Osseointegration

It is just as true in dentistry as in other disciplines that the more useful a technology, the more

rapidly are its limits challenged by the user and that, in turn, user demand drives the necessity

for refinements and improvements in the technology. An obvious example would be the rapid

evolution of computers over the last few decades that has led to our almost indispensable

reliance on the ubiquitous microchip. Similarly, in dentistry, over the last few decades there

has been an increasing use of endosseous (in-bone) implants as a means of providing a

foundation for intra-oral prosthetic devices, from full arch dentures to single crowns, or other

devices for orthodontic anchorage or distraction osteogenesis. While there is no question that

the popularity of endosseous implants for these treatment modalities is based on increasingly

convincing data of long-term clinical success rates, it is this very success that has prompted

the use of implants in more challenging clinical situations than were previously envisioned.

Thus, single root implants previously employed in only anterior mandibular and maxillary

sites are now commonly inserted into posterior regions where there is less cortical bone to

provide initial mechanical stabilization. Indeed, the clinical success of implant therapy has

led to the emergence of new operative procedures, such as sinus lifts, to increase local bone

stock to accommodate implant placement. Similarly, implants that would previously only be

placed into occlusal function after an extended initial healing period of several months are

now loaded increasingly earlier in a matter of weeks, days, or even hours!.

These radical changes in the practice of implant dentistry have been made possible through

the evolution of a more profound understanding of the essential requirements of individual

case treatment planning, improvements in surgical procedures, and the evolution of the

design of the implants themselves such that almost a million dental implant procedures are

now conducted, annually, worldwide. Therefore, the unequivocal success of endosseous

dental implants is driving the need for continuing refinements in implant design and

optimization of the biological healing response following implant placement.

The story of osseointegration began with an accidental discovery forty years ago. A young

Swedish scientist, Per-Ingvar Branemark, was studying the function of blood and marrow,

and wanted to be able to see inside the fibula bone in a rabbit's leg. He made a viewing

chamber by screwing a cylinder of titanium into the fibula. Titanium is a lightweight metal

that is resistant to corrosion even in hostile environments such as the body of a rabbit, and

Branemark was able to watch the marrow making blood cells. On completing his study,

however, he was irritated to discover that bone had grown into the threads of the titanium

cylinder so that he was unable to remove the expensive equipment.

A few years later, Branemark was studying the effects of eating, drinking and smoking on

blood cells, and developed a tiny titanium viewing chamber which he inserted into a fold of

soft tissue in the upper arm of medical student volunteers. The chambers were left in place

for months as the study proceeded and caused no adverse reaction. Only then did it occur to

Branemark that a metal which could form such a strong bond with bone, without triggering a

reaction from the body's immune system, could be extremely useful in surgery.

He was soon able to act on this finding. In 1965, Branemark's team operated on a man born

with deformed chin and jaw, who could neither eat nor speak normally. They inserted

titanium screws and posts into his mouth and attached a set of dentures. Almost three decades

later, the teeth were still in action.

Branemark, now professor of applied biotechnology at the University of Gothenburg, and his

group have since installed a million titanium fixtures in 300 000 patients, some with

deformities, others with severe dental problems. Ninety-five per cent of prostheses in the

upper jaw have been successful, and 99 per cent of those in the lower jaw.

The biocompatibility of titanium, or the body's lack of reaction to it, is due to the stable and

unreactive layer of oxide that forms on its surface. If the metal is scratched with a sharp

instrument, the oxide layer 'self-repairs' in nanoseconds, even when surrounded with saline or

bodily fluids, according to Tomas Albrektsson, professor of biomaterials at the University of

Gothenburg. With most implants, the body's immune system reacts to the material after

surgery, stimulating fibrous repair. Titanium, with its oxide layer, does not provoke a reaction

from the immune system, allowing normal bone repair to take place so that there is a secure

bond between implant and bone.

Per-Ingvar Branemark

OSSEOINTEGRATION is defined as a direct structural and functional connection between

ordered, living bone and the surface of a load-carrying implant.

