Title of Invention: Bioactive intraosseous dental implant

[0001] The subject of the invention is an intraosseous dental implant for the application of biologically active agents directly to the surrounding soft tissues and bone tissue, and their substitutes, and enabling the measurement of the newly formed or lost bone tissue volume immediately adjacent to the dental implant.

[0002] Intraosseous dental grafts (implants) used to rebuild lost tooth roots are known for common use. Implants as such have a conical, roller, cylindrical or trapezoidal shape, with a screw thread or grooving on the shaft. In the upper part, they are adapted to attach a connector serving as a support for the future prosthetic superstructure.

Implants are made of materials biocompatible in terms of bone tissue, titanium or zirconium in particular. The material from which the intraosseous dental implant is made guarantees, after its introduction into the recipient site in a patient, a close connection between the implant and the patient's bone tissue, called osseointegration. Due to the phenomenon of osseointegration, intraosseous dental implants enable, by means of a prosthetic superstructure fixed in their socket, to transfer occlusive loads to the bone, and ensure the restoration of proper aesthetics in patients who have lost their natural teeth partially or completely. On the one hand, the phenomenon of osseointegration prevents infection spread from the infected oral environment deep into the bone tissue along the dental implant, and on the other hand, it allows the transmission of occlusion forces. The phenomenon of osseointegration develops since the introduction of the intraosseous dental implant and depends on the apposition of the newly formed bone tissue on its surface. From the clinical point of view, it is important that the rate of osseointegration force build-up is sufficient to stabilize intraosseous dental implants. High stabilization values allow loading of intraosseous dental implants with prosthetic superstructures and termination of implant prosthetic treatment.

[0003] Increasing the dynamics of osseointegration growth directly results in the possibility of reducing the duration of the entire treatment protocol. This effect is highly anticipated by patients - the beneficiaries of therapy. In order to increase the dynamics of the osseointegration process in intraosseous dental implants, there is ongoing research on the type of material from which the implants are made, their design features, surface topography, as well as the formation of layered structures and coating applications.

[0004] The use of growth factors and other biologically active factors affects the increase in the dynamics of osseointegration strength in intraosseous dental implants. Substances with this effect were applied to the surface of the implants or applied through a system of hollow channels in the solid structure of the implant (Manzano, Vallet-Regi, 2012; KSmmerer et al„ 2016; Losic et al. 2015; Tuukkanen J, Nakamura M, 2017). There is a known method of sandblasting implant surfaces with bioactive tricalcium phosphate particles of various diameters, which increases the level of implant integration with bone due to the obtained porosity (Albrektsson, Wennenberg, 2004). Surface porosity can also be obtained through known techniques of acid etching, anodizing etc. (Albrektsson, Wennenberg, Coelho, 2009). The surface porosity at the nano and micro level maximizes the penetration of biological fluids immediately after implantation and significantly increases the BIC (bone to implant contact) growth dynamics, enabling faster loading of the implant and increases its maximum value, allowing the implant to transfer larger occlusive loads after the end of the osseointegration process (Kaluderovic et al., 2016).

[0005] However, the porous surface and canal formation in the solid implant structure are imperfect methods. The application of growth factors to the surface of the implant is subject to significant quantitative restrictions, prevents long-term effects (short half- life and reaplication possibilities) and is often ineffective due to the abrasion of these substances from the implant surface, as early as at the stage of its introduction into the bone saddle. On the other hand, the application of biological agents through a hollow channel system is associated with a very limited volume possible for single application. In addition, these channels, when contacted with condensed bone tissue during insertion of the intraosseous dental implant, practically prevent the biological agent from entering the surrounding bone tissue, often limiting its interaction only to the direct contact of the canal outlet with the surface of the patient's bone tissue.

Hollow channels in implants were often obstructed immediately after implant insertion or very quickly in the initial phase of bone tissue growth, preventing reapplication of a biologically active agent.

