History of periodontal regenerative therapy

Introduction:

With the introduction and advancements in the surgical periodontal pocket therapy, our understanding regarding bone defects and healing following flap surgeries improved dramatically. 1970’s and 80’s may be regarded as two decades when our basic understanding regarding surgical periodontal therapy improved and it was demonstrated that lost periodontal tissue can be regenerated. Many researchers working on outcomes of non-surgical and surgical periodontal therapy published their research work during this period.

The future of periodontal treatment is regeneration of lost periodontal structures. So, it becomes compulsory to understand the historical aspect of periodontal regenerative therapy. In the following discussion we shall study in detail, how regenerative periodontal therapy came into picture, advancements that took place in this field and where we stand now.

Important terminologies:

It is important to clearly understand following terms before we go ahead with our main discussion,

Regeneration:

Regeneration is defined as a reproduction or reconstruction of a lost or injured part in such a way that the architecture and function of the lost or injured tissues are completely restored 1. From periodontal point of view it means, formation and insertion of new periodontal ligament fibers in newly formed cementum on one side and newly formed alveolar bone on the other side. In 1969, Melcher defined regeneration as a biologic process by which the architecture and function of lost tissue is completely renewed.

New attachment:

It describes new cementum formation with inserting collagen fibers on a root previously denuded of its periodontal ligament. Periodontal regeneration is differentiated from new attachment in that it must include new bone formation 2.  

Reattachment:

It refers to repair in areas of the………………………..

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Repair:

It is the biologic process by which continuity of disrupted tissue is restored by new tissues which do not replicate the structure and function of the lost tissue  3. In simple words repair can be described as healing by formation of scar tissue. Repair can be mediated by formation of long junctional epithelium and bone fill. Root resorption, ankylosis and fibrous adhesion can also be seen.

Bone fill:

It is defined as the clinical restoration of the bone tissue in a previously treated periodontal defect. Presence of bone fill does not mean that new attachment has taken place (which can only be demonstrated by histological evaluation). It just indicates presence of new bone in the surgically treated periodontal bony defect.

Epithelial adaptation: 

It is the close apposition of gingival epithelium to the tooth without complete obliteration of pocket.

It must be understood that periodontal treatment may result in different outcomes depending upon various factors like type of bone defect, procedures utilized in treatment, healing response of the patient and additional regenerative methods used (discussed later). Following image shows the expected outcomes of periodontal therapy.

Expected outcomes of periodontal therapy

Outcomes of periodontal therapy

Historical aspect of periodontal regenerative therapy:

How it started?

Initial research work clearly demonstrated association of bacterial etiology of periodontitis. It was also clear that periodontitis leads to destruction of supporting bone and creates periodontal bone defects. The detailed description of periodontal bone destruction in periodontitis is available inPatterns of bone destruction in inflammatory periodontal diseases”. So, based upon these factors, the periodontal treatment was focused at achieving two objectives: Primary objective was to eliminate bacterial plaque and secondary objective was to eliminate the anatomical defects produced by periodontitis. There are two ways to eliminate these bony defects both of which are surgical,

Resective osseous surgery:

Wherein the bony architecture is modified by removal or reshaping of supporting bone. Details are available in “Osseous resective surgeries”.

Regenerative surgical procedures:

Wherein there is attempt to regenerate new bone and periodontal ligament thereby coronally displacing the attachment apparatus and thus gingival margin.   

Methods to evaluate regeneration/new attachment:

To evaluate the outcome of surgical therapy various procedures were employed which included pre and post-surgical probing measurements, examination of radiographs, re-entry procedures and histological examination 4. The periodontal probing procedure is widely used for pre and post-operative pocket depth reduction. This procedure can give us pocket depth measurements but cannot accurately determine the level of connective tissue attachment on toot surface which is required to determine whether regeneration has taken place or not. Similarly, radiographs can demonstrate the changes in pre and post-operative bone levels but cannot determine whether there is any periodontal ligament present between the bone and tooth surface which is indicative of new attachment. Surgical re-entry in the operated area………………

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Where the progenitor cell population resides?

