Introduction to the biological aspect of implant

The success of dental implant therapy largely depends on uneventful healing and proper osseointegration of implant with the bone. Along with this, the regeneration of firm soft tissues surrounding dental implants, especially in the transmucosal region is required for the long-term success of dental implants 1, 2. The healing process also depends on the surface topography of the implant. During the evolution of implants to their current status, several surface modifications have been developed and are currently used with the aim of enhancing clinical performance. These include machine-turned, blasted, acid-etched, porous-sintered, oxidized, plasma-sprayed and hydroxyapatite-coated surfaces, as well as combinations of these procedures. Details of surface modification of dental implants have been given in “Dental implant surface treatments”.

     Osseointegration which is a direct structural and functional connection between the implant surface and living bone is essential for implant stability and is considered as a prerequisite for implant loading and long-term clinical success of endosseous dental implants. But, how osseointegration takes place? We shall try to find out the answer to this question in the following discussion.



Biology of wound healing following implant placement

Any injury causes the initiation of the inflammatory reaction. The inflammatory process is a cascade of events that takes place in the wounded area for the healing process to continue. These events include recruitment of inflammatory cells, release of various chemical mediators like growth factors and chemotaxis of osteoprogenitor cells to the site of the lesion. Around implant a reparative bone formation which is similar to the fracture healing takes place. As the implant surface is biologically compatible or bioactive, bone apposition will take place on the implant surface. This process of bone formation on implant surface is called as osseointegration.

     It must be noted that an implant should be firmly placed (primary stability) in the bone because a micro-movement of more than 150 µm has been shown to inhibit the differentiation of osteoblasts and thus, fibrous tissue is laid down which causes implant failure 3. Another factor is the critical temperature of the bone cells. The critical temperature of bone cells is as low as ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

     Immediately upon implant placement, proteins from blood and tissue fluids are adsorbed on the surface of the implant 5. The basic steps of clotting mechanism take place and platelets become activated after contacting with the surface 6, 7 and release a number of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β) and many others. Because of these growth factors, the migration and proliferation of bone marrow-derived cells, as well as the proliferation of human osteoblasts, take place 8-10. Here lies the importance of implant surface roughness. The increase in the implant surface micro-topography with an appropriate surface roughness can enhance protein adsorption, promoting platelet adhesion and activation, eventually leading to the acceleration of the global healing process 11, 12. The chemotactic gradient produced due to inflammation causes neutrophils and macrophages to reach the site of injury. At the same time, a new peri-implant vascular network starts to form by means of the well-known mechanism of angiogenesis 13.

     During the healing process, osteogenic cells from the surface of the host bone migrate through the remnants of the clot towards the surface of the implant and differentiate into osteoblasts, that will later synthesize bone matrix. Woven or the immature bone is first to form in the gap between the implant and the bone which is gradually replaced by mature lamellar bone during the next few months. The rate of growth of woven bone is around 100 μm per day in all directions. The bone formation has been described by Davies (2003) 14 as,

Contact osteogenesis:

Here the bone first forms on the implant surface. The osteogenesis proceeds from the implant to the host bone.

Distance osteogenesis:

In this case, the bone first forms on the surface of host bone and progresses towards the implant surface.

     Implant surface plays an important role in osteogenesis. Experiments have shown that rough implant microtopography enhances osteoconduction and, therefore, contact osteogenesis. On the other hand, distance osteogenesis can be expected with polished surfaces and cortical host bone 15. Presently, we have different timings of implant placement which include immediate, delayed or late implant placement. Mayfield (1999) 16 has classified implant placement as immediate, delayed, and late describing time intervals of 0 weeks, 6 to 10 weeks, and 6 months or more after extraction, respectively. The interval between 10 weeks and 6 months was not addressed in this classification system.
Clinically, term osseointegration can be interchanged with ankylosis i.e. the absence of implant mobility. A firm non-mobile (osseointegrated) implant can be considered as a successful implant. The success criteria used by Alberektsson et al. (1986) 17 are the following:

