Osteointegration of Implants and Risk Factors of Disorders (Literature review)
Stanislav Bondarenko1*, Ahmed Amine Badnaoui1 and Yuriy Prudnikov2
1Department of Joint Pathology, Sytenko Institute of Spine and Joint Pathology, Ukraine
2Research Institute of Traumatology and Orthopedics, Science Research Institute of Traumatology and Orthopaedics, Ukraine
Submission: January 30, 2018; Published: February 26, 2018
*Corresponding author: Stanislav Bondarenko, Deptartment of Joint Pathology Sytenko Institute of Spine and Joint Pathology, National Ukrainian
Academy of Medical Sciences, Pushkinska, 61024, Kharkiv, Ukraine, Email: email@example.com
How to cite this article: Stanislav Bondarenko, Ahmed Amine Badnaoui, Yuriy Prudnikov. Osteointegration of Implants and Risk Factors of
Disorders(Literature review). Anatomy Physiol Biochem Int J: 2018; 4(3): 555638. DOI: 10.19080/APBIJ.2018.04.555638.
Biological fixation of the hip joint endoprosthesis today plays an important role in cementless total hip arthroplasty. The duration of stable fixation of endoprosthesis components largely depends on the osseointegration of bone tissue into the implant.
Objective: To determine the features of osseointegration around the implant and to identify the risk factors which affect this process.
Methods: More than 40 works from electronic databases PubMed, Medline, as well as abstracts, articles and other sources of scientific and medical information were analyzed.
Results:Mechanisms and stages of osseointegration, factors affecting peri-implantation osteogenesis and osseointegration at arthroplasty. Osteointegration goes through the following stages: inflammation, migration and differentiation of osteogenic cells, formation of bone tissue, in which the surface of the implant is surrounded by an osteoid and a mineralized matrix; bone tissue remodeling. Factors affecting peri-implantation osteogenesis and osseointegration in arthroplasty are also outlined. The following risk factors negatively influencing the process of osseointegration are highlighted: decrease in the amount or activity of osteoblasts, increase in the density of osteoclasts, imbalance between local and systemic factors affecting the formation and remodeling of the bone, violation of vascularization as a key factor affecting the differentiation of osteogenic cells.
Conclusion: The implant surface plays a great importance in the process of osseointegration: its composition, technological characteristics, hydrophilicity or hydrophobicity in the biological environment, tropicity to cells and possibility to perform the expression of the products of genes forming a macromolecular environment between the implant and the bone, followed by mineralization and characteristic structure.
Among various states that need total hip arthroplasty, about 90% of cases are osteoarthrosis, and others are: avascular necrosis of the femoral head, femoral neck fracture or traumatic joint injury, inflammatory arthropathy . Year after year, implants are inhanced, among other means, with the use of new biomaterials. In general, biomaterials are widely applied in orthopedics and traumatology. These are frames and carbon materials, bioactive glass, natural and synthetic polymers and composites developed on their basis [2-5]. Among biomaterials, we can mention metal materials and their alloys, titanium with different coatings, of which implants and devices for intramedullary and external fixation are made.
Setting implants in the bone tissue contributes to creation of a new condition, the interaction of the living tissue with non-alive material. Thereby osteointegration plays an important role, which is described by PI Brönemark , who
was investigating blood circulation in the bones of rabbits, in which titanium implant was set. Concluding the experiment, he noted that the implants are tightly connected with the bone. The author called this discovery “osteointegration”, that is the formation of direct connection between implant and bone tissue without interposition of soft tissues. The first observations of osteointegration of titanium implant allowed for the conception of several levels - clinical, anatomical, histological and ultrastructural [7,8]. Osteointegration and its components were described in more detail by T Albrektsson & C Johansson , modern specialists studying this process under conditions of implantation of different biomaterials, who explore and expand the conception of its mechanisms .
Review is to determine the features of osteointegration with the implant and to identify risk factors that affect this process.Mechanisms of osteointegration are based on such phenomena
as osteoconduction or osteoinduction, i.e. constituents of
successful implant interaction with surrounding tissues.
Osteoconduction is the attachment of cells that migrate from
the blood clot, bone marrow, endosteum and periosteum to the
implant surface with the subsequent differentiation of cambial
cells into osteogenic ones, their biosynthesis of macromolecular
matrix, its calcification and bone formation . Basing on
the process that takes place at an early stage, depending on
migration, cell adhesion, their proliferation and differentiation,
it is possible to predict the success of osseointegration.
