one of the challenges in implantology is to achieve and maintain the osseointegration as well as the epithelial junction of the gingival with implants . an intimate junction of the gingival tissue with the neck of dental implants may prevent bacteria colonisations leading to peri - implantitis while direct bone bonding may ensure a biomechanical anchoring of the artificial dental root ( figure 1 ) . the first step of the osseointegration of implants is called primary stability and is related to the mechanical anchorage , design of implants , and bone structure . this primary interlock decreases with time at the benefit of the secondary anchorage , which is characterized by a biological bonding at the interface between bone tissues and implant surface . between the primary mechanical and secondary biological anchorage , a decrease of implant stability could be observed . the aim is to provide metal implants with surface biological properties for the adsorption of proteins , the adhesion and differentiation of cells , and tissue integration . these biological properties are related to chemical composition , wettability , and roughness of metal implants surfaces . however , the control of these surface properties at the protein and cell levels , thus in the nanometre range , remains a challenge for researchers and dental implants manufacturers . nanotechnologies may produce surfaces with controlled topography and chemistry that would help understanding biological interactions and developing novel implant surfaces with predictable tissue - integrative properties [ 2 , 3 ] . various processing methods derived from the electronic industry such as lithography , ionic implantation , anodization , and radio frequency plasma treatments may be applied to the surfaces of dental implants to produce controlled features at the nanometer scale . for instance , specific protein adsorption , cell adhesion , and differentiation of stem cells should be studied in relation to the surface properties . following in vitro screening , nanostructured surfaces may then be tested in animal models to validate hypothesis in a complex in vitro environment . new coating technologies have also been developed for applying hydroxyapatite and related calcium phosphates ( cap ) , the mineral of bone , onto the surface of implants ( figure 2 ) . many studies have demonstrated that these cap coatings provided titanium implants with an osteoconductive surface [ 4 , 5 ] . following implantation , the dissolution of cap coatings in the peri - implant region increased ionic strength and saturation of blood leading to the precipitation of biological apatite nanocrystals onto the surface of implants . this biological apatite layer incorporates proteins and promotes the adhesion of osteoprogenitor cells that would produce the extracellular matrix of bone tissue . furthermore , it has been also shown that osteoclasts , the bone resorbing cells , are able to degrade the cap coatings through enzymatic ways and created resorption pits on the coated surface . finally , the presence of cap coatings on metals promotes an early osseointegration of implants with a direct bone bonding as compared to noncoated surfaces . the challenge is to produce cap coatings that would dissolve at a similar rate than bone apposition in order to get a direct bone contact on implant surfaces . this paper reviews the different steps of the interactions between biological fluids , cells , tissues , and surfaces of implants . . mechanisms of interaction with blood , platelets , hematopoietic , and mesenchymal stem cells on the surface of implants are described . these early events have shown to condition the adhesion , proliferation , and differentiation of cells as well as the osseointegration of implants . future implant surfaces may improve the tissue - integrative properties and long - term clinical success for the benefits of patients . in particular , the nanometer - sized roughness and the chemistry have a key role in the interactions of surfaces with proteins and cells . these early interactions will in turn condition the late tissue integration . in this prospect , different methods have been reported for enhancing bone healing around metal implant [ 2 , 6 ] . modifying surface roughness has been shown to enhance the bone - to - implant contact and improve their clinical performance [ 2 , 7 ] . grit blasting , anodisation , acid etching , chemical grafting , and ionic implantation were the most commonly used methods for modifying surface roughness of metal implants . combinations of these techniques could be used such as acid etching after grit - blasting in order to eliminate the contamination by blasting residues on implant surfaces . this grit blasting residue may interfere with the osteointegration of the titanium dental implants [ 810 ] . it has been shown that grit - blasting with biphasic calcium phosphate ( bcp ) ceramic particles gave a high average surface roughness and particle - free surfaces after acid etching of titanium implants . studies conducted both in vitro and in vivo have shown that bcp grit - blasted surfaces promoted an early osteoblast differentiation and bone apposition as compared to mirror - polished or alumina grit - blasted titanium [ 11 , 12 ] . anodization is a method commonly used to obtain nanoscale oxides on metals including titanium [ 13 , 14 ] . by adjusting the anodization condition such as voltage , time , and shaking shankar et al .   