repair. However, bone tissue is different from soft tissue in some aspects. In the first place bone will at least under ideal conditions, heal without any scar formation due to ongoing creeping substitution that will gradually replace the bone with newly formed hard tissue. Secondly, even if the repair process is disturbed so that no (or very little) healing ensures, the dead bone may (like a dead branch of a tree) still be capable of carrying some loads and thereby contribute to function. This may in clinical practice be the case in many hip and knee arthroplasties. Such replacements may tolerate the load put upon them by an elderly patient, but not the more heavy stress likely in young individuals where the results are much less good than with senior citizens. The delicate balance between bone formation and bone resorption may be exemplified through the known coupled function between bone cellular elements of opposing function such as osteoblasts and osteoclasts. Many authors claim that the one cell will need the other to be in an active state. This is further exemplified in the creeping substitution process.

Even if osseointegrated implants have been documented to result in excellent long-term results, this does not necessarily imply that every implant system claimed to be dependent on osseointegration will result in an acceptable clinical outcome. On the contrary, there are several reasons for primary as well as secondary failure of osseointegration. These failures may be attributed to an inadequate control of the six different factors known to be important for the establishment of a reliable, long-term osseous anchorage of an implanted device. These factors are:

1. Implant biocompatibility

2. Design characteristics

3. Surface characteristics

4. The state of the host bed

5. The surgical technique and

6. The loading conditions

There is a need to control these factors more or less simultaneously to achieve the desirable goal of a direct bone anchorage.

IMPLANT BIOCOMPATIBILITY :

Biological biocompatibility	Chemical composition Metals Polymers Ceramics
Biotolerant	Gold Cobalt-chromium alloys Stainless steel Zirconium Niobium Tantalum		Polyethylene Polyamide Poly-methyl methacrylate Poly-tetrafluoro ethylene Poly-urethane
Bioinert	Commercially pure titanium( CPTi) Titanium alloy (Ti-6Al-4V)	Aluminum oxide Zirconium oxide
Bioactive		Hydroxyapatite Tricalcium phosphate Calcium pyrophosphate Fluorapatite Carbon: vitreous, pyrolytic Bioglass

With respect to metals, commercially pure (c.p) titanium, niobium and possibly tantalum are known to be most well accepted in bone tissue. In the case of c.p. titanium, there is likewise a documented positive long term function. The reason for the good acceptance of these metals does probably relate to the fact that they are covered with a very adherent, self-repairing oxide layer which has an excellent resistance to corrosion. Whereas the load bearing capacity of c.p. titanium is sufficiently documented in the case of oral implants, there is less known about niobium in this aspect. Other metals such as different cobalt-chromoe-molybdenum alloys and stainless steels have demonstrated less good take in the bone bed, but it is uncertain if this is valid for every possible such alloy and if it is biocompatibility effect alone that is responsible for their less satisfactory incorporation into bone, compared with c.p. titanium. A significantly impaired interfacial bone formation compared to c.p. titanium has been found with titanium-6 aluminium-4 vanadium alloy, probably dependent on a less good biocompatibility of the alloy. One concern with metal alloys is that one alloy component may leak out in concentrations high enough to cause local or systemic side effects. Ceramics such as the calcium phosphate hydroxyapatite (HA) and various types of aluminium oxides are proved to be biocompatible and due to insufficient documentation and very less clinical trials, they are less commonly used. With respect to HA, the available literature points to at least a short term (<10 weeks) enhanced interfacial bone formation in comparison to various reference metals. This represents a potential clinical benefit of HA, whereas the risk or coat loosening with subsequent problems represents a potential risk.

IMPLANT DESIGN (MACRO STRUCTURE) :

There is at present, sufficient long-term documentation only on threaded types of oral implants that have been demonstrated to function for decades without clinical problems. However, unthreaded implants may function too, even if there is a total lack of positive documentation with respect to bone saucerisation, a problem that caused failure of many early types of oral implants. With currently used cylindrical implants, many authors reported more severe bone resorption than would have been expected with certain screw designs. It must be observed that there are other unthreaded implant designs that may give an excellent long term clinical result.