  • Clinically: Immobility, clear sound at percussion, absence of painful infectious syndrome, absence of permanent paresthesia.
  • Radiologically: No clear radiolucent peri-implant space, lower bone loss at 0.2 mm/year after the first year.
Tooth and Implant attachment
Tooth and Implant attachment



Healing following immediate implant placement

Immediate implant placement is frequently followed procedure these days. The advantages of immediate implant placement include reduction in the number of surgical interventions and the treatment time required 18, 19. The primary requirement during immediate implant placement is the ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

     After the implant has been placed in an extraction socket, the space between the implant periphery and surrounding bone is called, the jumping distance 28. The term jumping distance refers to the ability of bone to bridge the horizontal gap and fill the void. This distance has vertical and horizontal components. This gap can occur on any aspect of an immediately placed implant: buccal, lingual, or proximally.

     Before we discuss the healing around immediately placed implants lets first discuss the healing in an extraction socket. After the tooth extraction, socket is filled with a blood clot. The healing process leads to bone formation in the socket with reduced bone dimensions. It has been shown that healing sockets are associated with a mean 1.24 mm vertical bone loss (range: 0.9 to 3.6 mm) and an average 3.79 mm horizontal bone reduction (range 2.46 to 4.56 mm) after 6 months of extraction 29.

     In the same way, immediate implant placement is associated with bone loss. This has been shown by many animal 30-33 and human 34-37 clinical trails. This bone loss may vary from case to case depending on various factors like flap elevation or flapless surgery, angulation and orientation of the implant, the size of the implant, with or without the use of bone graft, etc. Usually, the bone loss is more on ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

 

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Biology of osseointegration

As already stated, a cascade of cellular and extracellular biological events take place after implant placement which ultimately leads to bone deposition on the implant surface known as osseointegration 42. The initial events during healing around an implant are same as of the bone healing which includes, cellular recruitment and release of growth factors by the activated cells at the bone-implant interface 43-45. It has been shown that the healing around implants is affected by factors like implant surface characteristics, the stability of the fixation and the intraoperative heating injuries that cause the death of osteocytes 42-44, 46.

     As discussed earlier, the bone formation can be contact osteogenesis (from implant towards the bone surface) or distance osteogenesis (from the bone surface towards the implant). From day 1, the osteoblasts and the mesenchymal cells can be seen migrating on the implant surface, depositing bone-related proteins and creating a non-collagenous matrix layer on the implant surface. This layer is then subjected to cell adhesion and binding of minerals. The initial calcification leads to the formation of poorly mineralized layer the osteoid. This layer is around 0.5 mm thick and is rich in calcium, phosphorus, osteopontin and bone sialoprotein 47, 48. Spaces without calcification are filled by blood vessels and mesenchymal cells 49, 50. Murai et al. (1996) 48 initially demonstrated a 20-50 μm thin layer of flat osteoblast-like cells, calcified collagen fibrils and a slightly mineralized area at a titanium implant-bone interface.

     Initially, a rapid formation of woven/ trabecular bone to fill the space between the implant and the bone takes place. This trabecular bone has a well organized three-dimensional structure which provides initial biological fixation of the implant to the surrounding bone 50, 51. The initial biological fixation should not be confused with the primary stability. Primary stability is basically a mechanical stability achieved during implant placement, whereas the initial biological fixation is the biological attachment of implant surface to the bone. With continued healing, woven bone is progressively remodeled and substituted by lamellar bone that may reach a high degree of mineralization.

Osseointegration versus fibro-osseous integration

Osseointegration:

Osseointegration is defined as “the formation of a direct interface between an implant and bone, without intervening soft tissue”. Applied to oral implantology, this thus refers to bone grown right up to the implant surface without interposed soft tissue layer. The direct contact of bone and implant surface can be verified microscopically. Brånemark proposed that implants integrate such that the bone is laid very close to the implant without any intervening connective tissue. The titanium oxide permanently fuses with the bone, as Brånemark showed in the 1950s.

