Received: 15 June 2019 Revised: 28 July 2019 Accepted: 10 August 2019

DOI: 10.1002/JPER.19-0352

REVIEW

Biologics-based regenerative technologies for periodontal soft

tissue engineering

Lorenzo Tavelli1 Michael K. McGuire1,2,3 Giovanni Zucchelli1,4

Giulio Rasperini1,5 Stephen E. Feinberg6 Hom-Lay Wang1
William V. Giannobile1,7

1 Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
2 Private practice, Houston, TX, USA
3 Department of Periodontics, Dental Branch Houston and Health Science Center at San Antonio, University of Texas, San Antonio, TX, USA
4 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
5 Department of Biomedical, Surgical and Dental Sciences, Foundation IRCCS Ca’ Granda Policlinic, University of Milan, Milan, Italy
6 Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI, USA
7 Department of Biomedical Engineering & Biointerfaces Institute, College of Engineering, University of Michigan, Ann Arbor, MI, USA

Correspondence Abstract
Dr. William V. Giannobile, Najjar This manuscript provides a state-of-the-art review on the efficacy of biologics in root
Professor of Dentistry and Chair, Department
of Periodontics and Oral Medicine, University
coverage procedures, including enamel matrix derivative, platelet-derived growth fac-
of Michigan, School of Dentistry, 1011 North tor, platelet concentrates, and fibroblast-growth factor-2. The mechanism of action
University Avenue, Ann Arbor, MI and the rationale for using biologics in periodontal plastic surgery, as well as their
48109-1078, USA.
Email: [email protected] anticipated benefits when compared with conventional approaches are discussed.
Although the clinical significance is still under investigation, preclinical data and
histologic evidence demonstrate that biologic-based techniques are able to promote
periodontal regeneration coupled with the provision of tooth root coverage.

KEYWORDS
gingival recession, growth factors, periodontal, regeneration, soft tissue grafting, tissue engineering

1 BIOLOGICS-BASED coverage purposes has had several limitations, including lim-

REGENERATIVE TECHNOLOGIES ited predictability in cases of shallow recession defects or
cases of thin gingival thickness.5 Thus, several authors have
Gingival recession is defined as the apical migration of the explored the use of biological agents or growth factors,
gingival margin from the cemento-enamel junction with the which are a group of proteins capable of inducing gene or
concomitant exposure of the root surface in the oral cavity.1 cell activation for cell recruitment, matrix biosynthesis, and
This condition also involves the resorption of the facial alve- cellular differentiation, in an attempt to regenerate the lost
olar bone and associated structures. Therefore, it is not sur- periodontium.6–10,50 This review aims to present the mecha-
prising that guided tissue regeneration (GTR) was one of nism of action, the rationale, and outcomes of biologics-based
the first approaches that was proposed for the treatment of regenerative technologies for the promotion of tooth root
gingival recessions.2–4 However, the use of GTR for root coverage.

J Periodontol. 2020;91:147–154. wileyonlinelibrary.com/journal/jper © 2019 American Academy of Periodontology 147

148 TAVELLI ET AL.

FIGURE 1 Root coverage procedure with connective tissue graft + EMD. A) Baseline defect; B) Split-full-split flap elevation; C) After root
conditioning with 24% EDTA, EMD was applied to the root surface; D) CTG sutured over the EMD and the root surfaces; E) Flap closure; F) 1-year
outcomes showing complete root coverage