have reported that the diameters of the nanotubes could be modified to a range from 20 to 150  nm in modifying voltage conditions . on the other hand , kang et al . found that tio2 nanotube arrays were more uniform on electro - polished than machined titanium . moreover , tio2 nanotubes on ti improved the production of alkaline phosphatase ( alp ) activity by osteoblastic cells . in particular , nanotubes with a diameter of 100  nm upregulated level of alp activity as compared to 3070  nm diameter nanotube surfaces . since alp is a marker of osteogenic differentiation , these surfaces may demonstrate enhanced bone tissue integrative properties . another approach for improving osseointegration of dental implants is to apply a cap coating having osteoconductive properties [ 1820 ] . different methods have been developed to coat metal implants with cap layers such as plasma spraying , biomimetic and electrophoretic deposition . nevertheless , plasma - sprayed ha - coated dental implants have been related to clinical failures due to coating delimitation and heterogeneous dissolution rate of deposited phases . an electrochemical process which consists of depositing calcium phosphate crystals from supersaturated solutions has been proposed for coating titanium implants with calcium phosphate layers [ 21 , 22 ] . upon implantation , these cap coatings dissolve and release ca and hpo4 ) increasing saturation of blood in the peri implant region . this dissolution led to the precipitation of biological apatite nanocrystals with the incorporation of various proteins . this biological apatite layer will promote cell adhesion , differentiation into osteoblast , and the synthesis of mineralized collagen , the extracellular matrix of bone tissue . in addition to dissolution , osteoclast cells are also able to resorb the cap coatings and activate osteoblast cells to produce bone tissue .   as a result , these cap coatings promote a direct bone - implant contact without an intervening connective tissue layer leading to a proper biomechanical fixation of dental implants . during surgery , blood vessels are injured and , thus , dental implant surfaces interact with blood components ( figure 3 ) . plasma proteins modified the surface while activated platelets are responsible of thrombus formation and blood clotting . subsequently , the migrations of various cell types interact with the surface through membrane integrin receptors . plasma contains dissolved substances such as glucose , amino acids , cholesterols , hormones , urea , and various ions ( figure 4 ) . all of these blood substances could interact with implant surface thus modifying their chemical properties like charge or hydrophobicity . blood interactions with implants lead to protein adsorption , which is dependent on the surface properties of the material and occurs through a complex series of adsorption and displacement steps known as the vroman effect . consequently , dental implants manufacturers have developed high hydrophilic and rough implant surfaces which in turn exhibited better osteointegration than conventional ones . adsorption of proteins such as fibronectin , vitronectin on surface of dental implants   could promote cell adhesion by cell - binding rgd domain ( arg - gly - asp ) . interactions between cell membrane integrins and proteins coated onto implant surface play a key role in adhesion of many cells types . after proteins absorption , the osteointegration is characterized by platelets adhesion and fibrin clots formation at the injured blood vessels site . it has been shown that implants in contact with platelet - rich plasma ( prp ) with a platelet concentration of approximately 1,000,000 protein/l have a positive effect on osteointegration . at lower concentrations of prp , the effect was not optimal , while higher concentrations resulted in a paradoxically inhibitory effect of bone regeneration . other studies were not in agreement with this prp beneficial effect on the osseointegration of dental implants . the assessment of bioactivity of surface - treated dental implants should be tested in vitro using biological fluids containing blood components . following blood clotting around dental implants , several cells interact with surfaces for tissue healing . mesenchymal stem cells ( mscs ) attracted to the injured site by chemotactic factors have a determinant role in peri implant tissue healing . mesenchymal stem cells ( mscs ) are stem cells derived from somatic tissue which can be differentiated into mesenchymal lineages such as bone , cartilage , fat , and skin . in addition , mscs are present in many conjunctive