Received: 16 April 2018 Accepted: 14 May 2018

DOI: 10.1111/cid.12711

REVIEW

On inflammation-immunological balance theory—A critical

apprehension of disease concepts around implants: Mucositis
and marginal bone loss may represent normal conditions and
not necessarily a state of disease
Tomas Albrektsson MD, PhD, RCPSG1,2 | Torsten Jemt DDS, PhD3,4 |
Johan Mölne MD, PhD5 | Pentti Tengvall PhD1 | Ann Wennerberg DDS, PhD4

1
Department of Biomaterials, Institute of
Clinical Sciences, Sahlgrenska Academy,
University of Gothenburg, Gothenburg,
Sweden
2
Department of Prosthodontics, University of
Malmö, Scania, Sweden
3
The Brånemark Clinic, Public Dental Health
Service, Gothenburg, Sweden
4
Department of Prosthodontics, Institute of
Odontology, Sahlgrenska Academy, University
of Gothenburg, Gothenburg, Sweden
5
Department of Pathology and Genetics,
Institute of Biomedicine, Sahlgrenska
Academy, University of Gothenburg,
Gothenburg, Sweden
Correspondence
Tomas Albrektsson, Department of
Biomaterials, Institute of Clinical Sciences,
Sahlgrenska Academy, University of
Gothenburg, Box 412, 405 30 Gothenburg,
Sweden.
Email: tomas.albrektsson@biomaterials.gu.se
Funding information
VR, Grant/Award Number: 2015-02971; VR
Swedish Research Council, Grant/Award
Number: E0370001
Abstract
Background: Oral implants have displayed clinical survival results at the 95%-99% level for over
10 years of follow up. Nevertheless, some clinical researchers see implant disease as a most
common phenomenon. Oral implants are regarded to display disease in the form of mucositis or
peri-implantitis. One purpose of the present article is to investigate whether a state of disease is
necessarily occurring when implants display soft tissue inflammation or partially lose their bony
attachment. Another purpose of this article is to analyze the mode of defense for implants that
are placed in a bacteria rich environment and to analyze when an obtained steady state between
tissue and the foreign materials is disturbed.
Materials and Methods: The present article is authored as a narrative review contribution.
Results: Evidence is presented that further documents the fact that implants are but foreign bodies
that elicit a foreign body response when placed in bone tissue. The foreign body response is charac-
terized by a bony demarcation of implants in combination with a chronic inflammation in soft tissues.
Oral implants survive in the bacteria-rich environments where they are placed due to a dual defense
system in form of chronic inflammation coupled to immunological cellular actions. Clear evidence is
presented that questions the automatic diagnostics of an oral implant disease based on the finding of
so called mucositis that in many instances represents but a normal tissue response to foreign body
implants instead of disease. Furthermore, neither is marginal bone loss around implants necessarily
indicative of a disease; the challenge to the implant represented by bone resorption may be success-
fully counteracted by local defense mechanisms and a new tissue-implant steady state may evolve.
Similar reactions including chronic inflammation occur in the interface of orthopedic implants that
display similarly good long-term results as do oral implants, if mainly evaluated based on revision sur-
gery in orthopedic cases. The most common mode of failure of orthopedic implants is aseptic loosen-
ing which has been found coupled to a reactivation of the inflammatory- immune system.
Conclusions: Implants survive in the body due to balanced defense reactions in form of chronic
inflammation and activation of the innate immune system. Ten year results of oral and hip /knee
implants are hence in the 90+ percentage region. Clinical problems may occur with bone resorption
that in most cases is successfully counterbalanced by the defense/healing systems. However, in
certain instances implant failure will ensue characterized by bacterial attacks and/or by reactivation
of the immune system that now will act to remove the foreign bodies from the tissues.

KEYWORDS

crestal bone loss, defense against disease, foreign body reaction, immunologic reaction,
inflammation, osseointegration, peri-implantitis

Clin Implant Dent Relat Res. 2018;1–7. wileyonlinelibrary.com/journal/cid © 2018 Wiley Periodicals, Inc. 1
2 ALBREKTSSON ET AL.

