Periodontology 2000, Vol.
62, 2013, 232–242
Printed in Singapore. All rights reserved
Regenerative periodontal
therapy: 30 years of lessons
learned and unlearned
C R I S T I A N O S U S I N & U L F M. E. W I K E S J Ö
This volume of Periodontology 2000 provides a un-
ique opportunity for researchers and clinicians alike
to reflect upon advances and, perhaps equally as
important, hindrances, over the last three decades in
the development of periodontology as a scientific
discipline. In this soul-searching pursuit we focus on
revisiting lessons learned that should guide us in the
quest for periodontal regeneration. We also examine
beliefs and traditions that should be unlearned in
order to enable us to continue to advance the field.
Readers interested in authoritative and systematic
reviews or specific topics related to periodontal
wound healing ⁄ regeneration are referred to recent
reports from our (44, 81, 84) and other (25, 33, 36, 72,
85) research groups.
In the late 1970s and early 1980s, the infectious
nature of periodontal diseases became established
(48, 60, 61, 77, 78). Classic clinical studies demon-
strated that cause-related therapy would not only
arrest periodontal disease progression but also pro-
vide patients with a healthy dentition that could last a
lifetime when subjected to high oral-hygiene stan-
dards (3, 46). Yet, regeneration of lost periodontal
tissues remained an elusive objective, and patients
had to live with the consequences of advanced peri-
odontal disease: a rollercoaster soft- and hard-tissue
anatomy; a barren landscape of gingival clefts and
fissures; exposed root surfaces; loss of a keratinized
attached gingiva; and alveolar valleys, ridges, craters,
ravines and caves. Then, reconstructive procedures
were mostly confined to various modifications in
surgical approach but also to the concurrent use of
autogenous bone grafts and ⁄ or cadaver-sourced or
synthetic biomaterials (14, 15, 26, 30, 70, 79). Other
attempts to modify the wound were targeted at the
232
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PERIODONTOLOGY 2000
root surface, mostly trying to convert it to become
more biocompatible in an attempt to facilitate
regeneration (65–67, 73, 90).
In perspective, periodontal regeneration remains a
challenging and complex endeavor, requiring syn-
chronous formation of all periodontal tissues via
cementogenesis, osteogenesis and formation of a
periodontal ligament, generating a similar form and
function found in the intact, native periodontal
attachment. It has consumed considerable time and
energy of generations of researchers and yielded
mixed progress, frustrating clinicians and patients
alike. As with any human endeavor, it is filled with
entrenched beliefs and passions. Table 1 provides an
overview of various approaches, including grafts, bi-
omaterials, biologics and devices, used ⁄ proposed in
support of periodontal wound healing ⁄ regeneration
over the last three decades. We herein focus on five
fundamental issues related to periodontal wound
healing ⁄ regeneration.
Is the innate regenerative potential
of the periodontium really
reduced?
Historically, once a periodontal defect had been
thoroughly debrided and the root surfaces decon-
taminated of polymicrobial biofilm, wound healing
and maturation were expected to include some
regeneration or remodeling of crestal alveolar bone,
but rarely (if ever) regeneration of the periodontal
attachment (i.e. insertion of extrinsic fiber cemen-
tum, including a perpendicularly or obliquely ori-
ented SharpeyÕs fiber attachment, into the newly

Table 1. Grafts, biomaterials, biologics and devices
used ⁄ proposed for periodontal regeneration
Grafts
Autogenous bone; fresh ⁄ frozen
Allogeneic bone; fresh ⁄ frozen (not used in dentistry)
Xenogeneic bone; fresh ⁄ frozen (not used in dentistry)
Cell constructs (experimental)
Biomaterials
Bone derivatives (processed cadaver bone)
Allogeneic bone implants
(Decalcified) freeze-dried allogeneic bone
(demineralized freeze-dried bone allograft ⁄
freeze-dried bone allograft)
Xenogeneic bone implants
Deproteinized bovine ⁄ equine
bone mineral [BioCera (OCT Inc., Cheonan,
Korea), Bio-Oss (Geistlich Pharma AG,
Wolhausen, Switzerland)]
CaCO3 coral exoskeleton (Biocoral, Inoteb,
Saint-Gonnery, France)
Bone substitutes (Ôsynthetic boneÕ)
Ceramics
Beta tricalcium phosphate
Hydroxyapatite