tissues and blood at low concentrations serving as a sort of internal repair system . first , they are unspecialized cells able to renew themselves through cell division , sometimes after long periods of inactivity . second , under certain physiologic or experimental conditions , they can be induced to become tissue- or organ - specific cells with special functions . mscs have high proliferative and multipotent capacity leading to differentiated cells under the guidance of various cues or niches . mscs are conventionally defined as adherent , nonhematopoietic cells expressing markers such as cd13 , cd29 , cd44 , cd54 , cd73 , cd90 , cd105 , and cd166 , and being negative for cd14 , cd34 , and cd45 [ 27 , 28 ] . while originally identified in the bone marrow , mscs have been extracted from numerous tissues including adipose [ 30 , 31 ] , heart , dental pulp , peripheral blood , and cord blood . one of the major properties of mscs is their ability to differentiate into various cells like adipocytes , chondrocytes , osteoblasts , neurons [ 38 , 39 ] , muscles [ 39 , 40 ] , and hepatocytes   in vitro after treatment with induction agents . the integration of implant with neighboring bone and gingival tissue depends on successful crosstalk between old tissue and implant surface . the challenge in dental implant research is the capability of the surface to guide cells colonization and differentiation . cell migration , adhesion , and proliferation on implant surfaces are a prerequisite to initiate the tissue regeneration ( figure 5 ) . authors have shown that some factors present in tissues and secreted during the inflammatory phase are able to attract mscs to the injured site [ 42 , 43 ] . mscs migration and proliferation were stimulated in vitro by many growth factors including pdgf [ 44 , 45 ] , egf [ 45 , 46 ] , vegf , tgf- [ 44 , 48 ] , and bmp-2 and bmp-4 [ 44 , 47 ] . these factors are certainly released in the injured sites by cells involved in tissue healing . furthermore , plasma clot serves as storage to fibrin molecules and releases system for a variety of bioactive factors including growth factors that attract and differentiate mscs into specific lineages [ 4951 ] . the formation of a clot matrix with a potent chemoattractive factor like pdgf , egf , or fibrin may further enhance mscs numbers and peri implant tissue healing surface . moreover , the plasma clot in contact with implant surface represents a three - dimensional microporous structure that allows diffusion of regulatory factors [ 53 , 54 ] and is involved in the migration , proliferation , and differentiation of mscs . after msc recruitment in the injured site , cells adhere on the local extracellular matrix as well as on the implant surface beginning an extensive proliferation in order to build up new tissue . again , surface modifications of implants in the nanometer range condition the biological responses . in the microenvironment , mscs are stimulated by some specific factors to differentiate into the adequate cell line . under the influence of these factors , mscs switch to osteoblastic cells in contact to bone tissue while they differentiate into fibroblastic lineage in the gingival tissue region . these two differentiation pathways are in concurrence around dental implants . in some cases , implants are encapsulated by fibrous tissue due to the proliferation and differentiation of mscs into fibroblastic cells . in response to cytokine , fibroblasts migrate and generate a capsule of collagen , the first step in generation of gingival tissue or rejection on contact to bone . this fibrous capsule prevents bonding between implant surface and juxtaposed bone and causes a failure of the implant . on the other hand , both the differentiation of mscs into fibroblastic lineage and the fibroblastic adhesion are desired in the gingival upper part of dental implants . fibroblasts adhesion has been shown to be lower on nanoscale surface compared to conventional surfaces . moreover , nanometer size features have been shown to decrease fibroblast adhesion and proliferation [ 57 , 58 ] . the micro- and nanoscale surface properties of metal implant , including chemistry , roughness , and wettability , could affect bone formation . numerous treatments such as machining , grit - blasting , ti / ha plasma spray , chemical etching , and anodization are available to modify the implant surface . research has specifically demonstrated that nanorough ti   and nanostructured ti can enhance osteoblast adhesion and differentiation compared to their nanosmooth control . furthermore , surfaces with micro- and nanopores have shown to enhance greatly osseointegration [ 62 , 63 ] . surface properties may control the steps of adhesion , proliferation , and differentiation of mscs and , thus , condition tissue integration . brnemark et al .   