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Citation: Dr. Ashank Mishra. “Implication of Growth Factors in Periodontal Tissue Engineering- A Literature Review” MAR Dental Sciences 1.4 (2020)

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Research Article

Implication of Growth Factors in Periodontal Tissue

Engineering- A Literature Review

Tazeen Dawood1, Ashank Mishra*

1.Assistant Professor, Periodontic Division, Department of Preventive Dental Science, College of

Dentistry, Jazan University, Kingdom of Saudi Arabia.

*Corresponding Author: Ashank Mishra*, Visiting Faculty Periodontology and Head of

Research Department – European Institute for Medical Studies, Malta.

Received Date: November 17, 2020

Publication Date: December 01, 2020

Abstract

Periodontitis, a recognized disease worldwide, is bacterial infection-induced inflammation of

the periodontal tissues that results in loss of alveolar bone. Once it occurs, damaged tissue

cannot be restored to its original form, even if decontaminating treatments are performed. For

more than half a century, studies have been conducted to investigate true periodontal

regeneration. Periodontal tissue engineering deals with the repair of alveolar bone, tooth-

associated cementum, and periodontal ligament. Polypeptide growth factors are a class of

naturally occurring biological mediators that regulate the proliferation, migration, and

extracellular matrix synthesis of a variety of cell types including those derived from the

periodontium.

In this review, we focus on the implications of growth factors in tissue engineering studies

and discuss future perspectives on periodontal regeneration.

Keywords: Periodontitis, Periodontal regeneration, tissue engineering, growth factors, gene

therapy.

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Tissue engineering is an emerging multidisciplinary field involving biology, medicine,

and engineering that is likely to revolutionize and improve the health and quality of life

for millions of people worldwide by restoring, maintaining, or enhancing tissue and

organ function. Periodontal tissue engineering deals with the repair of alveolar bone,

tooth-associated cementum, and periodontal ligament (PDL).(1)

For tissue to be engineered a triad of factors must be intricately incorporated and woven

together delicately for an apt outcome, the factors being, the scaffold, which acts as a

housing for the cells to grow, a continuous supply of cells, and the incorporation of

signaling molecules at an appropriate time. This totality of the factor needed is often

called Tissue engineering triad (1)

Figure 1

Mechanism of action of gene delivery system

The gene-delivery therapy for periodontal regeneration identifies a malfunctioning gene

and supplies the patient with functioning copies of that particular gene through an in-

vivo and ex- Vivo gene delivery system. The transfer of the therapeutic gene into the

patient's target cell requires a carrier called a vector, which are either viruses or D.N.A.

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plasmids. When the scaffold containing the gene constructs is implanted into the tissue

defect, the host cells migrate into the implant, take up the gene constructs and start

producing the encoded protein. (2)

Introduction to Growth Factors

Polypeptide growth factors are a class of naturally occurring biological mediators that

regulate the proliferation, migration, and extracellular matrix synthesis of a variety of

cell types including those derived from the periodontium.(3) They were first described

in 1960 in blood fluid of fetal calf serum. Recent advances in molecular cloning have

proven the application of growth factors in tissue engineering used as an alternative

treatment approach for periodontal regeneration. In general growth factors are

synthesized as pro-peptide forms which are biologically active and stored in the

cytoplasm. Growth factors and their cognates interaction mediate several intracellular

signaling pathways and modulate target cell response by altered gene activity, local

acting growth factors, regulate the development and function of cells, offer the potential

for regenerating tissue types. Growth factors are proteins that may act locally or

systemically to affect the growth and function of cells in several ways. The application

of growth factors to restore damaged tissues aims at regeneration through biomimetic

processes or mimicking the processes that occur during embryonic and post-natal

development. (4)

Types of signaling molecules/Biochemical mediators/growth factors include:

Bone morphogenic Proteins, fibroblast growth factor, platelet-derived growth factor,

transforming growth factor, epidermal growth factor, cementum derived growth factor,

parathyroid derived growth factor and insulin-like growth factor.