For periodontal regeneration we need to regenerate new periodontal ligament, alveolar bone and cementum and more importantly this re-formation of tissue is expected on previously diseased root surface. But, can regeneration occur on previously diseased root surface ? Where does the progenitor cell population resides which is expected to do regeneration ? Is it the alveolar bone, gingival connective tissue or periodontal ligament ?

Let us try to find out the answers for these questions by discussing some studies which were designed to address these questions,

Whether new attachment depends upon normal/diseased root surface or normal/reduced periodontium?

Polson and Caton 8 (1982) designed an experimental study on rhesus monkeys. Experimental periodontitis was induced around single maxillary central incisor. Then, both the maxillary central incisors were extracted and autotransplanted. Tooth with normal root surface was transplanted in reduced periodontium and tooth with diseased root surface (involved with periodontitis) was transplanted in normal periodontium. The teeth were splinted and left in place for 40 days. After 40 days radiographic evaluation showed a crestal bone loss around periodontitis affect tooth. Histological evaluation of teeth demonstrated that normal teeth which were transplanted in reduced periodontium demonstrated a connective tissue re-attachment which approximated the cementoenamel junction. The fiber morphology indicated continuity in attachment with cementum as shown by adjacent connective tissue.  In periodontitis affected teeth which were transplanted in normal periodontium, the epithelium that lined the sulcus extended in an apical direction along the cemental surface considerably apical to the crest of alveolar bone.

So, results of this study demonstrated that it is the exposed root surface and not lack of periodontium which inhibits a new connective tissue attachment.

Whether presence of alveolar bone has any influence on new attachment?

Lindhe et al 9 (1982) addressed same question in an experimental study done on monkeys. In this study maxillary and mandibular central incisors were extracted and placed in their own socket in four situations which included: non-root planed teeth placed in sockets with normal bone height, non-root planed teeth placed in sockets with reduced bone height, root planed teeth placed in sockets with normal bone height and root planed teeth placed in sockets with reduced bone height. After 6 months when histological examination was done, it was found that fibrous reunion was established in areas where at the time of re-implantation, periodontal connective tissue attachment was retained. In areas where root planing was done to remove connective tissue attachment, epithelium migration was seen irrespective of presence or absence of bone.

So, it was concluded that establishment of connective tissue attachment was not related to the presence of bone.

Melcher 10 (1976) in a review described that……………………

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Whether the progenitor cell population is derived from alveolar bone?

Karring et al. 11 (1980) carried out an experimental study on dogs where they extracted the roots of periodontitis affected teeth and placed them in surgically created sockets in edentulous areas of dog. These sockets were prepared in such a way that they prevented migration of epithelium and bacterial infection during wound healing.  After a healing interval of 3 months, histological examination was done. It was found that in apical areas where periodontal ligament was retained during implantation, it was again re-established. In coronal areas of root which were affected by periodontitis and were scaled and root planed ankylosis or root resorption resulted.

So, results of the study revealed that cells derived from bone lack potential to produce new attachment.

Whether the progenitor cell population is derived from gingival connective tissue?

Nyman et al. 12 (1980) in this study followed the same study design as above but, the bone cavities were prepared on the buccal surface of the jaw and root specimens were placed which were subsequently covered by flap. In this way half of the root surface was in contact with connective tissue and half surface was in contact with the bone. After a healing period of 3 months, histological examination was done. It was found that in apical areas of root where periodontal ligament was retained during implantation, it was re-established. Periodontitis affected root surface which was scaled and root planed, no new attachment was observed. These areas were covered by connective tissue with fibers oriented parallel to the root surface having no attachment to the root surface. Root resorption was seen in many areas.

So, the results of the study revealed that connective tissue lacks cells which have a potential to produce new attachment.

Whether the progenitor cell population is derived from periodontal ligament?

Karring et al. 13 (1985) in an animal experiment, examined whether a new connective tissue attachment was form on previously periodontitis-involved roots when reduced but healthy periodontal ligament tissue persists following periodontal treatment.  The migration of epithelial cells was prevented into the healing site. After producing experimental periodontitis, when 50% of bone support of teeth was lost, the periodontal treatment was done to remove pocket epithelium and granulation tissue. The crowns were resected and roots were covered with a mucosal flap. The animals were sacrificed after 3 months of healing and histological examination was done. It was found that………………

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Nymen et al. 14 (1982), in an experiment on non-human primates, created fenestration defects on the buccal aspect of maxillary lateral incisors and mandibular canines. A millipore filter was placed to cover the fenestration defects with the aim of preventing gingival connective tissue from contacting the root surface. New cementum with a functionally oriented periodontal ligament was observed within a 6-month healing interval. Then, they replicated the same experiment on humans and subsequently provided the first evidence that periodontal regeneration can be obtained at a periodontitis-affected tooth in a human 15.