1 | I N T RO D UC T I O N

The pioneering researcher behind foreign body reactions to medical

implants was Donath1,2 who identified principally four different reac-
tions to foreign materials; rejection, dissolution, resorption, or demar-
cation. Donath1 was further adamant in his conviction that implants
placed in soft tissues were demarcated by a soft tissue capsule,
whereas biocompatible foreign materials placed in bone tissues were
generally demarcated by bone, the latter reaction providing sufficient
stability of the implant. In one of his papers, Donath presented a fig-
ure of shrapnel in situ in the frontal bone of a human over 45 years
that indeed was “osseointegrated.”1 This important observation by
Donath seems to have been missed in many later publications where
the “concerted action of immune cells “mainly result in isolation from
the host by fibrotic encapsulation”.3 However, the notion of bone
demarcation is one easily understood from a cellular viewpoint. Differ-
entiated connective tissue cells of the body such as the fat cell, the
chondrocyte, the fibroblast, and the osteoblast all originate from a
common mother cell; the mesenchymal stem cell. Hence, it is not
strange that implants in a soft tissue environment become soft tissue
demarcated by a fibrous capsule and that implants in a hard tissue
environment commonly become embedded in bone (Figure 1). Con-
nective tissue proper is not very different from bone tissue from a FIGURE 1 Mesenchymal stem cells may, depending on the precise
developmental perspective. Based originally on Donath´s observa- stimuli, develop into different types of mature cells. As pointed out by
tions, bone embedment of a foreign body has resulted in the following Donath and colleagues,2 from a cellular point of view there is little
new definition “Osseointegration is a foreign body reaction where difference between soft tissue embedment of foreign bodies by
fibroblasts (connective tissue proper cells) and bone embedment of
interfacial bone is formed as a defense reaction to shield off the
foreign bodies by osteoblasts (other connective tissue cells)
implant from the tissues.”4
Another central observation by Donath1 is that foreign bodies display infection rates from 1% in primary replacements to 5% in revi-
provoke a chronic inflammation of the foreign body type. Recent sion surgery.11 BAI is difficult to treat with antibiotics as bacteria may
research points to that c.p. titanium presents a clear but not very be protected by their biofilm mode of growth or may not effectively
strong immune response, but that materials such as copper and PEEK be targeted by a compromised host immune system at the site of the
indeed display a quite strong immune reaction in animal studies5,6 This implanted device.12 Dental implants, although placed in unsterile envi-
strong immune response may be behind the fact that copper and ronments, display a relatively low infection rate of around 1%,13 possi-
PEEK are not directly bone anchored, but instead mainly display dis- bly due to adaptation or balancing of the innate immune system to
tance osteogenesis.7 the presence of the normal bacterial flora of the oral cavity. Hence,
“A key for long-term survival and function of biomaterials is that
biofilm formation may more or less disturb the implant protection for
they do not elicit a detrimental immune response.”8 One may look at
host immune responses and antimicrobial agents.14 Oral implants are
the successful implantation as being in a delicate positive immune bal-
thus placed in a bacteria rich environment of the mouth, commonly
ance based on the individual host immune system which, however,
resulting in biofilm formation on tissue protruding elements such as
may be disturbed by external impact factors that may lead to second-
abutments. However, bacteria may, after a healing period, be absent
ary implant problems and, possibly, implant failure due to strong
in the bone anchored part of the implant and, provided a proper bac-
immune and inflammatory reactivation.9
terial seal is established, in the soft tissue penetrating part of the
implant too. This generalized description of the inflammatory-immune
(I-I) balance is of course to be modulated by factors such as implant
2 | MATERIALS AND METHODS
design, material chemistry, mechanical stress, implant location, and
surgery. For instance, experimental studies have indicated that the
2.1 | On biofilm formation and the foreign body
surface of anodized titanium is capable of inhibiting or minimizing bio-
reaction film formation compared to surfaces of nonanodized titanium.14–16
Macromolecular and bacterial adhesion and the subsequent biofilm In the early inflammatory and healing phase (up to hours), both
formation in the anchorage part of an implant is suggested to be one the coagulation cascade and complement system interact closely on
of the main causes for their failure.10 The incidences of so defined or adjacent to the biomaterial surface and modulate each other's
Biomaterial-Associated Infections (BAI) depend on the application activities, thereby affecting inflammation and cell recruitment and
considered, where for example, total hip and knee arthroplasties binding onto surfaces.17 We further know from the biomaterials
ALBREKTSSON ET AL.
literature that virtually all types of solid macroscopic foreign bodies
elicit a foreign body response upon prolonged implantation times cov-
ering days up to weeks.18,19 Similar behaviors are observed within
soft- as well as hard tissues, and probably regardless of body loca-
tion.20 However, spherical nonself materials larger than 1.5 mm may
induce a milder response than smaller bodies21 and the physico/
chemical properties and implant surface properties of the material
modulate the degree of the FBR. It is further known as long from ani-
mal experiments that many types of foreign bodies (biomaterials)
induce a chronic inflammation after the acute inflammatory period21
and a cell-mediated immune reaction called delayed type 4 hypersensi-
tivity response8 may occur. A prolonged inflammation is characterized
in soft tissues by infiltration to the implant vicinity of low numbers of
T-cells, monocytes/macrophages, and large numbers of fibroblasts
which later are transformed into myofibroblasts. Macrophages during
