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 475

Minimally Invasive Surgical Technique in

Periodontal Regeneration:
A Randomized Controlled
Clinical Trial Pilot Study
Carlo Ghezzi, DDS1 The surgical approach to periodon-
Luca Ferrantino, DDS, MSc, PhD2 tal regenerative therapy has been
Luigi Bernardini, DDS3 progressively modified over the
Margherita Lencioni, DDS4 past 10 years, leading clinicians to
Silvia Masiero, DDS5 choose techniques that are even
more conservative when it comes
The purpose of this study was to compare two minimally invasive surgical to handling soft tissue. While the
techniques (MISTs) for the treatment of periodontal defects: (1) guided tissue meta-analysis by Tu et al1 had al-
regeneration (GTR) using resorbable minimembrane and particulate xenograft ready made clear that the success
(DBBM); and (2) inductive periodontal regeneration (IPR) using enamel matrix
of regenerative therapies is closely
derivatives and DBBM. A sample of 20 infrabony periodontal defects in 20
patients were randomly assigned to either the GTR or the IPR group. A follow- linked with the introduction of papil-
up was performed at 12 months postoperative. Significant improvement in la preservation techniques, research
clinical parameters was observed in both groups, although no intergroup in recent years has been directed to-
differences were found. MIST with GTR or IPR demonstrated very good ward the development and testing
outcomes 1 year after surgery, with no differences between treatment groups. of minimally invasive techniques.2,3
Int J Periodontics Restorative Dent 2016;36:475–482. doi: 10.11607/prd.2550
The objectives of minimal in-
vasiveness are numerous and in-
clude the following: (1) improve the
stability of the blood clot, (2) foster
primary intention healing, (3) im-
prove postsurgical morbidity, and
(4) reduce postsurgical contraction,
fostering the esthetic outcome.4 In
particular, the adhesion and matu-
ration of the blood clot on the root
surface without movement, togeth-
er with primary intention wound
closure, are essential to achieving
periodontal tissue regeneration as
Private Practice, Settimo Milanese, Italy.
1

UOC Chirurgia Maxillofacciale e Odontostomatologia, Università di Milano,

2 opposed to repair by means of a
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. long junctional epithelium.4
3Private Practice, Milan, Italy.
Harrel and his collaborators
4Reparto di riabilitazione orale Istituto Stomatologico Italiano,

Universitá degli studi di Milano, Milan, Italy

were the first to test the minimally
5Private Practice, Saronno, Italy. invasive approach, initially in 1995
and again in 1999,5 2005,6 and
Correspondence to: Dr Luigi Bernardini, via Carlo Imbonati, 20159 Milano, Italy.
2010.7 They developed and tested
Email: luigi.bernardini@gmail.com
their own surgical technique, calling
©2016 by Quintessence Publishing Co Inc. it “minimally invasive surgery” (MIS).

