Regenerative Periodontal Surgery

REGENERATIVE
PERIODONTAL
SURGERY
BY
DR. ANTARLEENA SENGUPTA
MDS, DEPT OF PERIODONTOLOGY
MCODS, MANGALORE
2020
BONE GRAFTS, GTR & TISSUE ENGINEERING

CONTENTS
◦ INTRODUCTION
◦ HISTORICAL REVIEW OF REGENERATIVE CONCEPTS
◦ CRITERIA FOR PERIODONTAL REGENERATION
◦ CONCEPT OF TISSUE ENGINEERING
◦ CLINICAL APPLICATIONS OF TISSUE ENGINEERING
◦ RECONSTRUCTIVE PROCEDURES
◦ GRAFT-ASSOCIATED
◦ NON-GRAFT-ASSOCIATED
◦ ASSESSMENT OF WOUND HEALING POST-SURGERY
◦ LIMITATIONS OF REGENERATIVE PROCEDURES
◦ FUTURE DIRECTIONS IN TISSUE ENGINEERING
◦ CONCLUSION
◦ REFERENCES
2

INTRODUCTION
◦ Ideal outcome of periodontal therapy: reconstruction/reconstitution of gingival and osseous structures lost through disease.
◦ GOLDMAN’s classification of infrabony defects– greatest chance for regenerative techniques.
 Offer osseous topography suitable for holding a blood clot
 Permit ingrowth of primordial vascular/osseous cells from bony lateral walls
o Bone grafts
1. Increase the bone level
2. Reduce crestal bone loss
3. Increase the clinical attachment level
4. Reduce probing depth when compared with open flap surgery
5. Increase clinical attachment level and reduce probing depth when combined with guided tissue regeneration (GTR) compared with grafts alone
6. Support formation of a new attachment apparatus
a. autogenous bone grafts
b. demineralized freeze-dried bone allografts (DFDBA)
c. xenografts (Bio-Oss®, Osteohealth, Uniondale, New York)
d. enamel matrix derivative (Emdogain®Straumann, Basel, Switzerland).
◦ “Replacement grafts provide demonstrable clinical improvements in periodontal osseous defects compared to surgical debridement alone.”
3

HISTORY
◦ Repair: Healing of a wound by tissue that does not fully restore the architecture or function of the part, as
in the case of a long junctional epithelium or ankylosis.
◦ Reattachment: The reunion of connective tissue with a healthy root surface on which viable periodontal
tissue is present without new cementum, as in the case of trauma or after a supracrestal fibrotomy.
◦ New attachment: The reunion of connective tissue with an unhealthy or previously diseased root surface
that has been deprived of its periodontal ligament. This reunion may or may not occur by formation of
new cementum with inserting collagen fibers, as in the case of GTR.
◦ Regeneration: Reproduction or reconstitution of the lost or injured parts by restoration of new bone,
cementum, and a periodontal ligament (reunion of connective tissue) on an unhealthy or previously
diseased root surface. Ideally, complete restoration would also restore total function.
Proceedings of the World Workshop in Periodontics (WWP)(1989)
AAP Glossary of Terms (2001)
4

HISTORY
Whether new attachment depends on normal/diseased root surface or normal/reduced periodontium?
Whether the presence of alveolar bone has any influence on new attachment?
Whether the progenitor cell population is derived from the alveolar bone?
Whether the progenitor cell population is derived from gingival connective tissue?
Whether the progenitor cell population is derived from periodontal ligament?
5

HISTORY
 GUIDED TISSUE REGENERATION: to prevent epithelial and other cells from gingival connective tissue to enter the site of healing to
facilitate regeneration by periodontal ligament cells.
 ROOT SURFACE BIOMODIFICATION:
- Marshall, 1833: pocket eradication with ‘presumable clinical re-attachment’ after aromatic H2SO4
- Stewart, 1890: mechanical removal of calculus and cementum with acid application
- URIST, 1965:
- Register, 1973:
 BONE GRAFTS:
- Hegedus, 1923: 1st use of bone grafting
- Beube & Silvers, 1934: boiled bovine bone powder
- MELCHER, 1962:
- Nabers & O’Leary, 1965: cortical bone chips for grafting
- Robinson, 1969; Jacobs & Rosenberg, 1984: osseous coagulum+bone blend
- Ross & Cohen, 1968; Soehren & Von Swol, 1979: intraoral cancellous bone and marrow as autogenous grafts
- Schallhorn, 1968: extraoral site grafting– anterior/posterior iliac crest for graft harvesting.
6

PREPARATION FOR REGENERATION AND NEW ATTACHMENT
Ratcliff, 1966; Glickman, 1972; Wirthlin, 1981
7

