Inducing controlled regeneration of soft tissue at placement sites of percutaneous dental devices

Abstract

The present invention relates to a percutaneous dental device which comprises a soft- tissue region with at least two distinct surface regions with different isotropic surface- topographies forming at their interphase an in situ CEJ (iCEJ), for use in improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the 5 supracrestal connective tissue at the placement site of the device A novel dental device is disclosed that mimics a natural tooth surface in the section of the device that is in direct contact with the soft tissue above and below its in situ CEJ (iCEJ), thus guiding and inducing the soft tissue healing and / or regeneration surrounding a dental device after implant or after placement.

Description

[0001] Inducing controlled regeneration of soft tissue at placement sites of percutaneous dental devices

[0002] Technical field

[0003] The present invention relates to the field of improved regrowth and / or regeneration of biological width at the placement site of percutaneous, such as transmucosal, dental devices, wherein a more natural supracrestal attached tissue is regenerated after placement.

[0004] The improved biological width is brought on by the use of a novel percutaneous dental device, comprising an at least biphasic surface in its soft tissue region, at their interphase forming an in situ cemento-enamel junction (iCEJ), wherein the at least two different surfaces are individually adapted to induce and / or guide soft tissue healing and / or regeneration of histologically more natural compositions of soft tissue type layers above and below the in situ cemento-enamel junction (iCEJ) of the device, respectively.

[0005] The current invention thus for the first time provides the means for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement site of a percutaneous dental device.

[0006] Background

[0007] Percutaneous devices penetrate the body through a surgically created defect in the skin or mucosa to provide a conduit between an implanted medical device or artificial organ and the extracorporeal space. Percutaneous devices include e.g., catheters, prosthetic attachments, dental implants, feeding and tracheal tubes, and needle-type glucose sensors. However, breaking the skin barrier provides a route to infection and increases complications associated with wound non-closure.

[0008] Often, percutaneous devices also fail from mechanical irritation (avulsion) or epithelial downgrowth that forms a pocket around the implant (marsupialization), resulting in inflammation and increased susceptibility to infection. Mechanical forces also prevent an epidermal seal from forming, again increasing risk of infection.

[0009] To reduce percutaneous device-related infections antibiotics are applied topically, administered prophylactically, or incorporated into the device. Antibiotics, while clinically effective, raise concerns about the development of antibiotic-resistant strains. Dermal integration is necessary to prevent infection, avulsion, and marsupialization, and to ensure the long-term performance of percutaneous devices. Several porous and textured biomaterials have been investigated to improve percutaneous device performance and longevity.

[0010] In general, while textured and porous surfaces encourage dermal integration, there are concerns that surfaces with irregular topographies may be more prone to harbouring bacteria. Bacteria may out-compete tissue cells in adhering to an implant surface, thus preventing tissue integration and promoting infection.

[0011] Percutaneous dental devices, such as dental implants and / or dental implant systems are often first of all optimized to facilitate biological fixation of the implants to the hard tissue, such as the jawbone. The key feature for such surfaces is the space afforded for osseous integration, improving the mechanical interlocking at the implant-surface / bone interface.

[0012] Traditionally, dental implants and / or dental implant systems are therefore designed to improve the osseointegration and enhance its stability. A major part of the dental implants currently used consist of titanium and / or its alloys, since titanium is biocompatible, has a sufficiently low elastic modulus and a relatively high strength. Osteointegrative properties can e.g., be reached by suitable treatment of the implant’s surface. To this end, the titanium surface has conventionally been mechanically roughened by a subtractive removing process, e.g., sandblasting, grinding, or etching. Alternatively, the surface has been subjected to additive processes, e.g., coating with a textured surface. Surface topography of the dental implant or dental implant system is thus optimized for osseointegration and the part of the implant in contact with soft tissue is left smooth, so as to leave as little as possible anchoring / attachments holds for microbes. Also, it is believed that a smooth surface is advantageous for soft tissue reformation around the implant above the hard tissue line.

[0013] To further improve the placement success of dental implants, a dental surgical procedure can be employed that uses barrier membranes to direct the growth of new bone and gingival tissue at sites with insufficient volumes or dimensions of bone or gingiva for proper function, aesthetics, or prosthetic restoration, called guided bone regeneration (GBR). Guided bone regeneration typically refers to ridge augmentation or bone regenerative procedures; In analogy, guided tissue regeneration (GTR) typically refers to regeneration of periodontal attachment. At present, guided bone regeneration is predominantly applied in the oral cavity to support new hard tissue growth on an alveolar ridge to allow stable placement of dental implants. When bone grafting is used in conjunction with sound surgical technique, guided bone regeneration is a reliable and validated procedure.

[0014] Aiming at an improved soft tissue integration of the implant system, EP-A-2161000 suggests an abutment comprising a soft tissue contact surface that is at least partially hydroxylated. In this context, improved soft tissue integration is explained by the loose connective tissue to become organized and replaced be newly formed collagen fibres.

[0015] Further, in WO2014195027A2, an abutment is described which comprises nanostructures formed on the soft tissue contact surface of the abutment basic body, said nanostructures extending in at least two dimensions to 200 nm at the most. The nanostructures form retention sites, allowing for an improved initial adherence of proteins of the cells of the surrounding soft tissue.

[0016] A functional and robust transmucosal barrier is crucial to protect the bone-implant interface of osseointegrated load-bearing implants from the bacterial-laden environment of the oral cavity. Irrespective of healing modality, this transmucosal barrier establishes with remarkable consistency, resulting in two major peri-implant soft tissue compartments, the epithelial tissues (ET), subdivided into sulcular and junctional epithelia (SE and JE, respectively) and the connective tissue (CT).

[0017] While structurally resembling, the soft tissue organization between peri-implant and periodontal soft tissues present subtle but important differences both at ET and CT levels. These differences have been associated with reduced mechanical robustness of the transmucosal barrier around implants, impacting their short and long-term success. A commonly reported difference between implants and teeth has been related to the lack of root cementum around implants. This component is vital for the formation of functional dental-gingival fibres, and it’s lack has been associated with the formation of a typical cufflike circular and oblique CT fibres organization around implants. A second difference is related to the dimensions of the JE attachment. Ultrastructural investigations have evidenced that this important structure of the transmucosal seal is shorter and restricted to the apical region of peri-implant ET around titanium implant surfaces when compared to the corresponding periodontal structures interfacing tooth enamel.

[0018] Enamel and cementum interfacing the JE and CT display inherently different microtopographies. Recent in vitro and in vivo studies, including 3D oral mucosal models, indicate that such surface properties may also affect the quality of soft tissue formation and attachment, and first attempts to improve the peri-implant soft tissue seal using transgingivally surface-modified titanium implants have been presented. However, none of the recent studies have systematically or in-depth tested the performance of surface topographical cues mimicking the ones of enamel or cementum on soft tissue attachment.

[0019] In summary, all currently available percutaneous devices, such as dental implants and / or dental implant systems have a less than optimal soft tissue interaction, often displaying infection, avulsion, and marsupialization, in severe cases leading to periimplantitis.

[0020] There is currently no device on the marked that induces true physical soft tissue interaction with a dental implant. Suggested technologies to improve soft tissue interaction are based on a single surface or coating that should improve the interaction with soft tissue in general, irrespective of the fact that the supracrestal attached tissue, i.e., the “soft tissue” in the oral cavity adjacent to the implant, histologically comprises a complicated layering of different types of soft tissues.

[0021] Summary of the invention

[0022] As can be seen in figure 1 , the supracrestal attached tissue is not one single tissue type but comprises at least two histologically distinctive layers (epithelial- and connective tissue layer), such as, but not limited to, the junctional epithelium and the supracrestal attached tissue. Interestingly, it was by the current inventors found that, when looking at the interface between a natural tooth and the surrounding soft tissue, the epithelial layer always attaches to the enamel and the connective tissue always attaches to the tooth cementum (see figure 7).

[0023] Based on this observation it was hypothesized that the natural tooth’s enamel surface is tailored for inducing formation of and / or attracting epithelial cells and the surface of the cementum is tailored for inducing formation and / or attracting connective tissue cells such as, but not limited to, fibroblasts and / or gingiva. In consequence, for an improved soft tissue healing and / or regeneration after the placement of a percutaneous dental device, the dental device should also have an at least biphasic surface in the region which is after placement in contact with the soft tissue and in which the surface of each of the at least two phases is tailored to induce formation and / or for attracting the epithelial tissue or the connective tissue of the supracrestal attached tissue, respectively and wherein the interphase between these two surfaces defines an in situ cemento-enamel junction (iCEJ) Concurrently, the current inventors found that the surface of a percutaneous dental device, such as a dental implant system, will induce and / or guide a histologically more natural healing and / or regeneration of the soft tissue layers surrounding the implantation and / or placement site, if its surface is at least biphasic in its soft tissue region, so as to be adapted to each of the at least two distinctive soft tissue layers of the supracrestal attached tissue, respectively. Thus, the region of the surface of the herein for the first time disclosed percutaneous and / or transmucosal dental device, implant and / or dental implant system, that is after implantation in contact, or at least closely adjacent to, the supracrestal soft tissue in the oral cavity, i.e. , the soft tissue region of the device, effectively mimics the surface of a natural tooth and is thus optimized for histologically more natural soft tissue healing around the implantation and / or placement site. The herein for the first time disclosed dental device thus comprises an at least biphasic surface in the soft tissue region that enables the soft tissue around said implant to heal and / or regenerate in a more natural manner. A dental device according to the current invention thereby attracts a true, physical epithelial and connective tissue attachment.

[0024] Investigating the adhesion, growth, cytokine release and differentiation of two protagonist cell types of epithelial and connective tissues, i.e. keratinocytes, as represented by keratinizing human epithelial keratinocytes (hEK) and a non-keratinizing OKF6 / TERT2 cell line and by human gingival fibroblasts (hGF), respectively, when interfacing model titanium implant surfaces with topographies emulating the ones of Enamel (M) or Cementum (MA) and in function of hydrophobic / hydrophilic surface modifications, proved this theory. As can be seen in experiment 3. Adhesion and growth experiments of individual and mixed cocultures on surface- modified substrates evidenced that MA, compared to M surfaces, inhibited the proliferation of keratinocytes but not fibroblasts. Immunofluorescence microscopy (IF) for vinculin indicated that the inhibitory effect corroborated with a decreased tendency of keratinocytes to establish focal adhesions on MA surfaces. Quantitative real-time polymerase chain reaction (qPCR), IF and immunoblotting experiments profiling keratinocyte differentiation markers evidenced that surface hydrophilicity of M surfaces reduced the keratinocyte-specific basal-to-suprabasal differentiation resulting in undifferentiated stratified cell-colonies corresponding to the phenotypes in attached junctional epithelia. Likewise, expression profiling of hGF grown on hydrophilic MA surfaces, compared to hydrophobic counterparts, evidenced a reduction in proinflammatory and proteolytic markers, comprising Matrixmetalloproteinase- 1 and lnterleukin-6. Collectively, the cell-discriminative and differentiation and expressionprofile influencing effects of the individual surfaces point to combining enamel-emulating M and cement-emulating MA surfaces into novel transgingival implant or abutment hybrid- designed surfaces with improved soft tissue attachment and transmucosal barrier properties.

[0025] The current invention therefore in one aspect relates to the use of a percutaneous / transmucosal dental device which comprises at least two surface regions with different surface-topographies in its soft-tissue region which mimic the surface of a natural tooth and which interphase and / or boundary forms an in situ cemento-enamel junction (iCEJ), for improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device.

[0026] Use of a percutaneous dental device according to the current invention in particular improves soft tissue healing and / or soft tissue regeneration of the junctional epithelium, the sulcular epithelium and / or the supracrestal connective tissue at the placement site of the device, i.e. , a supracrestal attached tissue, or a tissue resembling it histologically, is regenerated at the placement site of said percutaneous dental device. In essence leading to a true, physical epithelial and connective tissue attachment.

[0027] Thus, in one aspect, the current invention relates to the use of a percutaneous dental device according to the current invention for improving, controlling and / or guiding regrowth and / or regeneration of a biological width at the placement site of said percutaneous dental device which is histologically correct and / or resembles the natural biological width of the patient at the placement site.

[0028] In consequence, the current invention in one aspect relates to the use of a percutaneous dental device according to the current invention for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement site of the device.

[0029] In a herein envisioned use of a percutaneous dental device according to the current invention, the regenerated soft tissues are in direct contact or at least in close proximity with the soft tissue region of the device.

[0030] The current invention relates to the use of a percutaneous dental device, wherein said percutaneous dental device comprises at least two surface regions with different surfacetopography above and below the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device at their interphase, which are both in direct contact with soft tissue at the placement site. Through the herein for the first time described use of the percutaneous dental device according to the current invention, one of the at least two different soft tissue types is regenerated at one of the at least two distinct regions with different surface-topographies of the soft tissue region of said percutaneous dental device at the implantation site and another of the at least two different soft tissue types is regenerated at another of the at least two distinct regions with different surfacetopography of the soft tissue region of said percutaneous dental device at the placement site. Thus, the at least two different soft tissue types are regenerated in the form of at least two distinct layers of soft tissue and each distinct soft tissue layer is in direct contact with only one of the distinct regions with different surface-topography of the soft tissue region of said percutaneous dental device.

[0031] Typically, the use of a percutaneous dental device according to the current invention leads to one of the at least two distinct layers of soft tissue being regenerated above the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device and the other below the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device. Healing and / or regeneration of epithelial tissue is induced and / or guided above the in situ CEJ (iCEJ) of the percutaneous dental device and healing and / or regeneration of connective tissue is induced and / or guided below the in situ CEJ (iCEJ) of the percutaneous dental device.

[0032] A percutaneous dental device according to the current invention mimics the surfacetopography of a natural tooth and thus the placement of the in situ CEJ (ICEJ) of the percutaneous dental device is typically determined in analogy to the CEJ of the surrounding tooth and / or teeth to the implant or placement site.

[0033] The current invention also relates to a percutaneous dental device with at least two distinct regions with different surface-topography in the soft tissue region of the device. In aspects, the soft tissue region of said percutaneous dental device has an apical region with a first surface-topography facing bone and a distal region with a second surfacetopography facing the intra oral cavity (see figure 2).

[0034] The apical region and the distal region of the soft tissue region of the percutaneous dental device are divided by the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device. In the current context, the apical region is the region of the percutaneous dental device below the in situ cemento-enamel junction (iCEJ), facing the bone tissue and the distal region is the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) facing the intra oral cavity (see figure 2). A percutaneous dental device of the current invention comprises at least two distinct regions with different surface-topographies in the soft tissue region of the device, wherein the surface roughness (Sa) of the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as at least 0.2 pm, less than the surface roughness (Sa) of the region of the percutaneous dental below the in situ cemento-enamel junction (iCEJ).