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Figure 2

Mechanism of Action

The growth factors release may affect target cells either as autocrine, juxtracrine, or

intracrine fashion. In certain concentrations growth factors substantially increase the

rate of cell turnover through secondary intracellular messengers of phosphor di

esterase diacylglycerol and C. kinase that can regulate D.N.A synthesis, resulting in

mitosis. Few growth factors stimulate cell differentiation and regulate the synthesis of

the extracellular matrix. Platelet-derived growth factor acts as a chemo-attractant for a

variety of cells. Growth factors operate through highly complex intracellular pathways

in order to regulate intra-cellular PH. thereby influencing genetic activity. The activation

of receptor by growth factor initiates a cascade of intracellular biochemical changes.(5)

Growth Factors

Bone morphogenic

proteins

Platelet derived growth factor

Insulin like growth factor

Transforming growth factor

Cementum derived growth factor

Parathyroid derived growth factor

Epidermal growth factor

Fibroblast growth factor

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Implication of Growth Factors in Periodontal Tissue Engineering

Platelet-derived growth factor was first discovered by Lynch and his co-workers in late

1805 to promote regeneration of bone, cementum, periodontal ligament. It is the first

growth factor to be evaluated in preclinical periodontal and peri-implant regenerative

studies. As it contains biological mediators that regulate the proliferation and migration

of gingival and periodontal ligament fibroblasts, cementoblasts, pre- osteoblasts, and

osteoblastic cells at a wound site. (6) There are four isoforms of Platelet-derived growth

factors namely platelet-derived growth factor -A, -B, -C, -D. The mature parts of A and

B chains are 100 amino acids that share 60% of the amino acids. The C & D chains are

activated by proteolysis.

PDGF stimulates DNA synthesis and cell replication in osteoblasts, as well as increases

bone collagen synthesis and the rate of bone matrix apposition. (7) PDGF-BB is most

effective on PDL cell mitogenesis and matrix biosynthesis (8). Recombinant human

PDGF BB homodimer (rhPDGF-BB) is a potent recruiter and a strong mitogenic factor

for cells crucial to musculoskeletal tissue repair, including mesenchymal stem cells

(MSCs), osteogenic cells, and tenocytes. rhPDGF-BB also upregulates angiogenesis.

These properties allow rhPDGF-BB to trigger the cascade of bone and adjoining soft

tissue repair and regeneration.(9)

Howell et .al (10) conducted a study to evaluate the regenerative potential of a

combination of recombinant human (rh) platelet-derived growth factor-BB (PDGF-BB)

and (rh) insulin-like growth factor-I (IGF-I)in the treatment of periodontal infra-bony

defects in humans. They concluded that the local application of rhPDGF-BB and rhIGF-

I to periodontal lesions was safe and efficacious in regenerating lost bone. Several

studies were conducted by Park et.al11, Cho.et.al, (12,13)

Camelo et.al (14) Nevin et.al, (15) Jayakumar et .al (16) to evaluate the regenerative

potential of PDGF-BB either alone or in combination to allografts including

demineralized frozen dried bone graft and beta-tricalcium phosphate and have

concluded that PDGF –BB has proven to be a good adjuvant to bone grafts in the

regeneration of bone.

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Platelet-derived growth factor gene delivery Jin et al.(17) demonstrated that direct in

vivo gene transfer of PDGF-B stimulated periodontal regeneration in infra-bony

periodontal defects in rats. Descriptive histology and histomorphometry revealed that

human PDGF-B gene delivery promotes the regeneration of cementum and alveolar

bone, whereas PDGF-1308, a dominant-negative mutant of PDGF-A, has minimal effects

on periodontal tissue regeneration

Platelet-derived growth factor (PDGF) is an active growth factor, which is a product of

two distinct genes PDGF-A and PDGF-B. PDGF stimulates DNA synthesis and cell

replication in osteoblasts, (18) as well as increases bone collagen synthesis and the rate

of bone matrix apposition.(19)