[0006] Inflammation often develops around the implant during the use of intraosseous dental implants. The phenomenon called periimplantitis is one of the most common reasons of reducing the time of using intraosseous dental implants, while being the most common cause of losing integrated implants. Treatment of this phenomenon is difficult and the prognosis is doubtful. In periimplantitis therapy, surgical procedures, as well as photodynamic therapy and lasers, are used to clean the surfaces of the re-infected implant. These are highly invasive techniques. Pharmacotherapy is also a recognized treatment method for this condition. Drugs and biologically active agents are applied directly to the gingival pocket surrounding the implant. This method is of little precision and is exposed to ineffectiveness as a result of leaching the preparation with saliva directly into the patient's oral cavity (Paolantonio et al„ 2008). Attempts to administer biologically active preparations through the implant shaft, using a system of bored channels, are ineffective against their obstruction occurring as a result of implant's primary osseointegration. [0007] The correct stability of intraosseous dental implants is a key phenomenon enabling the proper transmission of occlusion forces in prosthetic superstructures based on them. A precise assessment of the implant stabilization force in the bone and the dynamics of changes in this parameter enables assessment of the effectiveness and safety of prosthetic implant treatment and is an important predictor of its longevity. The stabilization of intraosseous dental implants can be divided into primary, dependent on mechanical fixation in the implant bone immediately after insertion into a dedicated saddle, and secondary, resulting from the developing phenomenon of implant osseointegration. Measurements of the latter are possible on intravital basis only indirectly and are performed by means of tilting analysis of a mechanically activated implant or by vibration resonance analysis technique (Chatvaratthana et al., 2017). However, both techniques do not indicate the amount of bone growing or resorbed around the implant.

[0008] From the clinical point of view, the prior art presented illustrates three important technical problems which are solved by the presented invention. The first problem is the possibility of repeated, non-traumatic, from the patient's and tissues' point of view, application of biologically active agents to the tissues and biomaterials directly surrounding the intraosseous dental implant. The second problem is the ability to precisely measure changes in the volume of bone surrounding and then overgrowing individual structural components of the implant or tissue resorbed around it. The third problem is the possibility of applying unstable coatings or layers or even colonizing the dental titanium implant surface with the recipient cells.

[0009] The intraosseous dental implant according to the invention has a solid shaft and a solid thread with variable height and pitch, and is characterized in that in the middle part, the shaft has a reduced diameter in relation to the diameter of the shaft in the upper and lower part. Part of the implant in the area with reduced shaft diameter is made of material with open porosity from 0.1% to 90%, and with a pore diameter in the range of 0.3 μm to 1000 μm. In addition, the implant has at least two internal channels, of which at least one channel begins in the implant socket and has an outlet at the bottom of the implant, and at least one channel connects to the channel beginning in the implant socket and has an outlet in the porous section of the implant.

[0010] The middle part of the implant shaft may have a reduced diameter of at least two different dimensions.

[0011] Preferably, at least one channel is located axially along the implant, and at least one channel located at an angle of 1-179 degrees relative to the axial channel is connected to this channel. Preferably, the channels have a diameter in the range of 0.3-3000 μm.

[0012] Preferably, the implant has a cylindrical, conical or cylindrical-conical shape.

[0013] The implant may have a controlled or random distribution of the shape and size of the pores along and across the implant. The pores can have a spherical or nearly- spherical shape or the shape of elemental cells (cube, octahedron, diamond cell, etc.).

[0014] Preferably, the implant may have spiral recesses in the lower part and/or in the porous part, in which channel outlets are preferably provided for delivery of biologically active agents. Preferably, the number of recesses can be up to 5.

[0015] Preferably, the implant may be covered in its entirety or in part with a bioactive layer based on calcium phosphate or an osseointegration-enhancing layer. The implant may also be colonized with cells or have carriers of drugs or active substances applied.