Ca2SO4 (plaster of Paris)
Calcium phosphate cements (Ceredex, a-BSM;
ETEX Corp., Cambridge, MA, USA)
Bioactive glass (PerioGlas, BioGran, Biogran,
Orthovita, Malvern, PA, USA)
Polymers
Methylmethacrylate (HTR; Bioplant Inc., New York,
NY, USA [hard tissue replacement] synthetic bone)
Poly-a-hydroxy acids (poly[lactic acid] and poly
[lactic-co-glycolic acid])
Biologics
Matrix factors (fibronectin, vitronectin,
thrombospondin-1 and amelogenins)
Growth factors (platelet-derived growth factor,
transforming growth factor beta, insulin-like growth
factor-1, fibroblast growth factor-2 and vascular
endothelial growth factor)
Differentiation factors (bone morphogenetic proteins-2,
-3, -4, -6, -7 (Osteogenic protein-1) and -12, and
growth ⁄ differentiation factor-5)
Peptides (thrombin peptide TP508, cell-binding P-15)
Small molecules (prostaglandin E2 receptor antagonists)
Platelet-rich plasma
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Table 1. (Continued)
Guided tissue regeneration devices
Nonresorbable (expanded polytetrafluoroethylene)
Bioresorbable (poly[lactic acid],
poly[lactic-co-glycolic acid, collagen, hyaluronan])
Combinations
formed alveolar bone). This belief has been nurtured
by several preclinical (18, 19) and clinical (49, 83)
studies, suggesting that repair, in particular the for-
mation of an epithelial attachment, a long junctional
epithelium, was the likely outcome following peri-
odontal reconstructive therapy rather than peri-
odontal regeneration.
Contradicting these observations, others had
shown contrasting outcomes when periodontally
compromised teeth were debrided and allowed to
heal submerged within the tissues (13, 14, 20). Björn
(9) created periodontal defects around the premolar
teeth in dogs, the crowns of the teeth were then re-
sected and the teeth were submerged. Histological
observations demonstrated evidence of periodontal
regeneration, including resolution of associated bony
defects. Björn et al. (10) later reported similar results
from studies in humans. These early observations
were repeated by Bowers et al. (12–14) who treated
periodontally compromised teeth by submerging
them after open flap debridement in combination or
not with a demineralized bone matrix. The histolog-
ical evaluation showed that submerged teeth exhib-
ited periodontal regeneration encompassing new
connective tissue, cementum and bone, whereas
periodontal regeneration was not observed in non-
submerged controls. These intriguing results did not
gain much attention because its application would
not be acceptable in clinical settings. However, they
highlight the fact that under certain circumstances
the periodontal tissues display a remarkable innate
potential for regeneration.
Wikesjö et al. showed, in a series of studies using
the Ôcritical-size supra-alveolar periodontal defect
modelÕ, that under optimal circumstances for wound
healing, clinically relevant periodontal regeneration is
possible (28, 64, 75, 94, 98). In comparison, less bone
formation was observed when the same conditions
were applied for alveolar ridge augmentation (17, 62,
97). Recent randomized clinical trials on the treat-
ment of intrabony defects confirm, without a doubt,
the healing potential of the periodontium when
careful surgical techniques are applied coupled with
233
Susin & Wikesjö
optimized wound healing. Trombelli et al. (88) eval-
uated a minimally invasive surgical protocol as a
stand-alone approach or in combination with mem-
branes and a hydroxyapatite biomaterial. No signifi-
cant differences were observed between experimental
groups; sites treated with a minimally invasive tech-
nique exhibited clinical attachment gain averaging
4.7 ± 2.5 mm, probing depth reduction of 5.3 ±
2.4 mm and gingival recession of 0.4 ± 1.4 mm. Sim-
ilarly, Cortellini & Tonetti (21) evaluated a minimally
invasive surgical technique, alone, and combined
with an enamel matrix derivative and a bovine bone
biomaterial. No significant differences among inter-
ventions were observed with the minimally invasive
surgery without additions, achieving substantial
clinical attachment gain of 4.1 ± 1.2 mm and radio-
graphic bone fill of 77 ± 19%. In these clinical situa-
tions, skillful management of the wound and inherent
characteristics of the defects assured optimal condi-
tions for periodontal wound healing ⁄ regeneration,
rendering added protocols unnecessary.
