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Ståle LYNGSTADAAS, et al.

Bone Scaffold







http://www.apollon.uio.no/english/articles/2014/dentistry.html
Mar 18, 2014

Saves loose teeth and jaws damaged by cancer

By Yngve Vogt



Periodontitis can cause teeth to come loose. Mandibular cancer can disfigure a face. With the aid of artificial, foam-rubber-shaped scaffolding, the body can be helped to repair the damage by itself.

A new invention made at the Faculty of Dentistry, University of Oslo, Norway, helps the body generate new bone which is as strong as the original.

To begin with, the invention can save those who suffer from loose teeth and damaged mandibles. Periodontitis is a troublesome infection of the gums. When the infection causes the bone adjacent to teeth to break down, the teeth come loose. Mandibular bone can also be damaged by cancer, infections and accidents.

Using this new method, dentists can insert artificial scaffolding that will determine where the new bone tissue will grow.

To understand this method, we need to understand how bone can repair itself. After a fracture, the bone fragments can knit together only if they are in very close contact. Even if they have the ability to do this, there are major limitations. When a bone fractures, a lot of blood collects at the site of fracture. Blood contains organic molecules that coalesce into long strands. This coagulum is then populated with cells and turn into connective tissue that later calcify. The connective tissue functions as a porous growth platform for bone cells and blood vessels. The bone cells remodel the calcified structure and forms functional bone. New blood vessels help bring nutrients and oxygen.

The outer part of the bone is compact, while the inner part is porous. The porous part contains marrow cells, which are essential for maintaining the skeleton. Its porosity varies according to the type of bone.
Artificial help for bones

If there is too wide a gap between the two bone fragments, or if parts of the bone have been damaged, the body does not always succeed in repairing the damage by itself, as can happen when some of the bone has been removed during cancer surgery or when the bone has been damaged by radiotherapy.

“This is where our invention comes in,” says Ståle Petter Lyngstadaas, Research Dean at the Institute of Biomaterials, Faculty of Dentistry. Along with Professor Jan Eirik Ellingsen, Associate Professor Håvard Jostein Haugen and others, Lyngstadaas has developed and patented an artificial scaffolding that help the body to repair such “critical” damage.


Ståle Petter Lyngstadaas and Håvard Jostein Haugen are two of the researchers behind this invention.
Photo: Yngve Vogt

“With our new method, it’s sufficient to insert a small piece of synthetic, bone stimulating material into the bone. The artificial scaffolding is as strong as real bone and yet porous enough for bone tissue and blood vessels to grow into it and work as a reinforcement for the new bone”

Spicing it up with stem cells

If the defect is major, the bone cells will take a long time to grow into the scaffolding.

“To speed things up, we can take bone progenitor cells or bone marrow that contain committed stem cells from the patients and insert them into the scaffolding. This will cause the process to accelerate.”

“When bone needs to be built into defects where the distance between the bone fragments exceeds one centimetre or so, stem cells should be added to obtain a good result, but stem cells are normally not required to solve problems with loose teeth and periodontitis,” Haugen underscores.

The bone cells are dependent on nutrients and good growth conditions and a specific signal to differentiate into bone forming cells.

“One must therefore ensure that the surrounding bone tissue is healthy, and that there is ample blood supply to the site of surgery.”

Made from food additives

Manufacturing the material is a simple matter. A mixture of water and ceramic powder is poured through ultrapure foam rubber designed to look like trabecular bone. The ceramic powder consists of medical grade titanium dioxide monodisperse nano-particles. Titanium dioxide has already gone through numerous toxicity tests and is a very common additive to pharmaceuticals. The substance is also referred to as E-171 and is widely used for colour in sweets, toothpaste, biscuits, baked goods, ice cream and cheese. When the mixture has solidified, it is heated to a temperature that causes the foam rubber to dissolve into water vapour and carbon dioxide and the nano-particles to ligate into one solid structure. The result is a mirror image of the foam rubber structure.

“The structure is similar to that of the porous part of the bone.”

The material can be manufactured like cinder blocks and cut to shapes that fit into the bone defect.

The artificial bone scaffolding has an open porosity of ninety per cent containing mostly empty space that can be filled with new bone.

“A lot of empty space is important. The cavities are sufficiently large to make space not only for bone cells, but also for blood vessels that can bring in nutrients and oxygen and remove waste products. One of the big problems with current materials is that they do not provide space for both bone tissue and blood vessels.”
Today: bone from cows and dead people

Today, damaged bone is repaired by removing tissue from healthy bones, e.g. from the lower jaw, shin, thigh or hip and implanting it in the damaged location. The surgery is uncomfortable and often leads to complications. When the patient’s own bone tissue cannot be used, ground bone from other people can be used instead. In the USA, ground bone from deceased people is often used. Unfortunately, this solution is neither sufficiently strong, nor particularly porous. It also has the disadvantage of risk for disease transfer.