[0016] Preferably, the solid implant thread may be single or double and have a pitch in the range of 0.1 to 5 mm. The thread also constitutes ribbing (reinforcement) of the porous implant. Preferably, the thread height is in the range of 0.01 to 3 mm. The thread edge can be constant or variable over the entire thread length, both for double and single threads. The thread can have a triangular, trapezoidal symmetrical, trapezoidal asymmetrical, tubular or round shape. The thread opening angle can be constant or variable over the entire length of the implant, and range from 1 to 180°. In order to increase the implant's stability in the compacted bone plate, its upper part will have a thread that is a continuation of the thread in the remaining part of the implant with the same or different height and pitch, or recesses resembling milling cutter shaper, with a depth of 0 to 2 mm

[0017] The entire implant or porous section of the implant according to the invention can advantageously be produced by 3D printing through selective melting/sintering of biocompatible metallic, ceramic or metallic-ceramic composite powders with laser or electron beam. The materials of the implant according to the invention are preferably titanium or its alloys, tantalum, magnesium, alumina ceramics, Al ₂ O ₃ ZrO ₂ or combinations of these materials, i.e. metal-ceramic composites, in which the metal is the matrix for the ceramic particles. After the manufacturing process, the channels and pores in the implant are cleaned/unblocked chemically or electrochemically from unmelted material particles, e.g. in the case of production from titanium and its alloys, post-process purification can be performed in a mixture of HF/HN0 ₃ acids. In addition, the implant can be subjected to a chemical anodizing process to produce TiO ₂ nanotubes or other TiO _x stoichiometry.

[0018] The intraosseous implant according to the invention has a triple-zone structure in the vertical direction, with reduced shaft diameter in the middle section. The reduction of the shaft diameter leaves space for the porous section of the implant with controlled open porosity. The system of connected channels inside the implant, starting with an inlet in the implant socket and having outlets preferably on individual surfaces of the implant, or at least on the surface of the porous part, allows repeated, non-traumatic administration of biologically active agents to the implant socket without the need for surgical procedures. For this purpose, it is only required to unlock the implant socket by unscrewing the scar-screw, healing screw or abutment. In particular, the application of biologically active agents is possible due to the volume of space contained in the porous central part of the implant. Due to this design, the outlet openings of the implant shaft system cannot be blocked by condensed bone when inserting the implant into its saddle. The application of biologically active agents is both possible at the stage of osteogenesis occurring in the implant healing phase, and osteolysis occurring during the course of periimplantitis phenomenon.

[0019] In the implant according to the invention, it was possible to apply coatings, layers or cells on the porous part of the implant and on the internal surface of the channels, so that they do not get damaged or rubbed off during the implant insertion into the bone saddle, and can play their role conditioning the osseointegration process and secreting drugs or bioactive agents created by them or contained in them.

[0020] An important feature of the invention is the ability to measure the volume of ingrown or resorbing bone around the implant by measuring the volume of fluid necessary to fill the implant shaft system and the porous part thereof. The bone growing in the course of the osseointegration process into the porous space of the central part of the implant will reduce its free space possible to fill with fluid. In contrast to this process, the free space created during periimplantitis as a result of osteolysis of bone tissue will increase the volume needed to fill this part of the implant.

[0021] In particular, the system of connected tubules located inside the implant enables:

- non-invasive and targeted delivery (administration) of various agents from the outside to the tissues surrounding the implant, e.g. growth factors, drugs including antibacterial, antineoplastic drugs, cell therapy, to accelerate osseointegration, bone formation, treatment of the tissue area around the implant in the event of any lesions (bacterial contamination, bone loss around the implant), etc.

- monitoring and measuring the concentration and activity of biological agents in the implant area by collecting and analyzing fluids from the implant surroundings,

- monitoring and measuring the amount of bone grow into implant indirect implant osseointegration) by measuring the amount and pressure of fluid introduced into the tubules,

- cooling the implant while screwing it into the mandible by inserting coolant into the implant tubules.

[0022] The implant according to the invention simultaneously retains all the desired mechanical and biological features of the currently used dental implants.

[0023] The implant according to the invention in the embodiments is shown in the figures, wherein:

Fig.1 [0024] [fig.1 ] shows the implant view,

Fig.2

[0025] [fig.2] shows a longitudinal section of the implant shown in the view in Fig. 1,

Fig.3

[0026] [fig.3] shows a view of the implant according to Example 1 with cross sections,

Fig.4

[0027] [fig.4] shows a view of the implant according to Example 2 with cross sections,

Fig.5

[0028] [fig.5] shows a view of the implant according to Example 3 with cross sections.