Actual limiting factors to the innate regenerative
potential of the periodontium are just beginning to
be understood. Dickinson et al. (23), using the Ôcriti-
cal-size supraalveolar periodontal defect modelÕ,
identified pro-regeneration (originating from the
periodontal ligament and bone marrow) and pro-
scar-forming (originating from the gingival tissues)
domains that compete to populate the wound space.
The net effect of these competing forces modulated
by local and systemic factors determines how much
of the innate regenerative potential may materialize.
In summary, preclinical and clinical studies have
shown that given the appropriate conditions for
optimal wound healing, the innate potential of the
periodontal tissues can provide meaningful peri-
odontal regeneration. However, it is probably difficult
to achieve optimal conditions for wound heal-
ing ⁄ regeneration in all clinical settings owing to
constraining factors associated with the clinical
management of the wounds, the site and specific
patient characteristics. Local and systemic factors
may affect the expression of this potential and should
be managed to avoid a compromise of the results.
Is a long junctional epithelium the
inexorable healing outcome?
One of the most pervasive beliefs in periodontology is
that, regardless of treatment, the epithelial cells of the
gingival flap will migrate apically along the instru-
mented root surface, creating a long junctional epi-
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thelium precluding periodontal regeneration. Given
the perception that epithelial cells proliferate at a
higher rate than other cell populations in the peri-
odontal wound, it would be inevitable that after just a
few days a large proportion of the periodontal wound
would be effectively ÔblockedÕ by epithelium. It was in
this context that clinical procedures and devices were
envisioned to retard or block epithelial tissues from
early access to the root surface. Alterations in flap
design and repeat gingival curettage were among
other protocols used to hinder the epithelial lining of
the periodontal pocket. Nevertheless, these proce-
dures were eventually found not to support peri-
odontal regeneration.
Following the principles of wound compartmen-
talization (51) and the findings that periodontal
regeneration may occur when cells from the peri-
odontal ligament populate the root surface (37,
57–59), Nyman et al. (59), in a landmark proof-of-
principle study, demonstrate that periodontal
regeneration could be achieved by using a Millipore
filter to prevent the epithelial cells and fibroblasts
from the gingival flap from populating the peri-
odontal wound. These initial findings spurred the
adoption of a treatment concept that was eventually
named guided tissue regeneration. Industry em-
braced the concept, and technologies were devel-
oped, including nonresorbable ⁄ resorbable and
structurally reinforced membranes, to support the
surgical protocols (27, 69).
In contrast to these postulates, a series of preclin-
ical studies by Wikesjö et al., following historical
leads (31, 47), demonstrated that the apical migration
of the gingival epithelium did not occur when the
periodontal tissues healed under optimal circum-
stances. If, however, the adhesion of the fibrin clot to
the root surface was compromised by any means, this
led to formation of the long junctional epithelium
(28, 92, 93, 95, 96). In hindsight, the studies that
showed periodontal regeneration when periodontally
compromised teeth were debrided and allowed to
heal submerged within the tissues, should be rein-
terpreted to support the contention that wound sta-
bility, and perhaps space provision, explained these
histological findings rather than interference of the
gingival epithelium (9, 12, 13, 20).
The belief that, in order to achieve periodontal
regeneration, the wound should not be populated by
cells originating from the gingival flap, led to the
use of occlusive membranes. To test the validity of
this assumption, Wikesjö et al. (94) compared
macroporous and occlusive expanded polytetra-
fluoroethylene membranes using the Ôcritical-size

Intrabony defects (54)
Maxillary class II furca on (34)
Mandibular class II furca on (34)
0 1
Clinical a achment gain (mm)
Fig. 1. Guided tissue regeneration yielded greater clinical
attachment gain than open flap debridement for the
treatment of intrabony and furcation defects. Data derived
from two meta-analysis (34, 54). Bars represent means
and error bars represent 95% confidence intervals.
supraalveolar periodontal defect modelÕ. Whereas
sites receiving occlusive membranes exhibited
somewhat greater periodontal regeneration, clinically
meaningful results were also achieved using macro-
porous membranes. Importantly, healing complica-
tions (i.e., membrane exposures), frequently ob-
served using occlusive membranes, were rarely
observed with the use of macro-porous membranes
possibly due to a better nutritional support of the
gingival flaps. Similar results were observed when
occlusive and macroporous membranes were evalu-
ated for alveolar ridge augmentation (63).