The EU and most of the world prefer a more careful solution. To avoid the risk of human disease transfer, here ground and heat-treated bone from animals are used. To avoid disease, only animals from closed and controlled herds are used. Any what source for natural bone, after removal of organics and heat treatment the porosity never amount to more than 40 percent, far below the optimum, and the material is too brittle and weak to add support to the regenerated bone.

“One of the advantages of the current methods is that the added bone is gradually devoured by the cells of the body. Our material, on the other hand, will never disappear, but always remain as an integral part of the repaired bone, working as reinforcement. This calls for higher safety requirements,” Lyngstadaas explains.

Ready for clinical studies

The Norwegian dentists have tested the new method successfully on rabbits, pigs and dogs. In 2014, they wish to undertake clinical studies on patients with periodontitis and damage to the mandibular bone. To establish what method works best, it is advantageous to perform tests on patients with periodontitis in particular.

“The patients often suffer from bilateral periodontitis. This permits us to compare results by testing the material on one side and have the control on the other within in the same patient.”

The dentists also hope that orthopaedists will take an interest in their new method.

“We hope to have the product on the market within a few years from now. It’s a fairly large market. Many millions of kroner are spent annually on implanting new bone tissue in mandibles in Norway. Worldwide, we are talking about several million patients. We are now looking for a large industrial partner who can scale up production and bring the product to the market,” says Lyngstadaas, who has co-developed the new material in cooperation with thr company Corticalis, of which he presently is the acting CEO.



PATENTS

METAL OXIDE SCAFFOLDS
ES2431672 // WO2008078164
[ PDF ]

The present invention relates to a metal oxidE scaffold comprising titanium oxide. The scaffolds of the invention are useful for implantation into a subject for tissue regeneration and for providing a framework for cell growth and stabilization to the regenerating tissue. The invention also relates to methods for producing such metal oxide scaffolds and their uses.

BACKGROUND OF THE INVENTION

Conditions such as trauma, tumours, cancer, periodontitis and osteoporosis may lead to bone loss, reduced bone growth and volume. For these and other reasons it is of great importance to find methods to improve bone growth and to regain bone anatomy. Scaffolds may be used as a framework for the cells participating in the bone regeneration process, but also as a framework as a substitute for the lost bone structure. It is also of interest to provide a scaffold to be implanted into a subject with a surface structure that stimulates the bone cells to grow to allow a coating of the implanted structure by bone after a healing process

Orthopedic implants are utilized for the preservation and restoration of the function in the musculoskeletal system, particularly joints and bones, including alleviation of pain in these structures. Vascular stents are tubular implants arranged for insertion into blood vessels in order to prevent or counteract a localized flow constriction, i.e. they counteract significant decreases in blood vessel diameter.

Orthopedic implants are commonly constructed from materials that are stable in biological environments and that withstand physical stress with minimal deformation. These materials must possess strength, resistance to corrosion, have a good biocompatibility and have good wear properties. Materials which fulfill these requirements include biocompatible materials such as titanium and cobolt-chrome alloy.

For the purposes of tissue engineering it is previously known to use scaffolds to support growth of cells. It is believed that the scaffold pore size, porosity and interconnectivity are important factors that influence the behaviour of the cells and the quality of the tissue regenerated. Prior art scaffolds are typically made of calcium phosphates, hydroxyl apatites and of different kinds of polymers.

One principle of tissue engineering is to harvest cells, expand the cell population in vitro, if necessary, and seed them onto a supporting three-dimensional scaffold, where the cells can grow into a complete tissue or organ [1-5]. For most clinical applications, the choice of scaffold material and structure is crucial [6-8]. In order to achieve a high cell density within the scaffold, the material needs to have a high surface area to volume ratio. The pores must be open and large enough such that the cells can migrate into the scaffolds. When cells have attached to the material surface there must be enough space and channels to allow for nutrient delivery, waste removal, exclusion of material or cells and protein transport, which is only obtainable with an interconnected network of pores [9, 10]. Biological responses to implanted scaffolds are also influenced by scaffold design factors such as three-dimensional microarchitecture [11]. In addition to the structural properties of the material, physical properties of the material surface for cell attachment are essential.

Titanium and titanium alloys are frequently used as implant materials in dental and orthopedic surgery due to their biocompatibility with bone tissue and their tendency to form a firm attachment directly with bone tissue. This interaction between bone tissue and metal leading to this firm attachment is called "osseointegration".

Some of the metals or alloys, such as titanium, zirconium, hafnium, tantalum, niobium, or alloys thereof, that are used for bone implants are capable of forming a relatively strong bond with the bone tissue, a bond which may be as strong as the bone tissue per se, or sometimes even stronger.