Example 1

[0029] The implant according to the invention shown in the embodiment in Fig. 1, Fig. 2 and Fig. 3 has conical shape with a length of 11.5 mm. The solid shaft 1 has a thread 2. The solid upper part 3 of the implant has a length of 2 mm and the upper diameter 3.75 mm, the central porous part 4 has a length of 5 mm, and the solid lower part 5 has a length of 4.5 mm. Thread 2 located in the lower part 5 and the porous part 4 has a variable pitch in the range of 1 to 2 mm, and a variable edge thickness from 0.05 to 0.15 mm. In the upper part 3, thread 2 has a constant pitch of 0.2 mm, and a variable thread height from 0.01 to 0.125 mm. The porous part 4 has pores with a gradient size from 0.5 mm at the outer edge of the implant to 0.2 mm looking towards the implant axis. The porosity is 52% and 89%, respectively. The solid shaft 1 in the central porous part 4 has a diameter of 1.5 mm in the lower part and 2.5 mm in the upper part intended for implant socket 7. The lower part of the implant has two spiral recesses 6. Along the main axis of the implant from the implant socket 7 to the extreme lower surface of the implant, there is a main supply channel 8 with a diameter of 0.4 mm with outlet 10. The lateral supply channels 9 extend from the main supply channel 8. Three of them are located in the central part 4 and are inclined to the main axis of the implant at an angle of 60°, and are arranged relative to the transverse axis at angles of 240° (B-B cross-section), 120° (C-C cross-section) and 0° (D-D cross-section), and have ending 11 open in the porous area 4. Two side channels are located in the lower part 5 and are directed at an angle of 60° to the implant axis, they have an end 11 in spiral recesses 6 (one in each) and arranged in relation to the transverse axis at 0° and 180° (E-E cross-section). Implant made by 3D printing from Ti6A14V alloy powder (Grade 5).

Example 2

[0030] The implant according to the invention shown in the embodiment in Fig. 4 has a conical shape, 16 mm long. The solid shaft 1 has a thread 2. The solid upper part 3 of the implant has a length of 2 mm and the upper diameter 5 mm, the central porous part 4 has a length of 8 mm, and the solid lower part 5 has a length of 6 mm. The lower part

5 and the porous part 4 have a thread 2 with a constant pitch of 1 mm, and a constant edge thickness of 0.03 mm. In the upper part 3, there are recesses 12 of trapezoidal shape, with a depth of 0 to 0.2 mm. The porous part 4 has pores with a gradient size from 0.7 mm at the outer edge of the implant to 0.5 mm looking towards the implant axis. The porosity is 69% and 75%, respectively. The solid shaft 1 in the central porous part 4 has a diameter of 1.5 mm in the lower part, and 2.5 mm in the upper part intended for the implant socket 7. In the lower part 5 and the porous part 4, there are two spiral recesses 6. Along the main axis of the implant from the implant socket 7 to the extreme lower surface of the implant, there is a main supply channel 8 with a diameter of 0.4 mm, with outlet 10. The lateral supply channels 9 depart from the main supply channel, wherein four of them are located in the central part 4 and are inclined to the main axis of the implant at an angle of 60°, and are arranged relative to the transverse axis at an angle of 240° (B-B cross-section), 120° (C-C cross-section), 0° (D-D cross-section) and 240° (F-F cross-section) and have an ending 11 open in the porous area 4, two of them are in the lower part, and are directed at an angle of 60° to the main axis of the implant, they have an ending 11 in spiral recesses 6 (one in each), and are arranged in relation to the transverse axis at 0° and 180° (F-F cross-section). Implant made by 3D printing from Grade 2 titanium powder.