In retrospect, the main contribution of barrier
membranes resides in wound stabilization and space
provision, and to a lesser degree in tissue compart-
mentalization. As evident in Fig. 1, guided tissue
regeneration has achieved limited results in intrabony
and furcation defects (34, 54). Membrane placement
close to the flap margin (to prevent apical migration of
the epithelium) seems unnecessary and simply in-
creases the risk of exposure ⁄ infection and ultimately
of wound failure. Occlusive membranes challenge the
flap nutritional supply, increasing the chances of
wound dehiscence and a failing procedure. The clin-
ical reality of this biologic dilemma is well captured in
controlled clinical studies evaluating guided tissue
regeneration; whereas probing bone-level gain in ini-
tial 6.5-mm intrabony defects averaged 4.1 ± 2.3 mm
in nonexposed sites, bone-level gain was significantly
reduced to 2.2 ± 2.3 mm in exposed sites (86), point-
ing to the immediate relevance and mandate of con-
ditions for primary intention healing as part of the
periodontal regenerative protocol.
Is periodontal regeneration a slow
process?
A common belief is that periodontal regeneration,
when it occurs, is a slow process completed over a
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time period of several months. This generalized
assumption is based on the clinical and radiographic
improvements observed following nonsurgical, sur-
gical and reconstructive periodontal therapy, during
which clinical and radiographic evaluations were
intentionally captured late owing to the assumption
2 3 4 of a slowly progressing regenerative process!
In contrast, studies using the Ôcritical-size supra-
alveolar periodontal defect modelÕ have observed
new tissue formation, indicating periodontal regen-
eration within 4 weeks following surgical interven-
tion, and in turn suggesting a somewhat fast process
(28, 87, 96). Dickinson et al. (23), using the Ôcritical-
size supraalveolar periodontal defect modelÕ, as-
sessed early (2 and 5 days), intermediate (9 and
14 days) and late (4 and 8 weeks) healing events. Cell
activation in the periodontal ligament and alveolar
bone was observed in the early phase upon clot for-
mation. At 9 and 14 days, obvious cell proliferation
and migration, leading to osteoid, new attachment
and cementum formation, was observed in the
regenerative domain of the periodontal wound. A
reparative domain, dominated by fibrous tissue
formed in the outbound of the wound and separated
from the regenerative domain by remnants of the
clot, was also observed. This indicates that most new-
tissue formation in the periodontium is complete
within 14 days in this challenging model. Thus, we
postulate, assuming some delay in humans, that
near-final boundaries of the regenerated periodontal
tissues should be established within 4 weeks, if not
earlier.
These findings have important repercussions when
developing reconstructive periodontal therapies be-
cause they indicate that in order to positively influ-
ence periodontal regeneration, the wound-healing
process must be manipulated sooner rather than
later. Strategies based on the long-term availability of
biological factors, or slowly resorbing biomaterials
and devices, are unlikely to support clinically
meaningful improvements and should thus be
reconsidered.
Do biomaterials provide
space ⁄ scaffolding-enhancing
regeneration?
The concept of providing a scaffold for a local cell
population in order to direct wound healing ⁄ regen-
eration has considerable appeal. Biomaterials could
provide not only cell scaffolding, but may also support
wound stability and, depending on porosity, space
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Susin & Wikesjö
provision in noncontained defects. Some biomaterials
could also serve as a matrix, or release active mole-
cules and thus enhance the formation of new tissue.
Over time the construct would be completely substi-
tuted by newly formed tissue. However, as usual, Ôthe
devil is in the detailsÕ. Whereas clinical studies have
generally shown enhanced clinical outcomes (re-
duced probing depth and clinical attachment gain) in
sites receiving biomaterials (40, 55), the healing pro-
cess in these studies remains largely unknown.
Studies from our laboratories provide substantive
clues of the nature of tissue formation when
biomaterials are used (16, 17, 29, 38, 39, 76, 87, 91).