Although the bond between the metal, e.g. titanium and the bone tissue may be comparatively strong, it is often desirable to enhance this bond.

To date there are several methods for treating metallic implants in order to obtain a better attachment of the implant, and thus improved osseointegration. Some of these involve altering the morphology of the implant, for example by creating relatively large irregularities on the implant surface in order to increase the surface roughness in comparison to an untreated surface. An increased surface roughness gives a larger contact and attachment area between the implant and the bone tissue, whereby a better mechanical retention and strength may be obtained. A surface roughness may be provided by, for example, plasma spraying, blasting or etching. Rough etching of implant surfaces may be performed with reducing acids, such as hydrofluoric acid (HF) or mixtures of hydrochloric acid (HCI) and sulfuric acid (H2SO4). The aim of such a rough etching process is to obtain implant surfaces with rather large irregularities, such as pore diameters within the range of 2-10 [mu]m and pore depths within the range of 1-5 [mu]m.

Other methods involve altering of the chemical properties of the implant surface. This may e.g. be done by using low concentrated fluoride solutions, e.g. HF or NaF, to modify the surface chemistry as well as in same occasions the surface nano structure. For example one such method involves the application of a layer of ceramic material such as hydroxyapatite to the implant surface, inter alia, in order to stimulate the regeneration of the bone tissue. Ceramic coatings however may be brittle and may flake or break off from the implant surface, which may in turn lead to the ultimate failure of the implant.

Besides the above disclosed methods of implant surface modification, it shall be noted that in contact with oxygen, titanium, zirconium, hafnium, tantalum, niobium and their alloys are instantaneously covered with a thin oxide layer. The oxide layers of titanium implants mainly consist of titanium(IV)dioxide (TiO2) with minor amounts of Ti2O3 and TiO. The titanium oxide generally has a thickness of about 4-8 nm.

WO 95/17217 and WO 94/13334 describe different processes for treating a metallic implant with an aqueous solution comprising fluoride. Both these prior applications describe metallic implants having improved biocompatibility, and methods for producing such metallic implants. Specifically, the rate of bone tissue attachment is increased and a stronger bonding between the implant and the bone tissue is obtained. The improved biocompatibility of these implants is believed to be due to retaining of fluorine and/or fluoride on the implant surfaces.

Fluorine and/or fluoride is, according to J E Ellingsen, "Pre-treatment of titanium implants with fluoride improves their retention in bone", Journal of Material Science: Materials in Medicine, 6 (1995), pp 749-753, assumed to react with the surface titanium oxide layer and replace titanium bound oxygen to form a titanium fluoride compound. In vivo, the oxygen of phosphate in tissue fluid may replace the fluoride in the oxide layer and the phosphate will then become covalently bound to the titanium surface. This may induce a bone formation where phosphate in the bone is bound to the titanium implant. Moreover, the released fluoride may catalyse this reaction and induce formation of fluoridated hydroxyapatite and fluorapatite in the surrounding bone.

WO 04/008983 and WO 04/008984 disclose further methods for improving the biocompatibility of an implant. WO 04/008983 discloses a method for treating implants comprising providing fluorine and/or fluoride on the implant surface and providing a micro- roughness on the surface having a root-mean-square roughness (Rq and/or Sq) of <= 250nm and/or providing pores having a pore diameter of < 1 [mu]m and a pore depth of < 500 nm. WO 04/008984 discloses a method for treating a metallic implant surface to provide a micro-roughness with pores having a pore diameter of <= 1 [mu]m and a pore depth of <= 500 nm and a peak width, at half the pore depth of from 15 to 150% of the pore diameter.