The threaded implants provide more functional area for stress distribution than the cylindrical implants. The design of the threads may also influence the long term osseointegration. For e.g. V-shaped thread transfer the vertical forces in a angulated path, may not be efficient in stress distribution as that of the square shaped threads.

Threaded

Non Threaded

IMPLANT SURFACE (MICRO STRUCTURE, SURFACE TOPOGRAPHY:

With respect to the surface topography there is clear documentation that most smooth surfaces do not result in an acceptable bone cell adhesion. Such implants do therefore end up as being anchored in soft tissue despite the material used. Clinical failure would be prone to occur. Some microirregularities seem to be necessary for a proper cellular adhesion even if the optimal surface topography remains to be described. With a gradual increase of the surface topographical irregularities, problems due to an increased ionic leakage are prone to occur. With plasma sprayed titanium surfaces for instance, more than 1600 ppm titanium has been reported in implant adjacent haversian systems, probable resulting in an impairment of osteogenesis.

Another surface parameter is the energy state where a high surface energy has been regarded as positive for implant take due to an alleged, improved cellular attachment. One practical way of increasing the surface energy is the use of glow discharge (plasma cleaning). However, published reports have not been able to confirm the superiority of so artificially enhanced implant energy levels. One reason for this lack of confirmation of the surface energy hypothesis could be that the increased surface energy would disappear immediately when the implant makes in contact with the host tissues.

Many researchers recommended various procedures for improving the surface energy or surface characteristics of the implants to improve the osseointegration. Stefini C.M. et al. (2000) recommended to apply platelet derived growth factor and insulin like growth factors on the implant surface before placing into the cervical bed. According to their results this method showed better wound healing and rapid integration.

Musthafa K. et al (2000) reported to sand blast the titanium implants with titanium oxide particles (45-90m) to achieve higher rate of cell attachment.

Other authors like Lima Y.J. et al. (2001) and Orsini Z. et al. (2000) reported to perform acid etching of the titanium implants by hydrofluoric acid, aqueous nitric acid and sodium hydroxide to reduce the contact angle less than 10⁰ for better cell attachment and utilization of 1% hydrofluoric acid + 30% nitric acid to clean the implant surface and to remove the alumina particles after sand blasting which improves the osseointegration.

Nishiguchi S. et al (2001) reported to provide alkali + heat treatment to improve the amount of bone bonding, i.e. 5 mol/lt NaOH at 60⁰C for 24 hours and 600⁰C for 1 hour (Dog study).

Rich and Harris presented some of the salient features of fibroblasts during healing i.e. Rugophalia: attracted towards rough surfaces, Haptotaxis: the directional cell movement that depends upon adhesive gradients on the substratum, Contact guidance : the tendency of the cells to be guided in their direction of locomotion by the shape of substratum. These properties denotes that the implant fixture with rough surface topography and more surface energy promotes faster and complete osseointegration.

STATE OF THE HOST BED :

If available, the ideal host bed is healthy and with an adequate bone stock. However, in the clinical reality, the host bed may suffer from previous irradiation, ridge height resorption and osteoporosis, to mention some undesirable states for implantation. Previous irradiation need not be an absolute contraindication for the insertion of oral implants. However, it is preferable that some delay is allowed before an implant is inserted into a previously irradiated bed. Furthermore, some 10-15% poorer clinical results must be anticipated after a therapeutical dose of irradiation. The explanation for less satisfactory clinical outcome found in irradiated beds could be vascular damage, at least in part. One attempt to increase the healing conditions in a previously irradiated bed is by using hyperbaric oxygen, as a low oxygen tension definitely has negative effects on tissue repair. This is further verified by the finding that heavy smoking, causing among other things a local oral vasoconstriction, is one factor that will lower the expected outcome of an implantation procedure.

As stated by Branemark et al. and Misch, the bones with D1 and D2 bone densities shows good initial stability and better osseointegration. The bone densities D3 and D4 shows poor prognosis. Many authors have recommended to select suitable implants depending upon the quality and quantity of the available bone, i.e., HA coated or Ti plasma coated implants are better for D3 and D4 and conventional threaded implants for D1 and D2 bone qualities.

