Dental implants: Biological aspect

1) Introduction:

The success of dental implants therapy largely depends on rapid healing and proper osseointegration of implant surface with bone. Along with this, regeneration of firm soft tissues surrounding dental implants, especially in the transmucosal region is required for the long-term success of therapeutic dental implants 1, 2. The healing process also depends upon 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 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 Implants: Surface modifications”.

Osseointegration which is a direct structural and functional connection between the implant surface and living bone is essential for implant stability, and is considered 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 of this question in the following discussion.

Diagrammatic representation of  tooth and implant attachment to surrounding tissues

Tooth and Implant attachment

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2) Biology of wound healing following implant placement:

Any injury causes initiation of inflammatory reaction. Inflammatory process is a cascade of events that takes place in the wounded area for healing process to continue. These events include recruitment of inflammatory cells, release of various chemical mediators like growth factors, chemotaxis of osteoprogenitor cells to the site of 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 implant surface.  This process of bone formation on implant surface is called as osseointegration.

It must be noted that 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 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 47˚C at an exposure time of 1 min. Above this temperature the main bone cell enzyme alkaline phosphate denatures 4. This is why cooling during osteotomy procedure is mandatory along with using sharp drills at low speed.

Immediately upon implant placement, proteins from blood and tissue fluids are adsorbed to 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) and transforming growth factor beta (TGF-β) among many others. Because of these growth factors the migration and proliferation of bone marrow derived-cells as well as the proliferation of human osteoblasts takes place 8-10. Here lies the importance of implant surface roughness. Increase in the implant surface micro-topography with an appropriate surface roughness can enhance protein adsorption, promoting platelet adhesion and activation, eventually leading to an acceleration of the global healing process 11, 12. The chemotactic gradient produce due to inflammation causes neutrophils and macrophages 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 old host bone migrate through the remnants of the clot towards the surface of the implant and differentiate into osteoblasts, that will later synthesise bone matrix. Woven or the immature bone is first to form in the gap between implant and the bone which is gradually replaced by mature lammellar bone during next few months. Rate of growth of woven bone is around 100 μm per day in all directions. The bone formation has been described by Davies 14 as,

Contact osteogenesis:

Where 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 first 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 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 16. 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 & Col (1986) 17 are the following:

Clinically: Immobility, clear sound at percussion, absence of painful infectious syndrome, absence of permanent paresthesias.

Radiologically: No clear radio peri-implantar space, lower bone loss at 0.2 mm/year after the first year.

3) Healing following Immediate implant placement:

Immediate implant placement is frequently followed procedure these days. The advantages of immediate implant placement include reductions in the number of surgical interventions and the treatment time required 18, 19. The primary requirement during immediate implant placement is the absence of any infection/ infected tissue at the site of implant placement as it may lead to implant failure 20-22. Various advantages suggested with immediate implant placement include ideal orientation of the implant 23, 24, preservation of the bone at the extraction site 25-27, and optimal soft tissue esthetics 28.

After the implant has been placed in an extraction socket, the space between the implant periphery and surrounding bone is called the jumping distance 29. 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 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 30.

In the same way immediate implant placement is associated with bone loss. This has been shown by many animal 31-34 and human 35-38 clinical trails. This bone loss may vary from case to case depending upon various factors like flap elevation or flapless surgery, angulation and orientation of the implant, size of the implant, with use of bone graft or without use of bone graft etc. Usually, the bone loss is more on the buccal than the lingual aspect of an implant owing to less thickness of buccal plate as compared to lingual plate 39, 40. It is generally accepted that jumping distance of the bone is around 2 mm 41, 42. A gap < 2 mm wide will usually heals spontaneously without use of any biomaterial to fill the defect but if the gap is > 2 mm, spontaneous bone regeneration is less predictable. If the gap is > 2 mm, the use of biomaterial to fill the defect is indicated.

4) 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 implant surface known as osseointegration 43. The initial events during healing around implant are same as the of bone healing which include, cellular recruitment and release of growth factors by the activated cells at the bone-implant interface 44-46. 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 include death of osteocytes 44, 45, 47, 48.

As discussed earlier the bone formation can be contact osteogenesis (from implant towards the bone surface) or distance osteogenesis (from 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 layer that is rich in calcium, phosphorus, Osteopontin and bone sialoprotein 49, 50. Spaces without calcification are filled by blood vessels and mesenchymal cells 51, 52. Murai et al 53 Initially demonstrated a 20-50 μm thin layer of flat osteoblast-like cells, calcified collagen fibrils and a slight 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 implant to the surrounding bone 54, 55.