OVERVIEW OF REGENERATIVE PROCEDURES
SURGICAL APPROACH
ROOT SURFACE
BIOMODIFICATION
IMPLANT MATERIALS FOR
REGENERATION
GUIDED TISSUE
REGENERATION
USE OF GROWTH FACTORS
Regardless of the type of procedure used, the epithelial tissues always
proliferate at a faster rate than the underlying mesenchymal tissues, with the
resultant ‘‘long’’ junctional epithelium forming and attaching to the root
surface.
This form of healing is classified as repair and not regeneration because the
original form and architecture of the tissues have not been restored.
In order to create an environment suitable to cell repopulation it was considered that
the root surface needed to be cleaned and prepared in a manner conducive to cell
attachment and subsequent matrix synthesis.
Demineralization of root surfaces with acids or coating root surfaces with biological
attachment agents such as fibronectin, or both have received maximum attention.
1.Expose old collagen fibers with which newly formed fibers could interdigitate.
2.Discourage the attachment of unwanted epithelial cells.
However, this procedure did not yield predictable regeneration and often caused
ankylosis and root resorption as side effects.
Treatment of intrabony periodontal defects has often focused only on the bony defect,
and this has lead to the use of a number of grafting materials to stimulate bone repair.
Allografts and Alloplasts: Convenient for filling but contain very little osteoinductive
property.
Autogenous bone grafts are thought to be osteoinductive in vivo but are still of limited
value for inducing periodontal regeneration since their ability to induce new cementum
and PDL are limited.
Some gain in CAL and radiographic bone fill is seen due to encapsulation of the material
in a dense fibrous connective tissue.
In addition, JE forms between the graft and the tooth surface.
In the 1980s, a novel procedure was proposed in which a physical barrier was introduced
by surgically placing a membrane between the connective tissue of the periodontal flap
and the curetted root surface.
This guided tissue regeneration procedure presumed that the periodontal ligament
contained all of the progenitor cells required for the formation of bone, cementum and
periodontal ligament.
This method quickly gained wide clinical acceptance.
However, long-term studies and evaluations of this method have indicated that the
clinical improvements obtained by this procedure are of small magnitude and exhibit
large variability.
Growth factors are an attractive group of agents to target for potential wound
regeneration studies because of their regulatory effects on immune function and on the
proliferation and differentiation of cells from the epithelium, bone and soft connective
tissues.
Two of these GF, platelet- derived growth factor & insulin-like
growth factor-I, have been noted to enhance regeneration in beagle
dogs and monkeys with experimental periodontitis.
Bone morphogenetic proteins offer good potential for bone and
cementum regeneration.
Limitations of GF: Restricted understanding of the differentiation
repertoire of the periodontal cells, the exact target cells that are to be
modulated by these factors and the stability of the tissues.
8

CRITERIA FOR PERIODONTAL REGENERATION
1. A functional epithelial seal (length-2mm)
2. New connective tissue fibers (Sharpey’s fibers) must be inserted into the previously exposed root surface.
3. New acellular extrinsic fiber cementum must be reformed on previously exposed root surface.
4. Alveolar bone height must be restored to within 2mm of the CEJ.
TWO MAIN APPROACHES FOR PERIODONTAL REGENERATION:
1. Introduction of a ‘filler’ material into the defect in the hope of inducing bone regeneration
2. Techniques developed to guide and instruct the specialized cellular components of the periodontium to participate in the
regeneration
Periodontal regeneration attributes to a complete recovery of the periodontal tissues in both height and function, i.e. the
formation of alveolar bone, a new connective attachment through collagen fibers functionally oriented on the newly formed
cementum.
(Illueca FM et al, 2006)
Proposed by Langer et al. in 1993 as a possible technique for regenerating lost periodontal tissues.
The goal of tissue engineering is to promote healing, and ideally, true regeneration of a tissue's structure and function, more
predictably, more quickly, less invasively, and more qualitatively than allowed by previous passive techniques.
9

TISSUE ENGINEERING WITH BIOLOGIC MEDIATORS
SIGNALING
MOLECULES
(PDGF, BMP)
SCAFFOLD
(collagen, Ca
PO4)
CELLS
(osteoblasts,
fibroblasts)
REGENERATION OF
TISSUE/ORGANS
TIME
Appropriate
environment
Lynch et al, Tissue engineering: applications in oral and maxillofacial surgery and periodontics. 2008.
10

SIGNALING MOLECULES IN PERIODONTAL REGENERATION
◦ The molecules necessary for periodontal regeneration can be roughly grouped into three families:
1. Polypeptide growth factors,
2. Attachment or adhesion proteins
3. Structural components.
◦ The outcome of the action of each group of these molecules may vary depending upon the stage of healing and target cells available.
11

◦ INSULIN LIKE GROWTH FACTOR 1:
 found in substantial levels in platelets and is released during clotting along with the other growth factors.
 potent chemotactic agent for vascular endothelial cells resulting in increased neovascularization.
 promotes osteogenesis and cementogenesis.
• Matsuda et al. in 1992 demonstrated the mitogenic effects of insulin growth factor on periodontal ligament fibroblastic cells and concluded that a synergistic effect results from using a
combination of platelet derived growth factor and insulin like growth factor 1.
◦ TRANSFORMING GROWTH FACTOR β:
 found in highest concentration in bone and platelets.
 strong promoter of extracellular matrix production.
 selectively stimulates periodontal ligament fibroblast proliferative activity– type I collagen, fibronectin and osteocalcin biosynthesis, as well as bone matrix deposition and chemotaxis of
osteoblast.
 decreases synthesis of metalloproteinases and plasminogen activator, and also increases the synthesis of tissue inhibitor of metalloproteinases and plasminogen activator inhibitor. Thus,
resulting in the decrease of connective tissue destruction.
 Bone coupling factor (Dabra S et al. Dent Res (Isfahan) 2012)
12

◦ PLATELET-DERIVED GROWTH FACTOR:
 Material released from platelets is the principal source of mitogenic activity present in serum, and it is one of the principal growth factors related to wound healing by
growth of many cells. (Ross et al.; Kohler and Lipton,1974)
 enhances the proliferation and mitogenic activity of periodontal ligament cells.
 It enhances bone and cementum formation.
• Lynch and co-workers demonstrated that that platelet-derived growth factor-BB alone could significantly stimulate formation of new cementum and inserting collagenous
fibers.
◦ BONE MORPHOGENETIC PROTEINS:
 BMPs are bone growth factors synthesized and secreted by osteoblasts and incorporated into the organic matrix during bone formation.
 released during osteoclastic resorption and induce differentiation of mesenchymal cells into osteoblasts, stimulating osteogenesis in the remodeling and healing processes.
 Presently, 20 structurally related BMPs belonging to the TGF-β superfamily been recognized, and two of them, the BMPs 2 and 7, distinguish for their osteoinductive property,
emerging as an alternative for filling of bone defects.
 DRAWBACK: rapidly diffusible in biological media.
13

CELL SELECTION, DIFFERENTIATION AND MATURATION
 The cell types involved in periodontal regeneration are:
14

