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REVIEW ARTICLE
Year : 2018  |  Volume : 9  |  Issue : 3  |  Page : 119-124

Critical issues in periodontal regeneration


Department of Periodontology, VSPM Dental College and Research Centre, Nagpur, Maharashtra, India

Date of Web Publication27-Sep-2018

Correspondence Address:
Surekha Rathod
A/24 Ring Road, Mahalgi Nagar, Nagpur, Maharashtra
India
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DOI: 10.4103/srmjrds.srmjrds_17_18

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  Abstract 

Periodontal disease is an inflammatory disease of the periodontium. It begins with the relatively benign gingivitis and becomes more established and destructive depending on the host, genetic, and environmental factors such as long-term plaque and calculus deposition. Subsequently, the connective tissue attachment to the root surface is lost causing bone resorption and formation of a periodontal pocket. We are in a new age of synthesis that demands vision, capabilities, logical reduction, and critical analysis for a constructive progress. In contrast to the conventional approaches of anti-inflammatory periodontal therapy, however, the regenerative procedures aimed at repairing lost periodontal tissues, including alveolar bone, periodontal ligament, and root cementum, remain more challenging and rapidly progressive periodontitis is attained.

Keywords: Periodontal defect, periodontal tissue, regeneration


How to cite this article:
Maske B S, Rathod S, Wanikar I. Critical issues in periodontal regeneration. SRM J Res Dent Sci 2018;9:119-24

How to cite this URL:
Maske B S, Rathod S, Wanikar I. Critical issues in periodontal regeneration. SRM J Res Dent Sci [serial online] 2018 [cited 2018 Nov 14];9:119-24. Available from: http://www.srmjrds.in/text.asp?2018/9/3/119/242447


  Introduction Top


Periodontal disease is triggered by the host's immune response to the accumulation of oral microorganisms, resulting in the progressive destruction of the periodontium and premature loss of the teeth. It has also been linked to many systemic disorders, such as diabetes, rheumatoid arthritis, cardiovascular complications, and adverse pregnancy outcomes that significantly impact a patient's quality of life and financially impacts patients and public health-care system.[1]

Periodontal research has systematically attempted to identify clinical procedures that are predictably successful in regenerating periodontal tissues.

In contrast to the conventional approaches of anti-inflammatory periodontal therapy, the regenerative procedures aim at restoring lost periodontal tissues and remain more challenging.


  What is Regeneration? Top


To understand the outcomes of periodontal therapy precisely, the following terms have been defined (the American Academy of Periodontology, 1992):

  • Periodontal repair is the restoration of new tissue that does not replicate the structure and function of lost tissue and is analogous to scar tissue formation
  • Periodontal regeneration is defined histologically as reconstitution or reproduction of the tooth's supporting tissues, including alveolar bone, periodontal ligament, and cementum over a diseased root surface and restoring the lost function
  • New attachment of junctional epithelium to the tooth surface and connective tissue fibers to the root surface is very critical components of true periodontal regeneration.[1]



  Four Criteria for Periodontal Regeneration (Bartold et al., 2000) Top


  1. A functional epithelial seal must be reestablished at the most coronal portion of the tissues and no >2 mm in length
  2. New connective tissue fibers (Sharpey's fibers) must be inserted into the previously exposed root surface to reproduce both the periodontal ligament and the dentogingival fiber complex
  3. New acellular, extrinsic fiber cementum must be reformed on the previously exposed root surface
  4. Alveolar bone height must be restored to within 2 mm of the cementoenamel junction [Figure 1].[1],[2]
Figure 1: Differences between gingival and periodontal regeneration (1. tooth, 2. cementum, 3. calculus, 4. alveolar bone)

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Various therapeutic modalities employed for the treatment of periodontitis that leads to either repair or regeneration have been enlisted below:

  • Nonsurgical therapy includes scaling and root planning and curettage procedure
  • Surgical therapy consists bone graft, guided tissue regeneration, tissue engineering, endogenous regenerative therapy, gene and cell-based therapy, and root coverage.


