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DRJ Dent Res J Dental Research Journal Dental Research Journal 1735-3327 2008-0255 Medknow Publications Pvt Ltd India DRJ-11-154 Review Article Periodontio-integrated implants: A revolutionary concept Gulati Minkle Anand Vishal Govila Vivek Jain Nikil Rastogi Pavitra Bahuguna Rohit Anand Bhargavi Department of Periodontics, Babu Banarasi Das College of Dental Sciences, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India Department of Periodontics, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India Department of Periodontics, Babu Banarasi Das College of Dental Sciences, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India Department of Oral and Maxillofacial Surgery, Vinayaka Missions Sankarachariyar Dental College, Salem, Tamil Nadu, India Department of Periodontics, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India Department of Prosthodontics, Sardar Patel Post Graduate Institute of Medical and Dental Sciences, Lucknow, Uttar Pradesh, India Department of Prosthodontics, Sardar Patel Post Graduate Institute of Medical and Dental Sciences, Lucknow, Uttar Pradesh, India Address for correspondence:Minkle Gulati, C/O. Mr. Saranpal Singh Gulati, 54-L, Model Town, Karnal, Haryana, India mink_gulati@rediffmail.com Mar–Apr 2014 11 2 154 162 Copyright: © Dental Research Journal 2014

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Though the fields of regenerative dentistry and tissue engineering have undergone significant advancements, yet its application to the field of implant-dentistry is lacking; in the sense that presently the implants are being placed with the aim of attaining osseointegration without giving consideration to the regeneration of periodontium around the implant. The following article reveals the clinical benefits of such periodontio-integrated implants and reviews the relevant scientific proofs. A comprehensive research to provide scientific evidence supporting the feasibility of periodontio-integrated implants was carried out using various online resources such as PubMed, Wiley-Blackwell, Elsevier etc., to retrieve studies published between 1980 and 2012 using the following key words: "implant," "tissue engineering," "periodontium," "osseo-integration," "osseoperception," "regeneration" (and their synonyms) and it was found that in the past three decades, several successful experiments have been conducted to devise "implant supported by the periodontium"that can maintain form, function and potential proprioceptive responses similar to a natural tooth. Based on these staunch evidences, the possibility of the future clinical use of such implant can be strongly stated which would revolutionize the implant dentistry and will be favored by the patients as well. However, further studies are required to validate the same.

 Implant osseointegration periodontium tissue engineering </sec> <sec> <title>Introduction

Since, the description of the process of osseointegration by Brånemark et al., dental implants have become ideal replacements for missing teeth. 1 The term osseointegration was later defined by Albrektsson et al. 2 as the direct contact between living bone and implant at the light microscope level. This means that the implants are functionally ankylosed to the bone without periodontal ligament support. However, despite good success rates of osseointegrated oral implants, failures do occur, which can be attributed to the bone loss due to excessive occlusal load and/or infection. 3 Hence, the focus of implant dentistry has changed from merely obtaining osseointegration to the preservation and prevention of peri-implant hard and soft tissue loss. 4 Currently, lost teeth are being replaced by implants made of inert biomaterial, which are directly inserted into the alveolar bone to achieve osseointegration without considering the regeneration of periodontium. The field of oral and periodontal regenerative medicine has recently undergone significant advancements in restoring as close as possible the architecture and function of lost structures. However, to date, there has been a major "disconnection" between the principles of periodontal regeneration and oral implant osseointegration: the presence of a periodontal ligament to allow for a more dynamic role beyond the functionally ankylosed implant. 5 Therefore, an innovative approach is mandatory to create "periodontio-integrated implants" i.e., an implant suspended in the socket through periodontal ligament as opposed to functionally ankylosed osseointegrated implants. The authors of the present study believe that such advancement would revolutionize implant dentistry and would be significantly beneficial to patients.

