Implants Having a Bioactive Coating Comprising Partially Deacetylated Chitosan - Patent application

Abstract

Compositions useful for coating implants are provided, the compositions comprising microparticles containing partially deacetylated chitosan having a degree of deacetylation in the range of about 30% to about 75%, the microparticles generally having an average particle size of less than 50 μm. Also provided are surgical implants containing coated non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 30% to 75%, and methods of coating such implants.

Description

[Technical field]

[0001] The present invention is within the field of medical implants, such as implants used in orthopedic applications, and relates to chitosan-based coatings suitable for such implants, coated implants, and methods for preparing coating compositions. [Background technology]

[0002] Introduction By current industrial definition, chitosan refers to highly deacetylated chitin, usually with a degree of deacetylation greater than 70% (or 70% DD), and is soluble in weak acids. Chitin refers to less deacetylated chitic materials, generally less than 25% DD, and is insoluble in weak acids. The class between chitin and chitosan is called partially deacetylated chitin (PDC). Industrial use of PDC is currently rare due to its low solubility and technical difficulties in large-scale production.

[0003] Titanium implants are well known and are generally considered the gold standard in load-bearing orthopedic applications. The advantages of titanium and its alloys for biomedical implants and devices include (i) biocompatibility due to the spontaneous formation of an oxide layer, (ii) high corrosion resistance, (iii) high specific strength, and (iv) lack of toxicity. Osseointegration is a factor that has a significant impact on the life of the implant and its successful integration. The term refers to the direct structural and functional connection between the living bone and the surface of the load-bearing artificial implant. Osseointegration is observed in conventional titanium implants, but can be compromised by local conditions and the interaction of the implant with the surrounding implantation site. To improve the properties of the implant, the implant-tissue interaction, various coating materials have been considered and tested. Therefore, bioactive materials that enhance bioactivity, osseointegration, and implant stabilization are desirable. One of the materials tested is chitosan. A prerequisite for the preparation of chitosan coatings is the cationic nature of chitosan, as is the premise of its solubility in dilute acidic aqueous solutions.

[0004] Li et al. (Biomaterials 36 (2015) 44-54) described chitosan-coated porous titanium alloy implants implanted in diabetic sheep, and found that the coating improved the overproduction of ROS (reactive oxygen species), which is thought to cause poor osseointegration of implants in diabetic implant patients. Chitosan with a degree of deacetylation (DDA) of 85-90% was used.

[0005] Husain et al. (Materials (2017) 10, 602) discuss chitosan-coated dental implants and note that previous studies have reported promising results of chitosan coating of dental implants, and disclose that chitosan coatings can affect the surface and bone interface by altering the biological, mechanical and morphological properties. However, the review suggests that further studies were needed to verify whether such coatings are beneficial in inhibiting infection and promoting osseointegration. Summary of the Invention [Means for solving the problem]

[0006] The present invention provides a new and improved composition for coating implants, which contains amorphous partially deacetylated chitosan (PDC) that is soluble in aqueous acidic solutions and has a high swelling capacity.

[0007] PDC can be prepared by dissolving, in particular, deacetylated chitin in acid and purifying it by successive filtration, and the resulting regenerated PDC is completely soluble in aqueous acidic solutions and has a high swelling capacity in aqueous solutions, thus allowing PDC to absorb 10, 15, or even 20 times its weight in water or more.

[0008] Compositions containing PDC can be used, for example, as a coating on surgical implants. Thus, surgical implants coated with the coating of the present invention are also provided. In addition, the coating may incorporate active ingredients or cells to improve new bone formation. For example, the coating may contain growth factors, growth-promoting or growth-enhancing drugs, or other substances beneficial to bone formation. The coating may also contain antibacterial and / or antiviral compounds, such as antibiotics.

[0009] In one aspect, a chitosan-based coating for a surgical implant is provided, the coating comprising a non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 30-75%. In exemplary embodiments, the degree of deacetylation can be in the range of about 35%-70%, in the range of about 35%-60%, in the range of about 40%-75%, in the range of about 40%-60%, or in the range of about 45%-55%. It can be beneficial to have a degree of deacetylation near or at 50%, such as about 46%-54%, 47%-53%, 48%-52%, or 49%-51%.