•Dental Pulp Stem Cells:
•- In 2003, Shi and Gronthos isolated dental pulp stem cells through immunoselection.
•- Human pulp cells (odontoblasts) retain its ability to form functional odontoblast even when
fully developed. It has the ability to form reparative dentin when expose to deep caries and mild
trauma or pulp capping.
•- When third molar is extracted and it is cultured in suitable condition it produces dentin.
•Brar GS et al., Indian J Dent Res. 2012
Periodontal Ligament Stem Cells:
- Periodontal ligament stem cells (PDLSCs), which reside in the perivascular space of the periodontium,
possess characteristics of mesenchymal stem cells and are a promising tool for periodontal
regeneration. (Zu W et al., Stem Cell Int 2015)
- Principle of guided tissue regeneration is based on this principle that periodontal ligament cell have
the potential to give rise to various cells.
- Multipotent progenitors from human PDL were shown to generate bone. These cells have also been
shown to retain stem cell properties and tissue regeneration capacity even after recovery from solid-
frozen human primary tissue (Shi 2005).
- These findings suggest that cryopreserved PDLSCs from extracted teeth could prove useful for
clinically relevant therapeutic applications in the future.
(Tatullo M et al., Int. J Med Sci. 2015)
Dental Follicle Stem Cells:
- The dental follicle has long been considered a multipotent tissue, based on its ability to
generate cementum, bone and PDL from the ectomesenchyme derived fibrous tissue.
- Human dental follicle progenitor cells obtained from third molars exhibit a characteristic ability
to attach to tissue culture.
- Dental follicle stem cells express side population stem cell markers and the demonstrated
ability to differentiate into not only osteoblasts/cementoblasts but also adipocytes and neurons.
(Nayanjyoti Deka, IJADS, 2015)
Dental Epithelial Stem Cells:
- Once enamel is formed and maturation stage is reached, oral ectoderm-derived ameloblasts are unable to
proliferate or regenerate.
- However, a specialized structure located at the apical region of the labial cervical loop in mouse incisors
was characterized and named the ‘apical bud’, suggested to act as stem cell containing compartments that
could differentiate into ameloblasts through interaction with adjacent mesenchymal cells.
(Saito MT et al., World J stem cells, 2015)
CELL SELECTION, DIFFERENTIATION AND MATURATION
15

SELECTION OF CELLS FOR PERIODONTAL REGENERATION
HIERARCHY OF CELL POTENCY:
1Hima Bindu A, Srilatha B (2011) Potency of
Various Types of Stem Cells and their
Transplantation. J Stem Cell Res Ther
DPSCs SHEDs
PDLSCs DFPCs
SCAPs
  
16

EXCLUSION PRINCIPLE FOR TISSUE ENGINEERING IN
PERIODONTAL REGENERATION
Xu, Li, Wang et al., Stem Cells
Translational Medicine, 2018
17

SOLUBLE MEDIATORS AND REGULATORS OF CELL FUNCTION
◦ Critical messages for cell activity are provided by substances present in the local
environment and mediate their effects through specific cell surface receptors.
◦ Binding of soluble mediators to the cell surface receptors activates numerous
intracellular signaling molecules lead to CELLULAR RESPONSE
◦ Genes contain the necessary coding information for the production of proteins.
18

NEWER BIOLOGIC MEDIATORS
A. ENAMEL MATRIX DERIVATIVE (EMD)
- Effective in treatment of infrabony defects
- Histological evidence of EMD-induced periodontal regeneration (Heijl et al, 1997)
- New connective tissue attachment for EMD+ bone-derived xenograft (Sculean et al, 2003)
- Safe for clinical use
- Greater mean radiographic bone fill seen at 8, 16 and 36 months after surgery. (Heijl, 1997)
- Use in combination with other graft materials– controversial. Studies have failed to show clinical
improvement.
- EFFECTS OF EMD:
- induction of proliferation, migration, adhesion, mineralization and differentiation of cells in periodontal
tissue
- Appears to control inflammation induced by immune cells.
19

NEWER BIOLOGIC MEDIATORS
B. RECOMBINANT HUMAN PLATELET-DERIVED GROWTH FACTOR
- One of the earliest growth factors studied for its effect on wound healing
- potent mitogenic and chemotactic factor for mesenchymal cells
- Histologic evidence of regeneration reported in animal studies (Libin et al, 1975; Lynch et al, 1989)
- Nevins et al, 2003: rh PDGF used in conjunction to allogenic bone to correct class 2 furcations and interproximal intrabony defects on hopeless
teeth.
- Nevins et al, 2005: rh PDGF in combination with beta TCP in a multicenter clinical trial
- Stable results after 3-5 years
C. COMBINED TECHNIQUES
- To “enhance” the results of regenerative technique.
20

ROLE OF EVOLVING EXTRACELLULAR MATRIX
MATRIX
(Macromolecules, bound growth factors)
Cell Surface
(Integrins, Receptors)
Cytoskeleton
Nucleus
Gene Expression
Matrix Synthesis
21

The requirements for successful tissue engineering have been divided into two main areas. These include:
1. Engineering issues related to maintaining an in vivo cell culture substratum such as biomechanical properties of the
scaffold, architectural geometry and space maintaining properties.
2.The second group of requirements relate to the biological functions of the engineered matrix, including cell recruitment,
permission of neovascularization and delivery of the requisite morphogenetic, regulatory and growth factors for tissue
regeneration.
22

1. Provide physical support for the healing area– no collapse of surrounding tissue into wound site. E.g., bone
allografts, TCP
2. Selective barrier to restrict cellular migration– GTR e.g., non-resorbable PTFE, resorbable polylactate, PGA,
Ca2SO4
3. Scaffolding for cellular migration and proliferation. E.g., -- collagen matrix. Potentially can be modified by
selectively defining the types of cells permitted to attach to and proliferate on this matrix with the additions of
adhesins and or integrins
4. Time-release mechanism for signalling molecules.
23

