WO2011154171A1 - Implant intra-osseux, son procédé de préparation et trousse d'implant correspondante - Google Patents

Implant intra-osseux, son procédé de préparation et trousse d'implant correspondante Download PDF

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Publication number
WO2011154171A1
WO2011154171A1 PCT/EP2011/054989 EP2011054989W WO2011154171A1 WO 2011154171 A1 WO2011154171 A1 WO 2011154171A1 EP 2011054989 W EP2011054989 W EP 2011054989W WO 2011154171 A1 WO2011154171 A1 WO 2011154171A1
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WIPO (PCT)
Prior art keywords
collagen
implant
bone
endosseous
native
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PCT/EP2011/054989
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English (en)
Inventor
Maurizio Ludovichetti
Rino Biasiolo
Antonio Pompilio Gigante
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Bioteck Srl
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2011154171A1 publication Critical patent/WO2011154171A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials

Definitions

  • the present invention relates to an endosseous implant, wherein at least one part of its outer surface designed to come into contact with bone matter has a collagen coating.
  • the invention also refers to a method for preparing the endosseous implant.
  • the invention additionally concerns a kit for the preparation of such an implant.
  • the implant, the method for its preparation and the related implant kit are intended for use in the fields of dentistry, orthopaedics and neurosurgery.
  • This process is influenced by various physical parameters of the surface of the graft; it is a biological process wherein an intimately connected bone layer is deposited so that it adheres to the surface of the grafted object, thereby affording it a degree of mechanical stability.
  • the characteristics of the graft surfaces capable of influencing the process of osteointegration have been accurately studied with a view to further improving the efficacy of said process of osteointegration in order to increase said stability and consequently enable the successful grafting of such objects even in conditions where the surrounding bone tissue is limited, porous or atrophic.
  • This research has prompted two types of technical advance: the production of surfaces with particular roughness characteristics, i.e. with particular shapes and sizes of recesses created in the metal (and a consequent degree of surface porosity) mainly to facilitate the cells' adhesion to the metal, as well as supporting their cellular biology; and the coating of said surfaces with materials different from the metal involved, here again to stimulate cell adhesion and cell activity around the implanted object.
  • inorganic compounds e.g. hydroxyapatite
  • organic compounds e.g. peptides, denatured collagen derived from skin/tendon
  • the bone-implant contact area increased by 23.8% in the presence of the coating.
  • the object of the present invention is to further optimise the surface changes in order to further improve the osteointegration of endosseous implants, and therefore to produce an improved endosseous implant that enables better osteointegration of the same.
  • an object of the invention is to propose a method and a kit for preparing such an implant.
  • an endosseous implant of the initially-mentioned type wherein the collagen essentially retains the structure of native natural collagen.
  • the collagen essentially has the structure of native natural collagen is intended to mean that it may be collagen of natural origin that is not denatured during its extraction from the natural source, or it may be collagen of synthetic origin but with the same, or basically the same structure as native collagen (i.e. not denatured), or reconstituted collagen, i.e. collagens that are capable of performing the same functions as native natural collagen.
  • osteointegration-stimulating effect of denatured collagen is partially attributable, in all likelihood, to the amino acid sequence and to portions of the protein chain, which may locally retain their native conformation even though the whole protein has been denatured.
  • Protein denaturing is a gradual process that starts from a single, three- dimensional conformation and leads to severe stretching of the amino acid chain, with the rupture of all the intramolecular bonds.
  • osteointegration-stimulating effects are still detectable even if the protein loses its global native conformation and/or becomes fragmented during the denaturing collagen extraction process.
  • the ultimate effect on osteointegration is consequently greater because it facilitates the intimate, mechanically stable adhesion of the just formed bone tissue to the surface thus coated.
  • Collagen is a biocompatible material that also forms a coating that is degraded and absorbed during osteointegration, when the bone adheres directly to the implant, assuring its long-standing stability.
  • osteointegration-supporting growth factors When collagen is extracted from bone tissue, osteointegration-supporting growth factors can remain bonded to, or embedded in the collagen molecule, which can further increase the already stimulating effect of native collagen in scarcely denaturing conditions and with no need to adopt processes to remove said growth factors.
  • growth factors can be added to powdered collagen (e.g. by adding denatured collagen), or they may be already contained therein if the collagen is extracted using non-denaturing methods that do not destroy the growth factors.
  • the collagen is mainly collagen type I.
  • Collagen type I is the most widespread collagen and has demonstrated a good osteointegration- stimulating capacity.
  • the collagen is native bone collagen.
  • Bone collagen derives from the same tissue (i.e. bone tissue) as the tissue in which the endosseous implant is grafted, ensuring an implicitly strong "kinship" between the surface of the implant and the site of the implant.
  • the coating is produced by means of the deposition of collagen in powdered form in the presence of water on the outer surface of the implant and the subsequent lyophilization of the implant together with the deposited coating. Said deposition in the presence of water can be achieved by depositing an aqueous suspension of the powdered collagen on the implant or, as a feasible alternative, by depositing the collagen powder on the wetted implant.