The core of osteogenic induction is to stimulate lowdifferentiated
mesenchymal cells to differentiate into
osteoblasts. Osteoinduction can be primary or secondary, i.e
either the implanted material has inductive properties, or the
induction is likely due to the absorption of biologically active
substances from the interstitial fluid on the modified surface of
the implant, followed by stimulation of adhesion, proliferation
and differentiation of osteoblast precursor cells. Osteoinductors
include transplants from bone tissue, demineralized bone
tissues, implants saturated with biologically active substances
(growth factors, etc.)
On the border “implant - bone” there occur processes typical
to reparative osteogenesis in the following stages: inflammation,
proliferation and cell differentiation, formation of bone tissue
de novo where new, remodeling [10-12]. There emerges contact
and distance osteogenesis, processes that were first described
in 1980 on the basis of studies of osseointegration of titanium
implant . In conditions of contact osteogenesis, new bone
tissue is formed in the direction from the surface of the implant
to the injured bone. The minimum distance between the bone
and the implant is up to 1mm, the space between them is
filled with a blood clot, from which erythrocytes, platelets and
inflammation cells (polymorphic granulocytes and monocytes)
migrate to the surface of the implant.
Precursors of osteogenic cells on the surface of the implant
increase cytokines and growth factors, contribute to the further
differentiation of cells. On the implant surface all conditions
necessary for the adhesion of osteogenic cells are created
for their differentiation into osteoblasts with the expression
of macromolecular matrix, for the formation of osteoid and
reticles of bone trabeculae, between which blood vessels and
osteoblast cells-predecessors are located [14,10]. The newly
formed bone is connected to the matrix. Distance osteogenesis is
the formation of bone tissue in the direction from the surface of
the injured matrix bone to the implant; osteogenic cells migrate
on the bone surface from the bone marrow and blood clot and
form new bone tissue that grows into the surface of the implant.
Biological mechanisms are identical with contact osteogenesis.
The final result of both osteogenesis types is similar: the implant
is surrounded by the newly formed bone tissue associated with
the bone matrix .
We analyze in more detail the stage of inflammation,
which occurs in the case of contact and distance osteogenesis
and is aimed at increasing the pool of osteogenic cells. The
implantation of biomaterial in the bone is accompanied by a
cascade of disorders in the local area, namely: hemorrhage,
anoxia and apoptosis of cells . There take place thermic and
mechanical damage of the bone (bone tissue, periosteum and
endosteum) and bone marrow. In the same time this stage is
very important for further development of proliferation and
differentiation of osteogenic cells into osteoblasts. Some authors
clearly identify the stages of events in the time interval after
the implant placement . Within nanoseconds, the surface
of the implant is surrounded by a molecular layer of water, and
in the period from 30 seconds to several hours on the implant
surface fibrin and other protein components settle; the implant
is covered with a layer of matrix proteins, which first come from
the blood and interstitial fluid at the place of damage, and then
are emitted by cells, located in the implantation zone.
Cells interact with the surface of the material through the
protein layer that initiates cell migration and adhesion. In
fact, during the first day after surgery, platelets secrete on
the implant surface among fibrin fibers numerous growth
factors, namely: platelet, insulin-like factors (IGF-1, IGF-2),
fibroblast growth (FGF-α, FGF-β), bone morphogenetic proteins,
vasoactive factors - serotonin and histamine, that promote the
migration of multipotent mesenchymal cells, their proliferation
and differentiation, as well as the contact with the surface of the
established implant. However, along with common mechanisms,
the expression of chemokines and integrins differs on the
surfaces of different materials. In particular, during the first 24
hours after the implantation of titanium implants with oxide
coating to the cortical bone of rats, a significant density of cells
with high expression of chemokines, CXCR4 receptors, β1 and
β2 integrins and α-v compared to implants with mechanically
treated surfaces. Around them there is recorded rising in the
cells expression of pro-inflammatory cytokines, the necrosis
factor tumors-α and interleukin-1β .
The authors came to the conclusion that after a surgical
trauma depending on the implant surface, inflammatory
responses are modulated, cellular diferons and their adhesive
qualities are formed. The largest number of neutrophils was
detected in 24-48 hours , and according to other authors -
in the interval of 3-4 days and till the end of the first week ,
along with macrophages amount of lymphocytes (T, β-cells)
and killers (K, NK cells) grew. This process is regulated by
locally synthesized growth factors (autocrine and paracrine)
and cytokines . The differentiation of multipotent cells
into osteoblasts depends on oxygenation, supply of nutrients,
angiogenesis, and expression of regulatory factors. In the early terms after implantation, the expression of genes in cells on
the surface of titanium implants with a microshort surface (ATI)
and nanostructured (AT-II) was studied . Differences in
bone comportment are not revealed, but the authors established
significant differences in expression levels of regulatory genes.