SCAFFOLDS USED FOR PERIODONTAL REGENERATION
 Resorbable / Non-resorbable
 Synthetic / Natural
1. Ceramics: HA and TCP
• Osteoconductive, biocompatible, and do not stimulate immunological reaction.
• TCP is a naturally occurring material comprising of calcium and phosphorous and is used as a ceramic bone substitute.
2. Polymers:
a. Synthetic : PGA (polyglycolic acid) is a polymer of glycolic acid. PLA (polylactic acid) is the polymer of lactic acid. Copolymers of PGA have been used for many types of biomaterials, including
sutures (vicryl). PLGA (polylactic co glycolic acid) is a copolymer of PGA and PLA.
 Due to its biocompatibility, controlled structural and mechanical properties, tailored degradation rates, and its potential as growth factor delivery vehicles, it has been considered as the prime
candidate for use in regenerative medicine and dentistry
b. Natural:
• Chitosan: It is a biodegradable natural carbohydrate biopolymer that has been shown to improve wound healing and improve bone formation. It is nontoxic and nonimmunogenic, and have such
structural characteristics that makes it possible to be used as a bone substitute and as a scaffold for cell attachment.
• Collagen: Collagen can be process to make collagen foam, collagen fiber and collagen membrane which have favorable properties that can be used for scaffold of tissue engineering. 24

CLINICAL APPLICATIONS OF TISSUE ENGINEERING
A. GENE THERAPY
- Not effective clinically
- Subject to proteolytic breakdown
- Dependent on carrier stability
- May circumvent limitations to protein delivery in soft tissue wounds
B. PDGF GENE DELIVERY
- Plasmid and Ad/PDGF
- Expressed in gingival wounds for upto 10 days (Anusaksathein et al, 1996)
- PDGF- A: inhibitory effect on cememntum mineralization– upregulated osteopontin and enhanced multinucleated giant cells
- PDGF- B: induction of gingival fibroblasts– enhanced defect fill
C. BMP GENE DELIVERY
- Transduces stromal cells of bone marrow bone formation in animal model (Lieberman et al)
- Ad5/BMP 2 direct administration in vivo and ex vivo bone engineering (Abramson, 2006)
25

BASIC SURGICAL TECHNIQUE TO TREAT INTRABONY DEFECTS
26

BASIC SURGICAL TECHNIQUE TO TREAT INTRABONY DEFECTS
27

TREATMENT OPTIONS
1. Open flap debridement (OFD)
2. Bone grafts (DFDBA, Osteohealth, NY; Emdogain Bio-Oss)
3. Guided tissue regeneration
4. Biologic mediators (enamel matrix derivative)
◦ Bowers et al., 1982: in areas adjacent to bone implants, cementogenesis and osteogenesis appeared to be
enhanced. This was as opposed to nongrafted sites, which tended to show less bone fill, less
cementogenesis, and greater likelihood of heading by a long junctional epithelium.
28

GRAFTING FOR NEW ATTACHMENT
◦ RATIONALE: to enhance the regenerative capability of bone and achieve a new attachment apparatus.
◦ GOLDMAN & COHEN, 1979:
1. Osteoinduction (Urist & McLean, 1952): a process by which graft material is capable of promoting
a. Osteogenesis
b. Cementogenesis
c. New periodontal ligament
2. Osteoconduction (Urist et al., 1958): the graft material acts like a passive matrix, like a scaffold for new bone
3. Contact inhibition (Ellegaard et al. 1976): graft material prevents apical proliferation of the epithelium
o ADVANTAGES: overriding advantage is the potential regeneration of non-correctable periodontal defects
o DISADVANTAGES: according to Mellonig, 1992,
1. Increased treatment time
2. Longer post-operative treatment
3. Autografts require 2 sites
4. Increased post-op care
5. Variability in repair and predictability
6. Second surgical procedure
7. Greater expense
8. Availability of graft material
30

GRAFTING FOR NEW ATTACHMENT
◦ SELECTION OF GRAFT MATERIAL: determining factors according to Bell, 1964 and Schallhorn, 1976—
1. Osteoinductive potential
2. Predictability
3. Accesibility—ease of obtaining material
4. Availability—quantity of material obtainable
5. Safety
a. Biologic compatibility
b. Immunologic acceptability
c. Minimal sequelae—preoperatively and postoperatively
6. Rapid vascularization
CLASSIFICATION OF GRAFT MATERIALS
BY ORIGIN BY FUNCTION
1. Autografts
i. Extraoral– iliac crest marrow
a. Fresh
b. Frozen
ii. Intraoral
a. Osseous coagulum—bone blend
b. Tuberosity
c. extraction sites
d. Continuous autograft
2. Allografts
i. DFDBA
ii. FDBA
iii. Autogenous bone grafts (ABGs)
3. Xenografts– bovine, porcine, equine derived
4. Alloplasts
1. Resorbable— β-tricalcium phosphate
2. Non-resorbable– durapatite, HA
1. Osteoinductive: chemically converting the molecules present
in the grafts (e.g., BMP) to convert neighboring cells into
osteoblasts form bone.
2. Osteoconductive: graft matrix forms a scaffold that favors
external cells to penetrate graft and form new bone
3. Osteogenetic: forms new bone by cells contained in the graft
31

HISTORICALLY USED MATERIALS FOR GRAFTING OF BONE
DEFECTS
 SCLERA : originally used in periodontal procedures
Dense, fibrous connective tissue with poor vascularity and minimal cellularity
Low incidence of antigenicity and heightened immune response
Act as a barrier for apical migration of JE—protects the blood clot during initial healing
Does not induce osteogenesis/cementogenesis
Discontinued.
 CARTILAGE: used in animal and human studies
Serves as a scaffold– new attachment seen in several case studies
Limited evaluation—not in use currently.
 PoP: aka calcium sulfate
Biocompatible and porous– allows fluid exchange and prevents flap necrosis
Complete resorption in 1-2 weeks
Animal studies prove usefulness in periodontal defects– not proven in human studies yet.
 Calcium Phosphate biomaterials: excellent tissue compatibility– no inflammation/foreign body response
Osteoconductive—act as a scaffold for blood clots to be retained to allow bone formation
E.g., Hydroxyapatite (HA) and Tricalcium phosphate (TCP)
 Bioactive glass: Na and Ca salts, phosphates, SiO2– PerioGlas, BioGran etc.
 Coral-derived materials: natural coral and coral-derived porous HA 32