Fibro-osseous integration:

In fibro-osseous integration, soft tissues such as fibers and/or cells are interposed between the two surfaces. This encapsulation of the implant with connective tissue occurs much more quickly than actual osseointegration (bone is very slow-growing as compared to other tissues). During the 1980s, Dr. Charles Weiss 52 proposed the concept of fibro-osseous integration. He stated that there is a fibro-osseous ligament formed between the implant and the bone and this ligament can be considered as equivalent to the periodontal ligament found in the gomphosis. He interpreted it as ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

     Fibro-osseous integration in dental implants may show initial success, but they have been a disappointment in the long term. Implants that are fixed in the bone socket by the growth of connective tissue initially perform fine, but in the long term, they usually fail. The failed implants, when examined, show collagen fibers growing parallel to the implant rather than directly into contact with it like natural periodontal ligament.

Osseointegration versus Biointegration:

de Lange and de Putter in 1992 53 proposed two ways of implant anchorage or retention as mechanical and bioactive. Mechanical retention can be achieved in cases where the implant material is a metal, for example, commercially pure titanium and titanium alloys. In these cases, topological features like vents, slots, dimples, threads (screws), etc. aid in the retention of the implant. There is no chemical bonding and the retention depends on the surface area, i.e., greater the surface area, the greater is the contact.

     Bioactive retention can be achieved in cases where the implant is coated with bioactive materials such as hydroxyapatite. These bioactive materials stimulate bone formation leading to a physico-chemical bond. The implant is ankylosed with the bone.

     Presently, osseointegration is considered as the most reliable and long-lasting type of implant integration. This is because osseointegrated implants have shown long-term success in various studies without any controversy.



Factors affecting osseointegration

Patient-related factors:

Age of the patient:

It is a general perception that elderly patients may have a poor prognosis for implant therapy. The advanced age is not a contraindication for dental implants; the failure rate does not increase in the elderly patients. The matter of the fact is older patient usually present with more compromised bone quantity and quality which may affect the prognosis of the case.

Gender:

The implant therapy is successful in both males and females equally. The only point to note is the post-menopausal osteoporosis in females, which affects the quality of the bone.

Metabolic diseases:

Metabolic bone diseases: osteoporosis, osteomalacia, hyperparathyroidism, Paget’s disease, multiple myelomas can influence the osseointegration of the implant.

Rheumatic disorders:

Rheumatic disorders like rheumatoid arthritis, Sjogren’s syndrome, lupus erythematosus are not contraindications for implant surgery.

Smoking:

It is an important factor related to the failure of implant therapy.

Local factors:

Status of the host bone bed and its intrinsic healing potential:

Availability of the bone is a prime requirement for implant success. A good quality bone provides better initial stability as well as resistance for early loading of the implant. A poor quality bone with a poor healing response may lead to failure of implant osseointegration.

Improper implant placement and inappropriate surgical procedure:

A proper analysis of the available bone structure is required for accurate implant placement. If a proper surgical technique is not used, it may lead to the lack of osseointegration around the implant.

Other factors:

Other factors include an inappropriate porosity of the porous coating of the implant 54, radiation therapy 55, 56 and pharmacological agents such as cyclosporin A, methotrexate and cis-platinum 57-59, warfarin and low molecular weight heparins 60 and non-steroid anti-inflammatory drugs especially selective COX-2 inhibitors 61, 62.

Soft tissue interface around implants

Microscopic studies have shown that the interface between the gingiva and tooth enamel is characterized by the presence of an attachment apparatus composed of well-developed hemidesmosomes at the basal surface of the junctional epithelium and internal basement membrane 63, 64. The soft tissue interface around implants has been studied well. Following is a brief description of soft tissue around implants,

Sulcular Epithelium:

Various studies have compared the sulcular epithelium around the implant and tooth in animal models 65-67. The tissue adjacent to the implant consists of the free gingival margin composed of collagenous stroma, covered by stratified squamous epithelium. The outer epithelium of gingival margin is keratinized. As we move into the gingival sulcus around implant, the epithelium becomes non-keratinized. It is the same as in the natural teeth. The width of the sulcular epithelium narrowed as it progressed to the lower recesses of the sulcus. The intercellular spaces of basal cells are found infiltrated with scattered leukocytes as well as minor incursions of bacteria.