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 biological attachment of implant surface to bone. With continued healing, woven bone is progressively remodeled and substituted by lamellar bone that may reach a high degree of mineralization.

5) Osseointegration versus Fibro-Osseos 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 1950s.

Fibro-Osseous Integration:

In fibrosseous 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 compared to other tissues). During the 1980s, Dr. Charles Weiss 56  proposed the concept of fibro-osseous integration. He stated that states that there is a fibro-osseous ligament formed between the implant and the bone and this ligament can be considered as the equivalent of the periodontal ligament found in the gomphosis. He interpreted it as the peri-implantal ligament with an osteogenic effect and with fibro-osseous integration, the implant can generally be loaded immediately. He also professed the opinion that fibro-osseous integration is actually superior to osseointegration for most patients.

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 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 Putter et al in 1985 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: the greater the surface area, the greater 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 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.

6) Factors affecting osseointegration:

A) Patient related factors:

Age of the patient:

It is general perception that elderly patients may have 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. 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 myeloma – 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.

B) 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 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 lack of osseointegration around implant.

Other factors include inappropriate porosity of the porous coating of the implant 57, radiation therapy 58, 59 and pharmacological agents such as cyclosporin A, methotrexate and cis-platinum 60-62, warfarin and low molecular weight heparins 65 and non-steroid anti-inflammatory drugs especially selective COX-2 inhibitors 64, 65.

7) Soft tissue interface around implant:

Microscopic studies have shown that the interface between the gingiva and the 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 66, 67. The soft tissue interface around implants has been studied well. Following is a brief description of soft tissue around implants,

A) Sulcular Epithelium:

Various studies have compared the sulcular epithelium around implant and tooth in animal models 68-70. 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 natural tooth. 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.

B) Epithelium attachment around implants:

The epithelium 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 71, 72. Junctional epithelium plays an important role as it is the tissue providing attachment of soft tissue to the tooth surface.  Detailed description of the junctional epithelium is given in “The dynamics of junctional epithelium”.  At the tooth surface, a basal lamina is secreted by the junctional epithelial (JE) 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 substrate.

Many light microscopic studies have demonstrated eventual restoration of the junctional epithelium at the surface of implants 73-79.  Along with this many studies have provided excellent electron microphotographs of the hemidesmosome-implant interface 80-84. In case of implant surface, the interface between the epithelial cells and implant surface has been shown to have hemidesmosomes and a basal lamina. The structure of the hemidesmosomal attachment and basal lamina cannot be distinguished from those around teeth 85. Epithelial cells lining the implant surface are flattened, undifferentiated epithelial cells with few organelles, such as mitochondria and endoplasmic reticulum 86. The basal lamina contains laminin-1 and laminin-5 and shows feature in common with the external basal lamina of the natural junctional epithelium.

Obtaining a proper peri-implant mucosal seal is the pre-requisite for the long term success of dental implants 87. If this seal is not achieved, there are possibilities of partial or complete fibrous encapsulation of the endosseous implant 88, 89.

C) Biological width around implants:

The biological width of soft tissue around implants has been shown to be 3-4 mm where 2 mm is the epithelial attachment and about 1 mm is spuracrestal connective tissue attachment. In an experimental study Berglundh and Lindhe showed that by surgically reducing the thickness of the gingival flap prior to suturing, a corresponding crestal bone remodelling 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 90. These results show the same results as that of crown lengthening procedure and findings suggest that the biological width 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 85, on loaded and unloaded implants 91, different implant systems 92, different placements of implant abutment junction 94 and implants with different surface treatments 94. None of these were able to demonstrate any difference in peri-implant tissue dimension (thickness) around implants. So, all the principles of maintaining the biological width 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 neck of the implant. During the establishment of transmucosal attachment surgery, the soft tissue heals and re-organises itself according to the new environment 76. During the early phase of healing the gingival tissue appears to shrink. This is due to longitudinal arrangement of the major collagen fiber groups amplifies the process of collagen fibril contraction (as part of collagen maturation) in the vertical direction. This shrinkage is particularly important in anterior esthetic zone where exposure of implant margin may give unesthetic appearance.

The junctional epithelium around tooth is supplied by abundant nerve fibers derived from the trigeminal ganglion 95-97. These sensory nerve fibers contain the neuropeptides, calcitonin gene-related peptide and substance P 98-100. The peri implant mucosa is innervated by the sensory fibers in a similar way. The sensory nerve fibers contain calcitonin gene related peptide 101 and substance P 102. 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.