AUTOGENOUS BONE GRAFTS
◦ Historically– from the iliac crest. Discontinued now.
◦ Intraoral sites adjacent to defect– effective.
◦ Hegedus, 1923; Nabers & O’Leary, 1965: use of bone grafts
◦ Sources: bone from:
◦ EXTRAORAL BONE GRAFTS
- Previously used: fresh/preserved iliac cancellous marrow bone
- Used in orthopedics—useful and successful for furcation areas and supracrestal areas. (Schallhorn et al., 1972, 1976)
- DRAWBACKS:
1. Healing extraction wounds
2. Edentulous ridges
3. Trephined from jaw without damage to the roots
4. Newly formed in wounds especially created for the purpose
5. Removed from tubrerosity
6. Ramus and bone removed during osteoplasty and ostectomy
1. Post-op infections
2. Bone exfoliation
3. Sequestration
4. Varied healing rates
5. Root resorption
6. Rapid recurrence of defect– failure of treatment
7. Expensive
8. Difficult to procure donor material
ROBINSON, 1969: osseous coagulum (bone
dust+blood)
 small particles ground from cortical bone.
 Advantage: ease in obtaining of bone from an area
already exposed during surgery.
 Disadvantages:
 low predictability
 ability to procure adequate material for large
defects.
33

AUTOGRAFTS
◦ BONE BLEND: Diem et al., 1972.
- Overcome disadvantages of osseous coagulum
- Autoclaved plastic capsule + pestle
- Bone removed from a predetermined site triturated in the capsule to a workable plastic mass packed into bony defect
- Atleast as effective as iliac grafts or open curettage (Froum et al., 1975)
o CANCELLOUS BONE MARROW TRANSPLANTS
- Obtained from maxillary tuberosity, edentulous areas, healing sockets
o BONE SWAGING
- Requires an edentulous area adjacent to the defect bone is pushed into contact with the root surface WITHOUT fracturing the bone at its
base (Ross, Malamed, Amsterdam, 1966)
- Technically difficult; limited usefulness
34

ALLOGRAFTS
- Autograft harvesting requires inflicting surgical trauma on another part of the patient’s body
- Foreign material– provokes immune response
o ALLOGRAFTS: commercially available from tissue banks
o Obtained from cortical bone ~12 hours of death defatted cut in pieces washed in absolute alcohol deep-
frozen de-mineralized ground and sieved (particle size 250-750 m) freeze-dried vacuum-sealed in glass
vials.
◦ Elimination of viral infectivity from graft:
◦ Exclusion of donors from known high-risk groups
◦ Testing of cadaver tissues to exclude infections/malignancy
◦ Treatment with strong acids to inactivate residual viral matter
◦ Risk of HIV transmission via bone graft = 1: 8 million “HIGHLY REMOTE” (Mellonig et al., 1992)
FREEZE-DRIED BONE ALLOGRAFT (FDBA)
DE-MINERALIZED FREEZE-DRIED BONE ALLOGRAFT (DFDBA)
35

ALLOGRAFTS
 Freeze-Dried Bone Allografts (FDBA)
- readily obtainable from various bone banks
- Osteoconductive
- FDBA+ABGosteoinductive (Saunders et al, 1983).
- Yukna and Sepe (1982) used a combination of tetracycline and FDBA in a 4:1 ratio in 62 defects and were able to
achieve complete fill in 22 sites, >50% in 39 sites, and <50% in only 1 site.
- These results appear to be better than those when FDBA is used alone.
- FDBA>>> DFDBA in terms of osteoinductivity and -conductivity. (Yukna and Vastardis, 2005)
- Conclusion: “FDBA may stimulate earlier, more rapid, and larger quantities of new bone formations than DFDBA.”
FDBA, being readily available, appears to be an ideal material for use as a biologic expander when ABG material alone is
insufficient.
36

ALLOGRAFTS
Demineralized Freeze-Dried Bone Allografts (DFDBA)
◦ Urist (1965, 1968, 1971, 1980) showed the inductive capabilities of DFDBAs.
◦ isolated a bone morphogenetic protein (BMP) 3 or osteogenin that is capable of osteogenic induction by inducing primordial cells to
differentiate into osteoblasts.
◦ Demineralization exposes the collagen matrix that harbors the inductive proteins (BMP), thereby permitting greater inducibility.
◦ Done by processing the allograft to cold, diluted HCl exposes the components of bone matrix – BMPs.
◦ The ideal particle size is between 250-500 μm. This small size permits
1. High inductive potential
2. Easy resorption and replacement
3. Increased surface area for primordial mesenchymal cell interaction
o Particles smaller than 250 μm are absorbed quickly, and the larger ones are inadequately used.
o DFDBA meets all of the criteria for the ideal grafting material
Criteria for an Ideal Implant Material
Bone marrow Intraoral bone DFDBA Bio-Oss Alloplasts
Osteoinductive
Osteoconductive
Immediately osteogenetic
New cementum induction
Safety
Stability to remain in position
Replacement
Adequate supply
+++
+++
+++
+++
+
+++
+++
++
+
++
+
+
+++
+
+++
+++
++
++
++
++
+++
++
++
++++
–
++
–
++
+++
+++
+++
+++
–
+
–
–
+++
++
+
DFDBA = demineralized freeze-dried bone allograft.
*Bio-Oss Collagen.
Ref: COHEN’s Atlas of Periodontal Surgery 3rd edn
37