Zarb & Albrektsson (1991)

OSSEOINTEGRATION is a process whereby clinically asymptomatic rigid fixation of

alloplastic materials is achieved, and maintained, in bone during functional load.

Implant materials used

Ceramic : Aluminium Oxide, Zirconium Oxide, Carbon, Carbon-Silica compounds

Metallic : Titanium, Titanium alloy

Titanium

Metal with low weight, high strength/weight ratio, low modulus of elasticity, excellent

corrosion resistance, excellent biocompatibility and easy shaping and finishing

Grade 1 CP

Ti

Grade 2 CP

Ti

Grade 3 CP

Ti

Grade 4 CP

Ti

Ti alloy

Tensile strength (MPA)

240 345 450 550 930

Titanium alloys are far superior to pure titanium in terms of mechanical properties. Fatigue

strength of Ti Alloy is 4 times greater than Grade 1 Ti and almost 2 times greater than Grade

4 Ti. Hence long term fracture of implant bodies is greatly reduced when Ti Alloys are used

instead of pure Ti.

Titanium and its alloys represent the closest approximation to the stiffness of bone of any

surgical grade metal used as an artificial replacement of skeletal structures. Ti Alloy

represents the best compromised solution between biomechanical strength, biocompatibility

and the potential for relative motion at the bone-implant interface.

Interesting aspect of titanium implants (cpTi or Ti6Al4V) is that it immediately after

exposure to air forms an oxide layer over the surface (2 to 5nm in thickness)

THE OXIDE LAYER

Most pure metals are covered by an oxide layer.

It will be the surface of the metal that comes into contact with the host tissue.

Different surfaces have very different absorption properties which affect

biocompatibility.

This oxide is highly protective and prevents direct contact between the environment

and the metal itself.

It means, in the context of implants, that a contact is never established between the

implant metal and the host tissue, but rather between the tissue and the surface oxide

of the implant.

Because the latter has completely different chemical properties than the metal itself, it

is the biocompatibility of the oxide that is the relevant parameter from a chemical

point of view.

Therefore, one should choose a metal that forms a very stable surface oxide such as

TiO2, ZrO2, AL2O3, Ta2O5.

The surface is a dynamic interface, with increase in thickness of the oxide layer when

the implant is positioned in bone than is left in air.

Corrosion is caused by dissolution of the protecting oxide layer, which may be a

severe problem with some implant materials.

Albrektsson et al 1981: 6 factors for reliable osseointegration

1. Implant biocompatibility

2. Implant design

3. Implant surface

4. State of host bed

5. Surgical technique

6. Loading conditions

1. Biocompatibility

C.p. Titanium, Niobium and Calcium Phosphates such as HA are well tolerated

Titanium alloys, aluminum oxides, cobalt-chrome-molybdenum and stainless steels

are less well tolerated

2. Implant Design

Categorized as cylinder type, screw type, press fit or a combination

Cylinder or press fit : Has friction fit insertion, less risk of pressure necrosis from too

tight an insertion pressure, no need of bone tap even in dense bone, and cover screw

in place already since no rotational force reqd to insert implant. Popular in 1980s.

Reports of crestal bone loss aft 5 yrs of loading due to fatigue overload, shear loads,

less BIC.

More than 90 implant body designs available in market.

3 types of forces to counter by the implant design : compression, tension and shear

Bone strongest when loaded in compression, 30% weaker in tension and 65% in shear

Thread designs

‘V’shaped, Square or power threads, Reverse buttress and Buttress

Screw type Cylinder type

3. Implant surface

Turned surfaces

Sandblasted surfaces

Plasma sprayed surfaces

Titanium plasma spray

Acid etched surface

Anodized surfaces

Hydroxyapatite

TiUnite surface : Nobel biocare (pore size : 1-10μm)

Turned surface Sandblast acid etched surface

4. State of the Host bed

A good and healthy bone bed is preferrable

Low ridge height, osteoporosis and previous irradiation are not contraindications for

implant placement in contrast to ongoing bone infection

5. Surgical technique

Surviving cells and good, fitting preparation of the surgical site

6. Loading conditions

Implant incorporation may be compared to healing of fractures

Immediate occlusal-loading – Temporary or definitive restoration and loading within 2

weeks of implant insertion

Early occlusal loading – Between 2 weeks and 3 months

Delayed or staged occlusal loading – After more than 3 months

The safe procedure remains two stage surgery with unloaded periods 3-6 months.