a chronic inflammation play dual roles as inflammatory mediators and
wound healing regulators of the foreign body reaction.21 Soft tissue
myofibroblasts secrete enhanced amounts of collagen which dominate
the composition within the subsequent implant induration (fibrous
encapsulation).8 The mature fibrous capsule displays low vasculariza-
tion, low innervation, and low cell numbers close to the foreign
body.22 Thus, the innate immune system has effectively shielded it off
from the rest of the host tissue.21
In bone, much less is understood about FBR and type 4 hypersen-
sitivity.23 This may be due to the different cell and physical appear-
ances during the wound healing period, when compared to soft
tissues where the elimination of worn-out self-material and nonself,
according to Donath,1 “is rejection, solution, resorption or fibrous
encapsulation.” In bone, the exclusion process is instead “by demarca-
tion (if immobility), fibrous encapsulation (if mobility), or even by inter-
position of fat, as well as by resorption.”2 The important issue raised
here is; Is osseointegration of titanium in reality a physiological
immune driven demarcation towards the surrounding cancellous
and/or cortical bone? Recent progress in bone biology suggests this
to be the case.24–26 For instance, the innate/adaptive immune system
is closely connected to regulation of osteoclastogenesis via T-cell
secretion of the osteoclast activator RANKL, and counterbalanced by
T-cell secretion of interferon-Gamma.27 Furthermore, the most often
observed inflammatory markers IL-1 and Nfκb in animal experiments
are both connected to innate/adaptive immunity. 27
This and similar
information lead us to hypothesize that osseointegration is nothing
but an immune driven and balanced result of a matured foreign body
reaction.28
In a recent qPCR and histological comparison of bone heal-
ing between sham- and titanium-implant sites in rabbit tibiae, it was
observed that many immune and inflammation related RNA markers
adjacent to titanium were in comparison up or down regulated, and
bone resorption by osteoclasts was markedly down regulated at
5
1-4 weeks of observation. Presently, experiments are underway to
find out whether the immune and foreign body recognition persist
also after a longer time, or is down regulated at nondisturbed sites.
Eventually, the immune system close to a biomaterial is “silenced”
after a longer period of time, and the Foreign Body Reaction is possi-
bly an attempt by the host tissues to isolate the foreign body but
without overloading of the local immune reaction, that otherwise per-
petuates the inflammatory process. One indication is the suppression
3
of macrophage killing capacity observed in implant-close soft tissues,
where macrophages were capable of engulfing bacteria in vivo, but
were unable to kill the bacteria.12 The hypothesis now is that all solid
medical implants first are isolated via an immune driven chronic inflam-
mation and then eventually finds a relatively silent I-I (Inflammatory-
Immunological) steady state. This balance may be disrupted by new
generated microparticles (enhanced and new surfaces), mechanical
stress, material properties, and dissolution. This balance, or disruption
and re-establishment of it, may last throughout the lifetime of the
implant, often for decades, and regardless of bodily location (except a
few immune privileged locations such as the eye). In summary, solid
medical implants are at all times recognized as nonself by host tissues.
As the host seldom can expel them, it isolates them via fibrous encapsu-
lation or via a bone demarcation, sometimes progressing in the cancel-
lous bone of the marrow. Tentatively, this protective reaction possibility
persists as long as the implant remains in the tissue.
2.1.1 | Implications for oral implants
According to the literature,29,30 oral peri-implant diseases may present
as mucositis and peri-implantitis, both ailments caused by bacteria.29
Mucositis is a disease of the soft tissues characterized by bleeding on
probing and finding probing depths of 4 mm or more.30 Mucositis has
been reported to occur in 48% of implants and up to 80% in
subjects,29,30 however possibly with an underreported prevalence.30
Peri-implantitis is seen as a similar disease, but additionally character-
ized by loss of marginal bone around the implant. The prevalence of
peri-implantitis varies considerably in different reports depending on
the precise definition of the disease, where no fewer than eight differ-
ent definitions were reported by Rosen and colleagues.30 In recent
European papers, any bone loss has been regarded as indicative of dis-
ease31 which results in very high figures of implant problems. It seems
like these viewpoints on peri-implant disease originally were inspired
by findings from natural teeth and periodontitis where we now know
that quite different messenger RNA signals are displayed32 and that
bone loss of teeth is generally not simultaneous to bone loss around
implants in the same patient.33 However, with the knowledge
described in the previous paragraph that oral implants display a life-
long chronic foreign body inflammation, one may critically debate
whether mucositis is only an actual plaque driven inflammatory dis-
ease or a normal state around oral implants. The fact that the alleged
soft tissue disease of mucositis is diagnosed by probing represents
another factor that may be criticized against the background of very
poor specificity of probing analyses around oral implants.34 Thus, it
could be suggested that the chronic inflammation observed at the
implant site may be one part of the bacterial defense, another part of
this inflammation defense being the immunological response to the
implants with macrophages or macrophage-derived cells. This combi-
nation of Inflammation/Immunology is what we term the “I-I balance
theory”, a theory which moderates the presence of a soft tissue
inflammation as only being referred to as a “disease” called mucositis.
Having said this, there may be certain human genotypes that may
respond differently than other patients rendering them more suscepti-
ble to the inflammatory response from bacterial attacks following
implant placement.35,36
4 ALBREKTSSON ET AL.