BONE SUBSTITUTES
◦ IDEAL CHARACTERISTICS OF A BONE SUBSTITUTE GRAFT
(Gross, 1997):
1. Biocompatibility
2. Serve as a scaffold (framework) for new bone formation
3. Resorbable in the long term and have the potential for
replacement by host bone
4. Osteogenic, or at least facilitate new bone formation
5. Radiopaque
6. Easy to manipulate
7. Do not support growth or oral pathogens
8. Hydrophilic (to attract and hold the clot in a particular
area)
9. Available in particulate and older forms
10. Microporous (for added strength to the regenerating
host bone matrix; allow biologic fixation)
11. Availability
12. Nonallergenic
13. Have a surface that is amenable to grafting
14. Act as a matrix or vehicle for other materials (i.e., bone
protein inducers, antibiotics)
15. Have high compressive strength
16. Are effective in GTR procedures
38

XENOGRAFTS
◦ A xenograft (heterograft) is a graft taken from another species (AAP, 2001).
◦ HISTORY:
1. CALF BONE (Boplant)– treated by detergent extraction, sterilized, freeze-dried
2. KIEL BONE (calf/ox bone)– denatured with 20% H2O2, dried with acetone, sterilized with ETOX.
3. Anorganic bone (ox bone)– organic material is extracted by ethylenediamine, sterilized and autoclaved
39

XENOGRAFTS
Currently used: BIO-OSS (Geistlich Pharma)
- Successfully used in periodontal defects and implant surgery
- Osteoconductive material
- Porous bone mineral matrix derived from bovine cortical/cancellous bone
- Organic components are stripped– trabecular architecture and porosity are retained.
- Permit clot stabilization and revascularization—allow migration of osteoblasts osteogenesis
- Biocompatible
- No systemic immune reaction
40

NEWER TECHNOLOGY– CERABONE
• USES:
1. Sinus lift
2. Horizontal and vertical augmentation
3. Ridge preservation
4. Peri-implant defects
5. Socket preservation
6. Bone defect augmentation
7. Periodontal intrabony defects
8. Furcation defects (class I and II)
◦ PROPERTIES
 100% pure natural bone mineral
 Human-like bone structure
 Rough, hydrophilic surface
 Ultimate volume stability
 Easy handling
 better hydrophilic properties
 superior diffusion of blood throughout its granules
 faster ingrowth of vessels and neo-angiogenesis.
 higher degree of volume stability on the long term
 more presence of particles in Cerabone® than in Bio-
Oss®
41

NON—GRAFT-ASSOCIATED RECONSTRUCTIVE
PROCEDURES
◦ REGENERATIVE PROCEDURES OF HISTORICAL INTEREST:
A) LANAP
B) Removal of JE and Pocket epithelium
i. Curettage
ii. Chemical agents (in conjunction with curettage)- sodium sulfide, phenol camphor, antiformin, sodium hypochlorite.
iii. Biomodification of root surface- citric acid, fibronectin, tetracycline
iv. Surgical techniques- ENAP, gingivectomy to alveolar crest (Glickman and Prichard), modified Widman flap
C) Preventing/ impeding epithelial migration
 “Root submergence” : exclusion of epithelium by amputation of crown to cover root with the flap. (Caton et al, 1992)
 Total removal of IDP covering the defect and replace it with free autograft from the palate– delays proliferation of epithelium
 Coronally displaced flaps: increase the distance between the edge of the epithelial wound and the healing area.– most often used for successful outcomes.
D) Clot stabilization, wound protection and space creation
 Preservation of root surface fibrin clot– prevents apical migration of gingival epithelium; allows connective tissue attachment in early wound healing.
42

NON—GRAFT-ASSOCIATED RECONSTRUCTIVE
PROCEDURES
BIOMODIFICATION OF ROOT SURFACE
- aka root conditioning
- CITRIC ACID:
1. Accelerated healing and new cementum– surgical detachment of gingival tissue and root demineralization
2. Topical citric acid– no effect on non-planed roots; after acid: acid produces 4 m-deep demineralized zone+ exposed collagen fibres.
3. Root planing + non CA-treated roots– smear layer forms.– removed by citric acid
4. in vitro elimination of endotoxins and bacteria from diseased area
5. Early collagen fibre exposure+ early leakage of fibrin prevention of epithelium migration over roots
- FIBRONECTIN: glycoprotein that fibroblasts require to attach to surface of root
- TETRACYCLINE:
In vitro treatment of dentin surface with tetracycline increased binding of fibronectin stimulates fibroblast attachment and growth + suppression
of epithelial cell attachment and migration.
Recommended as an adjunct for root preparation in regenerative procedures.
43

GUIDED TISSUE REGENERATION (GTR)
◦ Used to prevent epithelial migration along the cemental wall of pocket
◦ Maintain space for clot stabilization
◦ Based on the assumption: PDL and perivascular cells– potential for regenerating attachment apparatus of the tooth.
◦ Placement of barriers of different types (membranes)– cover bone and PDL SEPARATING MEDIUM from gingival epithelium and CT
◦ RATIONALE: exclusion of the epithelium and connective tissue from the radicular surface during post-surgical healing
1. Prevents epithelial migration into the wound
2. Favours re-population of the area by cells from PDL and bone
44

CLASSIFICATION OF BARRIER MEMBRANES
A) According to type
1. Non-resorbable
i. Expanded Poly Tetrafluoroethylene (e-PTFE) Gore-Tex
ii. High density poly tetrafluoroethylene (d-PTFE)
iii. Titanium mesh
iv. Titanium reinforced PTFE
2. Resorbable
i. Polymeric ( vicryl, atrisor, Epiguide) &
ii. Collagen- derived.
B) According to generation
I generation membranes:
Cellulose acetate (Millipore)
Expanded poly tetra fluoroethylene (e-PTFE), Gore Tex
Titanium reinforced ePTFE
High-density- PTFE
Titanium mesh
II Generation Membranes :
Natural: collagen or chitosan
Synthetic membranes - polyesters (e.g. polyglycolic acid -PGA)
Polylactic acid (PLA)
Polycaprolactone (PCL) and their co-polymers
III Generation Membranes:
- Barrier membranes with Antimicrobial activity: Amoxicillin, Tetracycline, 25% Doxycycline,
Metronidazole
- Barrier membranes with Bioactive Calcium Phosphate incorporation
Nano-sized hydroxyapatite (HA) particles
Nano -carbonated hydroxyapatite (nCHAC)
- Barrier membranes with Growth Factor release.
- factor (FGF-2),
- Transforming growth factor (TGF-1),
- Bone morphogenic protein( BMP-2, 4,7 and 12) and
- enamel matrix derivative (EMD).
45