2 E NA M E L M AT R I X D E R I VAT I V E spersed connective tissue (interpreted to be organizing PDLs),

and islands of condensing bone found at a fixed distance
Enamel matrix proteins are deposited on the developing tooth from the root surface, were observed in the histologic sec-
roots prior to the formation of the cementum.11,12 It has tions of CAF + EMD specimens.8 The property of EMD
been shown that enamel matrix derivative (EMD) obtained to induce periodontal regeneration in GRs was later corrob-
from porcine fetal tooth EMD∗ biomimetically stimulates orated in a prospective case-control study involving a his-
cementogenesis by enhancing proliferation and migration of tologic and microcomputed tomography (micro-CT) analy-
periodontal ligament cells (PDL) and osteoblasts, mimick- sis by McGuire and coworkers22 (Fig. 2). A recent random-
ing the natural process of tooth development.13–15 While ized clinical trial evaluating the efficacy of several root cov-
EMD has been initially proposed for periodontal regenera- erage procedures (CAF alone, CAF + EMD, CAF + colla-
tion, these proteins have also been investigated for root cov- gen matrix and CAF + collagen matrix + EMD) showed that
erage procedures (Fig. 1) and soft tissue healing13 given CAF + collagen matrix + EMD was related to the greater per-
its properties of enhancing vasculogenesis and local growth centage of complete root coverage.23 Similarly, other stud-
factor expression.13,16,17 However, whether or not EMD ies have suggested that combining allografts to EMD may
adds clinical benefits in the treatment of gingival recessions enhance the clinical outcomes,24–26 probably due to the
(GRs) remains unclear. Modica and coworkers demonstrated scaffold role of the graft material that contributes to the stabil-
a greater mean root coverage and clinical attachment level ity of the wound and maintains the space necessary for peri-
(CAL) gain when EMD was used in combination with coro- odontal regeneration. In addition, the potential role of EMD in
nally advanced flap (CAF) when compared with CAF alone.18 improving the esthetic results and patient satisfaction has been
A multi-center study showed that the outcomes of root cover- reported.27,28 Lastly, it should be mentioned that the addition
age procedure by using CAF + CTG can be further enhanced of biologics has been found to be beneficial in smokers as
by the addition of EMD.6 However, other studies did not compared to surgery alone.24,26
demonstrate a significant enhancement when using EMD in
terms of greater root coverage results,7,19–21 leading Del Pizzo
et al. to conclude that the addition of EMD to CAF is not jus- 3 PLATELET-DERIVED GROW TH
tified for clinical benefits of root coverage, but as an attempt FAC TOR -B B
to obtain periodontal regeneration.7 Indeed, McGuire and
Cochran showed a tooth surface that received CAF + CTG Platelet-derived growth factor-BB (PDGF) is one of most
healed with long-junctional epithelium and connective tissue investigated growth factors in periodontal tissue engineering.
attachment at the root surface, while new cementum, inter- Since its early introduction in the late 1980s,29 several ani-
mal and clinical studies have confirmed its role in promot-
ing bone, cementum, and PDL regeneration.29–32 Regarding
∗ Emdogain, Straumann, Basel, Switzerland. its mechanism of action, it has been shown that PDL and
TAVELLI ET AL. 149

FIGURE 2 Clinical and histologic efficacy of EMD in the regeneration of recession defects. A) Test gingival recession defect 8 weeks after
the creation of the recession; B) Histologic marker being placed into root surface at the position of the free gingival margin after root planing and
application of EDTA; C) Full-thickness flap creating recipient bed showing notch at the gingival margin level and relationship to the alveolar bone
crest; D) Insertion of histologic notch into root surface at the level of the alveolar bone crest; E) Application of EMD over root surface; F) Healing at
9 months showing complete root coverage; G) Low-power ground section demonstrating both notches, newly formed bone (NB), and old and new
cementum (OC and NC, respectively); H) Ground section showing new bone (NB) separated from old cementum (OC) by newly-formed periodontal
ligament (PL); I) New bone (NB) covering previously exposed root surface. Root surface is covered by both old (OC) and new cementum (NC); J)
Continuing down the root surface, new bone (NB), periodontal ligament (PL) and cementum (NC) can be seen covering the notch at the original
gingival margin level; K) Section under polarized light showing newly formed periodontal ligament fibers (PL) between newly formed bone (NB)
and old cementum (OC). (Adapted with permission from Journal of Periodontology22 )

alveolar bone cells express multiple receptors for PDGF, 𝛽-TCP as a carrier of the rhPDGF-BB∗ is that 𝛽-TCP
which enhances proliferation and chemotaxis of these particles have a scaffolding role preventing the soft tissue
cells.30,33–35 In particular, Boyan et al. investigated the effect collapse and providing a matrix for the new bone forma-
of the various isoforms of recombinant human PDGF (AB, tion, also facilitating the stabilization of the blood clot. The
AA, and BB) on the mitogenic and chemotactic responses treatment was found to be effective in terms of root cover-
of PDL cells, showing that PDGF-BB was the most potent age and esthetic outcome, with no patients reporting adverse
one.36 McGuire and Scheyer were the first to investigate events. These findings led the authors to conclude that this
the use of rhPDGF-BB for the treatment of GRs in a case series provided proof-of-principle for the treatment of
case series involving the use of connective tissue graft GRs with rhPDGF-BB plus 𝛽-TCP and a collagen matrix,
(CTG) as controls.9 After flap elevation, rhPDGF-BB solu- without the need for autogenous CTG harvested from the
tion was applied to the exposed root surfaces and to the coro- palate.9
nal PDL fibers, and then a small amount of 𝛽-tricalcium Based on these promising results, the same group designed
phosphate (𝛽-TCP) saturated with the rhPDGF-BB solu- a split-mouth randomized clinical trial comparing CAF +
tion was placed over the root. A collagen matrix was sat-
urated with the rhPDGF-BB solution and adapted over the
graft before the suturing of the flap. The rationale of using ∗ GEM21S, Lynch Biologics, Franklin, TN.
150 TAVELLI ET AL.