Results of the study clearly showed new connective tissue attachment from cells originating from periodontal ligament.

Warrer et al. 16 (1993) did a study on dental implants, where implants were placed in contact with the retained root tips of teeth. The periodontal ligament around these retained roots served as source of cells during healing around implants. Results of the study demonstrated formation of distinct layer of cementum on implant surface with inserting collagen fibers which were most of the times oriented perpendicularly to the surface, embedded in the opposite bone.

Results of the study clarified that cells originating from periodontal ligament have potential to make new connective tissue attachment.

Later on many studies confirmed that it is the cells from the periodontal ligament (PDL) that are responsible for the re-establishment of periodontal attachment 17, 18. In addition, it was also shown that exclusion of the junctional epithelial cells from the treated root surface in the early stages of periodontal wound healing favours repopulation of the root surface by PDL cells, which favours the re-establishment of a normal connective tissue attachment 17, 19.

Concept of guided tissue regeneration:

From the above studies and many other studies it became clear that cells form periodontal ligament should be allowed to proliferate in order to achieve new connective tissue attachment. When healing takes place, every tissue has equal opportunity to proliferate and among all epithelium grows at fastest rate. Migration of the junctional epithelium into periodontal defects and the formation of sub-gingival plaque are thought to be the primary impediments to the re-establishment of normal connective tissue attachments 20. So, there should be some kind of barrier which should prevent epithelium and other cells form gingival connective tissue to enter the site of healing to facilitate regeneration by periodontal ligament cells.

Keeping all these factors in mind concept of guided tissue regeneration was given. The procedure involves…………………..

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Guided tissue regeneration

Guided tissue regeneration

The initial membranes used such as ePTFE were non resorbable, so they had to be removed later on. With due course of time, resorbable membranes such as made of glycolide and lactide polymers, collagen etc. were introduced which did not required additional surgery for removal. The detailed description of these is available in “Guided tissue regeneration”.

Root surface bio-modification:

The concept of root surface bio-modification is based upon the fact that root surface plays an important role in formation of new connective tissue attachment and modifications can be done on root surface to further enhance new attachment. This technique has the ability to modify the root surface by “detoxifying the surface” 25.

 The history of root surface bio-modification can be traced back to Marshall 26 (1833), who presented a case of pocket eradication with “presumable clinical reattachment” after the use of aromatic sulphuric acid. Later, Stewart in 1890’s recommended mechanical removal of calculus and cementum along with acid application 27. Work done by Urist brought acid demineralization of root surfaces under limelight. In 1965, Urist suggested that following acid demineralization, dentin possessed inductive properties 28. Then, using O.6N HCl they partially or totally demineralised allogenic dentin matrix and transplanted it in vivo in various animal models. Results of the studies demonstrated that these transplants induced the formation of new bone or cementum 29.

In 1973, Register performed a systematically designed controlled study were the potential of demineralization to induce cementogenesis, osteogenesis and new attachment was assessed. Results of the study showed that optimum cementogenesis and new connective tissue attachment occurred when roots were demineralised with citric acid at pH 1 for 2-3 minutes 30. Presently, various agents are used for root surface demineralization including citric acid, polyacrylic acid, fibronectin, laminin, tetracycline, doxycycline, ethylenediaminetetraacetic acid (EDTA) etc. A detailed description on this topic is available in “Root surface bio-modification”.

Bone grafts:

Another way of enhancing periodontal regeneration was putting bone graft in osseous defects. The use of bone grafts in periodontal therapy can be traced to the work of Hegedus 31 (1923). Beube and Silvers 32 in 1936 used boiled cow bone powder to successfully repair intrabony defects in humans. Anorganic bone (bovine bone from which the organic material is extracted by means of ethylenediamine) was used by Melcher in 1962 in 187 bone defects which were followed for three years. He reported sequestration and slow resorption of the graft 33.