With a controlled two stage technique, very good clinical results with steady state bone have

been reported (Friberg et al 2005).

Bone healing is certainly a fascinating biological accomplishment of the skeletal tissues and

one of the rare examples in which regenerative processes fully restore the original structure

and function. This is achieved by a sequence of cellular activities that closely resemble the

development and growth of bone during embryonic and postnatal life. In intramembranous

(or direct) ossification, bone is formed directly in the mesenchyme. The majority of bones in

the trunk and the extremities, however, are preformed as cartilaginous models and substituted

later on by bone in the process of endochondral (or indirect) ossification. Bone regeneration

follows similar pathways: in direct (or primary) healing, a scaffold of woven bone, closely

associated with an expanding vascular net, invades the granulation tissue that organizes the

initially formed blood clot. In indirect (or secondary) healing, connective tissue and/ or

fibrocartilage differentiates within the fracture gaps and is replaced by bone as in

endochondral

ossification.

Osseointegration clearly belongs to the category of direct or primary healing. Originally, it

was defined as

direct bone deposition on the implant surfaces (9), a fact also called “functional ankylosis”

(48). In a more comprehensive way, osseointegration is characterized as “a direct structural

and functional connection

between ordered, living bone and the surface of a load-bearing implant” (39).

Osseointegration can be

compared with direct fracture healing, in which the fragment ends become united by bone,

without intermediate fibrous tissue or fibrocartilage formation. A fundamental difference,

however, exists: osseointegration unites bone not to bone, but to an implant surface: a foreign

material. Thus the material plays a decisive role for the achievement of union.

Prerequisites for osseointegration

Material and surface properties Osseointegration shares many prerequisites with primary fracture healing, such as precise

fitting (anatomical reduction), primary stability (stable fixation) and adequate loading during

the healing period. In addition, osseointegration requires a bioinert or bioactive material and

surface configurations that are attractive for bone deposition (osteophilic).

Bioinert materials do not release any harmful substances and therefore do not elicit adverse

tissue reactions. Titanium, either commercially pure or in certain alloys, is generally

recognized as being bioinert and used extensively in both dental and orthopedic surgery. A

bioactive material is thought to cause a favorable tissue reaction, either by establishing

chemical bonds with tissue components (hydroxyapatite) or by promoting cellular activities

involved in bone matrix formation. Bioactivity is currently restricted to compounds of poor

mechanical quality and can only be applied as a coating (hydroxyapatite, carriers for

inductors and growth factors). The notion that surface properties of implants might influence

the elaboration of a bone-implant contact is relatively new. It could be anticipated that rough

surfaces will improve adhesive strength compared with smooth ones. This assumption is now

confirmed by numerous animal experiments that measured the push- and pull-out strength or

removal torque values. The observation that a rough surface favors bone deposition and thus

gradually increases the extent of the bone implant interface was somewhat surprising. It is

now supported by numerous experimental studies. Roughness can be further characterized by

the shape and dimension of the surface irregularities. The degree of mechanical interlock

increases with the roughness of the substrate. At the same time, the structure and function of

the bone implant contact changes. A smooth surface only transmits compressive forces, with

little resistance against shear, and apparently none against traction.

A mild roughness <10µm) augments the resistance against shear. Adhesion, however,

requires either a chemical bond or a microporosity (micro protrusions and micro undercuts of

20-50 µm) that leads to a micro indentation between bone and metal. Macroporosity (pore

size 100-500 µm) favors bony in-growth and is widely used as porous coatings (beads,

sintered wire mesh, multilayered lattices) in orthopaedic implants. Finally, the macro-design

or shape of an implant has an important bearing on the bone response: ongrowing bone

concentrates preferentially on protruding elements of the implant surface, such as ridges,

crests, teeth, ribs or the edge of threads, that apparently act as stress risers when load is

transferred.