FIGURE 3 Clinical and histologic efficacy of rhPDGF-BB in the regeneration of recession defects. A) Clinical photograph of recession defect
2 months after its surgical creation. Osseous and gingival reference notches were placed at the time of surgical correction of the recession defect; B)
In each case, the osseous crest was placed ≈ 3 mm apical to the pre-corrected gingival margin; C) Complete root coverage is maintained 9 months
after correction of the recession defect with rhPDGF-BB + 𝛽-TCP; D) Nine months after grafting with rhPDGF-BB + 𝛽-TCP, micro-CT reveals
coronal bone regeneration superior to the osseous notch; E through G) Ground sections demonstrated robust coronal bone regeneration and newly
formed cementum 9 months after grafting with rhPDGF-BB + 𝛽-TCP; G) Higher-power ground section revealing regeneration of all tissues of
missing periodontium. (Adapted with permission from Journal of Periodontology10 )

rhPDGF-BB + 𝛽-TCP + bioabsorbable collagen wound- Although the use of rhPDGF-BB may achieve compa-
healing dressing (test group) to CAF + CTG.10 Although the rable outcomes with autologous CTG in the treatment of
controls showed improved recession depth reduction after GRs, there is no evidence that a regenerated recession with
9 months, the growth factor-treated sites displayed greater new bone, cementum, and PDL has a greater long-term
PD reduction at the study completion. Similar KTW gain, stability than a recession treated with flap alone or CTG,
esthetic results, and patient satisfaction was observed for which exhibit healing by repair. In a 5-year follow-up study,
both groups. In addition, the study included a histologic and McGuire et al. showed good stability for 5 years compared
micro-CT analysis of six treated teeth requiring extraction for with the initial 6 months’ time point in terms of reces-
orthodontic therapy. After 9 months, while the CAF + CTG sion depth changes between CTG and rhPDGF-BB groups.
group showed healing with long-junctional epithelium and However, CTG showed superior results in recession reduc-
connective tissue fibers running parallel to the root surface, tion, percentage of sites with complete root coverage, and
the growth factor-treated sites showed evidence of periodon- KTW gain.41
tal regeneration. Regenerated bone was visualized coronal
to the notch by micro-CT evaluation, while the histologic
analysis showed osteocytes and cementocytes entombed in 4 PLATELET CONCENTRATES
newly formed bone and cementum. The newly regenerated
PDL exhibited Sharpey’s fibers obliquely inserting into the A patient’s own blood has been centrifugated as documented
newly formed cementum and bone. The study demonstrated in multiple fields of medicine to concentrate platelets in
that a correction of GRs and regeneration of the periodon- an attempt to increase the density of growth factors and
tium can be obtained using a PDGF-mediated approach10 enhance wound healing.50 Platelet concentrates (PCs) have
(Fig. 3). been considered wound healing promoters for infrabony
Subsequent studies using rhPDGF-BB, combined with 𝛽- defects and sinus floor elevation42,43 as well as used as a
TCP and collagen matrix37 , were compared with ADM38 scaffold matrix in root coverage procedures.44,45 Platelet-
or to CTG39 for root coverage applications. Deshpande and rich plasma (PRP) and plasma rich in growth factor (PRGF)
coworkers obtained a mean root coverage of 91.3% and 87.7% are considered the first generation of PCs.46 Their impact
using CTG and rhPDGF-BB + 𝛽-TCP + collagen membrane, on root coverage outcomes has been shown to be min-
respectively, while CAF alone achieved 68.6% of mean root imal and in general, non-significant.47–49 The biological
coverage at 6 months.40 limitation of autogenous platelet concentrates is that the
TAVELLI ET AL. 151