 Periodontio-Integrated Implants Versus Osseointegrated Implants

Localized bone loss around osseointegrated implants represent a clinical challenge. 6 Excessive stress that accumulate at the crestal region of the implants leads to bone loss at this region. 7 This concentration of stresses at the crestal region is mainly attributed to the lack of the periodontal ligament, which is essential for distributing the forces throughout the length of the root. Periodontal ligament additionally dissipates these forces through the compression and redistribution of its fluid elements, as well as through its fiber system and hence provides shock absorption and cushioning effect to the teeth in response to these forces. 8 Furthermore, the periodontal ligament has a sensitive proprioceptive mechanism and is therefore capable of detecting and responding to a wide range of forces applied to the teeth. When these forces are transmitted through the periodontal ligament, they result in the remodeling of the alveolar bone to allow tooth movements (as seen in orthodontics) or in the widening of the periodontal ligament space leading to an increase in tooth mobility in response to excessive forces (e.g., occlusal trauma). 9 The osseointegrated dental implants on the other hand, physiologically differ from natural teeth as they lack periodontal ligament support and hence when loaded mechanically, evoke a peculiar sensation, which has been termed as osseoperception. Hence the osseointegrated implants not only become a part of the body but also of the mind and this mental acceptance named as osseoperception 10 has been described as a kinesthetic oral perception, which is derived from temporomandibular joint, cutaneous, muscle, mucosal and periosteal mechanoreceptors that provides mechanosensory information on oral kinesthetic sensibility in relation to jaw function and contacts of artificial teeth, in the absence of a functional periodontal mechanoreceptive input. 11 , 12 Furthermore, the passive threshold level of implants determined by the application of an external stimulus has been found to be 50 times higher than that of natural teeth; 13 which means that patients with osseointegrated implants will subjectively feel tangible sensation only when a force greater than that required to evoke sensation in natural teeth is applied. Hence, one of the reasons for the diminished ability of dental implants to adapt to occlusal trauma can be attributed to this lack of periodontal proprioceptive mechanism, which results in microfractures of the crestal bone and ultimately leads to bone loss. Moreover, connecting teeth to osseointegrated implants presents a biomechanical challenge due to the differential support and mobility provided by the implant and the tooth and consequently have also shown a higher rate of failures and complications. 14 However, when tooth-implant supported restorations would be fabricated using support from periodontio-integrated implants higher success rates can be expected due to similar resilience of tissues supporting teeth and implants. Furthermore, considering the use of osseointegrated implants in growing patients and the influence of maxillary and mandibular skeletal and dental growth on the stability of these implants, it is recommended to wait for the completion of dental and skeletal growth 15 since, the osseointegrated implants behave as an ankylosed element and don′t follow the growth and evolution of the jawbones and certainly not of the alveolar process and hence, may disturb a normal development of the jawbones, leading to unesthetic situations, especially in the anterior region (e.g., resulting in "relative" infraocclusion or labioversion). 16 Nonetheless, with the provision of peri-implant tissue remodeling offered by the periodontio-integrated implants it would not only be possible to successfully place implants in patients undergoing craniofacial/skeletal growth process, but also to move them orthodontically. 5 It has been seen that peri-implant infections progress faster than the infections around natural teeth. Lindhe et al. 17 demonstrated larger inflammatory cell infiltrate and destruction around implants, which extended more apically when compared with a corresponding lesion in the gingival tissue around natural teeth. In addition, the tissues around implants are more susceptible to plaque-associated infections that spread into the alveolar bone, primarily due to the lack of a periodontal ligament, making them more prone to bone loss. Periodontal ligament by virtue of its rich vascular supply is a reservoir of defense cells and undifferentiated mesenchymal cells; hence, the presence of the periodontal ligament around implants would not only provide better defensive capacity, but also enhance repair and regeneration of bone defects in their vicinity. 5

Tissue Engineering: Foundation of Periodontio-Integrated Implants

Tissue engineering as defined by Langer and Vacanti 18 is an interdisciplinary field that applies the principles of engineering and life sciences for the development of biological substitutes that restore, maintain or improve tissue function. 18 The main requirements for producing an engineered tissue are: The appropriate levels and sequencing of regulatory signals, the presence and numbers of responsive progenitor cells, an appropriate extracellular matrix or carrier construct and an adequate blood supply. 19 The discovery of stem cells in periodontal tissue and the outstanding progress in biomaterial research has opened up many possibilities for periodontal regeneration. To achieve successful periodontal regeneration, it will be necessary to utilize and recruit progenitor cells that can differentiate into specialized cells with a regenerative capacity, followed by the proliferation of these cells and synthesis of the target specialized connective tissues. 20 Because periodontal ligament-derived cells have multipotential characteristics, these cells are harvested and utilized as sources for the regeneration of periodontal tissues containing bone, cementum and periodontal ligament. 21 Clearly, a tissue-engineering approach for periodontal regeneration will need to utilize the regenerative capacity of these cells residing within the periodontium and would involve the isolation of such cells and their subsequent proliferation within a three-dimensional framework. Recent advances in mesenchymal stem cell isolation, growth factor biology and biodegradable polymer constructs have set the stage for successful tissue engineering of many tissues, of which the periodontium is considered a prime candidate for such procedures. 20 Sonoyama et al. 22 demonstrated the possibility of constructing the entire root/periodontal complex by inserting a hydroxyapatite/tricalcium phosphate block coated with periodontal ligament-derived mesenchymal stromal cells into the tooth sockets of mini-pigs. Furthermore, to avoid repeated harvestings of therapeutic cells for each treatment, successful cryopreservation of the periodontal ligament derived mesenchymal stromal cells, was also demonstrated by Seo et al. 23 Another possible option for periodontal ligament regeneration is gene therapy that comprises the insertion of genes into an individual′s cells in order to promote a specific biological effect and requires the use of vectors or direct delivery methods to transfect the target cells. 24

The aim of this review article was to identify and analyze those studies that investigated the feasibility of the development of periodontium around an implant and it′s functioning in vivo.