Bone in-growth is known to preferentially occur in highly porous, open cell structures in which the cell size is roughly the same as that of trabecular bone (approximately 0.25-0.5 mm), with struts roughly 100 [mu]m (0.1 mm) in diameter. Materials with high porosity and possessing a controlled microstructure are thus of interest to both orthopaedic and dental . implant manufacturers. For the orthopedic market, bone in-growth and on-growth options currently include the following: (a) DePuy Inc. sinters metal beads to implant surfaces, leading to a microstructure that is controlled and of a suitable pore size for bone in-growth, but with a lower than optimum porosity for bone in-growth; (b) Zimmer Inc. uses fiber metal pads produced by diffusion bonding loose fibers, wherein the pads are then diffusion bonded to implants or insert injection molded in composite structures, which also have lower than optimum density for bone in-growth; (c) Biomet Inc. uses a plasma sprayed surface that results in a roughened surface that produces on-growth, but does not produce bone in-growth; and (d) Implex Corporation produces using a chemical vapor deposition process to produce a tantalum-coated carbon microstructure that has also been called a metal foam. Research has suggested that this "trabecular metal" leads to high quality bone in-growth. Trabecular metal has the advantages of high porosity, an open-cell structure and a cell size that is conducive to bone in-growth. However, trabecular metal has a chemistry and coating thickness that are difficult to control. Trabecular metal is very expensive, due to material and process costs and long processing times, primarily associated with chemical vapor deposition (CVD). Furthermore, CVD requires the use of very toxic chemicals, which is disfavored in manufacturing and for biomedical applications. Scaffolds available today are often resorbable, which means that they are degraded after implantation into a subject. Although this may be preferable in some cases, in other cases it may be a disadvantage as it also results in the loss of a stabilizing function of the implant itself. Also prior art scaffolds often trigger inflammatory responses and causes infections. For example, bone implant scaffolds of animal origin, may cause allergic reactions when implanted into another animal. Metal implants with a passivating oxide layer have a good biocompatibility which means that the above mentioned disadvantages may be overcome by the use of implants made of such materials. However, it has previously not been possible to produce metal oxide scaffolds comprising titanium oxide that have a mechanical stability high enough to be practically useful.

One of the most promising biocompatible materials in this sense has been proven in previous studies to be a bioactive ceramic, TiO2 [25 -28]. This material has shown particular biocompatible properties, where scaffolds were implanted in rats for 55 weeks without any signs of inflammatory responses or encapsuling [28]. Little work has been made in the three-dimensional open pore manufacturing of titanium dioxide [29, 30]. The objective of this work was to produce ceramic foams with their defined macro-, micro- and nano-structures and to show the possible application of ceramic foams as scaffolds for cell cultures.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a metal oxide scaffold to be used as a medical implant for implantation into a subject that overcome the above mentioned disadvantages, i.e. that have a good biocompatibility and does not cause any adverse reactions when implanted into a subject, which allow for cell growth into the 3- dimensional scaffold and which still has a mechanical stability which allows it to be practically useful as a stabilizing structure. Additionally it is an object of the present invention that the scaffold should have surface properties that result in improved condition for the bone producing cells resulting in faster bone growth on the scaffold surface and subsequently an interconnecting network of bone trabecuale.

The above defined objects are achieved by providing a metal oxide scaffold made of metal oxide comprising titanium oxide wherein the scaffold has a compression strength of about 0.1-150 MPa. More preferably, a metal oxide scaffold of the invention has a compression strength of 5-15 MPa. In a second aspect, the present invention provides a medical implant comprising such a metal oxide scaffold.

In another aspect the invention relates to a method for producing a metal oxide scaffold comprising the steps of a) preparing a slurry of metal oxide comprising titanium oxide, said slurry optionally comprising fluoride ions and/or fluorine b) providing the slurry of step a) to a porous polymer structure c) allowing the slurry of step b) to solidify d) removing the porous polymer structure from the solidified metal oxide slurry...

The present inventors have however surprisingly found that by utilizing a titanium oxide powder that is free of contaminations of secondary and/or tertiary phosphates (i.e. containing less than 10 ppm of such contaminations as described later) on the surface of the titanium oxide particles, metal oxide scaffolds comprising titanium oxide can be prepared. Titanium oxide that is free of secondary and/or tertiary phosphates on the surface of the titanium oxide particles may be obtained either by using a titanium oxide powder that already is free from such contaminations (e.g. the titanium oxide from

Sachtleben). Alternatively a titanium oxide powder comprising phosphate contaminations may be washed, such as with NaOH (e.g. 1 M) in order to remove the phosphate contaminations.

Titanium oxide scaffolds made of titanium oxide without phosphate contaminations have previously not been produced. Consequently, previously titanium oxide scaffolds having a mechanical strength which make them practically useful have not been able to produce. In the present context, the titanium oxide comprises less than 10 ppm of contaminations of secondary and/or tertiary phosphate. Such titanium oxide is in the present context considered to be free of contaminations of secondary and/or tertiary phosphate...



CONSENSUS PEPTIDE
US8367602 // HK1137186 // WO2008078167
[ PDF ]

The present invention relates to artificial peptides optimized for the induction and/or stimulation of mineralization and/or biomineralization. The invention also relates to the use of these artificial peptides for the induction and/or stimulation of mineralization and/or biomineralization in vivo and in vitro.

BACKGROUND ART

[0002] The hard tissues of organisms, e.g. teeth, bone, mollusk shells etc. are composed of minerals often in association with an organic polymeric phase.

