Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Bone
Reexamination Certificate
2000-07-26
2002-02-05
Beck, Shrive P. (Department: 1762)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Bone
C623S016110, C623S023570, C623S023500, C623S023560, C427S002270, C424S423000, C424S426000, C604S891100, C433S212100
Reexamination Certificate
active
06344061
ABSTRACT:
The present invention relates to an implantable device with a specific surface roughness that facilitates in vitro formation of a solution mediated coating, including calcium phosphate coatings, in which biologically active substances can be coprecipitated. The present invention further relates to a process of producing such a device and to the biomedical use of such a device.
U.S. Pat. No. 5,456,723 discloses an implant having a porous metallic surface which has been treated by sandblasting and reductive acid etching resulting in a surface micro-roughness having a maximum peak-to-valley height of about 20 to 30 &mgr;m and a roughness spacing of about 1-5 &mgr;m. The extremely sharp, comb-like structure is necessary in order to achieve sufficient adhesion between the implant and the coating material (hydroxyapatite) formed on it by anchoring the hydroxyapatite in the implant.
A drawback of most hydroxyapatite-coated implants is that the anchoring of hydroxyapatite onto the implant requires high processing temperatures, which limit the choice of substrate materials and result in higher processing costs. The previously preferred technique for coating implant materials with hydroxyapatite is plasma deposition (for a review, see P. Serekian, in
Hydroxylapatite Coatings in Orthopaedic Surgery
, Ed. Geesink and Manley, Raven Press NY, 1993, p. 81-87). Another disadvantage of the plasma deposition technique, in addition to the high temperatures involved, resides in the relatively large particle size, in the order of 30-70 &mgr;m.
The air of the present invention is to provide a coated implantable device that can be used in a wide variety of biomedical applications (surgery, bone-replacement, prosthodontics etc.). The device should give rise to effective bone formation and simultaneously result in a desired biological effect, such as assisting bone formation, preventing infection or rejection during or after implantation, induced by the presence of biologically active substances, such as proteins, growth-factors, lipids, (lipo)polysaccharides, cytostatic agents, hormones, antibiotics or other biological agents. In case a degradable coating is produced, degradation of said coating due to solution mediated processes or cell mediated processes should result in a further exposure or release of biologically active agents. The processing of the device and the temperature at which it is produced should not have an adverse effect on the biological activity of said agents.
The aim is achieved by a shaped article suitable as an implant of a solid, i.e. non-fluid, porous or non-porous material having a surface nano-roughness, giving rise to the formation of a composite coating when placed in certain solutions. Said solutions contain, but are not limited to calcium and phosphate ions, and biologically active agents (e.g. proteins, growth-factors, lipids, (lipo)polysaccharides, cytostatic agents, hormones, antibiotics) and may be saturated or supersaturated, but may also be relatively diluted. The coating can therefore be composed of both an organic phase, such as the biologically active agent and an inorganic (e.g. calcium phosphate) phase. The uniqueness about the present invention is that biologically active agents can be simultaneously co-precipitated during the formation of the solution mediated coating. As a result, a specified area in the coating or the whole thickness of said coating can be loaded with the biologically active agent(s), that expresses its use when exposed or released at the surface. Depending on the time at which the biologically active agent is added to the solution, said agent can be accurately co-precipitated anywhere throughout the thickness of the coating, as the coating formation is a time-dependent process and elimination of said agent from the solution results in the formation of an inorganic coating (i.e. a calcium phosphate coating). Utilizing such a co-precipitation technique where biologically active agents can either or not be co-precipitated at different time points and with different concentrations, can result in a wide variety of coatings, from relatively simple coatings in which a homogenous concentration of a co-precipitated biologically active agent is present, to a very complex coating containing, at different levels, different concentrations of different biologically active agents.
The surface roughness is an important factor of the device according to the invention. The surface roughness is defined herein by the average peak distance, i.e. the average spacing between protrusions on the surface (Ra value). This average peak distance can be determined e.g. by means of Scanning Electron Microscopy (SEM). In general, the average peak distance may be 1,000 nm or less, down to 10 nm. The most suitable roughness depends on the nature of the material of the article. For articles made of titanium, the average peak distance can be e.g. from 10 to 200 nm, for polymeric material, the preferred peak distance is from 20 to 500 nm, whereas for stainless steel the peak distance is advantageously between 50 and 1,000 nm. In general, the preferred average peak distance range is between 2 and 500 nm.
The depth of the surface roughness of the article is less critical than the peak distance. However, a minimum depth is desirable, in particular a peak height—with respect to the deepest sites on the surface—of at least 20 nm, up to about 2,000 nm. The preferred average depth is of the same order of magnitude as the average peak distance, and is in particular from 50 nm to 1,000 nm. The average depth can also be determined by means of Scanning Electron Microscopy.
The substrate of the implant article can be of various materials. These include metals, in particular biocompatible metals such as titanium, tantalum, niobium, zironcium and alloys thereof, as well as stainless steel. Another useful class of bio-compatible materials comprises organic natural and synthetic polymers such as polyethylene, polypropylene, polytetrafluoroethylene (Teflon®), which may also be bio-degradable polymers such as polyglycolic acid, polylactic acid or certain polysaccharides. Ceramic materials such as calcium phosphate, alumina or bioglass, as well as composite materials, can also be used as an implant substrate. The material may be porous or non-porour. Where it is porous, the pores are distinguished from the valleys of the surface roughness by the depth: i.e. the pores have depths substantially greater than 2 &mgr;m, and the surface roughness may be superimposed on the pore walls.
The substrate having the desired surface roughness can efficiently be coated in vitro with a layer of a calcium phosphate and one or more biologically acive agents. The composite coating can be relatively thin, in the order of from a e.g. 50 nm to 200 &mgr;m, especially from 1 to 50 &mgr;m. The calcium phosphate preferably forms small crystals, producing an amorphous-like structure. The calcium phosphate can be any combination of calcium and phosphate ions, optionally together with e.g. hydroxide, chloride, sulphate, nitrate etc. anions or hydrogen, sodium, potassium, magnesium etc. cations. For a faster process, the deposition steps can be preceded by a precalcification step using a solution of calcium and phosphate ions, or two solutions containing calcium ions and phosphate ions respectively and applied consecutively. The biologically active agent in the coating includes, but is not limited to, single or combinations or proteins, lipids, (lipo)polysaccharides, growth-factors, cytostatic agents, hormones, and antibiotics. Examples of such agents are bone morphogenetic proteins (BMP's), basic fibroblast growth factor (bFGF), transforming growth factor (TGF-&bgr;), osteogenic growth peptide (OGP), et cetera. The molecular weight of said biologically active agents can vary from several tens of Daltons, to thousands of kilo-Daltons.
The calcium coating can be applied from a solution containing calcium and phosphate ions and one or more dissolved biologically active agents. The solution may be saturated or even su
De Bruijn Joost Dick
De Groot Klaas
Leitao Eugenia Ribeiro de Sousa Fidalgo
Wen Hai-Bo
Beck Shrive P.
IsoTis N.V.
Kolb Jennifer
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