[0010] The present disclosure also relates to implants having at least a portion of their surface coated with a PDC-based coating, particularly a PDC-based coating as further disclosed herein.

[0011] The present disclosure also relates to methods for coating implants with PDC, including (i) completely dissolved PDC, i.e., coating of PDC in the form of a true solution, and (ii) heterogeneous or physically dispersed PDC, i.e., PDC that is not dissolved and provides a coating in colloidal form.

[0012] In this context, the term "true solution" refers to a homogeneous mixture (solution) of two or more components in which the particle size of the dissolved components (solutes) is less than 220 nm. As an example, a simple sugar solution in water is a true solution.

[0013] In the present context, the terms "dry thickness", sometimes called "dry film thickness", and "wet thickness", sometimes called "wet film thickness", refer to the thickness of a film or coating on a surface after drying and before drying, respectively. The two parameters are related by the volume fraction of solids in the film or coating, i.e.: (Dry thickness)=(Wet thickness)×%(solids by volume).

[0014] A "homogeneous coating" as described herein refers to a coating that covers substantially the entirety of the underlying surface, preferably 100% of the underlying surface. In contrast, a "heterogeneous coating" as described herein refers to a coating that covers less than 100% of the underlying surface, i.e., some of the underlying surface is not covered by the coating.

[0015] The PDC may be in the form of microparticles. The microparticles may be generally spherical in shape. The spheres may be generally circular or elliptical, such as spheroidal. The microparticles may also have a polyhedral shape, i.e., a three-dimensional shape with approximately flat polygonal surfaces. Alternatively, the microparticles may have an irregular shape. The microparticles may be homogeneous in shape (i.e., a population of particles is approximately identical in shape) and have a range of dimensions (sizes). Alternatively, the microparticles may be non-uniform in shape and / or size. For example, the microparticles may be partially spherical and partially irregular in shape.

[0016] Also provided is a composition comprising microparticles containing partially deacetylated chitosan having a degree of deacetylation in the range of about 30% to about 75%, the microparticles having an average particle size of less than 50 μm. The composition can have a degree of deacetylation in the range of about 35% to about 70%, in the range of about 35% to about 60%, in the range of about 40% to about 75%, in the range of about 40% to about 60%, or in the range of about 45% to about 55%.

[0017] The particle size may be less than 40 μm, less than 30 μm, or less than 20 μm, for example, in the range of about 5 to 50 μm, in the range of about 5 to 40 μm, in the range of about 5 to 30 μm, in the range of about 5 to 25 μm, in the range of about 5 to 20 μm, or in the range of about 5 to 15 μm.

[0018] The coating composition may be in the form of a colloidal suspension, preferably in an aqueous solution, such as water or a physiological fluid. Microparticles comprising PDC may be suspended or physically dispersed in the aqueous solution to provide a colloidal gel-like matrix comprising the microparticles suspended in the matrix.

[0019] Also provided is a surgical implant or a portion thereof, characterized in that its outer surface or a portion thereof is coated with a surface coating comprising non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 30-75%.

[0020] The term "part thereof" can be understood as one or more components of an implant that includes multiple (two or more) components. For example, a surgical implant may include two or more components, one or more of which include a surface coating according to the present invention. Thus, an implant can be assembled from two or more such components, some or all of which include a coating as disclosed herein.

[0021] The coating can have a wet thickness (i.e., containing water, either before or without subsequent drying to remove the water) in the range of 20 to 250 μm, in the range of 50 to 250 μm, in the range of 30 to 150 μm, or in the range of 40 to 100 μm.

[0022] The density of N-acetylglucosamine (NAG) on the surface of the implant or part thereof (i.e., in the coating) is between 0.01 and 15 mg / cm 2 , or 0.3 to 5 mg / cm 2 , preferably 0.3 to 1.5 mg / cm 2 The range may be:

[0023] The coating may be a heterogeneous coating, covering within about 10% to about 90%, preferably within about 25% to about 75%, of the outer surface or a portion of a unit area of ​​the implant. Alternatively, the coating may be a non-homogeneous coating, covering within about 10% to about 90%, preferably within about 25% to about 75% of the unit area (e.g., 1 to 5 mm 2 The coating may be non-homogeneous, with coverage in the range of 0.1 to 100%.