SURGICAL CONSIDERATIONS :

The main aim of the careful surgical preparation of the implant bed is to promote regenerative type of the bone healing rather than reparative type of the bone healing. If too violent a surgical technique is used, frictional heat will cause a temperature rise in the bone and the cells that should be responsible for bone repair will be destroyed. Bone tissue is more sensitive to heat than previously believed. In the past the critical temperature was regarded to be in the 56⁰C range, as this temperature will cause denaturation of one of the bone enzymes, alkaline phosphatase. However, the critical time / temperature relationship for bone tissue necrosis is around 47⁰C applied for one minute. At a temperature of 50⁰C applied for more than one minute we are coming close to a critical level where bone repair becomes severely and permanently disturbed. This critical temperature should be seen against observed frictional heat at surgical interventions. In the orthopaedic field, despite adequate cooling, temperatures of 90⁰C have been measured. High drilling temperatures in the dental field are to be expected when drilling, particularly in the dense mandible.

Erickson R.A. recommended the importance of using well sharpened drills, slow drill speeds, a graded series of drills (avoid making, for instance, a 4mm hole in one step) and adequate cooling by profuse irrigation. By using such a controlled technique it has been demonstrated in clinical studies that overheating may be totally avoided. The mechanical injury will of course remain and is quite sufficient to trigger a proper healing response. Erickson also recommended bone cutting speed of less than 2000 rpm and tapping at a speed of 15 rpm with irrigation.

Hence, the surgical preparation sequences as well as the instruments depend upon the quality of the bone as shown in the diagram.

Another surgical parameter of relevance is the power used at implant insertion. Too strong a hand will use in bone tension and a resorption response will be stimulated. This means that the holding power of the implant will fall to dangerous levels after a strong insertion torque. A moderate power at the screwing home of an implant is therefore recommended. With other implant designs there may be a need for implantation of the implant at insertion and other rules may apply.

Surgical fit of the fixture: The accurate fit consists of more surface contact, less dead space and thus better healing.

LOADING CONDITIONS :

From histological investigations of animal as well as human implants we know that, irrespective of control of surgical trauma and other relevant parameters, the implant will, in the early remodeling phase, be surrounded by soft tissue. This means that some weeks after implant insertion it will be particularly sensitive to loading that results in movements, as movement will stimulate more soft tissue formation, leading eventually to a permanent soft tissue anchorage. In essence, the situation is similar to that of a fracture. Loading of an unstabilized fracture will result in soft tissue healing and poor function, whereas stabilization with plates or plaster of Paris will ensure a satisfying rigidity leading to bone healing of the fracture. The case of an implant is, in principle, very similar. Premature loading will lead to soft tissue anchorage and poor long-term function, whereas postponing the loading by using a two stage surgery will result in bone healing and positive long term function. The length of time loading should be avoided is dependent on the implantation site as well as on the bone bed quality. Furthermore, there may be cases where an almost immediate loading would not disturb the bone healing response, but in general loading must be controlled if osseointegration is to occur. Branemark with his controlled implant system advocated the use of a 3 month loading delay in the mandible and a 4-6 month delay in the healthy maxilla where the bone is, as a rule, more cancellous in character. However, these precise unloaded times are empirically based and to the knowledge of the author there are no published studies comparing different unloaded periods and relating this to implant success. Furthermore, from a bone biologic point of view a more suitable design would be to have the implant unloaded and then gradually increase the load in the manner of the Sarmiento technique for functional braces in fracture healing. In the similar way Misch et al. recommended progressive loading criteria or staged loading and implant protective occlusion for better maturation of the bone surrounding the implants. The problem in the case of oral implants is how properly to define to the patient how a gradual increase of load should be controlled ; a complicated task not the least since the appropriate loading pattern also depends on individual patients factors.

Recently, many authors are reporting the results of immediate loading of the endosseous implants. According to them the physiological loading of the healing implants promotes better osseointegration.