Effective disease elimination is a key step to regeneration. Although nonsurgical therapy has been found to play no significant role in regeneration, its virtue in creating a conductive environment for regeneration cannot be disregarded. However, the surgical therapies for soft and hard tissue regeneration also have unpredictable outcomes.[3]

Nonsurgical therapy

Effective disease elimination is a key step to regeneration. Scaling and root planing using hand instruments and sonic/ultrasonic scalers or lasers effectively treats chronic periodontitis by removing bacterial biofilm, calculus, and contaminated cementum. It induces bacteremia; antibodies thus produced, act as vaccines, limit the local infection, and further enhance periodontal regeneration.[3]

Surgical therapy

Root biomodification leads to the formation of new attachment. Even though it fails to replenish the lost periodontium, it can be used as an adjunct in regeneration.[4]

Biologic concept behind root surface demineralization is to improve blood clot adhesion to expose collagen fibrile result effective wound healing and regeneration. citric acid has ability to detoxify root surface. some report shown that treatment with citric acid and phosphoric acid can result in root resorption and ankylosis and the chelating EDTA possesses higher pH than acid hence can be advocated as adjunct to regeneration procedure, for example, in combination with enamel matrix proteins.[5],[6]

Bone grafts

How predictable is the regeneration with bone grafts and bone substitute materials?

Bone grafts/substitutes, solely, do not possess the ability to regenerate the lost connective tissue attachment. Osteointegration between the preexisting bone and newly formed bone is important.[3] Various studies conducted on different bone fillers gave following conclusions [Table 1].[1]
Table 1: Various studies conducted on different bone fillers gave following conclusions[1]

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Amount of regeneration depends on as follows:

  • Clinical skills and expertise
  • Defect type
  • Particle size (>125 mm)
  • Porosity (100–135 nm)
  • Composition of the graft material dynamic loading due to stress. Differences between gingival and periodontal regeneration (1. tooth, 2. cementum, 3. calculus, 4. alveolar bone) [Figure 2]
Figure 2: Prevention of down growth of gingival epithelium using bone graft and bioresorbable barrier membrane that leads to the regeneration of bone PDL and cementum (1. tooth, 2. cementum, 3. periodontal ligament, 4. alveolar bone, 5. junctional epithelium, 6. bioresorbable barrier membrane)

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The formation of a connective tissue attachment may be absent or may not progress beyond what can be achieved with conventional therapy (i.e., open flap surgery alone).

The issue is despite acceptable osteogenic potential and unlimited availability of all the biomaterials, autografts are still considered as the gold standard. However, allografts are widely used for regeneration of contained defects.

Guided tissue regeneration

Can guided tissue regeneration with barrier membranes provide true regeneration?

The contribution of most grafts to regeneration was often tested together with a barrier membrane. Thus, the issue that arises is the often observed histological evidence of new connective tissue attachment. This is probably related to the barrier function and not to the supporting materials.

Two meta-analyses have concluded that guided tissue regeneration (GTR) yields greater clinical attachment gain than open flap debridement (OFD) alone for intrabony and furcation defects.[8] The predominant healing is through new connective tissue attachment to the root surface with minor contributions of new cementum and bone formation.


  The Critical Issues Faced on the Success of Guided Tissue Regeneration Top


  • Defect site, size, selection, and recall schedule
  • Degree of exposure of membranes to the oral environment
  • Degree of inevitable contamination with bacteria and harmful degradation products of synthetic membranes.


Some authors conclude that infrabony defects and Class II furcation defects successfully regenerated, but Class III furcation and 1-wall infrabony defects show unpredictable outcomes.[9],[10]

Endogenous regenerative therapy

The host immune system determines the response against this multifactorial disease and can be modulated by various bioactive molecules [Figure 3].
Figure 3: Various bioactive molecules

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Research on these factors supports positive outcomes reported that PepGen-15 is polypeptide growth factors of 15 amino acids which mimics the cell-binding domain of type I collagen combined with an organic bovine bone-derived hydroxyapatite matrix. Studies yield better clinical outcomes found to be stable up to 3 years, compared to the carrier alone.[11],[12]

Enamel matrix derivative which is produced by Hertwig's epithelial sheath shows causal relationship between enamel matrix proteins and cementogenesis, and periodontal attachment apparatus also used local adjunct to periodontal surgery, infrabony defects for stimulating regeneration of periodontal tissues, and maintained stable outcomes over the years.[13],[14],[15],[16],[17],[18]

Platelet-rich plasma used in various surgical fields, including maxillofacial and periodontal surgery with the expectation of enhancing bone and soft-tissue healing.[19]

Growth factors regulate cell proliferation, cell activity, chemotaxis, and cell differentiation heterogeneity in studies regarding study design, animal and periodontal defect model, types of growth factors, and carrier vehicles.