[0035] In one embodiment, a percutaneous dental device is envisioned which comprises at least two distinct regions with different surface-topographies in the soft tissue region, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) is no more than 0.4 pm, and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm, and the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as 0.2 pm less than the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ).

[0036] In embodiments, a percutaneous dental device of the current invention is characterized in that c. the surface roughness (Sa) of the soft tissue region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is no more than (0.185 ± 0.07) pm (Sa), and d. the surface roughness (Sa) of the of the soft tissue region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm such as (0.477 ± 0.12) pm(Sa).

[0037] In aspects of the invention, a percutaneous dental device comprises a transitional region between the two surfaces above and below the in situ CEJ (iCEJ), wherein the surface roughness of the transitional region successively roughens from the surface roughness above the in situ CEJ (iCEJ) of the percutaneous dental device to the surface roughness below the in situ CEJ (iCEJ) of the percutaneous dental device. The surface of the soft tissue region of a dental device according to the current invention is intended to mimic the surface of the soft tissue region of a natural tooth as closely as possible, thus the surface topography provided on the soft tissue region has an isotropic topography.

[0038] In aspects of the current invention, a percutaneous dental device is a dental implant system, comprising a dental implant, a crown and / or an abutment.

[0039] In aspects of the current invention, a percutaneous dental device comprises a soft tissue region with at least two distinct regions with different surface-topography which are located on the same part of the dental implant system. In other aspects, the at least two distinct regions of the soft tissue region with different surface-topography are located on at least two different parts of the dental implant system.

[0040] A percutaneous dental device according to the current invention can comprise a surface which comprises and / or consists of titanium, zirconium, titanium and / or zirconium alloys, dental ceramic, zirconia ceramic, , and / or yttrium-stabilized zirconium oxide (zirconia) in predominantly tetragonal form. The surface of the percutaneous dental device can, e.g., be (sand-)blasted and / or etched to achieve the final roughness / topography.

[0041] The current invention further relates to a method for producing a percutaneous dental device, characterized in that the surface of the soft tissue section of the dental device is roughened to achieve e. one surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (ICEJ) of no more than (0.185 ± 0.07) pm (Sa), and f. one surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) which is between 0.2-0.8 pm such as (0.477 ± 0.12) pm (Sa).

[0042] In such a method, the soft tissue section of the dental device can be roughened by any one or a combination of machining, application of a textured surface, employing spark erosive techniques, anodization techniques, plasma electrolytic oxidation, plasma etching, mechanical roughening, sintering, molding techniques, turning, milling, laser texturing, grinding, blasting with particles and acid etching. Alternatively, or in addition, the soft tissue section of the dental device can be topographically optimized by applying (a) growth factor(s), protein(s) and / or other material(s) that promote(s), enhance(s) and / or maintain(s) soft-tissue growth and / or regeneration.

[0043] In consequence, the current invention also relates to a percutaneous dental device produced by a method according to the current invention.

[0044] Definitions

[0045] Percutaneous dental device

[0046] In the current context, a percutaneous dental device is a transmucosal dental device, such as, but not limited to an implant, that is placed through the supracrestal attached tissue such that a permanent defect is created. Percutaneous medical or dental implants / devices are inserted into inner organs or other tissues by piercing through the skin and / or epidermal layer of the mucosa and then positioning the device into position by trespassing multiple layers of tissue. In the current context, the term “percutaneous device and / or implant” is used interchangeably with “transcutaneous device and / or implant” and “transmucosal implant and / or device”.

[0047] CEJ

[0048] The cemento-enamel junction (CEJ).

[0049] ICEJ

[0050] The in situ cemento-enamel junction (CEJ).

[0051] Peri-implantitis

[0052] “Peri-implantitis” or “periimplantitis” is a dental term used to describe the destructive inflammatory process affecting the soft and hard tissues surrounding dental implants. Compared to mucositis, the definition of peri-implantitis includes bone loss. Among others, smoking, accumulation of bacterial biofilms (plaque), oral hygiene and periodontal status are influential factors. In the present context, the term “periodontal diseases” encompasses peri-implant infections, such as periimplantitis.

[0053] Patient

[0054] The term “patient” as used herein refers to any mammal. Examples of mammals are humans, farm animals and domestic animals.

[0055] Osteointeg ration The term "osteointegration" herein interchangeably used with “osseointegration” designates the direct structural and functional connection between living bone and the surface of an implant / device. A good osteointegration means that the implant, after reaching a primary stability by screwing it into the bone, safely ossifies within a short healing time so that a permanent bond between implant and bone is obtained. In the past, much effort has been made to improve the osteointegrative properties of implants.

[0056] CMF

[0057] The abbreviation “CMF” herein stands for craniomaxillofacial complex, i.e., the anatomical area of the mouth, jaws, face, skull, as well as associated structures.

[0058] SLA®

[0059] In the present context, SLA® refers to a titanium surface which is produced by a large grit sand-blasting process with corundum particles that leads to a macro-roughness on the titanium surface. This is followed by a strong acid-etching bath with a mixture of HCI / H2SO4 at elevated temperature for several minutes. This produces 2-4 pm fine micropits superimposed on the rough-blasted surface. The surface is not micro-porous and therefore provides no enclosed volumes to reduce vulnerability to bacteria.

[0060] CIS

[0061] In the present context, Clean Implant Surface is abbreviated CIS.

[0062] Enamel

[0063] Tooth enamel is one of the four major tissues that make up the tooth in humans and many other animals, including some species of fish. It makes up the normally visible part of the tooth, covering the crown. The other major tissues are dentin, cementum, and dental pulp. Enamel is the hardest substance in the human body and contains the highest percentage of minerals (at 96%), with water and organic material composing the rest. The primary mineral is hydroxyapatite, which is a crystalline calcium phosphate.

[0064] Periodontal phenotype

[0065] The term “periodontal phenotype” herein means periodontal biotype.

[0066] Supracrestal attachment

[0067] “Supracrestal attachment” is in the present context interchangeably used with “the biological width”.

[0068] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

[0069] Figure legends

[0070] Figure 1 : Schematic picture of the supracrestal connective tissue comprising epithelium (1 ) attached to the enamel (4) of the natural tooth and connective tissue (2) attached to the cementum (3) of the natural tooth.

[0071] Figure 2: Schematic picture of the placement of a dental device either in the upper or the lower jaw bone comprising a dental implant (8), illustrating the orientation of the two different surfaces of the soft-tissue region of the dental device below / apical (5) and above / distal (6) the cemento-enamel junction (CEJ) (7), which on the dental device is called the in situ CEJ (iCEJ).

[0072] Figure 3: Schematic picture of a dental device (right panel) which mimics the at least biphasic surface of the soft-tissue region of the natural tooth (left panel) above and below the CEJ (7) / the in situ CEJ (ICEJ) (9). The soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9). Dental implant (8).

[0073] Figure 4: Schematic representation of two different biphasic test abutments. The soft- tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9). Dental implant (8).

[0074] Figure 5: Implantation into the minipig mandible.

[0075] Figure 6: SEM image of the border between the soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9). The machined surface (untreated surface) (6) is on the right side and the acid etched surface (5) is on the left. It can be seen that the manufacturing process led to a precise margin between the treated and untreated surface.

[0076] Figure 7: Histological section of a natural minipig tooth. Epithelium (1 ) attached to the enamel (4) of the natural tooth and connective tissue (2) attached to the cementum (3) of the natural tooth.

[0077] Figure 8: Histological section of a commercial smooth (machined) abutment. The whole abutment surface is covered with the epithelial layer (1). Figure 9: Histological section of the customized bi-modal abutment. The top half of the abutment was machined, and the bottom half was roughened (2.5 mm from the implant shoulder). The soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9), epithelial layer (1) and connective tissue (2).

[0078] Figure 10: Histological section of the customized abutment. The top 4 mm of the abutment was machined, and the bottom 1 mm was roughened. The soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9), epithelial layer (1 ) and connective tissue (2).

[0079] Figure 11 A and B: A ceramic abutment 2.5 mm, sample 1

[0080] Figure 12 A and B and C: Ceramic abutment 2.5 mm, sample 1

[0081] Figure 13 A and B: A ceramic abutment 2.5 mm, sample 2

[0082] Figure 14 A and B and C: Ceramic abutment 2.5 mm, sample 2

[0083] Figure 15 A and B: A Ceramic abutment 1 .0 mm, sample 1

[0084] Figure 16 A and B and C: Ceramic abutment 1 .0 mm, sample 1

[0085] Figure 17 A and B: A Ceramic abutment 1 .0 mm, sample 2

[0086] Figure 18 A and B and C: Ceramic abutment 1 .0 mm, sample 2

[0087] Figure 19: Fig.19a, schematic view of the placement of a one-piece dental implant (18). Epithelial layer (1 ) and connective tissue (2), soft tissue region of the implant (10), hard tissue region of the implant (12), hard tissue (11 ). Fig. 19b, schematic view of the placement of a soft-tissue level dental implant (13). Epithelial layer (1 ) and connective tissue (2), soft tissue region of the implant (10), hard tissue region of the implant (12), hard tissue (11), abutment (15), crown (14). Fig.19c, schematic view of the placement of a bone level dental implant (16). Epithelial layer (1 ) and connective tissue (2), soft tissue region of the implant (10), hard tissue region of the implant (12), hard tissue (11 ), abutment (15), crown (14), soft-tissue region of crown (17). Figure 20: Fig.20a, schematic view of a one-piece dental implant (18). Soft tissue region of the implant (10), hard tissue region of the implant (12), the in situ cemento-enamel junction (iCEJ) (9). Fig.20b, schematic view of a soft-tissue level dental implant. Soft tissue region of the implant (10), abutment (15), crown (14), the in situ cemento-enamel junction (iCEJ) (9). Fig. 20c, schematic view of a bone level dental implant. Soft tissue region of the implant (10), hard tissue region of the implant (12 / 16), abutment (15), crown (14), soft-tissue region of crown (17), the in situ cemento-enamel junction (iCEJ) (9).

[0088] Figure 21 : Fig.21a and b, schematic view of a biphasic crown. The soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9). Fig.21c, schematic view of a crown, wherein the soft-tissue region displays a surface topographic gradient from below / apical to above / distal across the in situ cementoenamel junction (iCEJ) (9). Fig .21 d , schematic view of a biphasic abutment, the soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cementoenamel junction (iCEJ) (9). Fig.21e and 21f, schematic view of a biphasic crown. The soft- tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9). Fi. 21g, schematic view of a placed dental device comprising a bone-level implant and a biphasic crown. The soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9), soft-tissue region of crown (17), hard tissue (11 ). Fig 21 h, schematic view of a placed dental device comprising soft-tissue level implant with a biphasic soft-tissue region. The soft-tissue region of the dental device below / apical (5) and above / distal (6) the in situ cemento-enamel junction (iCEJ) (9), soft tissue region of the implant (10), abutment (15), crown (14).

[0089] Figure 22: (A) Illustration of the different anatomical compartments of the masticatory gingival mucosa. Masticatory gingiva comprises three distinct compartments: Gingival and sulcular epithelia (GE and SE, both keratinized) and the non-keratinized junctional epithelium (JE). (B) Schematic representations comparing the stratification and composition of different types of oral mucosal epithelia, i.e. non-keratinized and keratinized oral mucosal (OM) epithelium and the specific characteristic differentiation markers. Non-keratinized epithelia may consist of up to 3 epithelial cell layers comprising basal, intermediate, and superficial layers. Keratinizing OM epithelium may consist of up to 4 layers, including the basal, spinous, granular and stratum corneum. K: Keratin;

[0090] TGM1 : Transglutaminasel ; IVL: Involucrin; LOR: Loricrin. (C) qPCR analyses of specific differentiation markers showing induction upon the addition of Ca2+in primary human gingiva-derived epithelial keratinocytes (hEK). Gene expression was normalized to the basal levels, set to 1 . *=p>0.05. (D) qPCR analyses of specific differentiation markers showing induction upon the addition of Ca2+in OKF6 / TERT2 cells. Gene expression was normalized to the basal levels, set to 1 . *=p>0.05. #=not detectable gene (Ct value >32). OKF6 / TERT2 cells were chosen as a model of non-keratinizing epithelial cells, modelling the stratification-independent differentiation of JE attachment.

[0091] Figure 23: Cell viability of primary gingiva-derived fibroblasts (green box) and OKF6 / TERT2 cells (light blue box) measured 2, 4 and 6 days after seeding on M and MA surfaces by MTT assay, d: days. *=p>0.05.

[0092] Figure 24: Interaction of human primary gingival fibroblasts (hGF), keratinizing epithelial keratinocytes (hEK) and non-keratinizing, immortalized OKF6 / TERT2 keratinocytes with enamel-like M and cementum-like MA titanium substrates. (A) Fluorescence micrographs of DAPI-labelled hGF, hEK and OKF6 / TERT2 cells on M or MA surfaces 3h, 24h and 7 days after seeding and corresponding cell count averages of five different regions of interest (ROIs) per substrate. Scale bar: 100pm*=p<0.05. (B) Fluorescence micrographs of 1 :1 ratio cocultured hGF and hEK cells on M and MA substrates after 7 days postseeding, stained for laminin 5 (LAM5, red) and fibronectin (FN, green) and nuclei (blue). The left images were taken at X magnification scale bar: 50pm, right images show the white framed regions at Y magnification scale bar 20pm. (C) Fluorescence micrographs of DAPI-labelled OKF6 / TERT2 keratinocytes on M or MA substrates 3h, 24h and 7 days post-seeding (Scale bar: 100pm) and corresponding averaged cell counts in five different regions of interest (ROIs), *=p<0.05. (D) Fluorescence micrographs of hGF, hEK and OKF6 / TERT2 cells on M and MA surface 24h after seeding and staining for vinculin (VINC, green) F-Actin (cytoskeleton, red) and nuclei (blue). Scale bar: 10pm.

[0093] Abbreviations: h: hours; d: days.