[0003] Biomineralization is the process by which mineral deposits within or outside cells of different organisms form the above described structures. Examples of minerals deposited include iron, gold, silicates, calcium carbonate and calcium phosphate. The cells themselves direct the process of biomineralization e.g. by the expression of proteins that act as nucleators and the production of enzymes that modify the functions of such proteins. Most proteins associated with biomineralization are anionic which allows them to interact with the charged mineral crystal surfaces.

[0004] Biomimetics is defined as microstructural processing techniques that mimics or are inspired by the natural way of producing minerals, such as apatites. The means by which organisms use organic substances to grow mineral is of interest in biomimetics. For example the mineral deposition properties of biopolymers and synthetic analogoues thereof have been utilized in industrial processes, e.g. in water treatment and in electronic devices. Many man-made crystals require elevated temperatures and strong chemical solutions whereas the organisms have long been able to lay down elaborate mineral structures at ambient temperatures. Often the mineral phases are not pure but are made as composites which entail an organic part, often protein, which takes part in and controls the biomineralization. These composites are often not only as hard as the pure mineral but also tougher, as at last, the micro-environment controls biomineralization. There is therefore a great interest in the utilization of biopolymers for industrial applications to induce mineral precipitation.

[0005] Also it is of great interest to utilize biopolymers in biological systems for various purposes. One such example is in medical prosthetic device technology. Bone medical prosthetic devices made of metal or metal alloys are commonly used. Some of the metals and alloys used for bone medical prosthetic devices, such as titanium, zirconium, hafnium, tantalum, niobium or alloys thereof, may form a strong bond with bone tissue. This bonding between the metal and bone tissue has been termed "osseointegration" (Brånemark et al. "Osseointegrated medical prosthetic devices in the treatment of the edentulous jaw, Experience from a 10-year period", Almqvist & Wiksell International, Stockholm, Sweden). When implanted into a subject, bone tissue grows onto the medical prosthetic device surfaces so that the medical prosthetic device is attached to bone tissue. However, this is a slow process under which the medical prosthetic device often may not be loaded. Therefore, it would be valuable to improve the rate at which medical prosthetic devices attach to bone.

[0006] It is also of great interest to develop methods for the regeneration of mineralized tissue, such as bone, e.g. after trauma, surgical removal of bone or teeth or in connection with cancer therapy.

[0007] A number of natural peptides have been shown to induce mineral precipitation. Examples include collagen 1 and 2, amelogenins, ameloblastin, bone sialoprotein, enamelin, and ansocalcin. However, it is not always practical to use natural proteins for the purpose of inducing mineral precipitation and/or biomineralization. For example, natural proteins are often long, which means they are difficult to synthesize, both chemically and by bioproduction. A natural protein only contains natural amino acids, and may therefore be susceptible to rapid degradation. Also, if purified from a natural environment, such as developing teeth, there is always a risk of contamination of other products which e.g. may cause allergic reactions. In addition, a long natural protein normally has many roles in a living body and may therefore not be optimized for the induction and stimulation of mineralization.

[0008] It is therefore of great interest to develop peptides and methods which allow for an improved mineralization in vitro and in vivo.

SUMMARY OF INVENTION

[0009] It is therefore an object of the present invention to provide an artificial peptide with improved properties for induction and/or stimulation of mineralization, in vivo and in vitro.

[0010] It is a further object to provide such a peptide which is easier to synthesize than natural proteins and to provide methods of using the peptides of the invention for the induction and/or stimulation of mineral precipitation and/or biomineralization.

[0011] The above defined objects are in a first aspect of the invention achieved by providing an artificial peptide according to any of SEQ ID NO 1-8.

[0012] In another aspect, the above identified objects are achieved by providing a pharmaceutical composition comprising one or more of the peptides of SEQ ID NO 1-8.

[0013] In another aspect, the invention relates to the use of the peptides of the invention for the induction and/or stimulation of mineralization and/or biomineralization.

[0014] Yet other aspects of the invention relates to a surface having a peptide of the invention provided thereon, and methods for providing such surfaces.

[0015] The invention also relates to the in vivo induction and/or stimulation of biomineralization, as well as to the regeneration of bone.

[0016] Since the amino acid sequences of the artificial peptides of SEQ ID NO 1-8 have been selected based on their mineralization inducing and/or stimulating activities, they have an improved activity in inducing and/or stimulating mineralization as compared to peptides available in the art. Further, due to their shorter length compared to natural mineralization inducing proteins, the artificial peptides of the invention are easier to synthesize.