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476
Cortellini and Tonetti later de-
veloped the concepts expressed in
MIS, associating them with papilla
preservation2 to create the mini-
mally invasive surgical technique
(MIST).3 Like Harrel and colleagues,
Cortellini and Tonetti associated
MIST with the use of enamel matrix
derivative (EMD).2 They obtained
encouraging results in terms of
clinical outcome and postoperative
morbidity: a preliminary study on
the application of MIST associated
with EMD in isolated intrabony de-
fects showed a clinical attachment
level gain of 4.8 ± 1.9 mm 1 year
after surgery.2 Other studies have
since confirmed the clinical efficien-
cy of MIST associated with EMD in
the treatment of singular8 and mul-
tiple9 intrabony defects.
Recently, a controlled random-
ized trial by Ribeiro et al compared
the clinical performance of MIST as-
sociated with EMD to that of MIST
alone in the treatment of intrabony
defects and found no statistically
significant difference in terms of
changes in clinical attachment level
(CAL), probing pocket depth (PPD),
or recession.10 A randomized con-
trolled trial conducted by Cortel-
lini and Tonetti in 2011 showed no
statistically significant improvement
with the use of MIST alone, MIST +
EMD, or MIST + EMD + graft mate-
rial, confirming the clinical potential
of the minimally invasive surgical
approach.11 In the present study,
a variant of MIST called modified
minimally invasive surgical tech-
nique (M-MIST) was used, in which
only a buccal flap is elevated, leav-
ing in place the interdental tissue
and the palatal flap. This technique,
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introduced by the present authors in
2009, showed results comparable to
those of MIST in terms of CAL gain
and PPD reduction, with almost no
soft tissue recession after 1 year.12
Also in 2009, Trombelli et al de-
veloped a surgical technique similar
to M-MIST called “single flap ap-
proach” (SFA).13 In another study, the
same authors used this new tech-
nique in addition to bone grafts with
or without resorbable membrane.14
While Cortellini et al are re-
sponsible for associating the use of
minimal invasiveness with EMD with
or without deproteinized bovine
bone mineral (DBBM),11 Trombelli
et al have focused their attention on
the application of resorbable mem-
branes with or without grafts.14 Both
EMD and DBBM with resorbable
membrane have proven their effi-
cacy in forming new cementum on
root surfaces with new periodontal
ligament.15,16
This study compares two MIST
options performed through the use
of (1) guided tissue regeneration
(GTR) with noncrosslinked collagen-
ic minimembrane and DBBM or (2)
inductive periodontal regeneration
(IPR) with EMD and DBBM. The aim
of the study was to assess which of
these demonstrated better clinical
results.
Materials and methods
This study was designed as a ran-
domized controlled clinical trial
with a 1:1 allocation ratio. All clini-
cal procedures were performed in
accordance with the Declaration of
Helsinki and the European Directive
(2005/28/EC) on Good Oral Practice
in clinical trials. All clinical proce-
dures were conducted in the private
practice of Dr Carlo Ghezzi in Set-
timo Milanese, Italy.
Participants in the study were
enrolled in accordance with the fol-
lowing inclusion criteria:
• Diagnosis of chronic or
aggressive periodontitis
• No systemic diseases that
contraindicated periodontal
surgery
• No pregnancy or lactation
• Full-mouth plaque score and
full-mouth bleeding score
< 20%
• Nonsmokers, former smokers,
or light smokers (< 10
cigarettes/day).
Among those patients who ful-
filled the inclusion criteria, those
with the following characteristics
were excluded from the study:
• Defects adjacent to third molars
to teeth with Class III mobility
or furcation involvement
• Interproximal crater
• Defects with < 6 mm of PPD at
the reevaluation visit and/or an
intrabony component < 3 mm
Full mouth disinfection (FMD)
was the treatment of choice for
causal periodontal therapy. Oral
hygiene instruction compliance as-
sessments were scheduled at 2, 4,
and 6 weeks after FMD.
The patients were reevaluated
at 8 weeks.17 For those who fulfilled
the inclusion criteria, baseline clini-
cal measurements were recorded