[0094] Figure 25: Influence of hydrophilicity of enamel-like M substrates, i.e. M vs. hM surfaces, on the differentiation of human keratinocytes. (A) Fluorescence micrographs of DAPI- labeled hEK and OKF6 / TERT2 7 days after seeding indicating equivalent proliferation on M or hM surfaces. Scale bar: 100pm. (B and C) Differentiation marker expression profiles of hEK and OKF6 / TERT2 cells grown to confluency and stratification on M and hM surface for 7 days relative to the basal control levels of subconfluent cultures. *=p>0.05. (D) Immunofluorescence micrographs of hEK and OKF6 / TERT2 cells grown to confluency and stratification on M and hM substrates for 7 days and stained for F-actin (red), K10, K13, TGM1 (green), and IVL (red for hEK, green for OKF6 / TERT2 cells). White dashed lines indicate zones of stratification. Scale bar: 100pm. (E) Qualitative comparison of expression levels of K13, TGM1 , IVL and VINC (control) between OKF6 / TERT2 cells cultured for 7 days on M and hM surface. Abbreviations: K: Keratin, TGM1 :

[0095] Transglutaminase 1 , IVL: Involucrin, VINC: Vinculin, kDa: kilo Dalton

[0096] Figure 26: Influence of hydrophilicity of cementum-emulating MA, i.e. MA vs. hMA surfaces, on gene expression of hGF cells. (A) Fluorescence micrographs of DAPI- labelled hGF cells evidencing comparable adhesion and proliferation on MA and hMA surfaces 7 days after seeding. Scale bar: 100pm. (B) Heatmap comparing the hGF expression of ECM molecules, metalloproteinases, and cytokines between hEK cells grown for 7 days on M, MA or hMA titanium discs. qPCR-derived gene expression levels were normalized to the expression levels on M surfaces. (C) Comparison of expression levels of metalloproteinase 1 (MMP1), interleukin 6 (IL6) and transforming growth factor beta 1 (TGFfil ) between hGF cells cultured on M, MA or hMA surfaces for 7 days. *=p>0.05.

[0097] Detailed description of invention

[0098] The present invention, for the first time, discloses a percutaneous dental device that comprises an at least biphasic surface in its soft-tissue region, i.e., the surface region of the dental device which is in contact with or which is adjacent to the soft tissue after the placement of the dental device in the patient’s oral cavity, and wherein each of the at least two surface phases is tailored to optimize the interaction with the epithelial layer or the connective tissue, respectively.

[0099] A dental device according to the present invention therefore for the first time provides the means for improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device.

[0100] The use of a dental device according to the present invention in essence facilitates histologically more natural healing, regeneration, regrowth and / or recovery of the soft tissue at the placement site of a percutaneous dental device.

[0101] The use of a dental device according to the present invention improves regrowth and / or regeneration of a histologically more correct and / or natural biological width at the placement site of said percutaneous dental device.

[0102] What is more, the use of a dental device according to the present invention for the first time makes it possible to determine and / or control the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement site of the device. The current invention thus relates to the use of, as well as to a percutaneous dental device with at least two distinct regions with different surface properties, such as with at least two different surface-topographies, in its soft-tissue region, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with and / or adjacent to the soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is no more than (0.185 ± 0.07) pm (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with and / or adjacent to the soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm such as (0.477 ± 0.12) pm (Sa).

[0103] Periodontium

[0104] The periodontium is the assembly of specialized tissues that both surround and support the teeth, maintaining them in the maxillary and mandibular bones. The tissues of the periodontium combine to form an active, dynamic group of tissues. The alveolar bone is surrounded for the most part by the subepithelial connective tissue of the gingiva, which in turn is covered by the various characteristic gingival epithelia. The cementum overlaying the tooth root is attached to the adjacent cortical surface of the alveolar bone by the alveolar crest, horizontal and oblique fibres of the periodontal ligament.

[0105] It consists of four principal components, namely:

[0106] 1. Gingiva

[0107] 2. Periodontal ligament (PDL)

[0108] 3. Cementum

[0109] 4. Alveolar bone proper

[0110] Each of these components is distinct in location, architecture, and biochemical properties, which adapt during the life of the structure. For example, as teeth respond to forces or migrate medially, bone resorbs on the pressure side and is added on the tension side. Cementum similarly adapts to wear on the occlusal surfaces of the teeth by apical deposition. The periodontal ligament in itself is an area of high turnover that allows the tooth not only to be suspended in the alveolar bone but also to respond to the forces. Thus, although seemingly static and having functions of their own, all of these components function as a single unit.

[0111] The attachment of the tooth to the surrounding and supporting structures (bone) is accomplished through the cementum of the tooth, periodontal ligaments and the alveolar bone. The junctional epithelium is located at the base of the sulcus. It is adjacent to the tooth and is that part of the gingiva that attaches the connective tissue to the tooth. The root of the tooth (cementum) is attached to the underlying bone by a series of periodontal fibres that make up the periodontal ligament and allow for minor movement of the tooth in the socket without damage to the tooth or the underlying structures. These fibres are classified apical, oblique, horizontal, alveolar crest and interradicular fibres.

[0112] Gingiva

[0113] The makeup of the gingival tissue varies according to its location and function. There are two types of gingivae and several important anatomic regions.

[0114] 1 . Alveolar mucosa - The area of tissue beyond the mucogingival junction. It seems less firmly attached and redder than the attached gingiva. It is non-keratinized and provides a softer and more flexible area for the movement of the cheeks and lips.

[0115] 2. Attached gingiva - This tissue is adjacent to the free gingiva and is keratinized and firmly attached to the bone structure. It can range from 3-12 mm in height.

[0116] 3. Free gingiva - This tissue is not attached and forms a collar around the tooth. The trough around the tooth is called the sulcus and its depth is normally 1-3 mm. It is lined with sulcular epithelium and attached to the tooth at its base by the epithelial attachment. The sulcular epithelium is that epithelium which lines the gingival sulcus. It is apically bounded by the junctional epithelium and meets the epithelium of the oral cavity at the height of the free gingival margin.

[0117] 4. Gingival margin - The border region of the gingiva that touches the tooth.

[0118] 5. Junctional epithelium - The part of the gingiva that attaches the connective tissue to the tooth. It is located at the base of the sulcus.

[0119] 6. Interdental papillae - The region of gingival tissue that fills the space between adjacent teeth. In a healthy mouth this is usually knife-edged and fills the interdental space.

[0120] 7. Muco-gingival junction - The scalloped line that divides the attached gingiva from the alveolar mucosa.

[0121] Periodontal ligament (PDL)

[0122] The periodontal ligament, commonly abbreviated as the PDL, is a group of specialized connective tissue fibres that essentially attach a tooth to the alveolar bone within which it sits. It inserts into root cementum one side and onto alveolar bone on the other.

[0123] The PDL consists of principal fibres, loose connective tissue, blast and clast cells, oxytalan fibres and Cell Rest of Malassez. The PDL is a part of the periodontium that provides for the attachment of the teeth to the surrounding alveolar bone by way of the cementum.

[0124] Cementum

[0125] The cementum is a specialized calcified substance covering the root of a tooth. The cementum is the part of the periodontium that attaches the teeth to the alveolar bone by anchoring the periodontal ligament.

[0126] Sharpey fibres are part of the principal collagenous fibres of the periodontal ligament embedded in the cementum and alveolar bone to attach the tooth to the alveolus.

[0127] If cementum can be observed on teeth, it can imply that the roots are exposed, showing that the clinical crown (the exposed part of the tooth) is bigger than the anatomical crown (the surface of the tooth covered by enamel). This is often due to gingival recession and may be an indication of periodontal disease.

[0128] Supracrestal attached tissue

[0129] The supracrestal attached tissues are histologically composed of the junctional epithelium and supracrestal connective tissue attachment. Infringement within the supracrestal connective tissue attachment is associated with inflammation and loss of periodontal supporting tissue.

[0130] As shown in the experimental section, epithelial tissue and connective tissue can easily be differentiated by ocular histological inspection.

[0131] There are two types of gingivae that are clearly recognizable, and they are known as the marginal gingiva that is mobile, and the attached gingiva.

[0132] The current invention relates to the use of a percutaneous dental device which comprises at least two surface regions with different surface-topographies in the soft-tissue region of the device, for improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device.

[0133] Such a use improves in particular the soft tissue healing and / or soft tissue regeneration of the junctional epithelium, the sulcular epithelium and the supracrestal connective tissue at the placement site of the device, so that the supracrestal attached tissue is regenerated or at least a tissue is regenerated that histologically closely resembles the supracrestal attached tissue at the placement site of said percutaneous dental device. Biological width

[0134] The natural barrier that develops around the teeth and dental implants to protect the alveolar bone from disease and infection is known as the biologic width. As such, biologic width is vital for the preservation of periodontal health and removal of irritation that could damage the periodontium.

[0135] The biologic width can be identified by probing under local anaesthesia to the bone level (referred to as “sounding to bone”) and subtracting the sulcus depth from the resulting measurement. If this distance is less than 2 mm at one or more locations, a diagnosis of biologic width violation can be confirmed. Increased probing depths have been associated with increased risk of peri-implant disease and implant failure.

[0136] The biologic width is unique to each patient and will typically vary from about 0.75-4.3 mm. The mean biologic width is 2.04 mm. Of this, the connective tissue attachment is 1.07 mm and about 0.97 mm is occupied by the junctional epithelium.

[0137] Use of a percutaneous dental device according to the current invention improves regrowth and / or regeneration of a histologically correct biological width at the placement site of said percutaneous dental device.

[0138] Since, as discussed above, the biologic width is unique to each patient, an improved regrowth of the biological width needs to be determined in relation to the natural biological width of the patient and can thus be from about 0.75-4.3 mm. As a rule, the use of a percutaneous dental device according to the current invention improves regrowth and / or regeneration of a histologically correct biological width at the placement site of said percutaneous dental device to a mean value of more than 2 mm.

[0139] Cemento-enamel junction (CEJ)

[0140] In the natural tooth, the cementum joins the enamel to form the cemento-enamel junction (CEJ), which is referred to as the cervical line.

[0141] The cemento-enamel junction, in the current context abbreviated as CEJ, is a slightly visible anatomical border identified on a tooth. It is the location where the enamel, which covers the anatomical crown of a tooth, and the cementum, which covers the anatomical root of a tooth, meet.

[0142] The cemento-enamel junction (CEJ) represents the anatomic limit between the crown and root surface and is defined as the area of union of the cementum and enamel at the cervical region of the tooth. In situ cemento-enamel junction (iCEJ) of the percutaneous dental device

[0143] A percutaneous dental device of the current invention comprises an artificial CEJ, a limit where two distinct surface regions of its soft tissue region with different surface properties meet. I.e., the different surface properties of the soft tissue region of the dental device mimic the different surface properties of a natural tooth, thereby effectively mimicking its biological effect on the surrounding soft tissues, in particular on the supracrestal attached tissue at the placement site of the device. In the current context, the artificial CEJ of the dental device is defined as “in situ CEJ (iCEJ / ’ or “in situ CEJ (iCEJ) of the dental device”.

[0144] The placement of the in situ CEJ (iCEJ) in the soft tissue region of the percutaneous dental device according to the current invention is preferably determined in analogy to the CEJ of the adjacent or surrounding tooth and / or teeth to the implant site or placement site. Alternatively, it can also be designed to not align, or to align with the CEJ of the adjacent or surrounding tooth only partly and / or teeth.

[0145] The in situ CEJ (iCEJ) can be placed so that the soft tissue region of the dental device is divided into equal parts with different surface properties, i.e., 50 / 50, or it can be placed so that the soft tissue region is divided into any other parts, such as between 1 / 99-99 / 1 , such as approximately into 10 / 90, 20 / 80, 30 / 70, 40 / 60, 60 / 40, 70 / 30, 80 / 20 or 90 / 10.

[0146] In this way, a percutaneous dental device according to the current invention can be designed to mimic the surface-properties of a natural tooth in its soft tissue region to achieve determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement site of the device.

[0147] In aspects of the current invention, a percutaneous dental device comprises a transitional region between the two surfaces above and below the in situ CEJ (ICEJ), wherein the surface of the transitional region successively changes from the properties of the surface above the in situ CEJ (iCEJ) of the percutaneous dental device to the surface properties below the in situ CEJ (iCEJ) of the percutaneous dental device.

[0148] Guided soft tissue regeneration

[0149] Guided tissue regeneration (GTR) is a treatment principle in surgical therapy. It implies that only those types of cells with the capacity of producing regeneration invade a surgically treated lesion during healing. Guided bone regeneration (GBR) typically refers to ridge augmentation or bone regenerative procedures; guided tissue regeneration (GTR) typically refers to regeneration of periodontal attachment.

[0150] In the art, the treatment principle, both GBR and GTR, refer to dental surgical procedures that use barrier membranes to direct the growth of new bone and gingival tissue at sites with insufficient volumes or dimensions of bone or gingiva for proper function, aesthetics, or prosthetic restoration.

[0151] In the present context, guided soft tissue regeneration (GTR) is achieved by presenting the soft tissue surrounding the implantation and / or placement site with a region of soft tissue attractive properties that is different above and below the in situ CEJ (ICEJ), thus mimicking the properties of the natural tooth and thus only attracting a certain type of soft tissue, or at least preferably attracting a certain type of soft tissue over other types of soft tissue.

[0152] It is possible to combine the herein for the first time presented GTR treatment principle with the traditional dental surgical procedures that use barrier membranes to direct the growth of new bone and gingival tissue at sites with insufficient volumes or dimensions of bone or gingiva.

[0153] In the present context, the phrase Guided Tissue Regeneration (GTR) is used to describe the regeneration of histologically more natural soft tissue surrounding the placement site of the percutaneous dental device, i.e., regeneration of the supracrestal attached tissue.

[0154] In the present context, regeneration of the soft tissue is not guided by a surgically introduced membrane but induced by adapting the soft-tissue region of the surface of the dental device in such a way that it selectively attracts the histologically correct soft tissue below and above the CEJ / ICEJ.

[0155] Thus, a dental device according to the current invention provides transmucosal surface properties that facilitate a regeneration and / or healing which results in a more natural soft tissue surrounding the implantation site, wherein both regenerated epithelium and regenerated connective tissue are in contact with the soft-tissue region of the dental device. This ensures attachment of both soft tissue types by offering tailored surfaces for both types of tissues, i.e., for both epithelial and connective soft tissue types, respectively.

[0156] Inducing histologically more natural soft tissue healing and / or regeneration

[0157] The current invention is based on the finding that a dental device that mimics the surface properties of a natural tooth will induce, guide and / or control the restoration of a histologically more natural or near natural soft tissue surrounding the placement and / or implantation site.

[0158] Without wishing to be limited to a scientific theory, the surrounding soft tissue is seemingly stimulated to grow back into the original layers of tissue arrangement by being selectively attracted to the different properties of the distinct phases of the soft-tissue region of the dental device that resemble the structuring of the natural tooth’s different regions.