D) Connective tissue around implants:

Many studies have analysed and compared the connective tissue surrounding the natural tooth and implant 103, 104. As far as 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 an 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 fibre content (and hence a lower cellular content) than that of gingiva around teeth. These findings were confirmed by Moon et al in their dog experiment. The results of their study showed two types of attachments, where the first did not consist of any blood vessels with presence of fibroblast that in aligned parallel to the vertical axis of the implant body (collagen 67%, blood vessel/nervous structure 0.3%, fibroblast 32%). The second type was found to exist external to the former type, that consisted of fewer fibroblasts but with higher constitution of collagen fibers and vascular nerve structures (collagen 85%, vasculature 3%, fibroblast 11%) 79.

In addition, the collagen fibres 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 fibre 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 75. The soft tissue seal around implants provides protection against bacterial ingression in the same way as around natural tooth.

Soft tissue attachment around teeth and dental implants

 

Attachment components

Blood vascular supply

Orientation of collagen fibers

Biological width

Teeth

Basal lamina and hemidesmosomes Periodontal ligament and periosteum Perpendicular to tooth JE = 0.97mm 105CT = 1.07mm

Implants

Basal lamina and hemidesmosomes Periosteum Parallel to the implant surface JE = 1.88mm 91CT = 1.05mm

E) 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 little or no difference in the success rate for implants to be placed in oral mucosa zone or keratinized gingival zone 106-110. The only significant consideration is that the plaque accumulation is more common when tissue around implant is mobile. If the patient is maintaining well, the success rate of implant is same in both the cases. As it is difficult to accurately establish the soft tissue movement around implant during function, more studies are required to enlighten this aspect of implant therapy.

8) Defence mechanism of peri-implant mucosa:

Junctional epithelium around natural teeth is a dynamic tissue participating actively in defence against the bacterial invasion. Polymorphonuclear cells actively migrate through this semi-permeable barrier to reach the site of bacterial overload to stop bacterial invasion by killing bacteria (phagocytosis) 111. Other mechanisms by which junctional epithelium helps in defence against bacterial invasion include outward flow of gingival sulcular fluid through the junctional epithelium 112, 113, fast turnover or apoptosis of junctional epithelial cells 114, endocytotic capacity of junctional epithelial cells for external pathogens 115-117 and neurotrophic modulation in the junctional epithelium 100, 118. Peri implant epithelium also shows similar defence properties as shown by the junctional epithelium. Laminin-1 and laminin-5 are major components of the basal lamina, and participate in the formation of a molecular network in the basal lamina. One major function of laminin 5 is formation of anchoring filaments in hemidesmosomes and promoting their assembly, indicating its strong binding function in the basal lamina. This structural arrangement acts as a barrier for bacterial invasion.

Polymorphonuclear cells migrate through the peri-implant mucosa in the same way as in junctional epithelium and function effectively to prevent peri-implant inflammation/disease by their phagocytotic capacity 117, 119.

Junctional epithelial cells have the ability to endocytose foreign substances. Peri-implant epithelium has also been shown to have 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 120. Enzymes such as Cystatin C which are present in gingival crevicular fluid (GCF) have been isolated from peri-implant sulcus fluid, which shows anti bacterial defence of peri-implant epithelium 120.

Substance P, a neurogenic peptide stimulates the chemotaxis of neutrophils and macrophages, the proliferation and migration of keratinocytes and fibroblasts, degranulation of mast cells, the expression of various adhesion proteins on endothelial cells, and the release of inflammatory cytokines from immune cells 121-123.

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 epithelium cells, endothelial cells, and intraepithelial neutrophils, and induce a variety of innate defense mechanisms in the peri-implant epithelium 102.

9) 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. A detailed description of type of hypersensitivity is available in “Hypersensitivity”

When implant is placed in the bone, the surface of the implant is coated by 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 presence of titanium 124. 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 125.

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 inflammatory reaction in the affected tissue 126.   

It is recommended that in patients with known metal allergies, should be considered at high risk of developing allergy against titanium metal and metal allergy assessment and allergy testing should be carried out before placing permanent of implants.

10) Conclusion:

The biological aspect of dental implants has become more and clearer with research during last few decades. Knowledge of healing around implants is must to understand the bio-mechanical aspect in implant dentistry. Primary implant stability between bone and implant may be considered as an essential factor during 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 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 near future we expect new implant materials, designs, and techniques which are more conducive for healing around implants. 

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