It is probably the remarkably strong defense in form of the I-I bal-

ance system that is behind the fact that oral implants display very
excellent clinical 10-year results37 with implant survival in the 95%-
99% range coupled to only 1%-2% of placed implants being threat-
ened by aggressive bone resorption.9,38,39

2.1.2 | Viewpoints of orthopedics

Orthopedic implants such as hip or knee arthroplasties have not been
proven to present osseointegration, at least not in the original meaning of
the term.40 Instead, the interface around joint replacements is preliminary
dominated by soft tissues, but there are clear signs of distance osteogen-
esis. We do not know for certain why orthopedic implants commonly dis-
play mainly distance osteogenesis, but it may relate to a combination of
FIGURE 2 Average bone resorption over time associated with
preferred materials, the very blunt surgery performed and the early load-
different restorative dentists. Despite the initial restorative dentists
ing in comparison to the situation with oral implants. We know that
involved in the study all used the same implant type placed in similar
orthopedic implants commonly display some micro movements in the ini- totally edentulous patients, the bone resorption pattern differed for
tial phase after implantation, but that they later display secondary stabili- different restorative dentists. This reaction with bone loss over time
zation.41,42 Nevertheless, the distance osteogenesis may be another may depend on complications to treatment rather than being
example of a bony demarcation of the implant and, with the new defini- indicative of any disease. Modified from Ross Bryant49