CRITERIA ESSENTIAL FOR BARRIER MEMBRANE
1. Biocompatibility: The membrane must be constructed of acceptably biocompatible material. The interaction between the material and
tissue should not adversely affect the surrounding tissue, healing result, or the overall safety of patient.
2. The membrane should exhibit suitable occlusive properties to prevent fibrous connective tissue (scar) invasion of the space adjacent to
the bone and provide protection from bacterial invasion if the membrane become exposed to the oral environment.
3. Space making: The membrane must be able to provide a suitable space into which osseous regeneration can occur.
4. The membrane should be capable of integrating with or attaching to the surrounding tissue. Tissue integration helps to stabilize the
healing wound, helps to create a ―seal‖ between the bone and the material. The membrane must be clinically manageable.
Madhuri SV, International Journal of Pharmaceutical Science Invention, 2016
46

EXPANDED POLYTETRAFLUOROETHYLENE (e-PTFE)
◦ Developed in 1969
◦ Standard for bone regeneration in the early 1990s.
◦ Pores between 5 to 20 microns in the structure of the material.
◦ PTFE subjected to high tensile stress.
◦ On one side of the membrane is an open microstructure collar of 1 mm
thick and 90% porous which retards the growth of the epithelium during
the early wound healing phase;
◦ On the other side, a 0.15 mm thick and 30% porous membrane which
provides space for new bone growth and acts to prevent fibrous
ingrowth.
◦ DRAWBACKS : Exposure to oral cavity because of high porosity Removal
of membrane is difficult- extensive releasing incisions needed.
47

HIGH-DENSITY POLYTETRAFLUOROETHYLENE (d-PTFE)
◦ Developed in 1993
◦ Pore size <0.3microns
◦ To overcome the problems with e-PTFE a high density PTFE membrane (d-PTFE)
◦ Results in good bone regeneration even after exposure.
◦ Removal of d-PTFE is simple –no tissue ingrowth into the surface structure.
◦ USES: when primary closure is impossible without tension– alveolar ridge preservation,
large bone defects, and the placement of implants immediately after extraction.
◦ dPTFE membranes can be left exposed—preserve soft tissue and the position of the
mucogingival junction
◦ enhances healing
◦ gold standard membranes available currently on the market.
◦ Disadvantage: Tendency for collapse of membrane towards defect.
48

TITANIUM (Ti) MESH
◦ Advanced mechanical support which allows a larger space for bone and tissue
regrowth.
◦ The exceptional properties of rigidity, elasticity, stability and plasticity make Ti mesh
◦ Ideal alternative for e-PTFE products as non-resorbable membranes.
◦ Due to the presence of holes within the mesh, it does not interfere with the blood
supply directly from the periosteum to the underlying tissues and bone grafting
material.
◦ It is also completely biocompatible to oral tissues.
◦ Ti mesh can be used before placing dental implants (staged approach) to gain bone
volume or in conjunction with dental implant placement (nonstaged approach)
◦ The main four main advantages of Ti-mesh membranes over their alternative PTFE
membranes
◦ Disadvantage: Increased exposure due to their stiffness and also a more complex
secondary surgery to remove these membranes.
1. rigidity, which provides extensive space maintenance and
prevents contour collapse
2. elasticity, which prevents mucosal compression
3. stability to prevent graft displacement
4. plasticity that permits bending, contouring and adaptation
to any unique bony defect
49

TITANIUM-REINFORCED PTFE
◦ The embedded titanium framework allows the membrane to be shaped to fit a variety of
defects without rebounding and provides additional stability in large, non-space
maintaining osseous defects.
◦ DISADVANTAGES of Non-resorbable Membranes
1. Second surgical procedure is needed to remove the membrane which causes discomfort
and increased costs for the patients, as well as the risk of losing some of the regenerated
bone, because flap elevation results in a certain amount of crestal bone resorption.
2. Early exposure of barrier membranes to the oral environment and subsequent bacterial
colonization.
3. Wound dehiscence
4. Due to the rigidity of the non-resorbable membranes, extra stabilization of the
membrane with miniscrews and tacks are often required
50

RESORBABLE MEMBRANES
◦ POLYMERIC MEMBRANES
◦ Made up of synthetic polyesters, polyglycolides (PGAs), polylactides (PLAs), or copolymers
◦ completely biodegraded to carbon dioxide and water via the Krebs cycle and by enzymatic activity of infiltrating macrophages and
polymorphonuclear leucocytes.
◦ Processing techniques by which these membranes are fabricated include melting (i.e., polymer is heated above the glass transition
or melting temperature) or Solvent casting/particulate-leaching and phase inversion.
◦ DRAWBACKS:
1. Presence of inflammatory infiltrate around the membrane.
2. Premature membrane exposure to the oral cavity.
51

RESORBABLE MEMBRANES
◦ COLLAGEN MEMBRANES
- Either type I or combination of types I and II
- Source: tendon, dermis, skin or pericardium of bovine, porcine or human origin.
- Physical or chemical cross-linking methods, such as ultraviolet light, hexamethylene diisocyanate (HMDIC), glutaraldehyde (GA),
diphenylphosphorylazide (DPPA), formaldehyde (FA) plus irradiation, genipin (Gp), have been used to modify the biomechanical properties,
collagen matrix stability of the collagen fibers.
- Cross-linking is associated with
- prolonged biodegradation,
- reduced epithelial migration,
- decreased tissue integration and
- decreased vascularization
 Disadvantages of resorbable membranes
 Lack of space making ability compared to non resorbable membranes.
 Unpredictable degradation profile.
 Risk of disease transmission.
52