Fibroblast Growth Factor -2

Takayama et al.(20), investigated the role of fibroblast growth factor -2 in periodontal

regeneration as a chemo- attractant for periodontal ligament cells during periodontal

wound healing. Terranova et al. (21) Kitamura et al. (22,23) investigated the efficacy of

the local application of recombinant human fibroblast growth factor-2 (FGF-2) in

periodontal regeneration They concluded that FGF-2 can be efficacious in the

regeneration of human periodontal tissue that has been lost by periodontitis. Basic

fibroblast growth factor (bFGF or FGF-2) has been demonstrated to have potent

angiogenic activity and the potential to induce the growth of immature PDL cells. The

mRNA level of laminin in PDL cells, which plays an important role in angiogenesis, is

up-regulated by FGF-2 stimulation. Thus it may in turn accelerate periodontal

regeneration.

Transforming Growth Factor-β is the name given to a group of homodimeric proteins

involved in the formation and development of many tissues. Once secreted, the ligand

binds to transmembranous heterodimeric receptors, activating a group of intracellular

proteins. The phosphorylated intracellular proteins start an intracellular signaling

pathway which activates a set of genes. (24)

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In vitro, transforming growth factor β has been observed to promote extracellular matrix

production in many cell types, such as periodontal ligament and fibroblast Transforming

growth factor.- β, when used alone or in combination with platelet, derived growth

factor-BB stimulates the proliferation of periodontal ligament fibroblast.(25) It enhances

collagen gel construction in vitro when combined with platelet-derived growth factor and

insulin growth factors. Besides Transforming growth factor β, stimulates the

biosynthesis of type I collagen fibronectin and induces depositions of bone matrix.(26)

In vivo transforming growth factor β increases bone regeneration when applied with

gelatin scaffold. Transforming growth factor. cementum-derived growth factor β when

applied with a biodegradable osteogenic material has proven to cause bone regeneration

in rabbits. In a recent study the application of rh transforming growth factor.- β in

conjunction with nonreasonable barrier membrane greatly enhanced bone regeneration

in oral osseous defects. Transforming growth factor.- β activates fibroblasts to form

procollagen, which results in the deposition of collagen within the wound.(27)

Transforming growth factor –β (TGF- β) is a multifunctional growth factor structurally

related to bone morphogenetic protein. Markopoulou et al. (28) evaluated the in vitro

effect of a combination of recombinant human transforming growth factor-beta 1

(rhTGF-β1) and calcified freeze-dried bone allograft (FDBA) and a porous biphasic

calcium phosphate (BC) bone graft on human PDL (hPDL) cell differentiation. They

concluded that TGF-β1 was an effective adjuvant to calcified freeze-dried bone allograft

(FDBA) and a porous biphasic calcium phosphate (BC) bone graft and had good

regenerative potential. TGF-β1 seems to play an important role in inducing fibroblastic

differentiation of PDL stem/progenitor cells and in maintaining the PDL apparatus

Bone Morphogenic Proteins

Another important therapeutic application of BMPs is for maxillary bone regeneration

to allow the replacement of lost teeth by osteo -integrated dental implants. This

approach involves the regeneration of peri-implant bone after implant fixation or bone

height improvement in areas below the maxillary sinus. Preclinical and clinical studies

have shown improved bone formation after treatment with BMP-2. However, the use of

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different carriers and the association of barrier membrane (GTR technique) or other

biomaterials seem to be critical factors in influencing the therapeutic

outcome.(29,30,31,32)

Bone Morphogenetic Protein Gene Delivery Bmp-2

Lieberman et al.(33) Baltzer et al. (34) demonstrated gene therapy for bone regeneration,

they transduced the bone marrow stromal cells with rhBMP-2 to form bone into a bony

segmental defect in rabbits. Franceschi et al. (35) investigated in vitro and in vivo Ad

gene transfer of BMP-7 for bone formation. Ad transduced nonosteogenic cells also were

found to differentiate into bone-forming cells and produce BMP-7 or BMP-2 in vitro and

in vivo. A study by Huang et al. using plasmid DNA encoding for BMP-4 with a scaffold

delivery system was found to enhance bone formation when compared with blank

scaffolds.(36)

BMP-7 or osteogenic protein-1 is a potent modulator of osteogenesis and bone cell

differentiation. Its effect in periodontal-regenerative treatment was evaluated in bony

defects around tooth roots in preclinical studies. Significant improvement in bone and

cementum regeneration was observed in dogs (37). An extensive cementogenesis was

considered the most significant effect of BMP-7 in bony defects in baboons 38.