tion of osseointegration based on shielding off of a foreign material, a provocations such as the host reaction to single ligatures (own data on
similar situation may apply for oral as well as orthopedic implants. For file) or excessive cement residues in the soft tissue close to oral implants
example, the chronic inflammation surrounding orthopedic implants is after cementation may give rise to marginal bone loss despite absence of
regarded to depend on implant debris that stimulates the innate immune any bacterial actions whatsoever (Figure 3).9 Problems with such addi-
43
system in form of macrophages that may cause localized bone resorp- tional foreign bodies combined with the other foreign body the implant
tion. The general clinical outcome of hip or knee replacements is very itself may be easily remedied by removing the ligature or the cement, at
positive and similar to the situation for oral implants, however for ortho- least if done in time. Further bone resorption may now automatically
pedic implants mainly based on revision statistics. With time, orthopedic cease. However, using other foreign body materials such as heterologous
implants may display some bone loss called “aseptic loosening” and is the bone grafts in compromised implant sites may cause increased risk for
most common reason for secondary implant failure, which is related to not only early but also late implant complications.36,50 There are numer-
wear products from the hip implant with activation of the innate and ous other both external impact factors as well as change in the host
adaptive immune systems.44 This orthopedic notion may be compared to response systems that may change the I-I balance leading to bone
a recent in vitro analysis of dental implants that demonstrated leaked out loss.9,51 In such situations, there may be no disease at all initially; our
45
metal ions to activate the regulation of bone resorbing mediators. The inflammatory and immunological defense mechanisms are being
aseptic loosening of a hip arthroplasty is similar to the dental implant in
that bone is gradually lost starting from the highest level of bone contact
and, if continuous, gradually will remove more and more bone along the
body of the implant. However, hip implant failure may be related to bac-
terial infections too, if in much smaller numbers compared to the aseptic
loosening. Infection at placement of an orthopedic implant is more com-
monly seen than infection at the time of placement of a dental implant,
probably due to a much greater surgical trauma for hip implants and, pos-
sibly, differently organized tissues and functions.

2.1.3 | Is there at all a disease around implants?

At a rapid glance, the definition of disease would be a simple proce-
dure relating to disorder of function that is not resulting from physical
injury. However, in reality, we lack a properly recognized definition
totally free from commercial influence and, furthermore, several “diag-
noses” such as osteoporosis, homosexuality and others have at one
time been termed disease, if at other times not.46,47 FIGURE 3 Cemented constructions commonly display excess cement
in the soft tissues. This may result in loss of marginal bone around
Having said this, there is very clear evidence that disease may not
implants due to one foreign body on another foreign body, a problem
always be behind implant marginal bone loss that instead may be related
easily remedied by rapid removal of the cement foreign body. This
to complications to treatment, involving implant-, patient-, and clinician- type of bone loss, even if occurring after the implants first year in situ,
related phenomena48 (Figure 2). Thus, it is known that certain implant is most unlikely to be associated with any form of disease
ALBREKTSSON ET AL. 5

TABLE 1 Distribution of numbers of jaws diagnosed with peri-implantitis and jaws with recorded “affected” implant failures (percentage of total
numbers within brackets) with regard to treatment during follow up52,53
Jaws Affected implants Bone loss
Treatment during follow up Treated Lost implants Total Lost implants Mean (SD)
Surgically treated 24 4 (16.7%) 64 5 (7.8%) 0.74 (1.00)
Only hygienist 50 4 (8.0%) 86 3 (3.5%) 0.39 (0.75)
No treatment 80 3 (3.8%) 173 7 (4.0%) 0.11 (0.39)
Total 154 11a (7.1%) 323a 15b (4.6%) 0.30 (0.74)

Total numbers of included “affected” and lost implants as well as overall mean bone loss during follow-up period are presented as well. Results are based
on further analysis of data presented by Jemt and colleagues.52
a
Failures of “unaffected implants” were recorded in another five jaws.
b
Another nine implants were lost, diagnosed as “unaffected” (2.0% of “unaffected” implants).