[0159] In the current context, the phrase “Histologically correct” or “histologically more natural” is used to indicate that the regenerated and / or regrown soft tissue mimics the natural soft tissue structure before the dental device was placed and / or implanted at the placement and / or implantation site. In particular, it mimics the original histology of the supracrestal attached tissue. The supracrestal dental device of the current invention is designed to attract a true, physical connective tissue attachment. It is to be understood that a complete regeneration to an absolute resemblance is not achievable even with the herein for the first time described new use, since the placing of a percutaneous device into and through the original soft tissue layers will of course disturb and / or distort the natural tissue and create a wound-like structure. Thus, the new tissue is of course only a replacement tissue and not the actual original tissue. Still, with the new use of the current invention, the replacement tissue at the placement and / or implantation site mimics the natural soft tissue structure of the original tissue, i.e., the regrown and / or regenerated tissue comprises both epithelial tissue and connective tissue in distinct tissue layers, the layers meeting at the in situ CEJ (iCEJ) (see figures 9 and 10).

[0160] Thus, the current invention relates to a use of a percutaneous dental device according to the current invention, wherein the regenerated soft tissues are in direct contact with the device at the soft tissue region of the device.

[0161] Since a percutaneous dental device of the current invention comprises at least two surface regions with different surface-topography above and below the in situ cementoenamel junction (iCEJ) in the soft tissue-region of the percutaneous dental device, both surface regions will at least partially come in direct contact with soft tissue at the implantation and / or placement site.

[0162] Use of a percutaneous dental device according to the current invention leads to one of the at least two different soft tissue types being attracted to and / or regenerated at one of the at least two distinct regions of the device’s soft-tissue region at the implantation and / or placement site and another of the at least two different soft tissue types being attracted to and / or regenerated at another of the at least two distinct regions of the device’s soft-tissue region at the implantation site and / or placement site.

[0163] The at least two different soft tissue types are regenerated in the form of at least two distinct layers of soft tissue and each distinct soft tissue layer is in direct contact with only one of the distinct regions of the soft-tissue section of the percutaneous dental device.

[0164] Each of the at least two distinct layers of soft tissue in contact with the percutaneous dental device is regenerated either above the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device or below the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device.

[0165] Thus, use of a percutaneous dental device according to the current invention will lead to improved healing and / or regeneration of epithelial tissue above the in situ CEJ (iCEJ) of the percutaneous dental device and improved healing and / or regeneration of connective tissue below the in situ CEJ (iCEJ) of the percutaneous dental device.

[0166] What is more, the current invention thus for the first time provides the means for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement site of a percutaneous dental device by controlling the location and / or level of the in situ CEJ (ICEJ) on the soft tissue surface of the percutaneous dental device.

[0167] Methods of measuring improved soft tissue healing at implant site

[0168] As can be seen in the experimental section, improved soft tissue healing can easily be detected with histological analysis, such as with ocular inspection and / or SEM imaging.

[0169] Wound healing in the soft tissue at implantation site

[0170] Soft tissue healing is defined as the replacement of destroyed tissue by living tissue in the body. This process consists of two parts - regeneration and repair. There are no defined boundaries between stages as the wound healing response “transitions” into the next stage of healing.

[0171] Oral wounds follow a similar pattern. The tissue specificities of the gingival, alveolar and palatal mucosa appear to be innately and not necessarily functionally determined. The granulation tissue originating from the periodontal ligament or from connective tissue originally covered by keratinized epithelium has the potential to induce keratinization. However, it also appears that deep palatal connective tissue may not have the same potential to induce keratinization as the palatal connective tissue originating from an immediately subepithelial area. Epithelial healing following non-surgical and surgical periodontal therapy appears to be completed after a period of 7-14 days. Structural integrity of a maturing wound between a denuded root surface and a soft tissue flap is achieved at approximately 14-days post-surgery. The formation of the biological width and maturation of the barrier function around transmucosal implants requires 6-8 weeks of healing.

[0172] At the implant-soft tissue interface, the creation of epithelial and connective tissue seals is essential to inhibit bacterial infiltration, prevent the development of peri-implant diseases, and ensure a long-term prognosis of dental implants.

[0173] The soft tissue seal around the dental implant is formed as a result of the wound healing process that starts immediately after the implant / abutment surgery when the blood proteins adsorb on the implant or abutment surfaces. This initial interaction may influence clot formation at the peri-implant wound site, which induces an inflammatory process and leads to tissue formation.

[0174] Typical healing in dentistry refers to periodontal tissue healing which occurs differently in regenerative versus resective procedures and in the latter, in first intention versus secondary intention closure. Regenerative procedures aim to produce new periodontal tissue as in guided tissue regeneration (GTR), while the aim of respective procedures is to remodel the existent periodontal tissues in order to eliminate the pockets and to facilitate oral hygiene maintenance. In first intention procedures, soft tissue flaps are repositioned to perfectly cover the underlying hard tissue, while, in secondary intention procedures, surgical flaps are placed in close proximity to the remodelled hard tissue to allow best new soft tissue attachment.

[0175] In dental implant surgery without bone augmentation procedures soft tissue healing differs from the standard 2-stage procedures in which soft tissues completely cover the surgical bed to 1 -stage procedures in which soft tissues are closely adapted around the implant neck which is left outside the surgical wound with a healing abutment or a provisional prosthesis. In this last condition, soft tissue healing is similar to that of the second stage of standard implant surgery performed for healing abutment connection in which wound margins are closely approximated to the abutment. In every case, a blood clot immediately fills the space between the implant cover screw or implant abutment / neck and the adjacent soft tissues, so that bleeding occurs on flap palpation through wound incisions or at the abutment-tissue margin interface during the first 2-3 days. In completely covered implants, first intention soft tissue healing occurs in about 1-2 weeks, while in all other cases the connective tissue aspect of the flap at the abutment-flap interface is visible for 2-3 days, at which point complete epithelialization of the abutment facing soft tissue occurs and, after the first 2 weeks peri-implant epithelium starts to migrate apically. A 3-4 mm high mature soft tissue barrier adjacent to titanium implants with about 60% of a new epithelium attachment is completely formed within 6-8 weeks and remains stable for at least 12-15 months, possibly reaching a greater final width in procedures different from conventional 2-stage procedures with implant insertion in healed sites.

[0176] In conclusion, oral soft tissue healing at teeth, implants and the edentulous ridge follows the same phases as skin wound healing.

[0177] In contrast to after placement of conventional dental devices, i.e., devices that have a uniform surface in its soft-tissue region, such as traditional dental implant systems with a single-phase surface in the soft-tissue region, whereafter the established peri-implant soft connective tissue resembles a scar tissue in composition, fibre orientation, and vasculature, use of a dental device according to the current invention leads to a regrowth of a histologically more natural peri-implant soft connective tissue as well as a histologically more natural peri-implant junctional epithelium.

[0178] Dental device

[0179] A percutaneous dental device according to the current invention can be a dental implant system. A dental implant system can in the current context comprise a dental implant, a crown and / or an abutment.

[0180] The at least two distinct regions with different surface-topographies of the soft-tissue region of the percutaneous dental device can be located on the same part of the dental implant system, or on at least two different parts of the dental implant system.

[0181] A percutaneous dental device according to the current invention such as a dental implant system, comprises and / or consists of titanium, zirconium, or titanium and / or zirconium alloys, dental ceramic, zirconia ceramic, , yttrium-stabilized zirconium oxide (zirconia) in predominantly tetragonal form and / or zirconia-alumina composite.

[0182] When using a titanium alloy, this is preferably a titanium zirconium (TiZr) alloy, typically comprising Zr in an amount of 13 to 17%. Alternatively, a titanium aluminium vanadium alloy, specifically Ti-6AI-4V (TAV), or a titanium aluminium niobium alloy, specifically Ti- 6AI-7Nb (TAN), can be used as a titanium alloy suitable for the purpose of the present invention. With regard to the use of titanium or a titanium alloy for an abutment basic body, it is further preferred that the nanostructures comprise titanium hydride and / or titanium oxide. In case the nanostructures comprise titanium hydride, they typically comprise TiH2, whereas in case the nanostructures comprise titanium oxide, they typically comprise TiCh.

[0183] A dental device can have a core of a high-strength material such as zirconia, titanium or alloys thereof, said core being coated with a ceramic material which can be chemically and / or mechanically processed. (See e.g., WO-A-2005 / 027771 and EP-A-0870478).

[0184] The term "ceramic material" encompasses any type of ceramic such as ceramics based on zirconia, alumina, silica or mixtures thereof, optionally comprising further constituents. Preferably, the ceramic material is based on zirconia, more preferably yttria-stabilized zirconia. This material has the advantage of a high fracture toughness and bending strength.

[0185] An example of an yttria-stabilized zirconia ceramic is described by the international standards ASTM F 1873 and ISO 13356, specifying the characteristics of, and a corresponding test method for, a biocompatible and biostable ceramic bone-substitute material based on yttria-stabilized tetragonal zirconia (yttria tetragonal zirconia polycrystals, Y- TZP) for use as material for surgical implants. Specific examples of an yttria-stabilized zirconia are ZrO2-TZP / TZP-A Bio-HIP® (ZrO2) Bioceramic available from Metoxit AG, Switzerland, and ZIOLOX® available from CeramTec AG, Plochingen, Germany. Both materials offer a particularly high mechanical stability and strength, in particular when prepared by hot isostatic pressing or by sintering with subsequent hot isostatic densification. A detailed description of the ZrO2-TZP / TZP-A Bio-HIP® (ZrO2) Bioceramic is given in US-B-6,165,925.

[0186] In particular, the composition of the yttria-stabilized zirconia comprises about 4.5 to about 5.5 weight-% of Y2O3 and less than about 5 weight-% of HfC>2, the total amount of ZrC>2, Y2O3 and HfO2 being more than about 99.0 weight-%.

[0187] In one aspect, the surface of the percutaneous dental device of the current invention comprises a conventional dental ceramic, full-contour zirconia , classical zirconia and / or dental porcelain.

[0188] Dental implant system

[0189] In the present context, the term “dental implant system” includes the actual implant as well as abutment and / or crown, the at least biphasic surface topographies are implemented on any of the individual parts of the dental implant system, depending on which part or parts of the implant system is / are in contact with or closely adjacent to the soft tissue at the implantation site, i.e. depending on which part or parts of the implant system comprise the soft tissue region of the dental device / dental implant system.

[0190] Dental implant

[0191] In general, a dental implant of the present invention is a one-part or a two-part dental implant comprising an anchoring part for anchoring the implant within the jawbone and a mounting part for receiving a prosthetic build-up construction.

[0192] Two-part systems are known in the art. They can either be inserted subgingivally or transgingivally. They are typically distinguished as either bone-level or soft-tissue level implants.

[0193] According to the (closed) subgingival system, the anchoring part of the dental implant is embedded until the bone ridge so that the mucoperiost cover can be seen above the implant. At the end of the primary healing phase, the mounting part and the desired bridge or crown is then applied in a second operation.

[0194] According to the (open) transgingival system, the anchoring part of the implant is sunk in up to about 3 mm of the bone ridge at mucosal level, thus avoiding a secondary operation. The wound edges can be directly adapted to the implant neck portion, thereby effecting a primary soft tissue closure to the implant. Then, the desired bridge or crown is screwed or cemented onto the mounting part of the implant, generally using an intermediate abutment.

[0195] Transgingivally applied dental implants are preferred. When implanting such an implant, the soft tissue attachment during the healing process is not disturbed by a secondary operation such as occurring with systems that heal with covered mucous lining.

[0196] For example, the dental implant of the present invention can be a two-part, transgingivally applied implant analogue to the titanium implant marketed by Institut Straumann AG, Basel / Switzerland, under the tradename "Straumann Dental Implant System".

[0197] In one aspect, the two-part dental implant preferably has an anchoring and a mounting part which are made of the same material. Thus, the anchoring part and the mounting part have the same thermal coefficient of expansion, allowing them to be closely fitted and avoiding the formation of gaps between them.

[0198] Alternatively, the dental implant of the present invention may also be a one-part dental implant. The mechanical stability of a one-part dental implant is generally higher than the one of a multi-part system. In combination with the high strength of the material used, the one-part dental implant of the present invention has thus a particularly high mechanical stability. The one-part dental implant has the additional advantage that there are no interstices and thus no starting points for the formation of bacteria which may cause periodontitis or gingivitis.

[0199] The dental implant of the present invention can be directly ground, allowing it to be adapted to further elements to be mounted in a simple way.

[0200] In one aspect, the dental implant of the present invention can either be made fully of a ceramic material or can have a core made of another material, such as a metal, for example titanium or an alloy thereof, or another ceramic material.

[0201] The present invention encompasses dental implants of which the whole surface is made of a ceramic material and dental implants of which only a part of the surface is made of a ceramic material.

[0202] The dental implant of the present invention may be an implant of which the bone tissue contacting region of the anchorage part’s surface has a topography that increases osteointegration. Typically, such a bone contacting region has a Sa of around 1.2 pm.

[0203] It is further preferred that the anchoring part comprises a threaded section. Thereby, the implant can be implanted with the necessary primary stability so that subsequently to the implantation directly a primary treatment is made possible by applying a temporary measure. The surface of the threaded section preferably has a topography that increases osteointegration.

[0204] In a presently preferred embodiment, the surface of soft-tissue region of the implant has the properties according to the present invention. It has been found that when using a dental implant which in the soft tissue contacting region has the bi-phasic topography according to the present invention, the blood coagulum is stabilized which further accelerates the healing process.

[0205] Abutment

[0206] In the current context, an abutment is an intermediate, i.e. , a secondary part used for mounting a suprastructure onto a dental implant, such as a bridge or a crown, as it is the case in a "two-part implant system" or "multi-part implant system". Crown

[0207] In the current context, a crown is a fixed prosthetic dental restoration which caps or encircles a tooth or dental implant. In the current context, the term “a crown” is used to denote any suprastructure, such as, but not limited to comprising a bridge. The term "suprastructure" relates to the prosthetic element of the dental restoration, and in particular relates to a crown or bridge.

[0208] The at least biphasic surface described herein can be located on different parts of the implant system, depending on which of the parts is / are in contact with the soft tissue surrounding the placement and / or implantation site, e.g., on the implant, the crown-tulip part of the implant, the tulip part of the implant, the crown, the abutment and / or the final abutment.

[0209] Surfaces

[0210] In order to mimic the natural surface of the tooth and thus to offer an optimal interface between a dental device and the surrounding soft tissue, a dental device of the current invention has an at least biphasic surface in the soft tissue region of its surface. I.e., its soft-tissue region comprises at least two sperate regions with different surface topographies which are divided by the in situ CEJ (iCEJ). After implantation, regeneration and / or healing of the supracrestal soft tissue surrounding the implantation and / or placement site, at least parts of the two separate regions of the soft-tissue region of the dental device will be in direct contact or at least in close proximity with the surrounding soft tissue, i.e. , with the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device.

[0211] A dental device according to the current invention comprises a soft-tissue region.