Collectively, these studies indicate that most of the
biomaterials currently used in periodontics remain
sequestered in dense connective tissue without major
evidence of active bone formation. It is important to
acknowledge that evidence of vital bone surrounding
biomaterial particles, especially in proximity to the
resident alveolar bone, is mostly an indication of
biocompatibility rather than a measure of osteocon-
ductive or osteoinductive properties. Therefore,
implanted biomaterials – cadaver-sourced or syn-
thetic – do not seem to improve the innate regener-
ative potential of the host. The negative correlation
between the remaining biomaterials and tissue
regeneration, observed by Trombelli et al. (87), was
troubling, indicating ÔosteobstructionÕ to be a com-
mon event following the use of biomaterials. Similar
observations have been made for alveolar ridge aug-
mentation (7), also reiterated in human case-series
providing histology from implanted mineral-
ized ⁄ demineralized bone matrices (6, 8) and
ceramics (26, 79).
The contention that the current commercially
available cadaver-sourced biomaterials contain
meaningful amounts of biological factors has been
long refuted (5, 17, 89). In a recent study from our
group using the critical-size calvarial defect model in
rats (80), a human demineralized bone matrix prep-
aration failed to display osteoinductive properties
when compared with controls (empty defects) at 4
and 8 weeks. Whereas it is true that demineralized
bone matrices contain sequestered growth ⁄ differ-
entiation factors (<100 lg of crude bone morphoge-
netic proteins per kilogram of demineralized bone
matrix), this dose ⁄ concentration may not be suffi-
cient to generate appreciable ⁄ relevant effects in
periodontal defects. Other (in perspective), less lim-
iting, factors for cadaver-sourced demineralized bone
matrix preparations include donor age (71), variabil-
ity in commercial preparations (1, 71) and particle
size (74).
236
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Whereas biomaterials probably represent a Ônec-
essary evilÕ for the management of clinically chal-
lenging wounds, they should necessarily have a very
porous structure to allow ingrowth of regenerating
tissues and should resorb within days ⁄ weeks without
disturbing tissue formation and maturation, whilst
maintaining structural integrity. In context, most of
todayÕs biomaterials will probably interfere with, ra-
ther than support, the wound-healing process.
Potentially, biologic factors could be used to alleviate
negative effects, while at the same time stimulate the
migration and the proliferation of targeted peri-
odontal cell populations. Only developments in
material sciences with a focus on craniofacial ⁄ peri-
odontal indications may change the nature of current
biomaterials and widen their clinical application (2).
Which wound-modification
technologies increase periodontal
regeneration?
Periodontists have used countless approaches in at-
tempts to influence periodontal wound healing. Flap
designs and devices have been designed and rede-
signed to deter epithelial migration and to promote
periodontal regeneration. Autogenous bone grafts
and allogeneic ⁄ xenogeneic cadaver-sourced and
synthetic biomaterials have been used to fill intrab-
ony and furcation defects, as a result of their (im-
materialized) bone-conductive ⁄ inductive potentials.
Root-surface modification, aimed at exposing the
dentin collagenous matrix, has been attempted to
enhance new attachment. Extracellular matrix factors
and blood-clot elements have been applied without
discernable effects. In perspective, the use of growth
and differentiation factors in support of craniofa-
cial ⁄ oral tissue regeneration can be traced back to
Marshall UristÕs concepts and their ramifications for
the dental field (4, 32). The first clinical studies car-
ried out to test growth factors directly for periodontal
regeneration were conducted during the late 1980s
and early 1990s (11, 50). The first generation of bi-
ologics approved for periodontal regeneration was
effectively introduced to the market in the late 1990s.
A recent systematic review of the effect of enamel
matrix derivatives on intrabony periodontal defects
combined findings from nine randomized clinical
trials with at least 1 year of follow up (24). Compared
with the control, intrabony defects treated with en-
amel matrix derivatives showed only an additional
1.1 mm of clinical attachment gain (95% confidence

rhGDF-5/βTCP (82, 99)
0.3% rhFGF-2/HPC (53)
rhPDGF-BB/βTCP (22)
EMD (24)
0 1 2 3
Clinical a achment gain (mm)
Fig. 2. Biologics yielded greater clinical attachment gain
than control intervention for the treatment of intrabony
periodontal defects. Data derived from two meta-analyses
(22, 24) and two studies (53, 83, 99). Bars represent means
and error bars represent 95% confidence intervals.
rhGDF-5 – recombinant human Growth/Differentiation
Factor 5; bTCP-2 – beta tricalcium phosphate; rhFGF-2 –
recombinant human Fibroblast Growth Factor 2; HPC –
hydroxypropyl cellulose; rhPDGF-BB – recombinant
human Platelet-Derived Growth Factor BB; EMD – Enamel
Matrix Derivative.
interval: 0.6–1.6) (Fig. 2) and 0.9 mm of probing
depth reduction (95% confidence interval: 0.3–0.8).