[0024] A coating can have a particular roughness or texture on its surface such that some parts of the coating have a greater thickness than other parts of the coating. Such coatings can be described as having peaks and valleys, where the peaks correspond to areas of relatively greater thickness and the valleys correspond to areas of relatively lesser thickness.

[0025] The chitosan-based coating can have a dry surface roughness, i.e., the roughness after drying the coating so that it is in a dry state, that is less than 500 μm, for example, in the range of about 2-500 μm, in the range of 5-250, in the range of about 20-100 μm, in the range of about 25-100 μm, in the range of about 5-100 μm, or in the range of 5-50 μm. Roughness can be defined as the difference between the maximum and minimum thickness of the coating on a surface.

[0026] Also provided is a method for coating a surface of a substrate, such as a surgical implant, with a non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation (DD) in the range of about 30-75%, the method comprising immersing the substrate surface in an aqueous solution containing such partially deacetylated PDC, removing the surface from the solution, and drying.

[0027] Additionally, homogeneous and heterogeneous coatings may be combined, for example, a substrate can be homogeneously coated with one layer of PDC and then coated with a layer of heterogeneous coating to provide a rougher surface for better cell attachment and proliferation.

[0028] The above features, along with additional details of the invention, are further described in the following examples, which are intended to further illustrate the invention but are not intended to limit its scope in any way.

[0029] Those skilled in the art will appreciate that the drawings described below are for illustrative purposes only and are not intended to limit the scope of the present teachings in any way. [Brief description of the drawings]

[0030] [Figure 1] Physical properties of partially deacetylated PDC: (Top) Powdered PDC, (Bottom) PDC at 1000x magnification obtained by scanning electron microscopy (SEM). [Figure 2a] FIG. 1 shows a coated titanium plate. [Figure 2b] FIG. 1 shows a coated plate, where half of the plate is gold coated. [Figure 2c] FIG. 1 shows the height difference (Solarius Profilometer) between the gold coated areas and the remaining areas, representing the thickness of the PDC coating. [Figure 3a] FIG. 3D diagram of the surface roughness of a typical titanium plate coated with 1% PDC (w / v). [Figure 3b] FIG. 2D view of a topographical image of a coated surface. [Figure 3c] FIG. 4 shows the actual recorded surface roughness along the line shown in FIG. [Figure 3d] FIG. 4 is a diagram showing the distribution of surface roughness along the line shown in FIG. [Figure 4a] FIG. 1 shows the effect of using only water to prepare a PDC solution on the swelling properties of PDC films. [Figure 4b] FIG. 1 shows the effect of using ethanol:water (1:1) in preparing the PDC solution on the swelling properties of the PDC film. [Diagram 5]FIG. 1 shows the relationship between the swelling index of PDC films before and after immersion in water for 4 weeks and the temperature used to dry the films. [Figure 6a] FIG. 1 shows a scanning electrode microscope (SEM) image at 2000x magnification of a titanium plate coated with PDC dissolved in acetic acid. [Figure 6b] FIG. 1 shows a scanning electrode microscope (SEM) image at 100,000x magnification of a titanium plate coated with PDC dissolved in acetic acid. [Figure 7a] FIG. 1 shows a PDC coating on a titanium substrate obtained by immersion in a fully dissolved PDC solution (true solution). [Figure 7b] FIG. 1 shows a PDC coating on a titanium substrate obtained by immersion in colloidal PDC. [Figure 8a] FIG. 1 shows a PDC coating on a bioglass substrate obtained by immersion in a fully dissolved PDC solution (true solution). [Figure 8b] PDC coating on a bioglass substrate obtained by immersion in PDC (top right) The surface coated by the colloidal method generates an organic structure, promoting better cell attachment. [Figure 9a] FIG. 1 shows a PDC coating on a hydroxyapatite substrate obtained by immersion in a fully dissolved PDC solution (true solution). [Figure 9b] FIG. 2 shows a PDC coating on a hydroxyapatite substrate obtained by immersion in PDC. [Figure 10] FIG. 13 illustrates material loss after prolonged immersion in water. [Figure 11a] FIG. 2 shows the surface distribution by SEM at 200x magnification upon treatment with PDC in PBS buffer. [Figure 11b] FIG. 2 shows the surface distribution by SEM at 2500x magnification upon treatment with PDC in PBS buffer. [Figure 12a]FIG. 1 shows an atomic force microscope (AFM) image of a PDC coating obtained by completely dissolving chitosan in acid and coating it on titanium in a homogenous manner. [Figure 12b] FIG. 1 shows an atomic force microscope (AFM) image of a PDC coating obtained by dispersing PDC in a PBS solution and coating it on titanium by a heterogeneous method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention describes highly stable bioactive surface coatings comprising non-crosslinked partially deacetylated chitosan, PDC. The coatings can be performed in either a homogeneous or heterogeneous manner, i.e., to cover substantially the entire surface or to only partially cover the substrate.