[0212] The dental device of the current invention can comprise a surface region that is in contact with soft tissue and a surface region that is in contact with hard tissue, such as bone.

[0213] Thus, in one embodiment of the invention, the dental device comprises a soft-tissue region and a hard-tissue region.

[0214] In one embodiment of the invention, the dental device does not comprise a hard-tissue region.

[0215] Soft-tissue region

[0216] The current invention relates to a percutaneous dental device with at least two distinct regions with different surface-topography in the soft tissue region. Figure 4 shows a schematic view of the soft-tissue region of a dental device according to the current invention. The soft-tissue region comprises at least two separate regions with different surface topographies which are divided / separated by the in situ CEJ (iCEJ) of the dental device. I.e., two of the at least two distinct surface regions in the soft-tissue region of the dental device connect at the in situ CEJ (iCEJ) of the dental device.

[0217] After implantation, regeneration and / or healing of the supracrestal soft tissue surrounding the dental device at the implantation site and / or placement site, at least parts of the two distinct surface regions of the soft-tissue region of the dental device will be in direct contact or at least in close proximity with the surrounding soft tissue, i.e., with the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device.

[0218] In the current context, the soft-tissue region of the dental device is also referred to as "soft tissue contact surface" or “soft tissue section”.

[0219] In the current invention, the surface of soft tissue region of the dental device is at least biphasic / bioregional, i.e., it has at least two distinct surface regions and / or phases that have different surface-properties, such as, but not limited to at least two different surfacetopographies. The at least two different phases / regions connect at the in situ CEJ (iCEJ) of the dental device.

[0220] The at least biphasic surfaces of the dental implant systems of the current invention facilitate improved soft tissue healing by promoting primary wound coverage, angiogenesis, space creation and maintenance, and clot stability, compared to traditional dental implant systems with a single-phase surface.

[0221] As is shown in the experimental part, the adhesion of the different soft tissue cell type layers is histologically more correct and / or natural on the dental implant systems of the current invention, compared to traditional dental implant systems with a single-phase surface in the soft-tissue region.

[0222] As can be seen in figure 2, the soft tissue region of a percutaneous dental device according to the current invention has an apical region with a first surface-topography and a distal region with a second surface-topography.

[0223] The apical region and the distal region are divided by the in situ CEJ (iCEJ) of the percutaneous dental device. I.e., the apical region and the distal region connect at the in situ CEJ (iCEJ) of the percutaneous dental device. In the current context, the apical region is the region of the percutaneous dental device below the in situ cemento-enamel junction (iCEJ) and the distal region is the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ).

[0224] In the current context, the terms “distal region” ad coronal region” are used interchangeably and the directions “below” and “above” indicate a position in relation to the apical end of the dental device and the jaw-bone into which the dental device is to be implanted (see figure 2).

[0225] Thus, the current invention relates to a percutaneous dental device that comprises a soft tissue region that comprises an apical region with a first surface-topography and a distal region with a second surface-topography which are divided by and / or connected at the in situ CEJ (iCEJ) of the percutaneous dental device.

[0226] In one aspect, a percutaneous dental device according to the current invention comprises a transitional region between the two surfaces above and below the CEJ, wherein the surface roughness of the transitional region successively roughens from the surface roughness above the in situ CEJ (iCEJ) of the percutaneous dental device to the surface roughness below the in situ CEJ (iCEJ) of the percutaneous dental device.

[0227] Hard-tissue region

[0228] In the current context, the hard-tissue region of a dental device is the region of said device that is in contact with bone. Among others, figures 2 and 19 show a schematic view of a hard-tissue region of a dental device according to the current invention. Surface topographies of hard tissue regions are well known in the art.

[0229] Surface properties

[0230] To facilitate an improved attraction of different soft tissues to the soft-tissue region of the dental devices, i.e., in order to mimic the natural surface of a tooth and to offer an optimal interface between a dental device and the surrounding soft tissue, there are several parameters of the surface that can play a role, such as surface properties, surface chemistry, material properties, choice of material, topographic properties and hydrophilic properties.

[0231] In the experimental section, the surface topography is shown to be a determining factor for soft tissue integration. Prior art discusses the different topographies of the soft tissue region of natural teeth as summarized in table 1.

[0232] Tablel

[0233] (“Internal measurements” in table 1 are not prior art values, but measurements performed by the current inventors in the experimental part for the first time disclosed herein)

[0234] In the current context, the surface of the dental device has in particular been designed with a certain set of different topographic properties, effectively mimicking the surfacetopography of a natural tooth. These surface topographic properties will be explained in the bellow.

[0235] A dental device of the current invention comprises a surface that is at least partially roughened, i.e., the surface of the dental device provides at least two distinct surface regions in the soft-tissue area that have a different surface roughness.

[0236] In the current context, the term “surface roughness” is used to describe the predominantly randomized distribution of valleys, peaks, depths and skewness of a surface, effectively mimicking the surface-topography of a natural tooth.

[0237] The surface of the soft tissue region of a dental device according to the current invention is intended to mimic the surface of the soft tissue region of a natural tooth as closely as possible, thus a surface topography is provided with at least two regions of individual isotropic topographies. The present invention relates to a percutaneous dental device which comprises a soft- tissue region with at least two distinct surface regions with different isotropic surfacetopographies forming at their interphase an in situ CEJ (iCEJ), for use in improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device. A novel dental device is disclosed that mimics a natural tooth surface in the section of the device that is in direct contact with the soft tissue above and below its in situ CEJ (iCEJ), thus guiding and inducing the soft tissue healing and / or regeneration surrounding a dental device after implant or after placement.

[0238] There are three related length scales that define heterogeneity: the width of the peak or 'high' roughness (W p), the width of the valley or 'low' roughness (W v) and the spacing between adjacent valleys (S). The term “isotropic topography “ or “isotropically patterned “ in the current context used interchangeably with “homogenous roughness” is in the current context used to describe that protrusions, peaks or 'high' roughness (W p) and valleys or 'low' roughness (W v) of the surface are randomized as well as randomly distributed over the surface region, i.e., the surface is randomly patterned and not in an ordered or directional pattern, as would be the case for a surface with anisotropic topography.

[0239] For the avoidance of any doubt, any surface of a dental device of the current invention is machined and / or turned and thus, certain regularities will be detectable on a micrometrelevel. Such a machined and / or turned surface is in the current context considered to be “smooth”, “relative smooth” and / or “close enough to smooth”. The currently described different homogeneous / isotropic degrees of topography, roughness and / or pattern are achieved by e.g., etching and / or sand-blasting of the “smooth”, “relative smooth” and / or “close enough to smooth” surface. In the current context, the (Sa) of a smooth surface is no more than 0.4 pm (Sa).

[0240] In the current context, the term “micrometre- level” is used to describe measurement of small lengths to a precision of 0.01 mm.

[0241] In consequence, the current invention relates to a percutaneous dental device comprising at least two distinct regions with different surface-topographies in the soft tissue region which are isotropically patterned, i.e., the surfaces have different isotropic topographies. Surface roughness

[0242] Typically, the topography of a surface is defined by the Core Roughness Depth (also known as "Kernel Roughness Depth" or “core height” as the distance between the highest and the lowest level of the core surface) Sk. The Core Roughness Depth Sk is a 3D specific value. These 3D specific values are well defined according to ISO 25178.

[0243] For two dimensions, an extra procedure for filtering with suppression of the depth of roughness leads to the roughness profile according to DIN 4776. The definitions therein can directly be transformed into three dimensions. In particular, the Core Roughness Depth Sk can, as the 2D specific Core Roughness Depth Rk, be derived from the so- called Material Ratio Curve (also known as "Abbott curve").

[0244] The Abbott curve represents the height distribution of the surface’s material. It is a cumulative function of the material portion of the surface at a particular depth below the highest peak of the surface. In other words, the Abbott curve describes the increase of the material portion of the surface with increasing depth of the roughness profile. At the highest peak, the material portion is 0%, while at the deepest recess (or "valley") the material portion is 100%. The minimal secant slope, i.e., a defined line of best fit, separates the Abbott curve into the three following ranges: a) the Core Roughness Depth Sk [mm], i.e., the depth of the roughness core profile, b) the reduced Peak Height Spk [mm], i.e., the averaged height of the peaks sticking out of the core range, and c) the reduced Groove Depth Svk [mm], i.e., the averaged depth of the grooves sticking out of the core range.

[0245] The concept how these values are derived from the Abbott curve are well known to the person skilled in the art. From an idealized Abbott curve the 2D specific Core Roughness Depth Rk, the reduced Peak Height Rpk and the reduced Groove Depth Rvk can be derived. These parameters can directly be transformed to the 3D specific Core Roughness Depth Sk, reduced Peak Height Spk and reduced Groove Depth Svk.

[0246] The Core Roughness Depth Rk or, in three dimensions, Sk corresponds to the vertical distance between the left and right intercepts of the line through the ends of the minimal secant slope window of the Abbott curve. The location of the minimal secant slope window can be determined by shifting it along the Abbott curve until the slope between the two intersection points becomes minimal. The topography can further be specified by the Skewness Ssk. The Skewness measures the symmetry of the variation of the surface about its mean plane. A Gaussian surface, having a symmetrical shape for the height distribution, has a Skewness of 0. A surface with a predominant plateau and deep recesses will tend to have a negative Skewness, whereas a surface having a number of peaks above average will tend to have a positive Skewness.

[0247] For a profile in two dimensions, the 2D specific Skewness Rsk is according to DIN EN ISO 4287 defined by the following formula: where zn is the height or depth of the respective peak or valley, respectively, z is the mean height and Rq is the root- mean-square deviation of the surface.

[0248] For determining the Skewness Ssk of the topography in three dimensions, the formula is transformed as follows: where Sq is the root-mean-square deviation of the surface according to the following formula:

[0249] It has been found that asymmetric topographies with deep grooves are highly osteointegrative, and that thereby the absolute roughness values (Sa, Rmax, etc.) for example referred to in EP-B-1450722 are irrelevant.

[0250] The current invention relates to a percutaneous dental device comprising two distinct regions with surface-topographies of different isotropic topographies in the soft tissue region, wherein the surface roughness (Sa) of the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as at least 0.2 pm less than the surface roughness (Sa) of the region of the percutaneous dental below the in situ cemento-enamel junction (iCEJ). In the current context, Sa is the “arithmetical mean height of the scale limited surface” according to ISO 25178 and it’s the most commonly used parameter to describe implant surface roughness.

[0251] In one embodiment, a percutaneous dental device of the current invention comprises at least two distinct regions with different surface-topographies in the soft tissue region, such as comprising two distinct regions with different surface-topographies in the soft tissue region, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) is no more than 0.4 pm (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm (Sa), and wherein the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as 0.2 pm less than the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ .

[0252] In another embodiment, a percutaneous dental device of the current invention comprises at least two distinct regions with different surface-topography in the soft tissue region, such as comprising two distinct regions with different surface-topographies in the soft tissue region, characterized in that c. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) is no more than (0.185 ± 0.07) pm (Sa), and d. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 such as (0.477 ± 0.12) pm (Sa).

[0253] In addition, in some aspects, the percutaneous dental device comprises a transitional region between the two surfaces above and below the CEJ, wherein the surface roughness of the transitional region successively roughens from the surface roughness above the in situ CEJ (iCEJ) of the percutaneous dental device to the surface roughness below the in situ CEJ (iCEJ) of the percutaneous dental device. In a currently preferred embodiment, in a percutaneous dental device according to the current invention, the placement of the in situ CEJ (iCEJ) of the percutaneous dental device is determined in analogy to the CEJ of the surrounding tooth and / or teeth to the implant or placement site.

[0254] Topographic optimization

[0255] The current invention in one aspect further relates to a method for producing a percutaneous dental device with at least two distinct regions with different surfacetopographies in the soft tissue region, characterized in that the surface of the soft tissue section of the dental device is roughened to achieve a homogenous surface roughness / isotropic topography (Sa) of the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) which is at least 0.1 pm, such as at least 0.2 pm, less than the surface roughness (Sa) of the region of the percutaneous dental below the in situ cemento-enamel junction (iCEJ).

[0256] There is a plethora of techniques known to the person skilled in the art to achieve preferred properties and / or topographies on the surface of a dental device, e.g., as disclosed in US-B-6, 174,167 said optimized surface is obtained by machining, application of a textured surface or blasting with particles. It also discloses acid etching, applying growth factor, protein or other materials that promote, enhance and / or maintain bonetissue growth and / or apposition. The implant is made from a biocompatible material, preferably from titanium or an alloy thereof. DE-A-4012731 describes a process for producing an implant made of titanium employing spark erosive techniques in order to provide a desired roughness to the implant’s surface. Mechanical roughening of the implant’s surface can further be combined with subsequent etching of the roughened surface, as is for example described in Li et al., J. Biomed. Mater. Res. 2002, 60 (2), pages 325-332. Titanium implants can be subjected to a blasting process and subsequent etching with a reducing acid, such as HF, HCI or HCI with H2SO4 (see EP-A-0388576).

[0257] WO-A-2005 / 027771 relates to a process for preparing a dental installation in which a dispersion is applied on a substrate having a first porosity, said dispersion forming upon sintering a ceramic layer with a second porosity.

[0258] EP-B-1450722 discloses a dental implant made of zirconia ceramic which after abrasive blasting is subjected to a treatment using phosphoric acid, sulphuric acid, hydrochloric acid or mixtures thereof. In one embodiment, a dental device of the present invention can be prepared by etching the surface made of titanium or a titanium alloy by an etching solution comprising mineral acids or mixtures thereof, in particular H2SO4 or HCI / H2SO4.

[0259] Sandblasting is generally performed using a pressure of 1 to 12 bar, preferably 4 to 10 bar. A considerably improved macroscopic roughness is achieved when using a hard material such as boron carbide. In a further preferred embodiment, AI2O3 particles having an average diameter of 250 to 500 mm are used.

[0260] As an alternative to sandblasting, in particular in a surface made of a ceramic material, the macroscopic roughness can also be provided by injection molding techniques. Injection molding techniques are known to a skilled person and are for example described in US-A- 2004 / 0029075. According to these techniques, casting molds with cavities are used, said cavities corresponding to the peaks of the molded implant’s macroscopic roughness. The cavities of the casting mold are slightly greater in proportion than the peaks to be provided, taking into account the shrinking of the ceramic after injection molding. The casting molds themselves may be treated by sand blasting, anodization, laser and / or by erosion techniques in order to produce the cavities or the structured surface on the inner surface of the molds.

[0261] It is also thinkable to provide a macroscopic roughness by milling or grinding. For this purpose, milling or grinding devices having a defined grain size are used in order to guarantee a desired macroscopic roughness of the surface.