Evidence of bias in the studies included in the anal-
ysis indicates that the actual effect might have been
even smaller. Few studies have assessed the effect of
enamel matrix derivatives in furcation defects (42); a
randomized clinical trial including 45 subjects with
bilateral Class II furcation defects showed horizontal
furcation-depth reduction of 0.75 mm (95% confi-
dence interval: 0.13–1.38) when comparing enamel
matrix derivatives with resorbable membranes (35).
Data regarding the use of recombinant human
platelet-derived growth factor are not as extensive.
Darby & Morris (22) pooled the results of two mul-
ticenter, randomized clinical studies (of 169 subjects)
that compared the efficacy of beta-tricalcium phos-
phate carrier, alone, or in combination with
0.3 mg ⁄ ml of recombinant human platelet-derived
growth factor-BB, for the treatment of intrabony de-
fects. At 6 months, mean clinical attachment gain
(Fig. 1) and percentage radiographic defect fill was
0.6 mm (95% confidence interval: 0.23–1.00) and
24.9% (95% confidence interval: 15.4–34.3) greater,
respectively, when recombinant human platelet-
derived growth factor-BB was combined with the
carrier. Increasing the concentration of recombinant
human platelet-derived growth factor-BB to
1.0 mg ⁄ ml did not have a significant effect on the
outcomes (56).
A commercially available cell-binding peptide has
been proposed for periodontal regeneration (100,
101). A multipractice, randomized clinical trial
including 33 subjects evaluated a combination of the
peptide with a xenogeneic carrier (101). A borderline
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significant difference was observed for clinical defect
fill at re-entry of the intrabony defects after
6 months, the combination achieving 2.9 ± 1.2 mm
compared with 2.2 ± 1.4 mm for carrier alone. No
differences were observed for other clinical
parameters.
Fibroblast growth factor has also been considered
4
as a candidate for periodontal regeneration (53). A
multicenter, randomized clinical trial of 253 subjects
evaluated 0.2%, 0.3% or 0.4% recombinant human
fibroblast growth factor 2 in a hydroxypropylcellulose
gel carrier in two- or three-wall intrabony defects
(41). Whereas no significant differences in clinical
attachment gain were observed among groups
(Fig. 1), 0.3% recombinant human fibroblast growth
factor 2 showed significantly increased radiographic
bone fill compared with the control (52.2 ± 38.1% vs.
15.9 ± 22.1%).
Growth ⁄ differentiation factor 5 represents another
potential protein-based therapy. It has been studied
extensively, and preclinical studies have shown
enhanced local bone formation, fracture healing ⁄
repair, cartilage and tendon ⁄ ligament formation,
and periodontal regeneration (43, 45, 52). A feasibility
randomized clinical trial, of 20 patients, evaluated the
effect of recombinant human growth ⁄ differentiation
factor 5 in a beta-tricalcium phosphate carrier in
intrabony defects (82, 99). Although not statistically
significant, an increase in clinical attachment gain
of approximately twofold was observed for the
recombinant human growth ⁄ differentiation factor
5 ⁄ beta-tricalcium phosphate-treated sites compared
with the control (3.2 ± 1.7 vs. 1.7 ± 2.2 mm, respec-
tively) (Fig. 1).
Current candidate and commercially available bi-
ologics (matrix ⁄ growth ⁄ differentiation factors), in-
tended for periodontal indications, appear safe, with
minimal (if any) adverse events associated with their
clinical application. Notably, this first generation of
biologics has delivered only modest clinical results.
Evidence of periodontal regeneration has been
shown in animal studies; heterogeneous results have
been observed in human histology studies. Animal
studies should be interpreted in light of the dis-
criminating nature of the animal platform and defect
model(s) used. Human histology studies should be
evaluated taking into consideration the prognosis of
the teeth treated, often highly compromised by ad-
vanced periodontal disease – clinical situations that
may never be intended for the regenerative protocol.
Thus, human histology must always be considered
with this background, and variable results should be
explained in perspective. Going forward, the clinician
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Susin & Wikesjö
must be promised predictable, clinically meaningful
results that deliver extended life, functional stability
and esthetics for the teeth concerned.