MOST RECENT ADVANCES IN GTR
1. ELECTROSPINNING (E-spinning) for membranes
2. Functionally graded multi-layered membranes
3. Membranes with antibacterial properties
4. Barrier membranes with growth factor release
5. PRF membrane
6. Amniotic membranes
- Amnion
- Chorion
- Umbilical cord
53

NEW CONCEPTS IN TISSUE ENGINEERING
54

NEW CONCEPTS IN TISSUE ENGINEERING
55

ASSESSMENT OF PERIODONTAL WOUND HEALING
A. HISTOLOGIC METHODS
- True definition of nature of repaired tissue
- Periodontal regeneration: when the newly formed functionally aligned periodontium is coronal to the apical extent of the
notches.
- Reparative tissue response: LJE, connective tissue adhesion, or root resorption+ankylosis
- This approach cannot be studied in humans– unethical: will require intentional extraction to examine
REF: Rose LF, Meaney BL, Genco RJ, Cohen DW: Periodontics: medicine, surgery, and implants, St. Louis, 2004, Mosby
56

B. CLINICAL METHODS:
- Compare pre- and post-treatment pocket probing depths
- Comparison of gingival findings, if any
** clinical determinations of attachment level are MORE USEFUL than probing pocket depths which may change as a result of displaced gingival
margin.
- Determined that the depth of penetration of a probe in periodontal pocket varies according to the degree of inflammation of the tissues
beneath the pocket
- Even though the forces used can be standardized via pressure-sensitive probes (use acrylic stent), there is an inherent margin of error that is
difficult to overcome
- Error = 1.2mm (Fowler et al, 1982)
- Hence, transgingival probing circumvents this error accurate measurement on par with surgical re-entry.
57

C. RADIOGRAPHIC METHODS:
- Allows assessment of bone adjacent to the tooth
- Carefully standardized techniques for reproducible positioning of the film and the tube
- Thin bone trabeculae may exist before treatment – may go undetected radiographically because a certain minimal amount of mineralized
tissue must be present to register on the radiograph
58

D. SURGICAL RE-ENTRY
- Provides a good view of the state of the bone crest that can be compared to the view taken during the initial surgical intervention
- Comparable with models of impressions of bone taken at initial surgery and later at re-entry to assess treatment results
- DRAWBACKS:
1. Second procedure
2. No clarity of attachment type (whether new attachment or LJE)
59

FACTORS AFFECTING SUCCESS/FAILURE OF REGENERATION
PROCEDURES
1. Plaque control
2. Underlying system disease (e.g., diabetes)
3. Root preparation
4. Adequate wound closure
5. Complete soft tissue approximation
6. Periodontal maintenance, short and long term
7. Traumatic injury to teeth and tissues
8. Defect morphology
9. Type of graft material
10. Patient’s repair potential
Mellonig, 1992
1.a. The selection of appropriate surgical technique
b. accurate assessment of the periodontal defect
c. clinician’s clinical experience
2.Importance of the tooth in the overall restorative treatment plan
3.The patient’s selection of the regenerative options
World Workshop in Periodontics, 1996; Proceedings of the 2nd European Workshop on Periodontology, 1997
60

LIMITATIONS OF REGENERATIVE TECHNOLOGIES
◦ Inability to control the formation of a long junctional epithelium
◦ Inability to adequately seal the healing site from the oral environment and prevent infection
◦ Restriction of regeneration to the bone compartment while ignoring regenerative processes in the cementogenic and fibrous compartments
◦ Inability to define precisely the growth and differentiation factors needed for regeneration
◦ The possibility that growth factors may not be sufficiently discriminative in their ability to induce regeneration, and thus the induction of
particular transcription factors as an earlier event of cell stimulation may be warranted.
◦ Infection of the implanted membrane or regenerative material postoperatively.
61

CLINICAL GUIDELINES TO GUIDE CLINICIANS IN THEIR PATIENT
MANAGEMENT
American Academy of Periodontology: J Periodontol 86[Suppl]:S77, 2015.)
62

FUTURE DIRECTIONS IN PERIODONTAL REGENERATION
1. BMP FOR PERIODONTAL AND IMPLANT SITE REGENRATION
63

2. USE OF rh- FIBROBLAST GROWTH FACTOR 2 FOR PERIODONTAL REGENERATION
64

3. CELL THERAPY
The use of stem cells provides a 3rd mechanism—suggestive that by grafting multipotent stem cells they can be organized to form a new
periodontium.
 proof-of-evidence still required.
Baboolal TG, Boxall SA et al, 2014
65

4. SCAFFOLD/SUPPORTING MATRIX
i. Allogenic/alloplastic bone-grafting materials: β-TCP + rhPDGF-BB
ii. Collagen carriers: modified forms– removal of antigenic N- and C- terminal telopeptides, Atelocollagen scaffold.
iii. Calcium Sulphate:
- Grafting
- Barrier property
- Induce angiogenesis
- Delivery vehicle for antibiotics, GFs
- Local pH decrease
iv. Others: bioresorbable polymers of polylactic-co-glycolic acid and polyglycolic acid.
66

CONCLUSION
◦ Therapeutic goal of periodontal regeneration is difficult to achieve– several limitations
◦ With the advent of new regenerative approaches, such as biologic modifiers such as EMD and growth factors, we must
critically evaluate how they may improve our ability to regenerate periodontal defects.
◦ Periodontal regeneration continues to be one of the primary therapeutic approaches towards the management of bone
defects.
◦ The crucial challenge for the clinician is to assess critically whether a periodontal defect can be corrected with a
regenerative approach, or whether it would be better managed with another approach.
◦ Significance of clinical success of the procedures and technique undertaken over studies.
67

REFERENCES
1. COHEN’S Atlas of Periodontal Surgery, 3rd Edition
2. CARRANZA’s Clinical Periodontology, 13th Edition
3. AAP Position Paper on Periodontal Regeneration, 2005
4. Elgali et al., Eur Jou Oral Sc, 2017
5. Xu, Li, Wang et al., Stem Cells Translational Medicine, 2018
68

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