for PPD and recession in six sides
per tooth. Intrabony defect mea-
surement took into account the
depth of the whole extent of the
defect (the one-wall, two-wall, and
three-wall components) as sug-
gested by Eickholz et al.18
All surgeries were performed by
one periodontal surgeon (C.G.) us-
ing ×4.3 magnifying loupes. Regen-
eration was performed after other
periodontal surgeries to eliminate
residual pockets.
A total of 20 defects were in-
cluded in the present study. All
defects were treated with the same
MIST. After administration of lo-
cal anesthesia with articaine with
adrenaline 1:100,000, access to
the defect was attained using the
simplified papilla preservation flap
(SPPF)19 or the modified papilla
preservation technique (MPPT)20 as
indicated. The mesiodistal exten-
sion of the flap was limited to the
buccal and lingual aspects of the
two teeth neighboring the defect,
and no vertical releasing incisions
were made. After minimal flap el-
evation, the defect was debrided
with a combined use of mini cu-
rettes (Gracey Mini Five, Hu-Friedy)
and an ultrasonic device (Piezon
Master 400, EMS). After the defect
was completely cleaned, patients
were randomly divided into two
groups by choosing assignments
previously sealed in opaque enve-
lopes. The first group was treated
with GTR and received DBBM (Bio-
Oss, Geistlich) + mini-membrane
(Bio-Gide, Geistlich), while the sec-
ond group was treated with IPR and
received DBBM + EMD (Emdogain,
Straumann). In the GTR group,
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DBBM was positioned in the defect
and covered with a narrow mini-
membrane without a fixation de-
vice. In the IPR group, the exposed
root surface was conditioned using
a 24% ethylenediaminetetraace-
tic acid (PrefGel, Straumann) for
2 minutes. After thorough rinsing
with saline, EMD was applied to
the root surfaces. A combination of
EMD + DBBM was then used to fill
the defect. In both groups, the flap
was repositioned and sutured with
internal mattress suture and single
interrupted suture in polytetrafluo-
roethylene (Gore-Tex CV-6, W.L.
Gore & Associates) eventually used
in combination with polypropylene
(Prolene 7/0, Ethicon). Amoxicil-
lin 875 mg + clavulanic acid 125
mg (Augmentin, GlaxoSmithKline)
was administered twice a day for
7 days from the day before the
surgery. Postoperative supportive
care included mouth rinses with
chlorhexidine 0.12% three times a
day for 1 month and professional
debridement once a week for the
first month. Patients were also di-
rected to abstain from mechanical
oral hygiene procedures in the sur-
gical area for 4 weeks. Sutures were
removed 2 weeks postsurgery.
The primary outcome variable
of the study was CAL gain, con-
sidering the site with the greatest
probing pocket depth at baseline
for each affected tooth. PPD and
recession were recorded immedi-
ately before the surgery and at the
12 -month follow-up visit by a single
operator (L.B.) blinded to the surgi-
cal treatment received by the pa-
tient. All clinical measurements were
recorded at six points per tooth with
477
a periodontal probe (UNC-PCP 15,
Hu-Friedy). During surgery, whether
the treated defect was mostly one-,
two-, or three-walled was recorded.
The power of the study was cal-
culated after data collection, using
CAL gain as the primary outcome
variable. Given a standard deviation
of 1.5 mm and a sample size of 20
patients (10 per group), the prob-
ability of detecting a statistically sig-
nificant difference between groups
was estimated at 9%.
Statistical analysis
Patients were randomly split into
two groups by a simple computer-
generated randomization sequence.
Sequentially numbered, sealed,
opaque envelopes containing treat-
ment allocation were opened only
after surgical defect debridement
was completed. The patients and
the examiner who assessed clinical
outcomes were blinded to the as-
signed treatment.
Demographic and clinical vari-
ables at baseline were compared
between the groups using Fisher
exact test and Student t test for in-
dependent variable to prove good
randomization. Between-group
comparison was performed us-
ing Student t test for independent
variables and Fisher exact test,
while within-group comparison was
performed using Student t test for
paired observation and Fisher ex-
act test. Data was collected using
Numbers (iWork 2009, Apple). The
patient was considered as the sta-
tistical unit. Statistical analysis was
performed with Stata11 (Stata Corp).
Volume 36, Number 4, 2016
478

diagram flow, and Table 1 gives the

Assessed for eligibility baseline data for the two groups. No
(n = 20)
statistically significant differences
in demographic and clinical vari-
Enrolled

Excluded
(n = 0) ables were found between groups
at baseline. Defect configuration (ie,
Randomized one, two, or three walls) and tooth
(n = 20) position were also well balanced be-
tween the two groups.