The future use of matrix, growth and differentiation
factors is promising; however, there is a need to
optimize this current first generation of biologics
designed for periodontal regeneration before general
clinical release and use. It is clear that when provi-
sions for optimal wound healing are attainable, bi-
ologics will be of limited value because the innate
regenerative potential of the periodontium should
suffice. When wound healing ⁄ regeneration is nega-
tively affected by the clinical characteristic of the
periodontal defects and other local factors, the
combined use of biomaterials and biologics appears
to be a desirable strategy. Biologics might have the
potential to offset any negative impact of a
biomaterial on wound healing. The possibility that
biological factors could also overcome the detri-
mental effects of systemic diseases ⁄ conditions on
wound healing ⁄ regeneration should be explored.
Whereas the immediate horizon for periodontal
regeneration in clinical settings is clearly centered in
the development of second-generation protein-based
technologies, cell-based therapies have received
considerable attention in all fields in medicine with
special emphasis on induced pluripotent stem cells
for clinical use (33, 68). If the development of pro-
tein-based technologies for periodontal indications
serves as a cautionary tale, there are several known
and unforeseen hurdles forging ahead to bring stem
cells into clinical practice.
Lessons learned
The past three decades in regenerative periodontal
therapy have offered a wealth of discoveries and
treatment options. A better understanding of peri-
odontal wound healing ⁄ regeneration, and of
local ⁄ systemic factors that influence its outcome,
have been achieved. We have explored ways to
manipulate the wounds so that the innate regenera-
tive potential of the periodontium can be unleashed,
and have learned that some of these interventions
actually hindered our efforts. In devising new bi-
omaterials, devices and biologics to support peri-
odontal wound healing ⁄ regeneration, it has become
(painfully) clear how challenging it can be, but at the
same time we have never been better positioned to
make meaningful advances. This learned body of
knowledge should be consolidated into core princi-
ples that should guide us in the development of new
238
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Table 2. Learned and unlearned lessons
The periodontium has a strong innate regenerative
potential that can be compromised by local and systemic
factors
A long junctional epithelium is not an inexorable
outcome; it is probably not the cause but a
consequence of wound failure
Space provision, wound stability and healing by primary
intention are necessary, but not always sufficient, to
achieve periodontal regeneration
Periodontal regeneration occurs within weeks, whereas
periodontal tissue maturation requires a longer time
for completion
Periodontal wound-modification strategies should be a
target at the early phase of wound healing
Tissue occlusion promotes some additional periodontal
regeneration but it also increases the likelihood of
wound failure
Bone biomaterials per se are unlikely to provide the
necessary conditions for periodontal regeneration
Bone biomaterials and devices can be used to overcome
local constraining factors; however, they may also
compromise wound healing
Biologic factors appear attractive to alleviate local ⁄
systemic factors counteracting periodontal wound
healing ⁄ regeneration and untoward effects of
biomaterials and devices as they become key
components of novel regenerative technologies
An ideal construct for periodontal wound
healing ⁄ regeneration would encompass a
combination of biologics with an ease-of-use,
moldable, space-providing, biocompatible,
bioadhesive, porous and biodegradable matrix for local
applications
therapeutic approaches to benefit our patients and,
ultimately, our society (Table 2). On the other hand,
several unproven beliefs or reinterpreted facts ⁄
findings, still lingering in our collective conscious-
ness, should be unlearned so that we can move
forward.
Final thoughts
It seems fair to state that periodontal regeneration, as
with most medical developments, evolves through
cycles. New treatments, based on biological and ⁄ or
clinical concepts, are developed and show promising
results validated in proof-of-principle studies and
case series. Then, scientific scrutiny reassesses the
true benefits, often reaching more modest results
and, importantly, risks and limitations are identified.

Therefore, the reader – knowing that few new con-
cepts stand the test of time – should be mindful of
becoming an early adopter.
While wound healing is largely a universal event,
the compromised periodontium offers unique chal-
lenges. It is probably fair to say that when the pro-
fession embarked on this journey some three decades
ago, most would have imagined that by now peri-
odontal regenerative therapy would be an everyday
activity. Perhaps the advent of oral implant osseoin-
tegration, in perspective an easier pursuit, somehow
shifted our focus? Nevertheless, researchers and cli-
nicians have never been better positioned to make
clinically meaningful advances toward periodontal
regeneration, an objective well worth pursuing.
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