OSSEOINTEGRATION

Osseointegration definition

‘a direct structural and functional connection between ordered, living bone and the
surface of a load-bearing implant’

Bosshardt et al 2017. Osseointegration of titanium, titanium alloy and zirconia dental implants. Perio 2000
 BONE
Cellular level
osteoprogenitor cells
osteoblasts and lining cells
osteocytes
IMPLANT osteoclasts
Macroscopic structure Molecular level
Microscopic structure minerals
hormones
growth factors
cytokines
extracellular matrix proteins
Implant surface characteristics influence cellular responses such as cell adhesion,
proliferation, differentiation and migration, thus affecting osseointegration

Feller L et al 2015. Cellular responses evoked by different surface characteristics. Biomed Res Int
OSSEOINTEGRATION
Series of events leading to osseointegration
Phase 1: hemostasis
Phase 2: inflammatory phase
Phase 3: proliferative
Phase 4: remodelling

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Series of events leading to osseointegration- duration
Phase 1: hemostasis (minutes to hours)
Phase 2: inflammatory phase (after 10 minutes to a few days)
Phase 3: proliferative (few days to a few weeks)
Phase 4: remodelling (few days to a few years)

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Series of events leading to osseointegration- initiating and concluding events
Phase 1: hemostasis (from trauma to the degranulation of platelets)
Phase 2: inflammatory phase (from degranulation of platelets to attachment of
fibroblasts)
Phase 3: proliferative (from attachment of fibroblasts to formation of woven bone)
Phase 4: remodelling (removal of woven bone and formation of lamellar bone)

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

MECHANISM OF OSSEOINTEGRATION
Blood clot (between fixture & bone)

Clot transformed by phagocytic cell

(1st to 3rd day)

Procallus formation
(containing fibroblasts &
phagocytes)
Procallus becomes dense connective tissue
(Differentiation of osteoblasts & fibroblasts)

Callus (Osteoblasts on the fixture)

Fibro cartilagenous callus (between fixture & bone)

Bone callus (Penetrates & matures)

16
Prosthesis attached to the fixtures stimulating bone remodeling
Phase 1- hemostasis
• trauma to bone
• growth and differentiation factors are unmasked and liberated from their heparin
binding domains by heparin hydrolases from blood platelets
• platelets release
• platelet derived growth factor (PDGF)
• transforming growth factor (TGF) β1 and β2
• insulin like growth factor (IGF)
• vascular endothelial growth factor (VEGF)
• basic fibroblast growth factor (bFGF)
• coagulative and vasoactive agents

• platelets initiate polymerization of fibrinogen to form an extracellular matrix by

thrombin (extrinsic system) and the intrinsic clotting cascade (Hageman Factor)
• platelets aggregate and form a white thrombus closing the vascular leak.

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Phase 1- hemostasis
• implant surface interacts with water molecules and ions- this can change the
charge pattern of the surface
• this is followed by plasma proteins present at high concentrations like albumin,
globulins or fibrin
• these will slowly be replaced by proteins with a lower concentration, but a higher
affinity for the surface such as vitronectin or fibronectin

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Phase 1- hemostasis
• platelets bind to vitronectin. This activates platelets, converting the major platelet
integrin αVβ₃ from a resting state to an active conformation.
• platelets also bind to collagen with glycoprotein receptors
• surface bound fibrin on the metal surface of the implant can bind platelets over
the glycoprotein receptor to the titanium implant surface.
• this binding results in activation and degranulation of the platelets
• the release of cytokines from degranulating platelets is the beginning of the
inflammatory phase.

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Cell to cell communication- Osseointegration. Quintessence Publishing
Phase 2: Inflammatory phase
• degranulated platelets release
• TGF-β
• PDGF
• bFGF
• bradykinin (increases the vascular permeability)
• histamine (increases blood flow, decreases the blood stream velocity and
induces hyperaemia).
• innate host defence systems are activated
• molecular (e.g. complement system)
• cellular elements (PML/ PMN and macrophages)

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Phase 2: Inflammatory phase- PML
• diapedesis is initiated by loose adhesion of lectins in the inner lining of blood
vessels.
• mediated by adhesion of L-selectin on the leucocyte with E-selectin on the
endothelial side
• later stronger adhesion molecules such as intercellular adhesion molecule-1
(ICAM-1), ICAM-2 and the vascular cell adhesion molecule-1 (VCAM-1) catch the
leukocyte out of the blood stream, binding to integrins on the leucocyte
• PMN produce elastase and collagenase which helps them in digesting the basal
lamina of the blood vessel and pass beyond the basal lamina.
• endothelial cells open a small gap, and the leukocyte migrates in amoeboid
fashion through the gap.
• PMLs kill bacteria through reactive radicals (oxygen species and hydroxygroups,
chlorine radicals and hypochlorites) which are also toxic for the host cells and the
healthy tissue surrounding the wound.