Epithelial attachment around implants:

The epithelial attachment in normal periodontium around natural tooth has been well studied. Its development, as well as its features in periodontal health and disease, have been well described 68, 69. Junctional epithelium plays an important role as it is the tissue, providing attachment of soft tissue to the tooth surface. A detailed description of the junctional epithelium is given in “Periodontium in health”. At the tooth surface, a basal lamina is secreted by the junctional epithelial cells, which is composed of three distinct layers: the lamina lucida, lamina densa, and sublamina lucida. The hemidesmosomes have been shown to be associated with epithelial attachment to underlying connective tissue or to the substrate.

     Many light microscopic studies have demonstrated eventual restoration of the junctional epithelium at the surface of implants 70-76. Along with this, many studies have provided excellent electron microphotographs of the hemidesmosome-implant interface 77-81. In case of implant surface, the interface between the epithelial cells and implant surface has been shown to have ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

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     Obtaining a proper peri-implant mucosal seal is the pre-requisite for the long-term success of dental implants 84. If this seal is not achieved, there are possibilities of partial or complete fibrous encapsulation of the endosseous implant 85, 86.

Supracrestal tissue attachment around implants

The supracrestal tissue attachment (biological width) around implants has been shown to be 3-4 mm where 2 mm is the epithelial attachment and about 1mm is supra-crestal connective tissue attachment. In an experimental study, Berglundh and Lindhe (1996) 87 showed that by surgically reducing the thickness of the gingival flap prior to suturing, a corresponding crestal bone remodeling will subsequently occur, allowing for the re-establishment of the “biological width” of the peri-implant soft tissue to its original dimension at the expense of reduced crestal bone height. These results show the same results as that of crown lengthening procedure and findings suggest that supracrestal tissue attachment is re-established around implants in the same way as around natural teeth.

     Studies have also been done on one stage and two-stage surgical procedures 82, on loaded and unloaded implants 88, different implant systems 70, different placements of implant-abutment junction 89 and implants with different surface treatments 90. None of these were able to demonstrate any difference in peri-implant tissue dimension (thickness) around implants. So, all the principles of maintaining the supracrestal tissue attachment are followed in the same way in implant therapy as they are followed with natural tooth restoration and prosthetic treatments.

     During the healing process, the gingival shrinkage can be observed around the neck of the implant. During the establishment of transmucosal attachment, the soft tissue heals and ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

     The junctional epithelium around the tooth is supplied by abundant nerve fibers derived from the trigeminal ganglion 91-93. These sensory nerve fibers contain the neuropeptides, calcitonin gene-related peptide, and substance P 94-96. The peri-implant mucosa is innervated by the sensory fibers in a similar way. The sensory nerve fibers contain calcitonin gene-related peptide 97 and substance P 98. The innervation of peri-implant epithelium is denser as compared to other parts of the epithelium. The nerve fibers terminate close to the peri-implant epithelium.

Connective tissue around implants

Many studies have analyzed and compared the connective tissue surrounding the natural tooth and implant 99, 100. As far as the epithelial attachment is concerned, there are many similarities between the implant and tooth covering epithelium. Major differences lie in the connective tissue compartment. The connective tissue zone close to the implant surface has been suggested to resemble a scar tissue that is poor in vascular structures. The connective tissue immediately next to the implant surface is characterized by the absence of blood vessels and abundant fibroblasts, which are interposed between thin collagen fibers. The connective tissue at a distance from the implant has a higher fiber content (and hence a lower cellular content) than that of the gingiva around the teeth.

     These findings were confirmed by Moon et al. (1999) 76 in their dog experiment. The results of their study showed two types of attachments, where the first did not consist of ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

     In addition, the collagen fibers are arranged parallel to the titanium surface in implants as compared to that of the tooth associated gingiva in which these fibers tend to be arranged perpendicular to the cementum surface of the tooth root with other fiber groups arranged in various patterns elsewhere in the marginal gingiva. Another important point to note is that surface roughness of implant has been found to have no bearing on the adherence of the soft tissue 72. The soft tissue seal around implants provides protection against bacterial ingression in the same way as around natural teeth.