[0262] For preparing the microstructure of the surface properties and / or topography, it is further preferred that the etching solution described above comprises at least 50 vol.-%, more preferably at least 80 vol.-% of concentrated hydrofluoric acid.

[0263] The etching solution can further comprise at least one compound selected from the group consisting of phosphoric acid, nitric acid, ammonium fluoride, sulfuric acid, hydrogen peroxide and bromic acid. Preferably, the etching solution comprises sulfuric acid in an amount of 50 vol.-% at most.

[0264] The etching time depends highly on the etching solution used and typically ranges from about 10 seconds to about 120 minutes. The etching time is preferably about 1 minute to about 60 minutes, about 20 minutes to about 40 minutes, such as about 30 minutes. In one aspect of the current invention, the etching time is between about 4 minutes to about 7 minutes. In embodiments the etching time is between1-20 minutes, such as between 1-10 minutes, 2-5 minutes, 3-6 minutes, 4-8 minutes, or 4-7 minutes. In embodiments, etching is performed for no longer than 20 minutes, such as no longer than 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 3 minutes or 1 minute, In embodiments, etching is performed for less than 20 minutes, such as less than 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 3 minutes or 1 minute,

[0265] In one embodiment, the etching is performed by acid etching with a mixture of HCI / H2SO4 of a titanium and / or a titanium alloy surface for 4-7 minutes.

[0266] Preferably, the etching is followed by washing the dental implant, the washing comprising the subsequent step or the subsequent steps of a) rinsing the dental implant with a NaCI solution and / or b) rinsing the dental implant with deionized water.

[0267] The performance of the washing step can be improved by using ultrasound. Thereby, grains, grain agglomerates or reaction products which loosely adhere to the surface are effectively removed.

[0268] In consequence, the current invention in aspects relates to a method for producing a percutaneous dental device, wherein the soft tissue section of the dental device is roughened by any one or a combination of machining, application of a textured surface, employing spark erosive techniques, mechanical roughening, sintering, molding techniques, milling or grinding, blasting with particles and / or acid etching (e.g. by a treatment using phosphoric acid, sulphuric acid, hydrochloric acid, nitric acid, ammonium fluoride, hydrogen peroxide and / or bromic acid), such as, but not limited to subsequent etching of the roughened surface. In another aspect, the soft tissue section of the dental device is topographically optimized by applying growth factor, protein or other materials that promote, enhance and / or maintain soft-tissue growth and / or apposition.

[0269] The current invention thus in one aspect relates to a method for producing a percutaneous dental device according, characterized in that the surface of the soft tissue section of the dental device is roughened to achieve a. one surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) of no more than (0.185 ± 0.07) m (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 such as (0.477 ± 0.12) pm (Sa).

[0270] The current invention also relates to a percutaneous dental device produced by a method according to the invention.

[0271] Uses of dental implant systems according to the current invention

[0272] The current invention relates to the use of a percutaneous dental device according to the current invention for inducing and / or guiding healing and / or regeneration of epithelial tissue above the in situ CEJ (iCEJ) of the percutaneous dental device and for use in inducing and / or guiding healing and / or regeneration of connective tissue below the in situ CEJ (iCEJ^) of the percutaneous dental device.

[0273] In particular, the current invention relates to the use of a percutaneous dental device according to the current invention for inducing and / or guiding histologically correct and / or more natural soft tissue healing and / or soft tissue regeneration in the supracrestal attached tissue at the implant site and / or placement site of said percutaneous dental device.

[0274] In a presently preferred embodiment, the current invention relates to the use of a percutaneous dental device according to the current invention for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement site of a percutaneous dental device.

[0275] Other embodiments and items

[0276] Items

[0277] 1 . A percutaneous dental device that comprises a soft tissue region with at least two distinct regions with different surface-topographies usable for improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device, wherein the soft tissue region has an apical region with a first surface-topography and a distal region with a second surface-topography, wherein the apical region and the distal region are divided by the in situ cemento-enamel junction (iCEJ) of the percutaneous dental device, wherein the two distinct regions with different surface surface-topographies in the soft tissue region are isotropically patterned, and wherein the surface of the percutaneous dental device consists of titanium, zirconium, titanium and / or zirconium alloys, dental ceramic, zirconia ceramic, and / or yttrium-stabilized zirconium oxide (zirconia), such as zirconia in predominantly tetragonal form.

[0278] 2. A percutaneous dental device according to item 1 that comprises a soft tissue region consisting of two distinct regions with different surface-topographies.

[0279] 3. A percutaneous dental device according to any one of items 1-2, characterized in that the surface roughness (Sa) of the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as at least 0.2 pm less than the surface roughness (Sa) of the region of the percutaneous dental below the in situ cemento-enamel junction (iCEJ).

[0280] 4. A percutaneous dental device according to any one of items 1-3, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) is no more than 0.4 pm (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm (Sa), and c. wherein the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as 0.2 pm less than the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ).

[0281] 5. A percutaneous dental device according to any one of items 1-4, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ i is no more than (0.19 ± 0.07) pm (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ i is between 0.2-0.8 pm (Sa) specifically (0.48 ± 0.12) pm (Sa).

[0282] 6. A percutaneous dental device according to any one of items 1-5 that is a dental implant system.

[0283] 7. A percutaneous dental device according to any of the preceding items for use in improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device. A percutaneous dental device according to any of the preceding items for use in improving soft tissue healing and / or soft tissue regeneration of the junctional epithelium, the sulcular epithelium and the supracrestal connective tissue at the placement site of the device. A percutaneous dental device according to any of the preceding items for use in inducing regeneration of the supracrestal attached tissue at the placement and / or implantation site of said percutaneous dental device, for improving regrowth and / or regeneration of a biological width at the placement site of said percutaneous dental device, and / or for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement and / or implantation site of the device. A percutaneous dental device according to any of the preceding items for use in healing and / or regeneration of epithelial tissue which is induced and / or guided above an in situ cemento-enamel junction (iCEJ) of the percutaneous dental device and healing and / or regeneration of connective tissue is induced and / or guided below the in situ CEJ (iCEJ) of the percutaneous dental device. Use of a percutaneous dental device which comprises a soft-tissue region with at least two distinct surface regions with different surface-topographies for improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device. Use of a percutaneous dental device according to item 1 , for improving soft tissue healing and / or soft tissue regeneration of the junctional epithelium, the sulcular epithelium and the supracrestal connective tissue at the placement site of the device. Use of a percutaneous dental device according to item 1 or 2, for inducing regeneration of the supracrestal attached tissue at the placement and / or implantation site of said percutaneous dental device, for improving regrowth and / or regeneration of a biological width at the placement site of said percutaneous dental device, and / or for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement and / or implantation site of the device. Use of a percutaneous dental device according to any of the preceding items, wherein healing and / or regeneration of epithelial tissue is induced and / or guided above an in situ cemento-enamel junction (iCEJ) of the percutaneous dental device and healing and / or regeneration of connective tissue is induced and / or guided below the in situ CEJ (ICEJ) of the percutaneous dental device. 15. A percutaneous dental device that comprises a soft tissue region with at least two distinct regions with different surface-topographies.

[0284] 16. A percutaneous dental device according to item 7 that comprises a soft tissue region consisting of two distinct regions with different surface-topographies.

[0285] 17. A percutaneous dental device according to item 7 or 8, wherein the soft tissue region has an apical region with a first surface-topography and a distal region with a second surface-topography.

[0286] 18. A percutaneous dental device according to any one of items 7- 9, wherein the interphase between both surfaces forms an in situ CEJ (iCEJ).

[0287] 19. A percutaneous dental device according to item 10, wherein the apical region and the distal region are divided by the in situ CEJ (iCEJ) of the percutaneous dental device.

[0288] 20. A percutaneous dental device according to any one of items 7- 11 , wherein the two distinct regions with different surface surface-topographies in the soft tissue region are isotropically patterned.

[0289] 21 . A percutaneous dental device according to any one of items 7-12, characterized in that the surface roughness (Sa) of the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as at least 0.2 pm less than the surface roughness (Sa) of the region of the percutaneous dental below the in situ cemento-enamel junction (iCEJ).

[0290] 22. A percutaneous dental device according to any one of items 7-13, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) is no more than 0.4 pm (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm (Sa), and c. wherein the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm, such as 0.2 pm less than the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ).

[0291] 23. A percutaneous dental device according to any one of items 7-14, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) is no more than (0.19 ± 0.07) pm (Sa), and b. the surface roughness (Sa) of the of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) is between 0.2-0.8 pm (Sa) specifically (0.48 ± 0.12) pm (Sa).

[0292] 24. A percutaneous dental device according to any one of items 7-13 that is a dental implant system.

[0293] 25. A percutaneous dental device according to any one of items 7-14, wherein the surface of the percutaneous dental device comprises and / or consists of titanium, zirconium, titanium and / or zirconium alloys, dental ceramic, zirconia ceramic, fullcontour zirconia (glazed), classical zirconia veneered with dental porcelain, yttrium-stabilized zirconium oxide (zirconia) in predominantly tetragonal form and / or hydroxyapatite coated zirconia-alumina composite.

[0294] It is to be understood that while the present invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims.

[0295] Other aspects, advantages, and modifications are within the scope of the following claims.

[0296] Experimental section

[0297] The present invention is further illustrated by the following non-limiting experiments.

[0298] Experiment 1

[0299] Objective

[0300] The objective of the following experiments was to mimic the natural surface of the tooth to offer an optimal interface between a dental device and the surrounding soft tissue (as schematically depicted in figure 3). There are several parameters of these two surfaces that could potentially play a role, like for example surface properties, surface chemistry, material properties, etc. For these experiments we focused on the parameter surface roughness, since it has been shown to be the determining factor for osseointegration and is known to affect soft tissue cells as well.

[0301] Materials & Methods

[0302] Surface roughness measurements of extracted pig teeth Extracted teeth from Gottingen Minipigs were measured for their surface roughness with confocal microscopy. Sa values were measured according to ISO 25178 using a Gaussian filter with a 30 pm cut-off. The results have shown that the enamel surface (4) above the CEJ (7) is significantly smoother compared to the cementum surface (3) below the CEJ (7) (Sa value of 0.185 ± 0.07 pm (Sa) for enamel (4) compared to 0.477 ± 0.12 pm (Sa) for cementum (3)).

[0303] Production of biphasic abutments

[0304] Commercial titanium abutments were used as a basis for the production of the biphasic test abutments. The surface roughness of the commercial abutments was measured and found to be in the range of the enamel surface of natural teeth (4) (Sa of 0.14 ± 0.02 pm (Sa)).

[0305] To introduce a rougher surface for part B (5), as shown in figure 3, the abutments were masked (part A (6) in figure 3) and acid etched such that the acid could only etch the bottom part (5) below the in situ CEJ (iCEJ) (9) of the abutment. Two different ratios of A (6) and B (5) were produced and compared to commercially available untreated abutments (see figure 4).

[0306] Minipig model

[0307] As shown in figure 5, bone level implants were placed in the mandible of Gottingen Minipigs and equipped with the test and control abutments and left 8 weeks for healing before histological processing.

[0308] Results

[0309] Production of biphasic titanium abutments

[0310] As shown in figure 6, the surface roughness (Sa value) of the etched part (Part B (5)) was confirmed to be 0.43 ± 0.02 pm (Sa) and part A (6) was unchanged by the process and remained at Sa of 0.14 ± 0.02 pm (Sa). The roughness values of the test abutments were in the range of the values of a natural tooth (Sa value of 0.185 ± 0.07 pm (Sa) for enamel compared to 0.477 ± 0.12 pm (Sa) for cementum).

[0311] Histological analysis after healing

[0312] Figure 7 depicts a histological section of a natural minipig tooth. The epithelial layer (1 ) stops around the enamel-cementum junction (CEJ).

[0313] Figure 8: Histological section of a commercial smooth (machined) abutment. The whole abutment surface is covered with an epithelial layer (1 ). Figure 9 shows a histological section of the customized bi-modal abutment (15). The top half of the abutment (6) was machined, and the bottom half (5) was roughened (2.5 mm from the implant shoulder). The transition between smooth and rough can be seen in the insert. It can equally be seen that similarly to the situation in the natural tooth, the epithelial layer (1) stops around the margin between smooth and rough. Below the “in situ CEJ (iCEJ)” (9) the connective tissue (2) layer is in contact with the abutment (15).

[0314] Figure 10 shows a histological section of the customized abutment (15). The top 4 mm of the abutment (6) was machined, and the bottom 1 mm (5) was roughened. The transition between smooth and rough can be seen in the insert. Also, in this example, the epithelial layer (1 ) stops around the margin defining the in situ CEJ (iCEJ) (9) between smooth and rough.

[0315] Experiment 2

[0316] Introduction

[0317] SEM-analysis of ceramic abutments, to check the leak-tightness of the Viton protection during the acid treatment.

[0318] Materials and Methods

[0319] Samples:

[0320] 2 ceramic abutments, height acid treated 1.0 mm

[0321] 2 ceramic abutments, height acid treated 2.5 mm

[0322] Method

[0323] The samples were analyzed using the Straumann scanning electron microscope (Zeiss Supra 55, QS Nr. 57113) with a field electron emitter (FE-SEM), and an EDX-detector (Oxford Instruments MicroAnalysis System) for the determination of chemical elements.

[0324] Results

[0325] The interface etched surface / machined surface is well delimited, and no leaks of acid are visible on rest of the machined surface.

[0326] The distance on the 2.5 mm abutments is respected.

[0327] The distance on the 1 .0 mm abutments is lower than expected.

[0328] See figures 11-18 and table 2. Table 2: Average measurements of different topographic parameters on the soft-tissue surface of the abutments. (Gaussian filter with cut-off of 30 pm, measured according to ISO 25178)

[0329] Experiment 3

[0330] Investigating human gingival keratinocytes (hGK) and fibroblasts (hGF) when interfacing model titanium implant surfaces with topographies resembling the ones of enamel or cementum.

[0331] Introduction

[0332] In an attempt to mimic the dental-gingival junction and improve the quality of the periimplant transmucosal barrier, this study investigated in depth the adhesion, growth, cytokine release and differentiation of two protagonist cell types of epithelial and connective tissues, human gingival keratinocytes (hGK) and fibroblasts (hGF) when interfacing model titanium implant surfaces with topographies resembling the surfaces of enamel or cementum and in function of hydrophobic / hydrophilic surface modifications.

[0333] Materials and Methods

[0334] Roughness

[0335] The surface roughness at the micrometre scale was measured with a confocal microscope (S neox 090 non-contact 3D optical profiler, Sensofar AG).