Primary stability and adequate load The tissue response to a freshly installed implant greatly depends on the mechanical situation.

As in direct fracture healing, it requires perfect stability if bone is expected to be formed. In a

fracture, a stable fixation is obtained by exact adaptation and compression of the fragments.

The primary stability of implants depends on their appropriate design and precise press fitting

at surgery.

Primary stability must counteract all forces that could create micromotion between the

implant and the surrounding tissues. Or, in other words, it should build up enough preload to

compensate for functional

load. It thus determines not only the size but also the direction of the forces that are

considered to remain adequate. All these parameters must be specified, and this makes it

understandable why immediate functional loading may be adequate for such systems as bar-

connected screws, whereas others require a prolonged, unloaded healing period before a

supraconstruction can be installed.

Biology of osseointegration

Events comparable to an extraction socket healing (Amler 1969)

The healing of a wound includes four phases:

1. Blood clotting

2. Wound cleansing

3. Tissue formation

4. Tissue modeling and remodeling.

These phases occur in an orderly sequence but, in a given site, may overlap in such a way that

in some areas of the wound, tissue formation may be in progress while in other areas tissue

modeling is the dominating event.

Important events in bone formation

1. Blood clotting: Immediately after tooth extraction, blood from the severed blood vessels

will fill the cavity. Proteins derived from vessels and damaged cells initiate a series of events

that lead to the formation of a fibrin network. Platelets form aggregates (platelet thrombi) and

interact with the fibrin network to produce a blood clot (a coagulum) that effectively plugs

the severed vessels and stops the bleeding. The blood clot acts as a physical matrix that

directs cellular movements and contains substances that are of importance for the

continuation of the healing process. Thus, the clot contains substances that (1) influence

mesenchymal cells (i.e. growth factors), and (2) affect inflammatory cells. These substances

will induce and amplify the migration of various types of cells, as well as their proliferation,

differentiation and synthetic activity within the coagulum. Although the blood clot is crucial

in the initial phase of wound healing, its removal is mandatory to enable the formation of new

tissue. Thus, within a few days after the tooth extraction, the blood clot will start to break

down, i.e. "fibrinolysis" starts.

2. Wound cleansing: Neutrophils and macrophages migrate into the wound, engulf bacteria

and damaged tissue and clean the site before tissue formation starts. The neutrophils enter the

wound early while macrophages come into the scene somewhat later. The macrophages are

not only involved in the cleaning of the wound but they also release several growth factors

and cytokines that further promote the migration, proliferation and differentiation of

mesenchymal cells. Once the debris has been removed and the wound has become

"sterilized", the neutrophils undergo a programmed cell death (i.e. apoptosis) and are

removed from the site through the action of macrophages. The macrophages subsequently

withdraw from the wound. In the extraction socket, a portion of the traumatized bone facing

the wound will undergo necrosis and will be removed by osteoclastic activity. Thus,

osteoclasts also may participate in the wound cleansing phase of the bone healing.

3. Tissue formation: Mesenchymal, fibroblast-like cells which migrate into the wound from,

for example, the bone marrow, start to proliferate and deposit matrix components in an

extracellular location. In this manner a new tissue, i.e. granulation tissue, will gradually

replace the blood clot. From a didactic point of view the granulation tissue may be divided

into two portions: (1) early granulation tissue, and (2) late granulation tissue. A large number

of macrophages, a few mesenchymal cells, small amounts of collagen fibers and sprouts of

vessels make up the early granulation tissue. The late granulation tissue contains few

macrophages, but a large number of fibroblast-like cells and newly formed blood vessels

present in a connective matrix. The fibroblast-like cells continue (1) to release growth factors,

(2) to proliferate, and (3) to deposit a new extracellular matrix that guides the ingrowth of

new cells and the further differentiation of the tissue. The newly formed vessels provide the

oxygen and nutrients that are needed for the increasing number of cells in the new tissue. The

intense synthesis of matrix components exhibited by these mesenchymal cells is called

fibroplasia while the formation of new vessels is called angiogenesis. Through the combined

fibroplasia and angiogenesis a provisional connective tissue is established. The transition of

the provisional connective tissue into bone tissue occurs along the vascular structures. Thus,

osteoprogenitor cells (e.g. pericytes) migrate and gather in the vicinity of the vessel. They

differentiate into osteoblasts that produce a matrix of collagen fibers which takes on a woven

pattern. The osteoid is hereby formed and the process of mineralization is initiated in its

central portions. The osteoblasts continue to lay down osteoid and occasionally cells are

trapped in the matrix and become osteocytes. The newly formed bone is called woven bone.