Exception of GEM 21S® a β-TCP/rhPDGF-BB combination achieved successful periodontal regeneration.[20]

Bone morphogenetic proteins responsible for formation of new cementum and new bone with inserting periodontal ligament fibers support wound healing and new periodontal tissue formation.

No studies have compared P-15® with the gold standard of GTR. Nevertheless, even the most promising growth factors appear to particularly include critical issues as follows:[21]

  1. The complexity of the periodontium, which consists of four different tissues; one therapeutically applied growth factor can restore the complexity of the periodontium?
  2. The use of very high doses of bone morphogenetic proteins
  3. The ideal carrier has still not been found
  4. The enormous costs that are associated with recombinant human bone morphogenetic proteins in relation to relatively small and nonlife-threatening periodontal defects for which other treatment options exist
  5. Restricted understanding of the differentiation repertoire of the periodontal cells the exact target cells that are to be modulated by these factors
  6. Stability of the tissues that are to be formed under the influence of these factors; use of very high doses of bone morphogenetic proteins.


However, further investigation is needed to facilitate the clinical translation of the polypeptide growth factors and their delivery systems.


  Gene and Cell-Based Therapy Top


How effective is gene therapy in regeneration?

Local application of growth factors encourages periodontal regeneration. Techniques to improve growth factor delivery and release become very crucial. In gene transfer, genes for regeneration-promoting growth factors using plasmid and adenovirus gene delivery methods are used [Figure 4].
Figure 4: Application of gene vectors for the transduction of growth factors producing target cells (1. tooth, 2. cementum, 3. periodontal ligament, 4. alveolar bone, 5. gene vector)

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Some author reported the use of adenoviral vectors encoding for growth factors such as platelet-derived growth factor and bone morphogenetic protein-7 sustained transgene expression for up to 10 days and enhanced bone and cementum regeneration at treated sites beyond this period compared to the sites treated with control vectors.[22]

An important issue is to optimize the number of cells that are virally transduced to express specific genes. The overall control of the process including both initiation and stoppage of the genes to modify the tissues becomes very crucial. In addition, research is required to assess the potential risks of the immunogenicity of viral recombination, which could significantly alter the success of gene transfer therapies for periodontal regeneration.[23]

Despite the commendable progress research has made in the form of gene delivery, this method stands unapproachable, expensive with a risk of multigene disorders and potential problems to the patient, for example, toxicity, immune and inflammatory responses and gene control and targeting issues.

Tissue engineering

Tissue engineering as proposed by Langer et al. comprises multiple progenitor cells, signaling molecules, and conductive extracellular matrix scaffold, along with an adequate blood supply.

Scaffolds act as the extracellular matrix creating an environment suitable for cell proliferation and differentiation for a limited period. Hence, scaffolds should fulfill certain requirements such as shape, pore size, and rate of porosity to provide a viable extracellular matrix to the cells.

Signaling molecules also referred to as immune modulatory polypeptides are essential to enhance cellular activities such as cell proliferation, differentiation, migration, and apoptosis. Finally, progenitor cells or stem cells thriving within the scaffolds process the signals and carry out tissue regeneration.

According to Hynes et al., the most critical component of tissue engineering is the choice of stem cell.[24] Stem cells can be extracted from the following sources [Table 2].
Table 2: Various stem cells and its advantages and issues

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  Root Coverage Top


Evidence indicates that the use of a graft under a coronally advanced flap results in the best short-term and long-term outcomes regarding root coverage and gain in keratinized tissue with the highest prevalence of success. A critical issue here is the choice of autogenous and allogenic soft-tissue graft material to promote regeneration.