Allocation Treatment effect

Allocated to Allocated to
intervention (n = 10) intervention (n = 10)
The treatment procedure for both
Follow-up groups is shown in Figs 2 to 5. No
Lost to follow-up Lost to follow-up
(n = 0) (n = 0)
complications (including infection of
the xenograft and membrane dehis-
Analysis cence) were recorded after surgery
Analyzed Analyzed or during the follow-up period in any
(n = 10) (n = 10)
patients. All patients showed a great
reduction of PPD. In the MIST + IPR
Fig 1 Study flow diagram.
group, the presurgical measurement
was 8.2 mm (95% CI = 7.26–9.14),
Table 1 Baseline patient and defect characteristics for the two while at the 12-month follow-up PPD
experimental groups was 3.3 mm (95% CI = 2.95–3.64). On
the other hand, in the MIST + GTR
MIST + IPR (n = 10) MIST + GTR (n = 10)
group, PPD decreased from 7.8 mm
Mean ± SD 95% CI Mean ± SD 95% CI P
(95% CI = 6.05–9.55) presurgery to
Age (y) 56 ± 8.15 50.17–61.83 52.9 ± 10.25 45.56–60.24 .46
3.1 mm (95% CI = 2.69–3.51) at the
Sex (M/F) 5/5 4/6 1.00 12-month follow-up. Paired t test
PPD (mm) 8.2 ± 1.30 7.26–9.14 7.8 ± 2.40 6.05–9.55 .65 demonstrated that both reductions
CAL (mm) 9.2 ± 1.90 7.82–10.58 8.5 ± 2.20 6.91–10.09 .46 were statistically significant (P < .01).
Recession (mm) 1.0 ± 1.10 0.17–1.83 0.7 ± 0.67 0.22–1.18 .68 Recession was 1 mm (95% CI = 0.17–
Infrabony defect 5.6 ± 1.20 4.76–6.44 5.4 ± 2.2 3.81–6.99 .80 1.83) in the MIST + IPR group at base-
(mm) line, and after 12 months it slightly
MIST = minimally invasive surgical technique; IPR = inductive periodontal regeneration; increased to 1.5 mm (95% CI = 0.66–
GTR = guided tissue regeneration; SD = standard deviation; CI = 95% confidence interval;
PPD = probing pocket depth; CAL = clinical attachment level. 2.34). In the MIST + GTR group,
baseline recession was 0.7 mm (95%
CI = 0.22–1.18) while at the 12-month
Results and 9 men and 11 women with a follow-up it was 1.4 mm (95% CI =
mean age of 54 ± 9 years (range: 34 0.63–2.17). The slight increase was
Baseline data to 68 years) participated in the study. not statistically significant in the MIST
All recruited patients were included + IPR group (P = .09), but it was sta-
Patient recruitment started in Janu- in the study and none were lost to tistically significant in the MIST +
ary 2011 and finished in May 2011, follow-up. Figure 1 shows the study GTR group (P = .045). Consistent and

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 479

a b c

d e f

Fig 2 GTR treatment sequence. (a) Baseline

PPD of 9 mm. (b) Minimally invasive surgical
approach. (c) 6 mm of intrabony defect. (d)
The defect was filled with osteoconductive
material (Bio-Oss, Geistlich). (e) The
collagenic membrane (Bio-Gide, Geistlich)
was prepared to cover the interdental
space. (f) A combination of mattress sutures
was done to perform primary closure of the
flap. (g) Healing tissue 7 days after surgery.
(h) 3.5 mm PPD at 6 months after surgery. g h

Fig 3 GTR treatment radiographic exams.

(a) Baseline. (b) Six months.

a b

statistically significant (P < .01) CAL
gain and PPD reduction were at-
tained in both groups. CAL gain was
4.4 mm (95% CI = 3.56–5.24) for the
EMD + DBBM group and 4 mm (95%
CI = 2.69–5.31) for the GTR group,
while PPD reduction was 4.9 mm
(95% CI = 4.04–5.76) and 4.7 mm
(95% CI = 3.01–6.39), respectively.
As shown in Table 2, neither the
primary (CAL gain) nor secondary
outcome variables demonstrated
statistically significant differences
between the two treatment groups.
Figure 6 shows defects distribu-
tion by CAL gain at the follow-up
visit, with no statistically significant
differences.

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480

a b c

d e f

Fig 4 IPR treatment sequence. (a) Baseline

PPD of 7 mm. (b) Minimally invasive
surgical approach. (c) Intrabony defect of
4 mm. (d) After suture preparation, EMD
was used at the bottom of the defect. (e)
The defect was filled with osteoconductive
material (Bio-Oss, Geistlich). (f) The suture
was drawn to attain primary closure of the
flap. (g) Healing tissue at 3 weeks after
surgery. (h) 3 mm PPD 1 year after surgery.
g h