Example 3

[0031] The implant according to the invention shown in the embodiment in Fig. 5 has a conical shape with a length of 13 mm. The solid shaft 1 has a thread 2. The solid upper part 3 has a length of 2 mm and an upper diameter of 2.9 mm. The central porous part 4 is 6.5 mm long. The solid lower part 5 has a length of 4.5 mm. The lower part 5 and the porous part 4 have a double thread with a variable pitch in the range of 4 to 2 mm, arid a variable edge thickness from 0.04 to 0.1 mm. In the upper part 3 there are millings 13 with a semicircular shape, 0.05 mm deep, oriented perpendicular to the implant axis. The porous part 4 has pores with a gradient size from 0.5 mm at the outer edge of the implant to 0.2 mm looking towards the implant axis. The porosity is 61% and 83%, respectively. The solid shaft 1 in the central porous part 4 has a diameter of 1 mm with a thickening for the implant socket 7 with a diameter of 2.2 mm. The lower part has two spiral recesses 6. Along the main axis of the implant from the implant socket 7 to the extreme lower surface of the implant, there is a main supply channel 8 with a diameter of 0.4 mm, with outlet 10. The lateral supply channels 9 depart from the main supply channel 8, wherein four of them are located in the central part 4 and are inclined to the main axis of the implant at an angle of 45°, and are arranged relative to the transverse axis at angles of 90° and 270° (B-B cross-section), 0° and 180° (C-C cross-section) and have an open ending 11 in the porous area 4, two of them are in the lower part 5 and are directed at an angle of 45° to the main axis of the implant, they have endings 11 in spiral recesses 6 (one in each), and are arranged with respect to the transverse axis at 90° and 270° angles (D-D cross-section). Implant made by 3D printing from Al ₂ O ₃ corundum ceramics.

Citation List

[0032] NPL 1: Manzano M, Vallet-Regi M.: Revisiting bioceramics: Bone regenerative and local drug delivery systems. Progress in Solid State Chemistry 40 17e30. (2012).

[0033] NPL 2: Kammerer TA, Palarie V, Schiegnitz E, Topalo V, Schrbter A, Al-Nawas B, Kammerer PW. A biphasic calcium phosphate coating for potential drug delivery affects earlyosseointegration of titanium implants. J Oral Pathol Med. 2017 Jan;46(l):61-66. doi: 10.111 l/jop.12464. Epub 2016 Jun 7.

[0034] NPL 3: Losic D, Aw MS, Santos A, Gulati K, Bariana M. Titania nanotube arrays for local drug delivery: recent advances and perspectives. Expert Opin Drug Deliv. 2015 Jan;12(l): 103-27. doi: 10.1517/17425247.2014.945418. Epub 2014 Nov 7.

[0035] NPL 4: Tuukkanen J, Nakamura M. Hydroxyapatite as a Nanomaterial for Advanced Tissue Engineering and Drug Therapy. Curr Pharm Des. 2017;23(26):3786-3793. doi: 10.2174/1381612823666170615105454.

[0036] NPL 5: Albrektsson T, Wennerberg A. Oral implant surfaces: Part 2— review focusing on clinical knowledge of different surfaces. Int J Prosthodont. 2004 Sep- Oct;17(5):544-64.

[0037] NPL 6: Albrektsson T, Wennerberg A. Oral implant surfaces: Part 1 —review focusing on topographic and chemical properties of different surfaces and in vivo responses to them. Int J Prosthodont. 2004 Sep-Oct;17(5):536-43.

[0038] NPL 7: Dohan Ehrenfest DM, Coelho PG, Kang BS, Sul YT, Albrektsson T. Classification of osseointegrated implant surfaces: materials, chemistry and topography. Trends Biotechnol

[0039] NPL 8: Kaluderovic MR, Schreckenbach JP, Graf HL. Titanium dental implant surfaces obtained by anodic spark deposition - From the past to the future. Mater Sci Eng C Mater Biol Appl. 2016 Dec 1;69: 1429-41. doi: 10.1016/j.msec.2016.07.068. Epub 2016 Jul 26.

[0040] NPL 9: Paolantonio M., D'Angelo M., Grassi R.F., Perinetti G., Piccolomini R., Pizzo G., Annunziata M., D'Archivio D., D'Ercole S., Nardi G„ Guida L.: Clinical and microbiologic effects of subgingival controlled-release delivery of chlorhexidine chip in the treatment of periodontitis: a multicenter study. J Periodontol.;79(2):271-82., Feb2008

[0041] NPL 10: Chatvaratthana K, Thaworanunta S, Seriwatanachai D, Wongsirichat N. Correlation between the thickness of the crestal and buccolingual cortical bone at varying depths and implant stability quotients. PLoS One. 2017 Dec 27;12(12):e0190293. doi: 10.1371/joumal.pone.0190293. eCollection 2017.