FIGURE 4 The left radiograms display implants in bone steady state and in an inflammatory-immunological balance. The radiograms in the middle
displays some interfacial bone loss, but may nevertheless be in steady state as the great majority of such implants will respond positively to an
activation of the inflammatory-immunological response. The implant on the right in the third radiogram has completely lost its bony anchorage
and may display septic interfacial reactions and represents a failed case. Properly documented implant systems placed by trained individuals may
see 1%-2% of such poorly functioning implants over follow up times of 10 years or more38

challenged but without evidence of any disease, that cannot be based on methodological reasons.55,56 Thus, the I-I defense may not have lost the
52
a given number of millimeters of bone loss. Jemt and colleagues battle and the implant may come into a second steady state if with some
recalled a sample of patients allegedly hit by a millimeter defined “peri- previous bone resorption, but which not necessarily may decrease the
implant disease” on average 9 years after the initial 5-20 years of follow long-term prognosis of implant survival that has been shown to be very
up in the original report.53 It was proven that more than 90% of the positive,57 as very few implants are lost after the first year in function.50
affected implants had seen no further significance bone resorption and However, with a continued attack on the implant defense mecha-
more than 95% of the affected implants were still functioning in the jaws nisms, due to the factors mentioned above, the defense may gradually
at an average of 20 years of follow up.52 Further analysis of the data in collapse. Now bacteria may attack the bone harboring the implants
this study revealed that patients with more invasive surgical treatment of and a state of disease may indeed evolve.28 The collapse of the I-I bal-
peri-implantitis resulted in more bone loss and more implant failure than
ance may occur quite rapidly in rare cases, resulting in loss of bone
if only handled by oral hygienists, without surgery (Table 1). Patients with
and subsequent infectious attack on the implant within months, but in
no treatment showed the lowest levels of bone loss and implant failures
most cases, the procedure may take many years before it may end in
during follow up, indicating that either the most severe situations were
disease.28 It is fortunate that this unwanted series of events is quite
provided with the most active treatment, or that the treatment interven-
rare and that few implants are lost during long-term follow-up.9,38
tion per se increased the problem (Table 1). Another recent follow-up
In essence, this article has criticized unnecessary diagnostics of
study of selected patients treated with surgery due to peri-implantitis
disease, in cases when in fact no disease may be present. This ques-
reported relatively good clinical outcome54 (Berglundh and colleagues).
tionable diagnostics has resulted in hugely inflated figures of implant
However, since only 50 patients were included over a 13 year period, it
problems, figures that are very far from the clinical reality at least of
is uncertain whether these results of a relatively small subgroup really
documented implant systems.4,37
differ from the results reported by Jemt and colleagues52 as seen in
Table 1. Taken together, it is indeed probable that so called peri-
implantitis with the severity of the alleged disease being regarded relat-
ing to the precise millimeter amount of marginal bone loss can be 3 | CONC LU SIONS
seriously challenged49(Figure 4). Reports are available that show difficul-
ties to predict further bone loss based on previous measurements and 1. Oral implants represent foreign bodies and osseointegration is but
that even an opposite trend may be observed, much related to a foreign body reaction
6 ALBREKTSSON ET AL.
2. Oral and orthopedic implants are characterized by a state of
chronic inflammation
3. Oral implants are placed in bacteria-rich environments and survive
this challenge due to innate inflammatory defenses and immuno-
logically derived cellular actions resulting in high clinical 10 year
survival rates.
4. The chronic inflammation observed around oral implants leads to
the conclusion that mucositis need not automatically be coupled
to disease
5. Marginal bone loss after the implants first year in situ need not be
automatically coupled to disease
6. Orthopedic implants have similarly good 10 year outcome as oral
implants.
7. Orthopedic implants fail most commonly due to aseptic loosening,
a gradual bone loss starting in the top anchorage portion of the
implant and continuing along the implant body. Aseptic loosening
seems to be caused by innate and adaptive immunological reac-
tions resulting in final rejection of the implant
CONF LICT OF IN TE RE ST
Author Albrektsson, Jemt, and Wennerberg have lectured in associa-
tion with different implant companies.
ORCID
Tomas Albrektsson https://orcid.org/0000-0001-5719-0157
Ann Wennerberg https://orcid.org/0000-0003-2957-1133
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How to cite this article: Albrektsson T, Jemt T, Mölne J,
Tengvall P, Wennerberg A. On inflammation-immunological
balance theory—A critical apprehension of disease concepts
around implants: Mucositis and marginal bone loss may repre-
sent normal conditions and not necessarily a state of disease.
Clin Implant Dent Relat Res. 2018;1–7. https://doi.org/10.
1111/cid.12711