Table 2 Clinical outcomes at 1 year

MIST + IPR (n = 10) MIST + GTR (n = 10)
Mean ± SD 95% CI Mean ± SD 95% CI P
PPD (mm) 3.3 ± 0.48 2.95–3.64 3.1 ± 0.57 2.69–3.51 .40
CAL (mm) 4.8 ± 1.40 3.80–5.80 4.5 ± 1.27 3.59–5.41 .62
Recession 1.5 ± 1.18 0.66–2.34 1.4 ± 1.07 0.63–2.17 .84
(mm)
CAL gain 4.4 ± 1.17 3.56–5.24 4.0 ± 1.82 2.69–5.31 .56
(mm)
∆ recession 0.5 ± 0.85 0.11–1.11 0.7 ± 0.95 0.02–1.38 .62
Fig 5 IPR treatment radiographic exams. (left) Base-
(mm)
line. (right) One year.
PPD 4.9 ± 1.20 4.04–5.76 4.7 ± 2.36 3.01–6.39 .81
reduction
(mm)
MIST = minimally invasive surgical technique; IPR = inductive periodontal regeneration;
GTR = guided tissue regeneration; SD = standard deviation; CI = 95% confidence
interval; PPD = probing pocket depth; CAL = clinical attachment level.

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Discussion
The aim of this study was to com-
pare MIST performed through the
use of GTR with minimembrane or
the well-known IPR with EMD and
bone substitute.
MIST with regenerative mate-
rials resulted in significant clinical
improvements at 12 months’ follow-
up. CAL gain was 4.4 ± 1.17 mm for
IPR and 4.0 ± 1.82 mm for the GTR
group, a result comparable with
those achieved in previous studies.
In a review paper on MIST and M-
MIST, Cortellini showed a CAL gain
range between 2.82 ± 1.19 mm and
4.9 ± 1.7 mm.21 PPD reduction, gin-
gival recession, and postoperative
complications were also compara-
ble with previous studies.
The surgical technique used in
the present study was the MIST in-
troduced by Cortellini and Tonetti
in 2007, which since its introduction
has shown excellent results in terms
of CAL gain, PPD reduction, and re-
cession whether it is used by itself
or in combination with EMD.2,3 The
most recent studies that have tested
MIST have achieved high levels of
CAL gain, suggesting that MIST (as
well as M-MIST or SFA) has great in-
trinsic regenerative potential.3,9,11,21
Use of amelogenins in combina-
tion with MIST has been examined
in several studies, but only Trombelli
et al tested the use of resorbable
membrane associated with a bone
substitute. 14 Compared with OFD,
the author obtained no statistically
significant difference between the
two groups.14
Comparing IPR and GTR with
the MIST, no statistically significant
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7
6
5
Treated defects (n)
3 5
4
3
3
2
2
1
1 1 1 1
1 2 3 4
CAL gain (mm)
Fig 6 Defect distribution by clinical attachment level (CAL) gain.
difference was found in primary or
secondary outcomes. However, the
study was a pilot study and sample
size may have been underesti-
mated. Nevertheless, in the pres-
ent authors’ opinion a reasonably
larger sample size will not achieve
statistically significant differences
in terms of CAL gain between MIST
+ IPR and MIST + GTR. MIST op-
timizes by itself a periodontal de-
fect’s regenerative potential. The
use of different biomaterials, in
the authors’ experience, is not the
most important factor from a clini-
cal point of view. To date, choice of
surgical technique and especially
the minimally invasive approach
that increases wound and blood
clot stability is the most important
aspect in regenerative therapy for
intrabony defects.1,4 Though a graft
material that provides significant
clinical advantages compared with
the others has not yet been identi-
fied, the use of conventional regen-
481
2 MIST + GTR
MIST + IPR
1
5 6 7 8
erative techniques such as GTR or
IPR are useful to achieve periodon-
tal regeneration.
Conclusions
Although the two groups show
similar results, GTR with minimem-
brane is more strongly affected by
the operator’s skills. No difference
was found between groups from a
statistical or clinical point of view in
soft tissue recession after periodon-
tal regeneration surgery. The results
obtained 1 year after surgery are
consistent with the results of previ-
ous studies.11,12,21 In both groups,
only 10% of cases had an insignifi-
cant CAL gain (≤ 2 mm) (Fig 6). Giv-
en the small number of cases and
the limited power of the study, fur-
ther studies are needed to be able
to state that there is no difference in
terms of clinical outcome between
the two test groups.
Volume 36, Number 4, 2016
482
Acknowledgments
The authors reported no conflicts of interest
related to this study.
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