growth factor (GF) composition is orders of magnitude lower In addition, early studies demonstrated that higher concentra-
than can be achieved with recombinant GFs such as PDGFs tions of factors typically expressed by platelets, such as IL-1𝛽
and FGFs. As such, it remains questionable that biologically and TGF-𝛽, resulted in an inhibitory interaction on PDGF-
relevant concentrations to promote significant regeneration AA by decreasing the number of PDGF-𝛼 receptors and avail-
can be achieved with these procedures.50 able binding sites, which may also explain the limited suc-
The second generation of PCs involves the centrifugation cess of platelet concentrates for root coverage.58,59 In sum-
of the blood without the addition of anticoagulants.46 Based mary, the use of platelet concentrates containing insignificant
on the processing speed and duration, platelet-rich fibrin enrichment of GF levels has failed to demonstrate significant
(PRF) is classified in A-PRF, L-PRF, and titanium prepared enhancements in wound repair and root coverage. As such, the
PRF. Among its advantages, the release of growth factors, clinical usage of these procedures is not recommended based
including PDGF, vascular endothelial growth factors (VEGF), on current evidence.
TGF-𝛽1, and insulin-link growth factors (IGF-1), has been
described.51,52 In root coverage procedures, PRF has been
investigated alone,45 in combination with tissue grafts53 or as 5 FIBROBLAST GROW TH
wound healing enhancer in the palatal donor site after harvest- FAC TOR -2
ing procedures.54,55 Nevertheless, it seems that the addition of
PRF did not further enhance the outcomes of the root cover- Fibroblast growth factor-2 (FGF-2) is a heparin-biding
age procedure53 and that autologous connective tissue graft- cytokine which is able to enhance the angiogenic and
ing remains the technique of choice.56,57 A possible explana- osteogenic activity of multiple cellular populations.60–62 In
tion is that gingival recessions benefit from the thickening of addition, FGF-2 can stimulate the proliferation and migration
the soft tissue margin and PRF membranes do not act as scaf- of mesenchymal cells within the PDL.62 Given these strong
folds promoting the migration of cells from adjacent tissues. wound healing characteristics, FGF-2 has been thoroughly

TABLE 1 Summary of the biologics-based technologies for application in root coverage procedures
Level of
evidence
Biological agent Origin Properties Carrier matrix (SORT) Reference(s)
Enamel matrix Porcine fetal tooth • Stimulating cementogenesis Can be used alone (gel) A Rasperini et al.,
derivative (EMD) • Enhancing proliferation, or with an absorbable McGuire et al.,
differentiation and migration of collagen sponge Sangiorgio
PDL cells and osteoblasts et al.6,22,23

• Enhancing blood vessels

formation
• Promoting growth factor
expression
Recombinant human Molecularly cloned • Promoting bone, cementum and Can be used alone (gel) B McGuire and
platelet-derived from human PDL regeneration or with different Scheyer, McGuire
growth factor PDGF-B gene • Enhancing proliferation and scaffolds (𝛽-TCP, et al., Simion
(rhPDGF-BB) chemotaxis of PDL and alveolar DFDBA, FDBA) et al.9,10,69
bone cells
Platelet-rich fibrin Centrifugation of • Releasing of low concentrations Has been used alone (as B Keceli et al., Kuka
the patient’s of growth factors (including a membrane) or in et al.45,48
own blood PDGF, VEGF, TGF-𝛽1, and combination with soft
without the IGF-1) tissue grafts
addition of
anticoagulants
Fibroblast growth Molecularly cloned • Enhancing angiogenic and Can be used alone, with C Ishii et al., Cha
factor-2 from human osteogenic activity an absorbable sponge, et al.66,68
FGF-2 gene • Stimulating the proliferation and a collagen matrix, or
migration of PDL cells 𝛽-TCP

DFDBA, demineralized freeze dried bone allograft; FDBA, freeze dried bone allograft; SORT, strength-of-recommendation taxonomy; SORT A: consistent, good-quality
patient-oriented evidence; SORT B: inconsistent or limited-quality patient-oriented evidence; SORT C: consensus, disease-oriented evidence, usual practice, expert opinion
or case series for studies of diagnosis, treatment, prevention, or screening.70
152 TAVELLI ET AL.

explored in periodontal and bone regeneration, alone or Straumann. Giulio Rasperini and Giovanni Zucchelli have
in combination with scaffolding matrices.61,63–65 Ishii and previously consulted for Straumann. Michael K. McGuire
coworkers were the first to evaluate the effect of FGF-2 on has received direct research support from Straumann and
root coverage outcomes in vivo.66 In a split-mouth random- Osteohealth. The other authors do not have any financial
ized design, recession defects were created bilaterally and interests, either directly or indirectly, in the products or
assigned to the treatment of FGF-2 alone or FGF-2 combined information associated with this manuscript. This work was
with a carrier matrix (𝛽-TCP). Microscopic and histometric partially supported by the University of Michigan Periodontal
analysis showed that both approaches were effective to inhibit Graduate Student Research Fund.
epithelial downgrowth while achieving some periodontal
regeneration. In particular, FGF-2 + 𝛽-TCP exhibited a O RC I D
greater amount of new bone and cementum formation than
FGF-2 alone, suggesting that the GF benefits when used Lorenzo Tavelli https://orcid.org/0000-0003-4864-3964
in combination with a scaffold, which allows cellular and Hom-Lay Wang https://orcid.org/0000-0003-4238-1799
vascular invasion, migration, and growth.66 When GR occurs, William V. Giannobile
the facial alveolar bone is resorbed resulting in an unfavorable https://orcid.org/0000-0002-7102-9746
defect architecture for regeneration.61,66,67 Therefore, it can
be speculated that a scaffold provides better stability to the
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