PUFA COVERED IMPLANTS
US2011166670 // WO2009144313 // EP2310059
[ PDF ]

A medical or dental implant which contains a metal material selected from the group consisting of titanium or an alloy thereof, wherein at least part of the surface of the metal material is coated with a layer of a polyunsaturated fatty acids (PUFA). In a preferred embodiment, the implant has been exposed to UV radiation for at least 30 seconds before, simultaneously with and/or after the coating with PUFA. Depending on the concentration of polyunsaturated fatty acids on the surface, at least parts of the implant exhibits improved effect on adhesion of mineralized and/or hard tissue, such as on bone remodeling and/or improved biocompatibility, or alternatively inhibits adhesion of mineralized and/or hard tissue to the implant. The metal material is preferably titanium, the polyunsaturated fatty acid is preferably EPA.

FIELD OF THE INVENTION

[0001] The present invention relates to a metal implant to be used as medical and/or dental implant, which actively facilitates controlled adhesion of hard and/or mineralized tissue to the implant, e.g. which actively induces adhesion of hard and/or mineralized tissue to the implant and/or exhibits improved effect on bone remodeling and/or biocompatibility of the implant due to at least part of its surface being coated with a low concentration layer of polyunsaturated fatty acids (PUFA). The present invention at the same time relates to a metal implant to be used as medical and/or dental implant, which actively inhibits hard and/or mineralized tissue adhesion to the implant, such as bone attachment, due to at least part of its surface being coated with a layer of polyunsaturated fatty acids (PUFA) in a high concentration. The invention further relates to a method for manufacturing said metal implant with either inducing or inhibiting effect on hard and/or mineralized tissue adhesion and/or bone remodeling, wherein the implant is coated with PUFA at a specific concentration, or alternatively is coated with PUFA at a specific concentration and irradiated with UV light.

BACKGROUND OF THE INVENTION

[0002] Medical implants, such as dental implants, orthopaedic implants, prosthesis and vascular stents are commonly made of titanium and/or a titanium alloy. Titanium is the material most frequently used as implant in bone, as it has outstanding physical and biological properties, such as low density, mechanical strength, and chemical resistance against body fluids.

[0003] Dental implants are utilized in dental restoration procedures in patients having lost one or more of their teeth. A dental implant comprises a dental fixture, which is utilized as an artificial tooth root replacement. Thus, the dental fixture serves as a root for a new tooth. Typically, the dental fixture is a titanium screw which has a roughened surface in order to expand the area of tissue contact. The titanium screw is surgically implanted into the jawbone, where after the bone tissue grows around the screw. This process is called osseointegration, because osteoblasts grow on and into the rough surface of the implanted screw. By means of osseointegration, a rigid installation of the screw is obtained.

[0004] Once the titanium screw is firmly anchored in the jawbone, it may be prolonged by attachment of an abutment to the screw. The abutment may, just as the screw, be made of titanium or a titanium alloy. The shape and size of the utilized abutment are adjusted such that it precisely reaches up through the gingiva after attachment to the screw. A dental restoration such as a crown, bridge or denture may then be attached to the abutment. Alternatively, the titanium screw has such a shape and size that it reaches up through the gingiva after implantation, whereby no abutment is needed and a dental restoration such as a crown, bridge or denture may be attached directly to the screw.

[0005] Orthopedic implants are utilized for the preservation and restoration of the function in the musculoskeletal system, particularly joints and bones, including alleviation of pain in these structures. Vascular stents are tubular implants arranged for insertion into blood vessels in order to prevent or counteract a localized flow constriction, i.e. they counteract significant decreases in blood vessel diameter.

[0006] As already mentioned above, titanium (Ti) is the implant material of choice for use in dental and orthopaedic applications and in vascular stents. The stable oxides that form readily on Ti surfaces have been reported to attribute to its excellent biocompatibility. However, it has also been reported that bone response to implant surfaces was dependent on the chemical and physical properties of Ti surfaces, thereby affecting implant success. As such, attention has been focused on the surface preparation of Ti implants.

[0007] The surface of Ti is only bioinert, thus current research on modification of implant surfaces focuses on making virtual bioinert materials become bioactive, or rather to influence the types of proteins absorbed at the surface readily after implantation. The assortment of surface modifications ranges from non-biological coatings, such as carbide, fluorine, calcium, hydroxyl apatite or calcium phosphate, to coatings that are to mimic the biological surroundings using lipid mono- or bi-layers, growth factors, proteins, and/or peptides.

[0008] E.g. several techniques, such as plasma spraying, laser deposition, ion beam dynamic mixing, ion beam deposition, magnetic sputtering, hot isostatic pressing, electrophoretic deposition, sol-gel, ion implantation, NaOH treatment, and electrochemical methods have been employed to deposit hydroxyapatite (HA) or calcium phosphate coatings on Ti surfaces.

[0009] It has been reported that implants coated with hydroxyapatite (HA) enhances osteoinduction. The superior performance of these implants being attributed to more rapid osseointegration and the development of increased interfacial strength, which results from early skeletal attachment and increased bone contact with the implant's surface.