  • collagen deposition on the implant in the presence of water is characterised by a good wettability, and that the subsequent co-lyophilization of the implant with the layer of collagen ensures an excellent adhesion of the collagen to the surface of the implant, consequently creating a very stable bond between the implant and the collagen.
  • Deposition of the collagen in the form of an aqueous suspension is particularly suitable.
  • This process of collagen deposition on the implant in the presence of water and subsequent lyophilization of the thus coated implant in order to coat the implant in a stable manner can also be applied to coatings with denatured collagen, obtained from skin or tendon for instance, thereby improving the adhesion of the collagen to the implant.
  • One type of collagen that has demonstrated excellent osteointegration- stimulating capacities is a collagen extracted from bone matter using non- denaturing or scarcely denaturing methods, and particularly by treating the bone matter with diluted hydrochloric acid. This gives rise to a collagen originating from bone, which is consequently particularly suitable for facilitating osteointegration.
  • Treatment with hydrochloric acid is an inexpensive and straightforward method for obtaining non-denatured collagen.
  • the preferred bone matter is of mammalian origin, and may be of autogenous, allogeneic or xenogeneic type
  • the endosseous implant is a dental implant, an orthopaedic implant, or a neurosurgical implant.
  • endosseous implant surfaces with native collagen to facilitate osteointegration is practically suitable for all types of endosseous implant made of various materials and in various shapes. Titanium implants are particularly preferred.
  • the material on the outer surface of the implant is preferably chosen from the group comprising the metals, and particularly titanium and zirconium, ceramics, hydroxyapatite, phosphates and polymers.
  • the outer surface is advantageously rough. This roughness increases the contact area between the implant and the collagen, and also enables the collagen to penetrate towards the inside of the implant, facilitating the interaction between the collagen and the implant surface.
  • Another important aspect of the invention is a method for preparing an endosseous implant comprising the following phases:
  • phase (b) deposition of collagen essentially having the structure of natural native collagen on at least one part of the outer surface of the implant that is intended to come into contact with bone matter.
  • This method enables the preparation of an endosseous implant according to the invention that is particularly suitable for the purpose of osteointegration.
  • the deposition takes place with collagen in powdered form and in the presence of water, and in such a manner that, after phase (b), there is a phase (c) comprising the dehydration of the collagen-coated implant by lyophilization.
  • phase (c) comprising the dehydration of the collagen-coated implant by lyophilization.
  • Said deposition in the presence of water is preferably achieved either by depositing an aqueous suspension of the powdered collagen on the implant or by depositing the collagen powder on a wetted implant.
  • the water may be physiological solution or demineralised water (e.g. distilled water for injection).
  • Any type of water suitable for producing a biocompatible, non-toxic and sterile implant may be used.
  • the collagen is extracted from bone matter (preferably mammalian), particularly by treating the bone matter with diluted hydrochloric acid;
  • the dehydrated native bone collagen is ground into a fine powder.
  • the extraction of bone collagen with diluted hydrochloric acid offers numerous advantages: it does not require any special chemical reagents (HCI in low concentrations suffices), it requires a very inexpensive raw material (bone tissue from slaughterhouse waste), and it takes place in non-denaturing conditions (i.e. the extracted bone collagen is a protein in its native conformation, a necessary condition for its stimulating biological activity).
  • This variant embodiment of the invention thus enable surfaces of objects intended for endosseous implantation to be coated with a non-denatured protein (collagen) obtained from the same type of tissue as the tissue involved in the implant (bone tissue) and with a considerable increase in the cost- benefit ratio.
  • a non-denatured protein collagen obtained from the same type of tissue as the tissue involved in the implant (bone tissue) and with a considerable increase in the cost- benefit ratio.
  • a standard non-denaturing method using low concentrations of HCI is as follows: the bone matter is immersed in diluted hydrochloric acid. Molar concentrations of approximately 0.15, corresponding to a pH of approximately 0.8, are particularly suitable.
  • the treatment time is preferably 48 hours.
  • the bone matter is demineralised during the treatment.
  • the remaining collagen, which is native (i.e. practically non-denatured) is separated from the solution. Then the separated collagen is washed, using osmotically purified water for instance.
  • the concentrations of hydrochloric acid can naturally vary within the limits that enable native, or scarcely denatured collagen to be obtained; the treatment time for dissolving the mineral part of the bone may also vary.
  • the characteristics identified and defined for the endosseous implant e.g. the quality of the implant's surface, the source of the collagen, etc.
  • the characteristics identified and defined for the endosseous implant can also be transferred to the method and the kit described below as a further aspect of the invention.
  • the invention also concerns a kit containing the following materials needed to prepare an implant according to the invention: collagen in powdered form, which essentially has the structure of native natural collagen, preferably native mammalian bone collagen, and an endosseous implant.
  • the kit may optionally also contain physiological solution or demineralised water (i.e. distilled and/or purified using osmotic and/or ion-exchange filtering methods).
  • physiological solution or demineralised water i.e. distilled and/or purified using osmotic and/or ion-exchange filtering methods.