The woven bone is the first type of bone to be formed and is characterized by (1) its rapid

deposition along the route of vessels, (2) the poorly organized collagen matrix, (3) the large

number of osteoblasts that are trapped in its mineralized matrix, and (4) its low load-bearing

capacity. The woven bone forms as finger-like projections along the newly formed vessels.

Trabeculae of woven bone are shaped and encircle the vessel. The trabeculae become thicker

through the deposition of further woven bone, cells (osteocyts) are entrapped and the first set

of osteons, the primary osteons are organized. The woven bone is occasionally reinforced by

the deposition of so called parallel- fibered bone that has its collagen fibers organized not in a

woven but in a concentric pattern.

4. Tissue modeling and remodeling: The initial bone formation is a fast process. Within a

few weeks, the entire extraction socket will be occupied with woven bone or as this tissue is

also called, primary bone spongiosa. The woven bone offers (1) a stable scaffold, (2) a solid

surface, (3) a source of osteoprogenitor cells, and (4) ample blood supply for cell function

and matrix mineralization. The woven bone with its primary osteons is gradually replaced by

lamellar bone and bone marrow through the processes of modeling and remodeling as

described earlier. In the remodeling process the primary osteons are replaced with secondary

osteons. The woven bone is first through osteoclastic activity resorbed to a certain level. This

level of the resorption front will establish the so-called reversal line, which is also the starting

point for the new bone formation building up a secondary osteon. Although the modeling and

remodelling may start early it will take several months until all woven bone in the extraction

socket is replaced by bone marrow and lamellar bone.

Incorporation by woven bone formation

The first bone tissue formed is woven bone. It is often considered as a primitive type of bone

tissue and characterized by a random, felt-like orientation of its collagen fibrils, numerous,

irregularly shaped osteocytes and, at the beginning, a relatively low mineral density. But it

has an outstanding capacity: it grows by forming a scaffold of rods and plates and thus is able

to spread out into the surrounding tissue at a relatively rapid rate. The formation of the

primary scaffold is coupled with the elaboration of the vascular net and results in the

formation of a primary spongiosa that can bridge gaps of less than 1 mm within a couple of

days. Woven bone is the ideal filling material for open spaces and for the construction of the

first bony bridges between the bony walls and the implant surface. Woven bone usually starts

growing from the surrounding bone towards the implant, except in narrow gaps, where it is

simultaneously deposited upon the implant surface. Woven bone formation clearly dominates

the scene within the first 4 to 6 weeks after surgery.

Adaptation of bone mass to load (deposition of parallel-fibered and lamellar

bone)

Starting in the second month, the microscopic structure of newly formed bone changes, either

towards the well-known lamellar bone, or towards an equally important but less known

modification called parallel-fibered bone. Lamellar bone is certainly the most elaborate type

of bone tissue. Packing of the collagen fibrils into parallel layers with alternating course

(comparable to plywood) gives it the highest ultimate strength. Parallel-fibered bone is an

intermediate between woven and lamellar bone: the collagen fibrils run parallel to the surface

but without a preferential orientation in that plane. This is clearly seen in polarized light:

lamellar bone is strongly birefringent (anisotropic), and parallel-fibered bone is not

(isotropic). Another important difference is found in the linear apposition rate: for human

lamellar bone, this amounts to only 1-1.5 μm/day; for parallel-fibered bone it is 3-5 times

larger. As far as the growth pattern is concerned, both types cannot form a scaffold like

woven bone, but merely grow by apposition on a preformed solid base. Considering this last

condition, three surfaces are qualified as a solid base for deposition of parallel fibered and

lamellar bone: woven bone formed in the first period of osseointegration, pre-existing or

pristine bone surface and the implant surface.