Significance of attached gingiva

The protective role of attached gingiva around implants has been studied in the same way as that of natural teeth. Based on long-term studies on implant success, it has been found that there appeared to be a little or no difference in the success rate for implants to be placed in the oral mucosa zone or keratinized gingival zone 102-106. The only significant consideration is that the plaque accumulation is more common when the tissue around the implant is mobile. If the patient is maintaining well, the success rate of the implant is same in both the cases. As it is difficult to accurately establish the soft tissue movement around the implant during function, more studies are required to enlighten this aspect of implant therapy.

Defense mechanism of peri-implant mucosa

Junctional epithelium around natural teeth is a dynamic tissue participating actively in defense against the bacterial invasion. Polymorphonuclear cells actively migrate through this semi-permeable barrier to reach the site of bacterial overload to stop the bacterial invasion by killing bacteria (phagocytosis) 107. Other mechanisms by which junctional epithelium helps in defense against bacterial invasion include the outward flow of gingival sulcular fluid through the junctional epithelium 108, 109, fast turnover or apoptosis of junctional epithelial cells 63, endocytotic capacity of junctional epithelial cells for external pathogens 110 and neurotrophic modulation in the junctional epithelium 96, 111.

     Peri-implant epithelium also shows similar defense properties as shown by the junctional epithelium. Laminin-1 and laminin-5 are the major components of basal lamina and participate in the formation of a molecular network in the basal lamina. One major function of laminin 5 is the ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..

     Junctional epithelial cells have the ability to endocytose foreign substances. Peri-implant epithelium has also been shown to have an endocytotic system which, along with the presence of neutrophils may play an important role in the local defense of the transmucosal region around dental implants 112. Enzymes such as Cystatin C which are present in gingival crevicular fluid (GCF) have been isolated from peri-implant sulcus fluid, which shows antibacterial defense of peri-implant epithelium 113.

     Substance P, a neurogenic peptide, stimulates the chemotaxis of neutrophils and macrophages, the proliferation and migration of keratinocytes and fibroblasts, degranulation of mast cells, expression of various adhesion proteins on endothelial cells, and release of inflammatory cytokines from immune cells 114-116. Substance P-containing sensory nerve terminals and neurokinin-1 receptors have been identified in the peri-implant mucosa which suggests that released substance P may bind to neurokinin-1 receptors on peri-implant epithelial cells, endothelial cells, and intraepithelial neutrophils, and induce a variety of innate defense mechanisms in the peri-implant epithelium 98.

Allergic potential of titanium

Although titanium is an inert metal, hypersensitive reactions have been reported demonstrating its allergic potential. Type-I and Type-IV hypersensitivity has been reported with titanium. When the implant is placed in the bone, the surface of the implant is coated with body fluid. The concentration of Ti ions in the surrounding tissue after implant placement has been reported to be around 100-300 ppm. Also, the lymph nodes of the surrounding draining areas also show the presence of titanium 117. Titanium has been shown to activate macrophages, which may secrete cytokines involved in various disease processes. This mechanism may be related to the cell-mediated immune response against the metal 118.

     It has been suggested that the acidic environment around the implant such as peri-implantitis condition may cause titanium corrosion and subsequent release of titanium ions or micro-particles in the surrounding tissue. Also, overload on the implant may cause dislodgement of micro-particles from the implant surface in the surrounding tissue. These particles may induce ………Contents available in the book…………..Contents available in the book………….Contents available in the book………….Contents available in the book…..



Conclusion

The biological aspect of dental implants has become more and more clearer with the research during the last few decades. Knowledge of healing around implants is essential for understanding the biomechanical aspect of implant dentistry. Primary implant stability between bone and implant may be considered as an essential factor during the healing period. Immediate loading of implants is becoming more and more popular these days. But, it must be remembered that all the factors that are essentially required during immediate loading must be taken into consideration.

     The information presented above should be helpful for the clinicians to accurately plan the treatment for a patient considering all the local and systemic factors that may influence the healing process around implants. Implant dentistry is evolving fast and in the near future, we expect new implant materials, designs, and techniques which are more conducive for healing around implants.

References

References are available in the hard-copy of the website.

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