[0010] Especially plasma spraying has been employed frequently, however with numerous problems, including variation in bond strength between the coating and the metallic substaret, non-uniformity in the layer thickness, and poor adhesion between the coating and the metal surface (Satsangi et al., 2004).

[0011] It has also been proposed to improve the biocompatibility of prostheses or implants by binding or integrating various active biomolecules to the surface of the prosthesis, e.g. on to the metallic surface of a titanium prosthesis. It has been the aim with implants prepared this way that they have improved fit; exhibit increased tissue stickiness and increased tissue compatibility; have a biologically active surface for increased cell growth, differentiation and maturation; exhibit reduced immunoreactivity; exhibit antimicrobial activity; exhibit increased biomineralisation capabilities; result in improved wound and/or bone healing; lead to improved bone density; have reduced "time to load" and cause less inflammation. Such binding has often been proposed carried out using for example chemical reactants having two reactive functionalities such as formalin or glutaraldehyde, but the reactive nature of these agents often leads to the biomolecules becoming biologically inactive and/or with enhanced immunoreactivity, which is of course undesirable.

[0012] An alternative surface modification is using phospholipids coating which is reported to induce the deposition of calcium phosphate. The role of phospholipids has also been suggested in the initiation of calcium phosphate deposition in cartilage, bone, healing fracture callus and calcifying bacteria. It has been proposed that an implant surface coated with a calcium-phospholipid-phosphate should be able to attract hydroxyapaptite.

[0013] Surface coatings of lipid mono- or bilayers are presumed to mimic cell surfaces and therewith to prevent foreign body reactions. Lipid coatings have been shown to influence the attachment of proteins to a surface that occurs immediately after the implantation and were found to prevent cell adhesion and blood clot formation (Kim et al., 2005). Certain phospholipids were furthermore reported to decrease bacterial adhesion.

[0014] Lipid coatings are usually based on physical adhesion, where ordered layers are obtained e.g. by using Langmuir-Blodgett technique. Lipids of the cell membrane are not only forming passive surroundings for the proteins incorporated into the membranes but rather influence the cell metabolism actively. Chemical methods for coating of metal substrates with a layer of biological molecules usually involve a foregoing step for obtaining reactive groups on surfaces (Khan W et al., 2007; Muller R et al., 2006) in order to bind the biologically active molecules without altering their structure and therewith possibly their function in the body.

[0015] Still, the coatings mentioned above all struggle from several draw-backs, due to unresolved technical difficulties.

SUMMARY OF THE INVENTION

[0016] The present invention for the first time describes a metal implant to be used as medical and/or dental implant, which actively facilitates control of hard and/or mineralized tissue adhesion to the implant, such as bone, cartilage or dentin addition to the implant surface.

[0017] A typical implant of the present invention either actively facilitates improved hard and/or mineralized tissue adhesion to the implant, improved bone addition to the implant surface, improved bone remodeling and/or biocompatibility of the implant, or it actively inhibits and/or reduces hard and/or mineralized tissue adhesion to the implant, such as inhibits and/or reduces bone attachment to the implant. The effect of the implant on mineralized and/or hard tissue adhesion being directly attributable to at least part of its surface being coated with a low, or with a high concentration layer of polyunsaturated fatty acids (PUFA).

[0018] The present invention at the same time relates to a metal implant with improved biocompatibility which can facilitate a solid incorporation into the bone, and to an implant which is easy to remove again, wherein the high concentration of available double bounds from the polyunsaturated fatty acids hinder tissue adherence to a semi-permanent and/or temporary implant, a so called "slippery" implant.

[0019] The invention further relates to a method for manufacturing said metal implant with either inducing or inhibiting effect on hard and/or mineralized tissue adhesion and/or bone remodeling, wherein the implant is coated with PUFA at a specific concentration, or alternatively is coated with PUFA at a specific concentration and irradiated with UV light, either before, simultaneously with, or after the coating step.

[0020] The invention consequently relates to a novel and simple surface modification method to chemically bind PUFA molecules to a surface comprising Ti or a titaniumoxide by utilizing UV irradiation. A method is thus presented for manufacturing a metal implant which facilitates improved hard and/or mineralized tissue adhesion, improved bone addition, improved effect on bone remodeling and/or biocompatibility, wherein the implant is coated with PUFA at a specific concentration and irradiated with UV light, before and/or after the coating.



MATRIX PROTEIN COMPOSITIONS FOR DENTIN REGENERATION
US7304030 // ES2334977 // WO0197834 // JP5095063
[ PDF ]

The present invention relates to the surprising finding that enamel matrix, enamel matrix derivatives and/or enamel matrix proteins induce dentin regeneration. The invention thus relates to the use of a preparation of an active enamel substance for the preparation of a pharmaceutical composition for the formation or regeneration of dentin following dental procedures involving exposure of vital dental pulp tissue. In another aspect, the invention relates to a method of promoting the formation or regeneration of dentin following dental procedures involving exposure of vital dental pulp tissue, the method comprising applying an effective amount of an active enamel substance on exposed vital dental pulp tissue after dental procedures.