[0336] Three samples of each group were selected at random, and each sample was assessed at three random positions. 3D images were obtained with the confocal microscope equipped with a 20x lens on a measurement area of 842 x 707 pm2with a lateral resolution of 0.69 pm. The 3D roughness parameters were calculated with the software SensoMAP Premium (Sensofar AG) by applying a Gaussian filter with a cut-off wavelength of 30 * 30 pm2. The Sa value was selected to represent the surface roughness which is defined by the average height deviation from the mean plane, measured in pm and represents a pure height descriptive parameter.

[0337] Contact Angle Measurements The wettability was assessed through water contact angle measurements. Water droplets of 0.3 pl were used for hydrophobic samples, and 0.1 pl droplets were used for hydrophilic samples. The measurements were conducted using a sessile-drop test with ultrapure water (EasyDrop DSA20E, Kriiss GmbH). For each type of sample, three replicates were analyzed.

[0338] Titanium Discs Fabrication

[0339] The same method was used as for the abutments in experiment 1 . Except, the discs did not have to be protected and were fully immersed in the acid (for both MA groups). The M- discs were machined and not further processed, (enamel-like (M) or cementum-like (MA))

[0340] Cell culture

[0341] Human primary gingiva-derived keratinocytes (hEK) and fibroblasts (hGF) were isolated and purified using the explant culture technique from gingiva discarded biopsies from the retromolar area of patients undergoing dental treatments in the Department of Periodontology, University of Bern (Degen et al. 2018; Parisi et al. 2021 ). Keratinocytes were grown in keratinocyte serum-free medium (KSFM, Thermo Fisher Scientific, Waltham, MA, USA) containing 25pg / ml bovine pituitary extract, 0.2ng / ml epidermal growth factor, 0.4mM CaCh and 1% Penicillin and Streptomycin (PenStrep, Thermo Fisher Scientific). Fibroblasts were cultured in Dulbecco’s modified Eagle’s medium with 10% fetal calf serum (FCS, Sigma-Aldrich, St. Louis, MO, USA) and 1 %PenStrep as described elsewhere (Degen et al. 2018; Parisi et al. 2021 ). The immortalized oral mucosa keratinocytes OKF6 / TERT2 (derived from the floor of the mouth) were a kind gift of Dr. Gabriele Leyhausen, Hannover, Germany. OKF6 / TERT2 cells were cultured in complete KSFM. For co-culture experiments, hEK and hGF were seeded in a 1 :1 ratio with 5000 keratinocytes and 5000 fibroblasts / disc and cultured in a 1 :1 as previously reported (Degen et al. 2018). Details about non-commercial primary cells used in this study are reported in Table 3.

[0342] Table 3: Characteristics of primary cells and immortalized cell lines used.

[0343] Cell adhesion hEK, hGF and OKF6 / TERT2 cells were seeded on M and MA titanium discs at 10000 cel Is / disc density in their complete culturing medium. After 3h, 24h, and 7 days, cells were gently washed with phosphate-buffered saline (PBS) and fixed in 4% paraformaldehyde (PFA) for 20min at room temperature (RT). After extensive washing with PBS and doubledistilled water (ddH2O), cells were coverslip-mounted with the Vectashield Mounting Medium containing DAPI (Vector Laboratories, Burlingame, CA, USA). Samples were examined under an Olympus BX-51 phase / fluorescence microscope (Olympus Life Science Solutions, Tokyo, J) equipped with fluorescence filters U-MWIBA3 for Alexa Fluor 488, U-MWIGA3 for Alexa Fluor 568, and U-MNUA2 for DAPI (Olympus Life Science Solutions) detection. Images were analyzed using the Imaged software (https: / / imagej.nih.gov(ij / ).

[0344] Cell viability

[0345] To evaluate the number of hGF and OKF6 / TERT2 viable cells on M and MA titanium implant surfaces, an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed 2, 4 and 6 days after seeding 10OOcells / disc in their complete culturing medium. At each experimental time point, cells were incubated with MTT solution at a final concentration of 0.5mg / ml for 4h to allow MTT conversion into formazan in metabolically active cells. After two PBS washes, converted MTT was solubilized with a 4N HCI solution, and the absorbance read at 570nm on an EL808 BioTek microplate reader (BioTek, Winooski, VT, USA).

[0346] Immunofluorescence (IF) staining

[0347] For IF staining, cells were washed twice with PBS before fixation in 4%PFA for 20min at RT. Cells were then washed 3X with PBS, permeabilized in 0.1 % Triton-X-100 for 5min and rinsed three times with PBS prior to incubation with primary antibody for 2h at RT in 3% bovine serum albumin (BSA) solution. Afterwards, cells were extensively rinsed in PBS and incubated with fluorescent-labelled secondary goat anti-mouse / rabbit antibodies (Molecular Probes, Thermo Fisher Scientific) and / or with or without tetramethylrhodamine (TRITC)-phalloidine (Sigma-Aldrich) for 1 h at RT in the dark. Finally, cells were washed 3X in PBS and once with ddFkO before being coverslip-mounted with the Vectashield Mounting Medium containing DAPI (Vector Laboratories, Burlingame, CA, USA). Samples were examined under an Olympus BX-51 phase / fluorescence microscope (Olympus Life Science Solutions) equipped for fluorescence.

[0348] Primary antibody used for IF: FN K13 TGM1 IVL Mouse monoclonal antibodies anti- Vinculin (V9131 , Sigma-Aldrich), anti-Laminin5 (P3H9, Developmental Studies Hybridoma Bank, Iowa City, IA, USA), anti-Keratin 10 (DE-K10, Thermo Fisher Scientific) and anti- Involucrin (SY5, BIO-RAD, Hercules, CA, USA). Rabbit polyclonal antibodies anti- Fibronectin (Wehrlehaller et al. 1991 ), anti-Keratin 13 (Proteintech, Manchester, UK) and anti-Transglutaminase 1 (Thermo Fisher Scientific).

[0349] In vitro differentiation of keratinocytes

[0350] To induce hEK and OKF6 / TERT2 differentiation, a cell density-dependent assay was applied. In brief, keratinocytes were grown in complete KSFM, plated on M or hM titanium discs (hM:hydrophilic Machined, hMA = hydrophilic Machined Acid etched) at 1000 cel Is / disc density, and grown for 7 days to reach full confluence (high density, HD) before harvesting. In parallel, cells were also seeded on plastic (1000 cells / well of a 24-well plate) and collected after 2 days of culture, as the emergence of the first colonies was observed. Cells grown on plastic were used as the normalizing low-density (LD) sample.

[0351] Alternatively, for cell characterization, hEK and OKF6 / TERT2 cells were cultured in basal KSFM medium (0.1 mM CaCh) to induce a basal differentiation state. After 3 days in basal medium, 100000 cells were seeded into 60mm tissue culture dishes in basal medium.

[0352] Twenty-four hours later, CaCh was adjusted to a final 1 ,8mM concentration (Calcium switch) to induce differentiation.

[0353] RNA extraction, cDNA synthesis, and quantitative real-time polymerase chain reaction (qPCR)

[0354] Total RNA from cells was extracted using the innuPREP RNA Mini Kit (Analytic Jena AG, Jena, D) following the manufacturer’s instructions. RNA concentration was measured with a NanoDrop 2000c (Thermo Fisher Scientific) and stored at -80°C until use. cDNA was synthesized starting from 500ng of total RNA using an Oligo(dT)is primer (Microsynth AG, Balgach, CH) and the M-MLV Reverse Transcriptase (Promega, Dubendorf, CH). Gene expression was analyzed by qPCR using the GoTaq® qPCR Master Mix (Promega) on a QuantStudio 3 instrument (Applied Biosystems, Thermo Fisher Scientific). Data analysis was performed using the dC? method when absolute mRNA normalized to GAPDH levels were reported or by ddCr method when absolute levels were further referenced to a control sample.

[0355] The sequence of the qPCR primers used is listed in Table 4. Primers were taken from the NCBI primer designing tool and tested for specificity and efficiency using cDNA standard curves.

[0356] Table 4: qPCR primer sequences.

[0357] Immunoblotting

[0358] Cell extracts were prepared in 1X RIPA buffer (10mM Tris-HCI pH 8.0, ImM EDTA, 0.1 % Na deoxycholate, 0.1 % SDS, 1% NP40, 140mM NaCI) supplemented with complete Mini™ Protease Inhibitor cocktail and PhoSTOP EASYpack (both from Sigma-Aldrich). Protein concentrations were measured using a Bicinchonic acid assay (Pierce, Thermo Fisher Scientific) following their standard protocol. Ten micrograms of total protein were diluted in sample loading buffer (62.6mM Tris-HCI pH 6.8, 2% SDS, 10% glycerol, 0.01 % bromophenol blue) containing 100mM dithiothreitol (Sigma-Aldrich), boiled for 5min at 95°C, and separated under reducing conditions by SDS-PAGE. Proteins were blotted onto nitrocellulose membranes (Sigma-Aldrich). After extensive washing, membranes were blocked for 1h at RT in 5% skim milk dissolved in Tris-buffered saline (pH 7.4) with 0.05% Tween (TBS-T) and then incubated overnight at 4°C with the primary antibodies. Blots were washed 3X in TBS-T and incubated with horseradish peroxidase-conjugated anti- mouse / rabbit secondary antibodies (Thermo Fisher Scientific) for 1 h at RT. After three more rinses in TBS-T, blots were developed using the SuperSignal West Dura or Pico (Thermo Fisher Scientific) and scanned by an Imager (Chemi Premium Imager Instrument, VWR, Darmstadt, D). The primary antibodies used for blotting are the same as the ones used for IF.

[0359] Statistical Analysis

[0360] Experiments were performed at least three times in multiple replicates. Data were analyzed using Prism 7 (GraphPad, La Jolla, CA, USA) and reported as means ± standard deviation (SD). Multiple comparisons were performed using one- or two-way analysis of variance (ANOVA) with Tukey’s post hoc test. Data were considered significant when P<0.05.

[0361] Results Titanium model substrates emulating the topography of root cementum exert cell selectivity for gingival fibroblasts by suppressing epithelial keratinocyte proliferation.

[0362] In a first set of experiments, isolated primary human gingival fibroblasts (hGF) and keratinocytes (hGK) were cultured on enamel-like (M) or cementum-like (MA) surfaces to investigate whether the topography may promote a preferential adherence and proliferation of gingival or epithelial cells (Figure 24). As illustrated by nuclei counterstain and quantification after 3h, 24h and 7 days, the proliferation of hGK was significantly impeded on MA compared to M surfaces (Figure 24A). In contrast, hGF proliferation was not affected by surface topography.

[0363] Next, hGF and hGK were co-coltured on M and MA surfaces to test the corresponding surfaces' possible cell- and tissue-selectivity in a simulated transgingival wound healing environment encompassing multiple competing cell types (Figure 24B). After 7 days of incubation and staining for epithelial (Laminin V, LAM5) or mesenchymal (Fibronectin, FN) specific extracellular matrix (ECM) markers, MA surfaces selectively promoted the growth of hGF in disfavour of hEK, resulting in almost pure hGF cultures on MA surfaces, while M surfaces resulted in confluent layers consisting of both hGK and hGF.

[0364] Keratinocyte differentiation, expression, and function have been shown to vary based on the specific dento-gingival or peri-implant compartment location and tissue type, i.e. JE vs SE and their basal to suprabasal maturation state (Figure 22). Compared to SE or lining mucosa (LM) epithelia, JE attachment is, e.g. mediated by specific non-keratinizing epithelial cells lacking phenotypic stratification, a characteristic thought to be essential for their ability to establish a tight gingival seal at the epithelial junction. GE or SE are, on the other hand, characterized by a broader range of differentiation states, which is related to the physiological maturation and continuous transition of keratinocytes from basal to spinous and granular layers ensuring protective epithelial functions and homeostasis Figure 22B). In this context, gingiva-derived hEK cells are, based on the tissue types they are derived from, usually characterized as keratinizing cell types exhibiting a relatively broad range of differentiation states and, thus, not necessarily representative of the corresponding cell types found at the JE. As a result, a separate set of experiments was performed to test the cell reaction to topographical variations between M and MA surfaces using alternative non-keratinizing epithelial cells displaying a more representative differentiation state of the target tissues establishing the transmucosal seal, i.e. JE.

[0365] Specifically, a non-keratinizing keratinocyte cell line originating from the floor of the mouth, OKF6 / TERT2, lacking expression in Keratin 1 (K1) and 10 (K10) as well as Loricrin (LOR) (Figure 22C) was considered in addition to the keratinizing primary hGK cell cultures (Dickson et al. 2000). As evidenced by nuclei counterstain for OKF6 / TERT2 cells on M and MA surfaces 3h, 24h and 7 days after seeding (Figure 24C), the results resembled that observed for hGK (Figure 22A). Outcomes between hGK and OKF6 / TERT2 cells were highly equivalent, confirming the impeded proliferation of epithelial cells on MA compared to M surfaces for non-keratinizing epithelial cells as models for the cell-types involved in transmucosal sealing. Cell-number outcomes based on metabolic assays confirmed these outcomes (Figure 23).

[0366] Finally, to identify whether impairment of proliferation was related to an aberrant attachment of the cells, we investigated whether surface topography induced any changes in the expression and organization of cytoskeletal and adhesion-ligand cellular components in fibroblasts and keratinocytes. Figure 24D reports fluorescence images of hGF, hGK and OKF6 / TERT2 cells on M and MA surfaces 24h after seeding, stained for actin cytoskeleton and for vinculin, the main component of focal adhesions. Both hGK and OK6 / TERT2 cells were found to adhere and form colonies on both surfaces. Especially OK6 / TERT2 cells displayed a surface-topography-dependent ability to form focal adhesions on the individual surfaces. Specifically, while vinculin was found to organize into well-developed and elongated focal adhesions on M surfaces, corresponding structures on MA surfaces remained less pronounced, and vinculin remained partly diffusely organized in the cytoplasm. Correspondingly and corroborating the observations related to cell adhesion and growth, fibroblasts showed a healthy, spindle-like morphology with focal adhesions distributed along the cell soma on both surfaces.

[0367] These data indicate that titanium model substrates with a topography resembling root cementum as opposed to enamel may exert cell- and potentially tissue-selective capabilities by a surface-mediated suppression of epithelial keratinocyte proliferation.