On day 2, cells are expressed by 392 genes, and on the 4th,
by 649. Functionally the corresponding categories of genes
associated with mineralization, differentiation of osteoblasts,
bone development, and biomineralization of tissues were
increased on the surface of titanium AT-I (day 4 versus day 2),
comparing with AT-II. The number of genes that were associated
with the category of inflammation-immune response, was
higher for AT-I than AT-II. It is proved that trabecular titanium
also modulates expression genes encoding collagen proteins of
the extracellular matrix - collagen type 1α1 (COL1A1) and 3α1
(COL3A1) . However, it must be taken into account that
transcriptomic analysis of the whole genome shows complex
molecular pathways that can play an unpredictable role in
osteointegration [19, 20]. The presence of osteoblasts launches
a cascade of transformations in the cycle of osseointegration and
bone formation de novo . Formation of bone tissue de novo.
On the 16th day an osteoid and a mineralized matrix are formed
around the implant . Osteoblasts synthesize organic matrix
of bone, collagen type I, non-collagen proteins, fibronectin,
thrombospondin, osteonectin, osteopontin, bone sialic protein.
Among the latter, an important role in the mineralization of the
matrix is played by osteopontin and bone sialoproteins.
On the 28th day, mineralized bone tissue appears on
the surface of the implant, depending on its condition and
microenvironment. Peri-implant bone remodeling. The resulting
bone tissue that contacts with the implant, after being induced
to stress and mechanical strain is reconstructed, i.e. remodeled
. Signs of remodeling are the presence of osteoclasts in the
bone marrow between bone trabeculae adjacent to the implant,
osteoblasts and osteoid, blood vessels and lymphatic vessels.
Newly formed osteons are located in parallel to the implant
surface and perpendicular to its long axis. Bone remodeling
can spread up to 1 mm from the surface of the implant. It is
proved that osteointegration processes in compact and spongy
bone tissue differ in molecular profiles of gene expression .
Normally, in trabecular bone high expression of osteogenesis
markers (alkaline phosphatase and osteocalcin) and bone
resorption (Tartarate-resistant acid phosphatase and cathepsin
K) are observed, which indicates increased metabolism. In
the cortical bone, increased expression of pro-inflammatory
cytokines (necrosis factor tumors-α, interleukin-1β) and
osteocalcin [16,22] is noted.
When using titanium implants with an oxide surface in cells,
that attach to them in the area of the trabecular bone, on the
third day higher levels of expression of Interleukin-1β, and in the
cortical layer - alkaline phosphatase and osteocalcin are revealed.
That is, different bone sites show definite constitutive expression
of genes- markers of inflammation and remodeling. The authors
believe that there are biological differences between compact
and spongy bone tissue both in normal stationary state, and in
response to the introduction of biomaterials. Factors affecting
peri-implantation osteogenesis and osseointegration. Molecular
and cellular mechanisms that regulate the unique tissue reaction
leading to osseointegration are not completely revealed. The fate
of the implant in the bone depends on various factors, affecting
its osseointegration and duration [12,23,24] anatomy of the
implant – conformity in shape, cavity size, in which the material
is implanted), state of the adjacent tissues, biocompatibility
or biointeraction of the material, adequacy (compliance of the
mechanical and physic-chemical characteristics of the implant
with the properties of adjacent tissues or replaced structures),
a-traumatism (minimal damage to adjacent tissues during
insertion and functioning of the implant), functionality (the most
complete and painless reconstruction of functions of substituted
natural tissues), mechanical stability (parts and components
of the endoprosthesis can function for longer period without
corrosion, abrasive and other types of wear and tear, without
intoxication with the products of the latter, microcirculation).