Matrix protein compositions for guided connective tissue growth
US7033611 // HK1058488 // WO02080994 // EP1361905 // DE60222633

The present invention relates to the use of enamel matrix, enamel matrix derivatives and/or enamel matrix proteins as therapeutic and/or cosmetic agents. Said substances are used for the manufacture of a pharmaceutical and/or cosmetic composition for actively inducing guiding and/or stimulating connective tissue growth and thus to prevent connective tissue scaring and/or contraction in a wound cavity and/or tissue defect that is characterised by a substantial loss of tissue. Comprised in the invention is in particular the use of active enamel substances for guided connective soft tissue growth and resistance to contraction in deep cavity shaped wounds following loss or removal of significant volumes of tissue, such as e.g. after surgical removal of a tumour and especially in combination with radiation therapy.

ENAMEL MATRIX PROTEIN COMPOSITIONS FOR MODULATING IMMUNE RESPONSE
PL369029 // WO03024479 // US7897180 // US7608284

The present invention relates to the use of a preparation of an active enamel matrix substance, such as an amelogenin, for the manufacture of a pharmaceutical composition for modulating an immune response. The composition can be used in preventing and/or treating a condition or disease in a mammal that is characterised by said mammal presenting an imbalance in its native immune response to an internal and/or external stimuli, i.e. wherein at least a part of said mammal's immune system is stimulated non-discriminatingly, reacts hypersensitivity to said immunogen, or fails to react to said stimuli. Said condition can typically either be systematic or local, such as a systemic and/or post-traumatic whole-body inflammation or an autoimmune disease.

Matrix protein compositions for grafting
AU2821200  // WO0053197 // JP4726300 // ES2215028 // EP1165102

Enamel matrix, enamel matrix derivatives and/or enamel matrix proteins are used in the preparation of a pharmaceutical composition for promoting the take of a graft, e.g. in soft tissue such as skin or mucosa or mineralized tissue such as bone.

MATRIX PROTEIN COMPOSITIONS FOR INDUCTION OF APOPTOSIS
US7960347 // ES2215027 // WO0053196 // JP2002538211 // EP1162985

Enamel matrix, enamel matrix derivatives and/or enamel matrix proteins or peptides may be used as therapeutic or prophylactic agents for inducing programmed cell death (apoptosis), in particular in the treatment or prevention of cancer or malignant or benign neoplasms.

MATRIX PROTEIN COMPOSITIONS FOR INHIBITION OF EPITHELIAL CELL GROWTH
WO0197835

The present invention relates to the use of an active enamel substance for the preparation of a pharmaceutical composition for application on a medical implant or device and/or on tissue in contact with said implant or device so as to inhibit attachement, proliferation and/or growth of epithelial cells thereon, or to inhibit epithelial downgrowth along the surface of said implant or device. The preparation is utilised to bio-engineer surfaces of medical implants and devices which are in contact with epithelial tissue in such a way that growth of epithelial cells on or along the surfaces of such implants or devices is substantially inhibited. Accordingly, the present invention relates to a method of inhibiting attachment, proliferation and/or growth of epithelial cells on a medical implant or device. The invention also relates to medical implants or devices on which enamel matrix, enamel matrix derivatives and/or enamel matrix proteins have been applied.

FUNCTIONALIZATION OF MICROSCOPY PROBE TIPS
WO2009001220

The invention comprises a method of functionalizing scanning probe microscope (SPM) tips to image and/or measure interactions between surfaces, including the surfaces of inorganic, organic-inorganic hybrid, organic, magnetic/conductive, hard coatings and biological materials. The invention further comprises the use of atomic layer deposition (ALD) to functionalize SPM tips.

SELECTIVE CHEMOKINE MODULATION
NO20091420 // WO2008033069 // US2010203089

The present invention teaches the use of a metal or an oxide of a metal having a capability of reducing the amount of the chemokine IP-IO in a sample and/or reducing the production of IP-IO in cells. The metal is a metal of group 4 or 5 in the period table of the elements and preferably titanium. These metals and metal oxides can selectively bind IP-IO to its surface to thereby scavenge IP-IO from the surrounding medium. In addition, a metal-cell contact induces a reduction in the production of IP-IO from IP-IO producing cells. The metals and metal oxides of the present invention can therefore be used for treating and/ or preventing medical conditions characterized by adverse IP-IO expression, such as inflammatory reactions.




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