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Concept of foreign body equilibrium

• first published by a German pathologist Karl Donath in 1992

• although neutrophils are recruited on the basis of a pure wound healing
phenomena, macrophages are only recruited if a biomaterial is present
• macrophages are found frequently on the surface of titanium oral implants and
justify the concept of osseointegration being a foreign body reaction, because oral
implants are in themselves foreign bodies.

Trindade et al 2015. Current Concepts for the Biological Basis of Dental Implants. Oral Maxillofac Surg Clin North Am
Concept of foreign body equilibrium

a) osseointegration is the result of a foreign body reaction that, with the right
intensity in the inflammatory response, will balance itself out and allow for bone
to grow on the implant surface
b) similar to soft tissue implants, which end up encapsulated in poorly enervated
and vascularized fibrous tissue, dental implants also become surrounded by
condensed bone that is very poor in vascularization and enervation, the typical
result of a foreign body reaction that has reached equilibrium
c) the ongrown bone may be seen as a manner of shielding off the foreign entity
from the tissues, that is, as a protective mechanism.

Albrektsson et al 2014. Is marginal bone loss around oral implants the result of a provoked foreign body reaction?
Phase 2: Inflammatory phase- macrophages

• PML are relatively short-lived and are replaced by lymphocytes and macrophages.
• macrophages remove tissue debris
• macrophages also secrete TIMPs (tissue inhibitors of metalloproteinases) which
antagonize the digesting enzymes of PMN and therefore protect the extracellular
matrix proteins like proteoglycans. These in turn can protect growth factors which
are stored in the extracellular matrix.
• macrophages secrete angiogenic and fibrogenic growth factors.
• high concentration of fibronectin allows attachment of fibroblasts
• cells can hereupon crawl into the wound
• this is the beginning of the proliferative phase

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Cell to cell communication- Osseointegration. Quintessence Publishing
Phase 3: Proliferative phase- the formation of new ECM, angiogenesis and woven bone

FORMATION OF NEW ECM

• this newly formed tissue is called granulation tissue.
• macrophages release FGF which leads to migration of fibroblasts from the
surrounding healthy tissue into the blood clot.
• metalloproteinases degrade the blood derived fibrin in the clot und uncover
integrin binding sites in the fragments.
• to replace the degraded provisional clot matrix, they produce insoluble cellular
fibronectin and other insoluble proteins of the extracellular matrix like collagens,
vitronectin, decorin and other proteoglycans.

Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.

Phase 3- focal adhesion

Feller et al 2015. Cellular Responses Evoked by Different Surface Characteristics of Intraosseous Titanium Implants.
Phase 3: Proliferative phase- the formation of new ECM, angiogenesis

ANGIOGENESIS
• in parallel, angiogenesis is stimulated by hypoxia.
• hypoxia attracts macrophages, which are able to survive under hypoxic conditions
by adjusting their metabolism to an oxygen independent generation of ATP. In
macrophages, vascular endothelial growth factor (VEGF) expression is stimulated
by an intracellular transcription factor called hypoxia inducible factor (HIF-1).
• In response to VEGF, pericytes detach from the outer walls of the vessel. These
cells use matrix metalloproteinases to digest the basal lamina around the vessels.
• The pericytes give rise to the new endothelial progenitor cells, which migrate to
the place of low oxygen tension where they are chemotactically attracted by the
chemokine stromal cell derived factor (SDF-1) which is produced by cells in the
wound. This process is called homing of endothelial cells.
• The cells proliferate to form condensed groups and they arrange themselves to
form tubes and these tubes are connected to an existing blood vessel.
• A new vascular loop is created and blood can flow through.
Terheyden et al 2012. Osseointegration – communication of cells. Clin Oral Impl Res.
Phase 3: Proliferative phase
FORMATION OF WOVEN BONE
• new bone formation begins with the secretion of a collagen matrix by osteoblasts
• depending on the process of ossification (endochondral or intramembraneous),
this can be collagen type II or type III, which is ultimately replaced by collagen
type I.
• bone formation within the alveolar process is a process of intramembranous
ossification, starting by the secretion of collagen type III.
• this matrix is subsequently mineralized by hydroxyapatite.
• then nanometer-sized, uniaxially oriented hydroxyapatite crystal plates are
formed within the collagen fibres.
• removal of the woven bone by osteoclasts is the beginning of remodelling and
thus the fourth and last phase.

Bosshardt et al 2017. Osseointegration of titanium, titanium alloy and zirconia dental implants. Perio 2000
Cell to cell communication- Osseointegration. Quintessence Publishing
Phase 4: remodelling phase
• osteoclasts appear in the wound after a few days.
• primary bone implant contacts are removed.
• lamellar bone formed after remodelling
• in contrast to woven bone which is oriented in the
grooves of the
parallel to the titanium
threads, surface
lamellar bone attaches rather to the tips of the
macrothreads.

Bosshardt et al 2017. Osseointegration of titanium, titanium alloy and zirconia dental implants. Perio 2000