Although freeze-dried bone allografts (FDBA) were being used in orthopaedic medicine since 1950’s, they were introduced to periodontics during early 1970’s. Bioplant, derived from bovine bone which was prepared by detergent extraction, chloroform methanol extraction to reduce lipid content, sterilization in propiolactone, and freeze drying was introduced during this period, but due to un-successful results, it was discontinued.

Autogenous grafts have osteoinductive properties. Their application for periodontal bone defects can be traced back to Nabers and O’Leary  34 (1965), who used cortical bone chips as grafting material. Later on, Robinson 35 in 1969 and Jacobs and Rosenberg 36 in 1984, introduced the application of osseous coagulum and bone blend (Intra-oral bone obtained with high or low speed round burs and mixed with blood). Intraoral cancellous bone and marrow grafts were used as autogenous grafts by various authors including Hiatt and Schallhorn 37, Ross and Cohen 38, Soehren and Von Swol 39, Halliday 40 and Rosenberg 41. Extra-oral sites for autogenous graft harvesting have been suggested by many authors. Schallhorn 42 (1968) suggested either the anterior or the posterior iliac crest for graft harvesting.

The problems associated with autogenous bone graft harvesting namely, morbidity accompanying a second surgical site and the need for a sufficient quantity of material to fill multiple defects led to development of allograft materials. Presently, three types of bone allografts are used clinically. Undermineralized (mineralized), freeze-dried bone allograft (FDBA) and demineralized freeze-dried bone allograft (DFDBA).

Initially, various researchers had their reservations regarding bone graft usage in periodontal defects. According to some, bone grafting materials will enhance regeneration of a new attachment apparatus 43. While others disapproved usage of bone grafts in periodontal defects saying that there was no evidence in human trials that clearly demonstrated new attachment 44.

The first field test study was initiated in 1972 in United States in………….

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Presently, we have a large database regarding applications of different types of bone grafts, their success rate and long term stability of results. A detailed description of graft associated regenerative techniques is available in “Bone grafts in periodontics”.

Presently a combination of procedures is usually done, where barrier membrane as well as bone graft is placed in the defect for better regeneration. 

Guided tissue regeneration with bone graft placement in the defect

Guided tissue regeneration with bone graft placement.

Know more…………Classification of periodontal regenerative procedures:

From the above discussion it is clear that there are multiple techniques which are utilized for achieving new attachment. For the ease of understanding these procedures can be divided into two groups,

  • Non-graft associated periodontal regenerative techniques
  • Graft associated periodontal regenerative techniques

But, it must be remembered that this classification is just for theoretical purpose. Presently, combination of non-graft associated and graft associated procedures suitable for a particular patient are applied to achieve best clinical results.

 

Application of growth factors in periodontal regeneration:

Presently, we have sufficient scientific evidence which supports an important role of growth factors and other molecules in periodontal regeneration. Growth factors are proteins that may act locally or systemically to affect the growth and function of cells in several ways. The concept behind this therapy is to create an environment which is close to that present during embryonic and post-natal development. The signalling molecules that have been most intensively investigated in periodontal regeneration include bone morphogenetic proteins (BMPs, e.g. BMP-2, BMP-7, & BMP-12) 48-57, transforming growth factor (TGF)-β1 58, 59,  platelet-derived growth factors (PDGFs, such as PDGF-BB) 60-63, insulin-like growth factor (IGF)-1 64-66, and basic fibroblast growth factor (b-FGF) 67-70. Detailed description on this topic is available in “Growth factors in periodontal regeneration”.

Conclusion:

My aim through above discussion was to give a brief idea to the readers regarding, where we started in the field of periodontal regeneration where do we stand presently. With clear understanding of historical aspect of periodontal regeneration, now we can go ahead with the discussion of recent techniques, materials and other advances in this field. A detailed description of above stated techniques is available in “Root surface bio-modification”, “Guided tissue regeneration”“Bone grafts in periodontics” and “Guided bone regeneration”. For a better understanding of application of growth factors in periodontal regeneration, readers must go through “Biology of periodontal regeneration”.

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References:

References available in the hard copy of the website

Periobasics: A textbook of periodontics and implantology

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