Sagara et al (1993) also showed evidence of osseointegration when titanium screw implants were immediately loaded with a unilateral prosthesis. Their findings showed that osseointegration did occur, although the immediately loaded implants exhibited less direct bone contact than with the delayed loading which were used as controls.

Salama et al (1995) reported on two patients in whom titanium root form implants were immediately loaded and successfully utilized to support provisional fixed restoration in the maxilla and mandible. Both the patients were followed from 37 to 40 months after implant placement and immediate loading. All implants osseointegrated and were restored with a fixed prosthesis.

Babbush and co-workers (1986) showed implant success rate of 88% to 97% over 5 to 13 years with immediate loading implants.

Lederman and colleagues (1998) histologically confirmed osseointegration with 70% to 80% bone to implant contact in a mandibular symphysis necropsy specimen after 12 years of implant and prosthesis function in a 95 year old patient.

Peitelli and colleagues (1997) found significantly greater bone-to-implant contact in 24 immediately loaded mandibular implants compared with 24 unloaded.

THE SUCCESS CRITERIA (ALBERKTSSON ET AL) :

1) The individual unattached implant should be immobile when tested clinically.

2) The radiographic evaluation should not show any evidence of radiolucency.

3) The vertical bone loss around the fixtures should be less than 0.2 mm per year after first year of implant loading.

4) The implant should not show any signs of pain, infection, neuropathies, parasthesia, violation of mandible canals and sinus drainage.

5) The success rate of 85% at the end of 5 year and 80% at the end of 10 service.

METHODS OF EVALUATION OF OSSEOINTEGRATION :

Invasive methods :

1) Histological sections (10 microns sections).

2) Histomorphometric – to know the percentage of bone contact.

3) Transmission electron microscopy

4) By using torque gauges

5) Pull out tests.

The invasive methods are usually used in the animal experiments.

Non-invasive methods :

1) Tapping with a metallic instruments: The fixture produces ringing sound, it osseointegrated, produces dull sound if fibrous integration.

2) The radiographs

3) Perio test: Checks mobility and damping system.

Normal value : -5 to + 5 PTV

4) Dental fine tester: evaluates the mobility, should be less than 5m.

5) Reverse torque test with 20 N cm.

6) Resonance frequency analysis: this method gives the idea of amount, rate of osseointegration. This method can be utilized for healing or failing implants.

SCOPE OF THE OSSEOINTEGRATION :

The osseointegrated endosseous implants are utilized for providing the prosthesis or stabilizing the various structure of the body. A schematic representation of the scope of the osseointegration is depicted in the diagram.

CONCLUSION :

The “osseointegration” is a multifactorial entity. Achieving the osseointegration of the endosteal dental implants needs understanding of the many clinical parameters.

References:

1) Osseointegration in clinical dentistry – Branemark, Zarb, Albrektsson

2) Osseointegration and occlusal rehabilitation – Sumiya Hobo

3) Contemporary Implant Dentistry – Carl. Misch

4) Endosseous implants for Maxillofacial reconstruction – Block and Kent

5) Implants in Dentistry –Block and Kent

6) Dental and Maxillofacial Implantology – John. A. Hobkrik, Roger Watson

7) Endosseous Implant : Scientific and Clinical Aspects – George Watzak

9) Adell R, Lekholm U, Rockler B, Branemark PI: A-15-year study of osseointegrated implants in the treatment of the edentulous jaw. Int J oral Surg 1981; 10:387.

10) Akagawa Y, Tsuru H: Interface histology of unloaded and early loaded partially stabilized zirconia endosseous implant in initial bone healing. Journal of Prosthetic Dentistry; June 1993; 69:6:599-603.

11) Albrektsson T, Jansson T: Osseointegrated dental implants. Dent Clin North Am 30:151, 1986.

12) Albrektsson T, Bergman B, Folmer T, et al: A multicenter study of oseointegrated oral implants. J Prosthet Dent 60:75, 1988

13) Albrektsson T, Jacobsson M: Bone-metal interface in osseointegration. J Prosthet Dent 57:597, 1987.

14) Albrektsson T, Lekholum U: Osseointegration, Current state of the art – Dental clinics of North America. 33 : 537 – 557, 1987