  • a typical procedure for the production of collagen suited to be applied according to the invention involves treating bone matter of mammalian origin with diluted hydrochloric acid: the bone matter is immersed in hydrochloric acid diluted to a concentration of 0.15M, corresponding to a pH of approximately 0.8, for 48 hours.
  • the bone matter is demineralised during this treatment.
  • the remaining collagen which is native (i.e. practically non-denatured), is separated from the solution. Then the separated collagen is washed with osmotically purified water.
  • the bone collagen thus extracted according to this non-denaturing method is dehydrated by lyophilization and then ground to form a fine powder.
  • the lyophilised collagen in powdered form is suspended in physiological solution or in distilled water for injection.
  • the resulting suspension is deposited on the surface of the implantable object.
  • the implant thus impregnated is dehydrated by lyophilization.
  • the implant thus prepared is ready for use.
  • the endosseous implant to be coated is wetted with physiological solution or distilled water for injection.
  • the wetted implant is then sprinkled with the lyophilised collagen powder.
  • the implant thus coated is dehydrated by lyophilization.
  • the implant thus prepared is ready for use.
  • the surface of a titanium device was coated as described above with native bone collagen.
  • the device came into contact with cells extracted from human bone marrow, there was a dose-dependent increase in cell viability (with respect to a negative control consisting of an identical device without the coating) up to 1 .6 times (+ 60%).
  • MTT assay the so-called MTT assay
  • MTT assay the acronym indicates the compound 3-(4,5-dimethythiazol-2-yl)-2,5- diphenyltetrazolium bromide.
  • This is a standard colorimetric assay for measuring the activity of the enzymes that reduce MTT to formazan, lending the substance a purple-blue colour; this happens mainly in the mitochondria.
  • Example 2 in vitro study: The surface of a titanium device was coated as described above with native bone collagen.
  • TGF-beta-1 pro-regenerative factors
  • the concentration of factor TGF-beta-1 was measured by ELISA (enzyme- linked immunosorbent assay) using commercial kits.
  • TGF-beta-1 The increase in TGF-beta-1 demonstrates that the presence of the collagen coating is capable of positively stimulating the paracrine modulation of osteoblast activity via the secretion of at least one diffusible pro-regenerative growth factor.
  • the surface of a titanium device was coated as described above with native bone collagen.
  • the device came into contact with osteoblastic cell cultures from donated human bone, there was a 1 .7-fold (+70%) increase in the activity of the alkaline phosphatase enzyme (a typical marker of metabolic activity in this type of cell) by comparison with a negative control consisting of an identical device without the coating.
  • the activity of the alkaline phosphatase enzyme was determined by means of another colorimetric test, by delivering the substrate PNP (p-nitrophenylphosphate) to the cells, which is degraded by the enzyme into p-nitrophenol, a colorimetrically detectable compound.
  • PNP p-nitrophenylphosphate
  • the surface of a titanium device was coated as described above with native bone collagen. After implantation in the femur of a laboratory animal (rabbit), there was a 1 .94-fold (+94%) increase in the final area of bone-implant contact (BIC) by comparison with an identical uncoated device implanted in the contralateral femur, i.e. a nearly two-fold increase.
  • the surface of a titanium device was coated as described above with native bone collagen. After implantation in the femur of a laboratory animal (rabbit), there was a 3.7-fold (+370%) early increase in the bone-implant contact area (early BIC, measured by administering a specific fluorochrome to the animal on the day of the implantation procedure, that was detectable in the bone sections in methacrylate resin containing the subsequently explanted device) by comparison with an identical uncoated device implanted in the contralateral femur.
  • the bone-implant contact area was measured by performing analyses on sections of implants obtained by coring 45 and 90 days after placing the (coated and uncoated) implants in the animal.
  • the animals were injected at various times with fluorescent markers (calcein green, xylenol orange, doxycycline, %) to enable early bone deposition to be distinguished from intermediate and late bone deposition.
  • the success rate could be raised to 99.1 %.
  • the parameters for judging the success (or failure) of the implant consisted in the percussion test (a quality test), the screw loosening test (countertorque test), and the radiographic assessment according to the criteria proposed by Albrektsson and Zarb (Albrektsson T., Zarb G., Worthington P., Erikkson A.R., "The long-term efficacy of currently used dental implants: a review and proposed criteria of success", Int. J. Oral Maxillofac. Implants 1986, 1 , 1 1 -25).
  • the implant shall be mechanically stable and the extent of peri-implant bone resorption shall not be greater than 1 .5 mm in the first year and 0.2 mm in subsequent years.
  • the endosseous implant and the related method and kit for its preparation may undergo further modifications or variants not described herein. Should any such changes or variants come within the scope of the following claims, they shall all be protected by the present patent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention porte sur un implant intra-osseux dont au moins une partie de la surface externe destinée à venir en contact avec un matériau osseux est revêtue de collagène. Le collagène a essentiellement la structure d'un collagène naturel natif. L'invention porte également sur un procédé apparenté et sur une trousse correspondante pour la préparation d'un tel implant intra-osseux.
PCT/EP2011/054989 2010-06-10 2011-03-31 Implant intra-osseux, son procédé de préparation et trousse d'implant correspondante WO2011154171A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000032U ITVI20100032U1 (it) 2010-06-10 2010-06-10 Applicazione di collagene osseo a superfici impiantabili in tessuto osseo allo scopo di favorirne l'osteointegrazione nei settori dell'odontoiatria, dell'ortopedia e della neurochirurgia.
ITVI2010U000032 2010-06-10