 Materials and Methods

To provide the scientific evidence supporting the feasibility of periodontio-integrated implants, a literature search was conducted using various online resources such as Medline through PubMed, Wiley-Blackwell, Elsevier, Google scholar etc., to retrieve studies published between 1980 and 2012 using the following key words are: "implant," "tissue engineering," "periodontium," "osseointegration," "osseo-perception," "regeneration" (and their synonyms). A total of 608 articles were found, out of which only 17 were considered appropriate to be included in this review. The results from the studies that were reviewed are summarized in Table 1 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 as well as discussed below.{Table 1}

Evidence based periodontio-integrated implant dentistry

Extensive research and several experiments have been carried out to develop periodontal ligament around an implant, i.e., for the creation of a bio-root, which would provide ideal conditions for the implant-supported treatments in future. 42 Nyman et al. 43 suggested that the cells of the periodontal ligament possess the ability to reestablish connective tissue attachment. Nunez et al. 44 have further validated the regenerative potential of periodontal ligament-derived cells in a proof of principle study. Several in vivo experiments have demonstrated the formation of cementum-like tissue with an intervening periodontal ligament, when the dental implants were placed in proximity to tooth roots. 25 , 28 , 31 , 36 The mechanism of this phenomenon appeared to be due to the migration of cementoblast and periodontal ligament fibroblast precursor cells towards dental implants due to contact or proximity of the tooth-related cell populations to those implants. 5 Although partial regeneration of the periodontium consisting of cementum, periodontal ligament and alveolar bone, was possible, application of such methods in patients seemed impossible due to technical and physical factors. 42 Yet, the potential for the clinical implementation of customized periodontal biomimetic hybrid scaffolds for engineering human tooth-ligament interfaces has been demonstrated by Park et al. 45 There is indeed a growing body of evidence validating the significant potential of the in vivo formation of ligamentous attachments to the biomaterials. Takata et al., 29 in an animal study examined whether connective tissue attachment could occur on implant materials by repopulating periodontal ligament derived cells and found that while new connective tissue attachment occurred on bioactive materials such as bioglass and hydroxyapatite, little or no cementum deposition was seen on bioinert materials such as titanium alloy and partially stabilized zirconium, i.e., the formation of new connective tissue attachment was influenced by bioactivity of the materials. Choi, 32 placed implants with the cultured autologous periodontal ligament cells in the mandibles of the dogs and histologically revealed that after 3 months of healing, a layer of cementum-like tissue with inserting collagen fibers had been achieved on some implant surfaces, demonstrating that cultured periodontal ligament cells can form tissue resembling a true periodontal ligament around implants. In 2005, researchers also explored the formation of periodontal tissues around titanium implants using a novel dentin chamber model, which demonstrated newly formed periodontal ligament, alveolar bone and root cementum, filling the space between the implant and the wall of the chamber. This study displayed a remarkable capacity for new periodontal tissue formation at a site where no such tissues ever existed. 35 In a yet another study, implantation of titanium fixture with porous hollow root-form poly (DL-Lactide-co-Glycolide) scaffold seeded with autogenous bone marrow-derived mesenchymal stem cells in goats exhibited periodontium-like tissue with newly formed bone both at 10 days and after 1 month, substantiating that undifferentiated mesenchymal stem cells were capable of differentiating to provide the three critical tissues required for periodontal tissue regeneration: Cementum, bone and periodontal ligament around the titanium implants. 37 The cellular seeding methodology utilizing bioreactors to culture and maintain the ′′stemness′′ of these cells during the in vitro culture period before transplantation has allowed for a spatial distribution of cells over the surfaces of the prototype implant devices to eventually form the ligamentous constructs. 5 However, it was a scientific breakthrough when Gault et al. 38 demonstrated for the first time the tissue engineering of the periodontal ligament and cementum-like structures on oral implants in humans, to promote the formation of implant-ligament biological interfaces or ligaplants capable of true, functional loading. One of the interesting facts in the Gault research-work was that periodontal ligament fibroblasts could be harvested from hopeless teeth of mature individuals and cultured in bioreactors to preserve their state of differentiation. Out of the eight implants inserted, one implant was still in place and functioning even after 5 years and even exhibited substantial bone regeneration in the adjacent bone defect 2 years after implantation. This implies that future clinical use of ligaplants might also be able to avoid bone grafting, its expense, inconvenience and discomfort to the patient. 38 Lately, Kano et al. 41 have suggested that implants surrounded by periodontal ligament-like tissue could be developed, when immediately after the extraction, tooth-shaped hydroxyl-apatite coated titanium implants were placed into the tooth socket where some periodontal ligament still remained; maintenance of original periodontal tissue domains most likely being the cause of prevention of osseointegration of the implants. 41

Conclusion

Although it has been revealed that generating a periodontal-like tissue around implants is possible, still a predictable and feasible method for producing dental implants with periodontal-like ligament has not been innovated. A major concern being the rational application of stem cell based tissue-engineering technology in clinical practice. Besides, the costs and time required from a practical standpoint for such tissue engineering applications is significant. Yet, this revolutionary approach to develop periodontio-integrated implants; however, opens up exciting possibilities for both periodontologists and oral implantologists and offers many interesting possibilities of utilizing ready-made, off-the-shelf biological tooth replacements that could be delivered to serve as hybrid-material-living oral implants. 5

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