Woven bone formed in the first period of osseointegration

Deposition of more mature bone on the initially formed scaffold results in reinforcement and

often concentrates on the areas where major forces are transferred from the implant to the

surrounding original bone.

Pre-existing or pristine bone surface

This becomes obvious in sites where implants are surrounded by cancellous bone. Quite

frequently, the trabeculae become necrotic due to the temporary interruption of the blood

supply at surgery. Reinforcement by a coating with new, viable bone compensates for the loss

in bone quality (fatigue), and again may reflect the preferential strain pattern resulting from

functional load.

The implant surface

Bone deposition in this site increases the bone-impIant interface and thus enlarges the load-

transmitting surface. Extension of the bone-implant interface and reinforcement of pre-

existing and initially formed bone compartments are considered to represent an adaptation of

the bone mass to load. Dental implants are less suitable for the demonstration of this inter-

relationship than prostheses such as artificial hips, which are preferentially surrounded by

cancellous bone that responds almost predictably and rapidly to changes in magnitude and

direction of load. This justifies the inclusion of some samples taken from our studies

dedicated to orthopedic implants in this chapter that otherwise deals with the dental aspects of

osseointegration.

Adaptation of bone structure to load (bone remodeling and modeling)

Bone remodeling characterizes the last stage of 0sseointegration. It starts around the third

month and, after several weeks of increasingly high activity, slows down again, but continues

for the rest of life. In cortical, as well as in cancellous bone, remodeling occurs in discrete

units, often called a bone multicellular unit, as proposed by Frost. Remodeling starts with

osteoclastic resorption, followed by lamellar bone deposition. Resorption and formation are

coupled in space and time. In cortical bone, a bone multicellular unit consists of a squad of

osteoclasts (cutting cone) that form a sort of drill-head and produce a cylindrical resorption

canal with a diameter equal to an osteon, that is, 150-200 μm. The cutting cone advances with

a speed of about 50 pm per day, and is followed by a vascular loop, accompanied by

perivascular osteoprogenitor cells. About 100 μm behind the osteoclasts, the first osteoblasts

line up upon the wall of the resorption canal and begin to deposit concentric layers of

lamellar bone. After 2-4 months, the new osteon is completed. In the healthy skeleton,

resorption and formation are not only coupled, but also balanced, thus maintaining the

skeletal mass over a longer time period. If formation does not match resorption, a local deficit

in bone mass occurs that accumulates with time and may cause osteoporosis.

Histological section illustrating a bone multicellular unit (BMU). Note the presence of a

resorption front with osteoclast (OC) and a deposition front that contains osteoblasts (OB),

and osteoid (OS). Vascular structures (V) occupy the central area of the BMU. RL = reserval

line; LB = lamellar bone.

Osborn and Newesley 1980

Drawings to show the initiation of distance osteogenesis (A) and contact osteogenesis (B)

where differentiating osteogenic cells line either the old bone or implant surface

respectively. The insets show the consequences of these two distinctly different patterns

of bone formation. In the former the secretorily active osteoblasts, anchored into their

extracellular matrix by their cell processes, become trapped between the bone they are

forming and the surface of the implant. The only possible outcome is the death of these

cells. On the contrary, in contact osteogenesis, de novo bone is formed directly on the

implant surface, with the cement line in contact with the implant (insert) and is

equivalent to the osteonal interface.

Contact osteogenesis

Cells participating in contact osteogenesis

Platelets : 1st cells to migrate towards implant surface (property of

microtopography of the rough implant surface)

Further activation of platelets at a distant site leading to release of

cytokines and growth factors like PDGF and TGF-β

Activation of osteogenic cells and migration of these cells through the 3

dimensional fibrin matrix towards implant surface

Attachment/adhesion of osteogenic cells over implant surface

Change in cell polarity and secretion of collagen poor calcified osteoid

matrix : 1st formed matrix (cement line)

Osteoblasts get entrapped to form osteocytes as the new collagen rich

osteoid matrix begins to form over the implant surface