described the osseointegration as a direct structural and functional bone to implant contact under load . as previously discussed , the biological events occurring at the tissue - implant interface are influenced by the chemistry , topography , and wettability of dental implant surfaces . the challenge in developing new implant surface consists in increasing the clinical success rate as well as decreasing the tissue healing time for immediate loading of implants , particularly in aesthetic situations [ 6567 ] . one of the objectives is to develop implant surface having predictable , controlled , and guided tissue healing . for instance , surfaces that promote contact osteogenesis rather than distance osteogenesis would be desired in bony site while intimate fibrous tissue healing in gingival tissue ( figure 1 ) . in order to enhance this intimate contact between tissues and implant , surface treatments at the nanometer scale implant surface with various roughnesses have been used to increase the total area available for osteo - apposition . kubo et al .   observed a substantial increase by 3.1 times in bone - titanium interfacial strength by ti nanotube ( 300  nm ) at 2 weeks of implantation in femur rats . moreover , ogawa et al .   have prepared ti nanostructure by physical vapour deposition and tested their osseointegration in femur of rats . they found an increased surface area by up to 40 % and a greater strength of osseointegration for the nanostructured compared to an acid - etched surface . some authors have correlated the initial events in bone formation adjacent to surface with the long - term tissue response to these materials in humans [ 69 , 70 ] .   by mimicking the chemical composition of natural bone , hydroxyapatite and cap coatings on ti greatly enhance osteointegration .   as shown in figure 6 , a greater direct bone apposition was observed on cap - coated than on bare ti - coated implants . during the bone healing process , calcium and phosphate ions are released from the cap coating in the peri - implant region and saturate body fluids to precipitate a biological apatite , which serves as a substrate for osteoblastic cells producing bone tissue . several authors have shown the benefit of using cap - coated titanium implants for improving the osteointegration [ 71 , 72 ] . in particular , le guehennec et al .   have studied the osteointegration of four implant surfaces in the femoral epiphyses of rabbits after 2 and 8 weeks of healing . in this study , the bone - implant contact and bone growth inside the chambers were compared for four different implant surfaces and shown that biomimetic coating method may enhance the bone apposition onto titanium . in order to prevent coating delamination and implant loosening , the cap coating should dissolve or degrade under osteoclastic activity at a similar rate than bone apposition . the final result should be a direct bone - implant coating without the presence of fibrous tissue . another advantage of these cap coatings is related to their preparation by biomimetic methods at physiological temperature and ph from simulated body fluids . furthermore , it is possible to incorporate biologically active drugs such as antibiotics or growth factors during the precipitation of cap coatings on ti implants . these molecules could be locally and gradually released in the peri implant reguion for either preventing bacterial infections or stimulating bone growth . many reports have shown that nanometer - controlled surfaces have a great effect on early events such as the adsorption of proteins , blood clot formation , and cell behaviours occurring upon implantation of dental implants . these early events have an effective impact on the migration , adhesion , and differentiation of mscs . nanostructured surfaces may control the differentiation pathways into specific lineages and ultimately direct the nature of peri - implant tissues . despite an active research in dental implants ,
the long - term clinical success of dental implants is related to their early osseointegration . 
 this paper reviews the different steps of the interactions between biological fluids , cells , tissues , and surfaces of implants . immediately following implantation , 
 implants are in contact with proteins and platelets from blood . 
 the differentiation of mesenchymal stem cells will then condition the peri - implant tissue healing . 
 direct bone - to - implant contact is desired for a biomechanical anchoring of implants to bone rather than fibrous tissue encapsulation . 
 surfaces properties such as chemistry and roughness play a determinant role in these biological interactions . 
 physicochemical features in the nanometer range may ultimately control the adsorption of proteins as well as the adhesion and differentiation of cells . 
 nanotechnologies are increasingly used for surface modifications of dental implants . another approach 
 to enhance osseointegration is the application of thin calcium phosphate ( cap ) coatings . 
 bioactive cap nanocrystals deposited on titanium implants are resorbable and stimulate bone apposition and healing . 
 future nanometer - controlled surfaces may ultimately direct the nature of peri - implant tissues and improve their clinical success rate .