[0368] Hydrophilic modifications of implant surfaces with enamel-like topography may promote a basal- and junctional epithelium-like human keratinocyte phenotype

[0369] Ultrastructural investigations have indicated that non-keratinizing JE cells contribute vitally to the overall quality of the peri-implant biological seal. Specifically, these cells have been reported to establish tight adhesions to the transgingival implant surface via hemidesmosomes and an implant-surface-associated internal basal membrane. These findings raised the question of whether additional surface cues of enamel-like M-surfaces, i.e. surface hydrophilicity, can be exploited to specifically guide the differentiation of adhering keratinocytes towards non-keratinizing undifferentiated phenotypes characteristic of attached JE. As evidenced in Figure 25A, comparing hydrophobic (M) or hydrophilic (hM) variants, hydrophilicity did not influence cell adhesion and proliferation, and both surface types resulted in comparable hGK and OKF6 / TERT2 cell numbers after 7 days of incubation. The comparable growth behaviour was considered ideal for comparing the influence of M or hM surfaces on the differentiation status of adhering keratinocytes upon stratification from confluent layers.

[0370] The latter was considered as an indicator for the respective phenotypes associated with the individual dental-gingival compartments and basal to suprabasal maturation stadium, respectively (Figure 25B and C), Specifically keratinocyte differentiation markers characteristic for junctional (K19), sulcular or marginal (K4, K13), and oral epithelial (K1, K10) were used. These markers were characteristic for suprabasal cells except for K19, which is associated with basal and suprabasal phenotypes and related to the fact that the JE does not exhibit phenotypic differentiation, respectively. Additionally, the tissuecompartment unspecific, but maturation-dependent markers, Transglutaminase 1 (TGM1), Involucrin (IVL), and Loricrin (LOR) were tested see Figure 25D. As indicated by Figure 25B and C, hGK cell cultivation on hM compared to M surfaces resulted in a significant reduction of all markers, except for K4, which remained below the threshold for significance, indicating that hGK cells on hydrophilic surfaces attained a less mature, basal-like and potentially junctional-epithelial like phenotype, compared to corresponding cells on hydrophobic M surfaces. K19 did not allow a clear attribution, as this marker is expressed in basal and suprabasal JE keratinocytes. The differentiation pattern of nonkeratinizing OKF6 / TERT2 showed a less pronounced response to surface hydrophilicity, with TGM1 being the only marker significantly reduced when transitioning from M to hM surfaces. Again, and in line with the results obtained using hGK cells, this result suggests that cultivating keratinocytes on hM surfaces may promote a less mature and basal-like differentiation state when compared to corresponding cells on M surfaces.

[0371] Complementary immunofluorescence and immunoblot experiments confirmed and further substantiated these findings. Specifically, the fluorescence images of hGK and OKF6 / TERT2 cells indicated that 7-day cultivation on both M and hM surfaces led to confluent cell layers displaying zones of stratification (Figure 25D, F-Actin, white dashed lines). Furthermore, stratifying cells positive for K10, K13, TGM1 , and IVL, thus showing a stratification-dependent differentiation, appeared more abundant on M compared to hM surfaces. In line with these findings, immunoblot experiments of OKF6 / TERT2-cells cultivated on M surfaces resulted in higher K13 and TGM1 levels than corresponding cells on hM surfaces, while IVL levels appeared comparable (Figure 25D). These aggregate observations suggest that hydrophilic modified enamel-like M surfaces, compared to hydrophobic counterparts, may represent attractive candidates to guide the differentiation state of adhering epithelial keratinocytes towards less differentiated, basal- like phenotypes reported essential for the constitution of peri-implant junctional epithelial attachment.

[0372] Enhanced hydrophilicity of MA surfaces contrasts the production of metalloproteinases and inflammatory cytokines while promoting the transcription of ECM-stimulating molecules

[0373] A third set of experiments addressed the question of whether a similar hydrophobic to hydrophilic surface modification of the fibroblast-affine and keratinocyte-discriminating MA surface may potentially affect fibroblast growth or expression behaviour with a potential effect on peri-implant connective tissue quality (Figure 26).

[0374] As evidenced by nuclei counterstain of hGF on regular and hydrophilic MA surfaces after 7 days of culture, hydrophilicity did not appear to influence cell adhesion and proliferation (Figure 26A). However, a distinct effect of surface hydrophilicity and surface roughness on the expression of various ECM components, proteases and cytokines related to tissue inflammation and wound healing was identified (Figure 26B). Specifically, hydrophilic modification of MA surfaces resulted in a decreased expression of matrix metalloproteinase 1 (MMP1) and lnterleukin-6 (ILS), but vice versa an increased expression of transforming growth factor beta 1 (TGFIS1). Furthermore, this modification led to a further increase in collagen 3 expression (COL3). Interestingly, when compared to M surfaces, fibroblasts further exhibited markedly elevated expression levels of COL3 and reduced levels of collagen 1 (COL1) when cultivated on MA or hMA surfaces.

[0375] These data suggests that a change from regular to hydrophilic cementum-like MA surfaces may not directly affect fibroblast ECM expression but modulate the level of inflammatory cytokines and proteases associated with wound healing and remodelling.

[0376] Discussion

[0377] Adequate peri-implant tissue quality and attachment represent one of the unresolved whilst crucial problems in modern implant dentistry. A multitude of concepts comprising, e.g. platform switching, subcrestal implant placement, soft tissue thickening and many more, have been proposed to improve the peri-implant soft tissue complex and prevent crestal bone loss to compensate for the inferior performance of the peri-implant transmucosal barrier compared to the one around natural teeth. It remains unclear to which extent the individual soft tissue compartments, i.e. peri-implant CT and ET, contribute to the implant's transmucosal barrier, while the notion that both structures appear vital to support a mechanically stable and tight seal against the invasion of oral pathogens may remain undisputable.

[0378] A pertinent perspective on the structural organization of the dento-gingival, and potentially also, on the implant-gingival complex revolves around the hypothesis that the phenotype of the JE establishes out of a self-instructed adaptation of oral mucosa in contact with solid and metabolically inactive tooth or implant surfaces penetrating it The herein- and elsewhere observed ability of surface cues, herein specifically hydrophilicity, to influence the differentiation of keratinocytes into a JE-like phenotype is well in line with this hypothesis. At the same time, they reinforce the notion that topographical and surfaceenergy modifications may represent an attractive strategy to modify and improve JE attachment and the transmucosal seal quality.

[0379] In this context, it is interesting to note that a crucial aspect regarding epithelial cells' ability to effectively establish a junction between two dissimilar tissues or with an artificial implant surface has been associated with a requirement of epithelial cells to adopt a distinctly undifferentiated and stratification-independent phenotype - a pattern which appears to be specifically induced in contact to hydrophilic enamel-like M surfaces. Other central elements of epithelial surface attachment of undifferentiated keratinocytes are related to the formation of specialized adhesion complexes, i.e. hemidesmosomes, which attach to a surface-bound specialized ECM termed the internal basal lamina. Laminin V and aep4- integrins have been identified as characteristic elements of epithelial attachment, formed by the epithelial cells in the absence of the immediate vicinity of connective tissue. To this extent, an epithelial-affine and focal-adhesion-promoting surface topography, like the enamel-like M surface, may be favourable to promote the formation of epithelial attachment. Likewise, the analysis of cieP^integrin, Laminin V or Collagen VIII as characteristic elements of pre-hemidesmosomes and attachment, respectively, may further substantiate the promotion of epithelial attachment by such surfaces.

[0380] CT attachment apically to the JE comprising functionally oriented, i.e. cementum anchored dento-gingival collagen fibres, represents a further element of central importance for the quality of the transmucosal barrier (Schupbach and Glauser 2007). The herein-studied cementum-like MA surface and its epithelial-cell discriminating and fibroblast growth-promoting properties may clearly suggest a CT-favorable environment preventing possible epithelial down growth.

[0381] Another important observation related to hydrophilic surface-modified MA surfaces was the decrease of inflammation and proteolytic factors. A similar effect was recently reported in the context of osteogenic cell expression and macrophage activation and may be evaluated as generally beneficial in maintaining tissue integration and homeostasis at the transmucosal barrier.

[0382] The herein-presented in-depth observations point to combining M and MA surfaces into novel transgingival implant or abutment hybrid-designed surfaces for optimized and improved soft tissue attachment and transmucosal barrier properties. Specifically, such hybrid surfaces may consist of a coronal hydrophilic enamel-emulating M surface zone and an apical hydrophilic cementum-emulating MA surface zone. This combination may promote optimized soft tissue compartmentalization and attachment of individual ET and CT compartments through surface-specific cell-selectivity and the induction of specific attachment-promoting differentiation and expression patterns in the individual compartments. These assumptions require taking into account that the validity of the herein reported observations may be tempered by considering only two main protagonist cell types in an in vitro setting, acknowledging that transmucosal wound healing around an implant may be governed by many different cell types, and their complex interaction and competition with oral pathogens, all of which may interfere with the observed surface- related effects.

[0383] List of Reference Numbers in Figures and Description

[0384] 1 : Epithelium / epithelial layer

[0385] 2: Connective tissue / connective tissue layer

[0386] 3: Cementum

[0387] 4: Enamel

[0388] 5: Soft-tissue region of dental device below / apical the cemento-enamel junction (CEJ) 6: Soft-tissue region of dental device above / distal the cemento-enamel junction (CEJ) 7: Cemento-enamel junction (CEJ) 8: Dental implant

[0389] 9: In situ cemento-enamel junction (iCEJ)

[0390] 10: Soft tissue region of implant

[0391] 11 : Hard tissue

[0392] 12: Hard tissue region of implant 13: Soft-tissue level dental implant 14: Crown 15: Abutment

[0393] 16: Bone level dental implant 17: Soft-tissue region of crown 18: One-piece dental implant List of References

[0394] 1. WC2014195027A2-EP3003203

[0395] 2. WC2014195025A2-EP3003204

[0396] 3. EP-A-2161000

[0397] 4. EP1982671

[0398] 5. Degen M, Wiederkehr A, La Scala GC, Carmann C, Schnyder I, Katsaros C. 2018. Keratinocytes isolated from individual cleft lip / palate patients display variations in their differentiation potential in vitro. Frontiers in Physiology. 9.

[0399] 6. Parisi L, Knapp PO, Girousi E, Rihs S, La Scala GC, Schnyder I, Stahli A, Sculean A, Bosshardt DD, Katsaros C et al. 2021. A living cell repository of the cranio- / orofacial region to advance research and promote personalized medicine. Frontiers in Cell and Developmental Biology. 9.

[0400] 7. Wehrlehaller B, Koch M, Baumgartner S, Spring J, Chiquet M. 1991 . Nervedependent and -independent tenascin expression in the developing chick limb bud. Development. 112(2):627-637.

[0401] 8. Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, Louis DN, Li FP, Rheinwald JG. 2000. Human Keratinocytes That Express hTERT and Also Bypass a p16 INK4a -Enforced Mechanism That Limits Life Span Become Immortal yet Retain Normal Growth and Differentiation Characteristics. Molecular and Cellular Biology. 20(4):1436-1447.

[0402] 9. Hotchkiss KM, Ayad NB, Hyzy SL, Boyan BD, Olivares-Navarrete R. 2017. Dental implant surface chemistry and energy alter macrophage activation in vitro. Clin Oral Impl Res. 28(4):414-423.

[0403] 10. Schupbach P, Glauser R. 2007. The defense architecture of the human periimplant mucosa: A histological study. The Journal of Prosthetic Dentistry. 97(6):S15-S25.

Claims

Claims1 . A percutaneous dental device that comprises a soft tissue region (10) with at least two distinct regions with different surface-topographies usable for improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium (1) and the supracrestal connective tissue (2) at the placement site of the device, wherein the soft tissue region has an apical region (5) with a first surfacetopography and a distal region (6) with a second surface-topography, wherein the apical region and the distal region are divided by the in situ cemento-enamel junction (iCEJ) (9) of the percutaneous dental device, wherein the two distinct regions with different surface surface-topographies in the soft tissue region are isotropically patterned, and wherein the surface of the percutaneous dental device consists of titanium, zirconium, titanium and / or zirconium alloys, dental ceramic and / or zirconia ceramic. .

2. A percutaneous dental device according to claim 1 , wherein the the surface of the percutaneous dental device consists of the surface of the percutaneous dental device consists of yttrium-stabilized zirconium oxide (zirconia) in predominantly tetragonal form.

3. A percutaneous dental device according to claim 1 or 2 that comprises a soft tissue region consisting of two distinct regions with different surface-topographies.

4. A percutaneous dental device according to any one of claims 1-3, characterized in that the surface roughness (Sa) of the region of the percutaneous dental device above the in situ cemento-enamel junction (iCEJ) (6) is at least 0.1 pm (Sa), such as at least 0.2 pm less than the surface roughness (Sa) of the region of the percutaneous dental below the in situ cemento-enamel junction (iCEJ) (5).

5. A percutaneous dental device according to any one of claims 1-4, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) (6) is no more than 0.4 pm (Sa), and b. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) (5) is between 0.2-0.8 pm (Sa), and c. wherein the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cemento-enamel junction (iCEJ) is at least 0.1 pm (Sa), such as 0.2 pm less than the surface roughness (Sa) of the region of the percutaneousdental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ).

6. A percutaneous dental device according to any one of claims 1-5, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) (6) is between 0.1 and 0.4 pm (Sa).

7. A percutaneous dental device according to any one of claims 1-6, characterized in that a. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (epithelium) above the in situ cementoenamel junction (iCEJ) (6) is no more than (0.19 ± 0.07) pm (Sa), and b. the surface roughness (Sa) of the region of the percutaneous dental device which is in contact with soft tissue (connective tissue) below the in situ cemento-enamel junction (iCEJ) (5) is between 0.2-0.8 pm (Sa) specifically (0.48 ± 0.12) pm (Sa).

8. A percutaneous dental device according to any one of claims 1-7 that is a dental implant system.

9. A percutaneous dental device according to any of the preceding claims for use in improving soft tissue healing and / or soft tissue regeneration of the supracrestal epithelium and the supracrestal connective tissue at the placement site of the device.

10. A percutaneous dental device according to any of the preceding claims for use in improving soft tissue healing and / or soft tissue regeneration of the junctional epithelium, the sulcular epithelium and the supracrestal connective tissue at the placement site of the device.11 . A percutaneous dental device according to any of the preceding claims for use in inducing regeneration of the supracrestal attached tissue at the placement and / or implantation site of said percutaneous dental device, for improving regrowth and / or regeneration of a biological width at the placement site of said percutaneous dental device, and / or for determining and / or controlling the transition between junctional epithelium and supracrestal connective tissue in the supracrestal attached tissue at the placement and / or implantation site of the device.

12. A percutaneous dental device according to any of the preceding claims for use in healing and / or regeneration of epithelial tissue which is induced and / or guided above an in situ cemento-enamel junction (iCEJ) (9) of the percutaneous dental device and healing and / or regeneration of connective tissue is induced and / or guided below the in situ CEJ (iCEJ) (9) of the percutaneous dental device.

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