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WO2011154171A1 true WO2011154171A1 (fr) 2011-12-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014024171A1 (fr) 2012-08-10 2014-02-13 Akimedix S.R.L. Procédé de préparation d'un revêtement biocompatible pour des greffons osseux, ainsi que revêtement et implant obtenus par ce procédé

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169001A2 (fr) * 1984-07-17 1986-01-22 Collagen Corporation Implants osseux avec revêtement en collagène
US4591456A (en) * 1984-04-03 1986-05-27 Bioetica, S.A. Process for obtaining homogeneous layers of native collagen, its application in covering or encapsulating various supports and the supports thus covered
FR2922434A1 (fr) * 2007-10-18 2009-04-24 Rech S Et De Fabrication Serf Implant dentaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4591456A (en) * 1984-04-03 1986-05-27 Bioetica, S.A. Process for obtaining homogeneous layers of native collagen, its application in covering or encapsulating various supports and the supports thus covered
EP0169001A2 (fr) * 1984-07-17 1986-01-22 Collagen Corporation Implants osseux avec revêtement en collagène
FR2922434A1 (fr) * 2007-10-18 2009-04-24 Rech S Et De Fabrication Serf Implant dentaire

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALBREKTSSON T., ZARB G., WORTHINGTON P., ERIKKSON A.R.: "The long-term efficacy of currently used dental implants: a review and proposed criteria of success", INT. J. ORAL MAXILLOFAC. IMPLANTS, vol. 1, 1986, pages 11 - 25
LEKHOLM U., ZARB G. A., KIEFERANATOMIE, GEWEBEINTEGRIERTER ZAHNERSATZ - OSSEOINTEGRATION IN KLINISCHER ZAHNHEILKUNDE, 1985, pages 197 - 199
MISCH C.E.: "Density of bone: effect on treatment plans, surgical approach, healing, and progressive bone loading", INT. J. ORAL IMPLANTOL., vol. 6, no. 2, 1990, pages 23 - 31
MORRA M., CASSINELLI C., CASCARDO G., CAHALAN P., CAHALAN L., FINI M., GIARDINO R.: "Surface engineering of titanium by collagen immobilization. Surface characterization and in vitro and in vivo studies", BIOMATERIALS, vol. 24, 2003, pages 4639 - 4654, XP004452457, DOI: doi:10.1016/S0142-9612(03)00360-0

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014024171A1 (fr) 2012-08-10 2014-02-13 Akimedix S.R.L. Procédé de préparation d'un revêtement biocompatible pour des greffons osseux, ainsi que revêtement et implant obtenus par ce procédé

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