Improvement of bone formation around titanium implants was also demonstrated by

studies in animals (39).

The potential of BMP-12 to repair the tendon and PDL tissues has been shown in vitro

and in vivo studies (40). A preliminary study in dogs compared rhBMP-12 with rhBMP-

2 for the treatment of periodontal defects. The results showed less bone and more

functionally oriented PDL between the new bone and new cementum after BMP-12

treatment, contrasting with a more parallel fiber arrangement of BMP-2-treated defects

(41).

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Type of B. M. P Studies Conducted Results

Bone

Morphogenetic

protein gene

delivery BMP-

2

Lieberman et al.33

Baltzer et al. 34

Demonstrated gene therapy for bone

regeneration, they transduced the bone

marrow stromal cells with rhBMP-2 to form

bone into a bony segmental defect in rabbits.

BMP-7 Franceschi et al

(2000)

Investigated in vitro and in vivo Ad gene

transfer of BMP-7 for bone formation. Ad

transduced nonosteogenic cells also were

found to differentiate into bone-forming cells

and produce BMP-7 or BMP-2 in vitro and in

vivo

BMP-4 Huang et al.

(2005)

Study was conducted using plasmid DNA

encoding for BMP-4 with a scaffold delivery

system was found to enhance bone formation

when compared with blank scaffolds. 36

BMP-7 or

osteogenic

protein-1

Giannobile WV

et.al (1998)

Concluded a Significant improvement of bone

and cementum in dogs37

An extensive cementogenesis was considered

the most significant effect of BMP-7 in bony

defects in a study conducted on baboons 38

Improvement of bone formation around

titanium implants was also demonstrated by

studies in animals39

BMP- 12 Wolfman NM

(1997)

Studied the potential of BMP-12 to repair

tendon and periodontal tissues through vitro

and in vivo studies

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Bone Morphogenetic protein gene delivery

In an early approach to regenerate alveolar bone in an animal model, the ex vivo delivery

of Ad-encoding murine BMP-7 was found to promote periodontal tissue regeneration in

large mandibular periodontal bone defects. BMP-7 gene transfers not only enhanced

alveolar bone repair but also stimulated cementogenesis and PDL fiber formation. Of

interest, the alveolar bone formation was found to occur via a cartilage intermediate

When genes that encoded the BMP antagonist were delivered, inhibition of periodontal

tissue formation resulted. (42,43) A recent study by Dunn et al. (44) showed that direct

in vivo gene delivery of Ad/BMP-7 in a collagen gel carrier promoted successful

regeneration of alveolar bone defects around dental implants. These experiments

provide promising evidence that shows the feasibility of in vivo and ex vivo gene therapy

for periodontal tissue regeneration and peri-implant osseointegration.

Gene therapy for periodontal tissue engineering causes the transfer of genetic

information into cells leading to the synthesis of a protein of interest which would

aid in the regeneration of lost periodontium. Hence gene therapy could be

considered as an advancement towards achieving periodontal regeneration.

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http://www.ncbi.nlm.nih.gov/pubmed/?term=Friedlaender%20GE%5BAuthor%5D&cauthor=true&cauthor_uid=23432673

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lin%20S%5BAuthor%5D&cauthor=true&cauthor_uid=23432673

http://www.ncbi.nlm.nih.gov/pubmed/?term=Solchaga%20LA%5BAuthor%5D&cauthor=true&cauthor_uid=23432673

http://www.ncbi.nlm.nih.gov/pubmed/?term=Snel%20LB%5BAuthor%5D&cauthor=true&cauthor_uid=23432673

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lynch%20SE%5BAuthor%5D&cauthor=true&cauthor_uid=23432673

http://www.ncbi.nlm.nih.gov/pubmed/23432673

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MAR Dental Sciences


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Volume 1 Issue 4 December 2020

©All rights reserved by Dr. Ashank Mishra.