Choice can be made depending on the objectives of treatment and flap design, thickness of keratinized gingiva, width of the attached gingiva, flap tension, flap position, adaptation, and stability.[27] Prato et al. have proposed a decision-making tree which aids in deciding the approach for recession coverage. Nevertheless, success is equally dependent on the operator skills.[28]


  Evaluation of Regeneration Top


The outcome of any regenerative periodontal treatment is clinically assessed by parameters and reentry evaluations. Although these age-old techniques are simple, they are inappropriate to assess true attachment gain. Histological evaluation of the regenerated tissues is the only reliable method of assessing true attachment. However, it is invasive technique, so new methods to evaluate regeneration should be researched.[1]

Future prospects

Three-dimensional complex shapes or structures can be computer generated, constructed in a three-dimensional printer, and then used as protein or cellular carriers for custom implantable bone graft substitutes. Various interactions between the different types of periodontal cells and the effect of mechanical stress on periodontal regeneration in the periodontium need to be assessed. A deeper understanding of the molecular signaling (both intra and extracellular) and cellular differentiation processes involved in the regenerative processes would help in making a much wiser decision regarding true periodontal regeneration.


  Conclusion Top


The surgical protocols for regenerative procedures are skill demanding that positively affects the outcome of both soft and hard tissue regeneration. However, the clinical success for periodontal regeneration still remains limited in many cases due to lack of practicability for some clinicians.

In addition, whether the slight clinical improvements offered by these procedures over routine OFD procedures are of cost or patient benefit with regard to improved periodontal health and retention of the teeth remains to be established. Further advancements in the field will continue to rely heavily on multidisciplinary approaches, combining engineering, dentistry, medicine, and infectious disease specialists in repairing the complex periodontal wound environment.

“Making good decisions are crucial at every step.”

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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2.
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8.
Jepsen K, Heinz B, Halben JH, Jepsen S. Treatment of gingival recession with titanium reinforced barrier membranes versus connective tissue grafts. J Periodontol 1998;69:383-91.  Back to cited text no. 8
    
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Eickholz P, Pretzl B, Holle R, Kim TS. Long-term results of guided tissue regeneration therapy with non-resorbable and bioabsorbable barriers. III. Class II furcations after 10 years. J Periodontol 2006;77:88-94.  Back to cited text no. 9
    
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Bhatnagar RS, Qian JJ, Wedrychowska A, Sadeghi M, Wu YM, Smith N, et al. Design of biomimetic habitats for tissue engineering with P-15, a synthetic peptide analogue of collagen. Tissue Eng 1999;5:53-65.  Back to cited text no. 11
    
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14.
Kalpidis CD, Ruben MP. Treatment of intrabony periodontal defects with enamel matrix derivative: A literature review. J Periodontol 2002;73:1360-76.  Back to cited text no. 14
    
15.
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Sculean A, Schwarz F, Chiantella GC, Donos N, Arweiler NB, Brecx M, et al. Five-year results of a prospective, randomized, controlled study evaluating treatment of intra-bony defects with a natural bone mineral and GTR. J Clin Periodontol 2007;34:72-7.  Back to cited text no. 17
    
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Koop R, Merheb J, Quirynen M. Periodontal regeneration with enamel matrix derivative in reconstructive periodontal therapy: A systematic review. J Periodontol 2012;83:707-20.  Back to cited text no. 18
    
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20.
Trombelli L, Farina R. Clinical outcomes with bioactive agents alone or in combination with grafting or guided tissue regeneration. J Clin Periodontol 2008;35:117-35.  Back to cited text no. 20
    
21.
Ripamonti U, Petit JC. Bone morphogenetic proteins, cementogenesis, myoblastic stem cells and the induction of periodontal tissue regeneration. Cytokine Growth Factor Rev 2009;20:489-99.  Back to cited text no. 21
    
22.
Anusaksathien O, Webb SA, Jin QM, Giannobile WV. Platelet-derived growth factor gene delivery stimulates ex vivo gingival repair. Tissue Eng 2003;9:745-56.  Back to cited text no. 22
    
23.
Imperiale MJ, Kochanek S. Adenovirus vectors: Biology, design, and production. Curr Top Microbiol Immunol 2004;273:335-57.  Back to cited text no. 23
    
24.
Hynes K, Menicanin D, Gronthos S, Bartold PM. Clinical utility of stem cells for periodontal regeneration. Periodontol 2000 2012;59:203-27.  Back to cited text no. 24
    
25.
Yamada S, Murakami S, Matoba R, Ozawa Y, Yokokoji T, Nakahira Y, et al. Expression profile of active genes in human periodontal ligament and isolation of PLAP-1, a novel SLRP family gene. Gene 2001;275:279-86.  Back to cited text no. 25
    
26.
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27.
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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Gene and Cell-Ba...
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