Factors that violate periimplanting osteogenesis include
the decrease or activity of osteoblasts, increased density of
osteoclasts, imbalance between local and system factors,
influencing the formation and remodeling bone, violation of
vascularization as a key factor of differentiation of osteogenic
cells . For successful osteointegration the structure of
material surface is of great value, since osteoconductive qualities
are highly dependent on its physical and chemical characteristics,
relief, hydrophilicity or hydrophobicity [25-29]. The behavior
of cells on the hydrophilic surface differs significantly from
hydrophobic. On the hydrophilic surface a faster coagulation of
the blood and fibrin attachment occurs , the fiber of which
forms on the implant a matrix for further migration of cells
and their differentiation . Hydrophilic qualities of implants
promote the stimulation of an early osteoblast migration and
bone formation. Gene expression of cells is enhanced on the
hydrophilic surface of the implants . It was revealed that the
structure of the surface is important for cells adhesion. To the
rough surface of the cell the appendages attach better than to
the smooth one, which raises the indicators of contact “bone -
implant”. The porosity of the surface or material is also of great
value. Of course, the bearing effect on the part of the skeleton in
which the biomaterial is implanted is important.
In the bearing parts of the skeleton restructuring bones
activity is more agile. Factors that disrupt osteointegration
include some pharmacological products, such as cyclosporine,
methotrexate, cisplatin, warfarin and low molecular weight
heparins, non-steroidal anti-inflammatory drugs (NSAIDs),
especially high-performance COX-2 inhibitors [10,30].
Cyclosporine has anti-anabolic effect on osteoblasts and
suppresses T-lymphocytes, which play a critical role in remodeling of bone tissue, which leads to the development of
osteopenia . Negative effect on osseointegration is produced
by glucocorticoids in conditions of chronic use, which is proved
in an experiment on animals . They reduce bone formation
and increase its resorption. However, it’s expedient to conduct
randomized clinical trials to confirm the effect of glucocorticoids
on bone formation around implants in humans. The negative
effect of NSAIDs on osseointegration has been proved, its
mechanism is associated with violation of the transformation
of arachidonic acid into prostaglandin, which is needed for
bone regeneration, osteoclasts activity, bone formation and
All NSAIDs inhibit COX-2, which is involved in the
differentiation of osteoblasts. In experimental conditions,
violation was found in rats osteointegration of titanium
implants in sponge and compact bone tissue after exposure to
meloxicam and diclofenac sodium [31,33-35]. Negative impact
on osseointegration is produced by radiation therapy .
Radiation therapy has negative impact on osseointegration .
A significant role is played by the patient’s condition, because
osteoporosis, rheumatoid arthritis, kidney failure reduce
osseointegration. Smoking is also one of the negative factors
of osseointegration. Some mechanisms of osseointegration
disorders in patients with chronic alcoholism have been studied.
Alcohol affects the nervous system, the gastrointestinal tract,
the immune and cardiovascular system, the liver, acts as a risk
factor for osteoporosis, slows the bone regeneration [31,37]. In
experiments on rabbits and rats it was revealed that alcoholic
diet decreases mineral density of bone tissue and direct contact
between titanium implant and bone [38,37].
It is proved that vitamin D deficiency has negative effects
on the formation of the contact “bone-implant” . In the
model of rats after ovariectomy and a diet with a low level of
vitamin D, a failure of implant’s contact with the cortical bone
was noted. However, in case of sufficient income of vitamin
D with food a close contact of the bone with the implant was
recorded. Basing on genetic research, auxiliary mechanism to
support osseointegration in a context of vitamin D deficiency
it can be system circadian rhythms . Positive effect on the
osseointegration is observed at the use of bisphosphonates.
Their anti-resorption action contributes to the prevention of
bone loss due to the reduction of its local remodeling around
the implant . Statins which might be used either locally or
systemically, stimulate osteogenesis and increase bone density
around the implants . The positive role of melatonin is
determined by osteointegration, introduced locally (3mg) .
Osseointegration is a complex process associated with
the formation of bone tissue around the implant. It consists of
osteoconduction, osteoinduction, which can occur secondary.
Osteointegration flows according to classical scheme of
reparative osteogenesis and passes characteristic stages -
inflammation, proliferation and cell differentiation, de novo bone
formation with its subsequent remodeling. Osteointegration
was investigated at histological, cellular and molecular levels.
A new approach to this problem contains the genetic level, a
study of genes expressed in the process of osseointegration.
Human genome complex has individual properties, which can
affect the final result. Till now a number of factors of exogenous
and endogenous origin that affect osseointegration is being
studied. Among them, technical and medical ones are defined. Of
course, the surface of the implant is important: its composition,
technological, hydrophilic or hydrophobic characteristics in the
biological environment, tropism to cells and the possibility of
performing their basic function - expression of genes products
that form a macromolecular matrix between the implant and
the bone, followed by mineralization and the formation of a