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https://www.google.com/search?sxsrf=ALeKk02brq6eSbGEXK_-BNg55xYIPHJsTg%3A1605872910362&ei=Dq23X4LUFeGp3LUPssmHWA&q=%E2%80%9CBMP+gene+delivery+for+alveolar+bone+engineering+at+dental+implant+defects%E2%80%9D.+&oq=%E2%80%9CBMP+gene+delivery+for+alveolar+bone+engineering+at+dental+implant+defects%E2%80%9D.+&gs_lcp=CgZwc3ktYWIQAzoHCCMQrgIQJ1CDqAFYg6gBYJCrAWgAcAB4AIABjgGIAfMDkgEDMC40mAEAoAECoAEBqgEHZ3dzLXdpesABAQ&sclient=psy-ab&ved=0ahUKEwiCk4HjhpHtAhXhFLcAHbLkAQsQ4dUDCA0&uact=5



https://www.google.com/search?sxsrf=ALeKk007ghhuT2KAaQCds-6NO2Nb9Lj-TQ%3A1605872933900&ei=Ja23X6m_NqOhmgeRsbfoAg&q=%E2%80%9CPeriodontal+regeneration%3A+focus+on+growth+and+differentiation+factors%E2%80%9D.&oq=%E2%80%9CPeriodontal+regeneration%3A+focus+on+growth+and+differentiation+factors%E2%80%9D.&gs_lcp=CgZwc3ktYWIQAzoHCCMQrgIQJ1CCgAFYgoABYOWEAWgAcAB4AIABkwGIAf4DkgEDMC40mAEAoAECoAEBqgEHZ3dzLXdpesABAQ&sclient=psy-ab&ved=0ahUKEwjp5Z3uhpHtAhWjkOYKHZHYDS0Q4dUDCA0&uact=5

https://www.google.com/search?sxsrf=ALeKk007ghhuT2KAaQCds-6NO2Nb9Lj-TQ%3A1605872933900&ei=Ja23X6m_NqOhmgeRsbfoAg&q=%E2%80%9CPeriodontal+regeneration%3A+focus+on+growth+and+differentiation+factors%E2%80%9D.&oq=%E2%80%9CPeriodontal+regeneration%3A+focus+on+growth+and+differentiation+factors%E2%80%9D.&gs_lcp=CgZwc3ktYWIQAzoHCCMQrgIQJ1CCgAFYgoABYOWEAWgAcAB4AIABkwGIAf4DkgEDMC40mAEAoAECoAEBqgEHZ3dzLXdpesABAQ&sclient=psy-ab&ved=0ahUKEwjp5Z3uhpHtAhWjkOYKHZHYDS0Q4dUDCA0&uact=5

https://www.google.com/search?sxsrf=ALeKk00TGHIsQuT2_AeCZfCkVMhhWj8N3w%3A1605872952514&ei=OK23X5L7Hujtz7sP_eax2Ak&q=%E2%80%9CA+review+on+endogenous+regenerative+technology+in+periodontal+regenerative+medicine&oq=%E2%80%9CA+review+on+endogenous+regenerative+technology+in+periodontal+regenerative+medicine&gs_lcp=CgZwc3ktYWIQAzIJCAAQyQMQFhAeOgcIIxCuAhAnUOS8AVjkvAFg-8ABaABwAHgAgAFxiAGgA5IBAzEuM5gBAKABAqABAaoBB2d3cy13aXrAAQE&sclient=psy-ab&ved=0ahUKEwiS9433hpHtAhXo9nMBHX1zDJsQ4dUDCA0&uact=5



mar dental sciences...mar dental sciences citation: dr. ashank mishra. “implication of growth...

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