[0032] PDC can preferably be prepared by a regenerative process, where chitosan, prepared by partial deacetylation of chitin material, is first dissolved in acid, followed by purification by filtration and reprecipitation from the acidic solution.

[0033] Chitosan is prepared by deacetylation of chitin. Thus, chitin can be deacetylated in concentrated sodium hydroxide to deacetylate it to an appropriate extent, in the case of the present invention, generally providing a 30-75% deacetylated material. Deacetylation can be carried out at relatively low temperatures, such as within the range of about 20-60°C, e.g., 30-60°C, 40-60°C, 45-55°C or about 50°C, to minimize the formation of block distribution of N-acetylglucosamine (NAG) in the resulting chitosan material, thereby minimizing the crystalline character of the resulting material. More clustered NAG increases the inter-chain interactions, which hinders chain separation upon protonation of the polymer and thus the solubility of the material. Furthermore, clustered NAG increases the interaction forces between the chains upon drying of the material, resulting in a less amorphous material.

[0034] After deacetylation, the alkali is removed by washing and the chitosan material is recovered. The chitosan is then dissolved in acid to facilitate removal of any insoluble material in the resulting fluid, for example by one or more filtration steps (e.g., coarse filtration followed by ultrafiltration). The solution is then neutralized using a suitable base, such as NaOH and salt, and the chitosan is precipitated from the solution to obtain pure PDC. The PDC can optionally be dried, for example by spray drying, to obtain a dry, white, particulate PDC material. An example of this process is described in Example 1 herein.

[0035] The resulting PDC has certain defining properties that make it particularly useful for the present purpose.

[0036] Thus, the reprecipitated (regenerated) PDC is generally amorphous (i.e., not crystalline) in nature and consists of uniform or nearly uniform fine particles, which are usually less than 50 um in diameter and may generally be spherical in shape.

[0037] Classical chitosan, in contrast, is crystalline and usually very difficult to dissolve. Therefore, dissolution of solid chitosan to obtain a chitosan solution may take a long time or even be carried out overnight. In contrast, dissolution of PDC obtained by the present regeneration method is almost instantaneous. For example, when PDC is dispersed in a fluid, such as water, the addition of an appropriate acid converts the colloidal fluid into a clear / homogeneous crystalline solution within a few seconds. This PDC solution is more resistant to precipitation near and above physiological pH than classical chitosan.

[0038] PDC can have a nearly equal ratio of NAG and GluN, or a more balanced hydrophobic / hydrophilicity. As a result, PDC can easily form stable mixtures with either aqueous or most oil-based fluids. Furthermore, the amorphous and fine-particle nature of dry PDC allows it to absorb more than 20 times its weight in pure water.

[0039] The homogeneous coatings disclosed herein achieve up to 100% coverage and are firmly attached to the substrate surface, i.e., the coating covers up to 100% of the surface without any signs of incomplete coating, which is a way to control the thickness of the coated film. The coatings exhibit good stability and remain firmly attached after 4 weeks of immersion in water with no signs of film peeling or fouling.

[0040] However, in other useful embodiments, heterogeneous coatings are provided, and methods for producing such coatings in a controlled manner are provided. As used herein, the term "heterogeneous coating" refers to a coating that covers less than 99% of the underlying surface, such that the coated surface is interspersed with coated and also uncoated areas.

[0041] The conditions of the coating process can be advantageously adjusted to achieve different coverages of the coating and different spatial roughnesses to meet the requirements of the intended purpose. The non-uniformity can be determined by analyzing a unit area. Such a unit area can have a coating coverage in the range of about 10% to about 95%, such as in the range of about 25% to about 75%, more typically in the range of about 10% or about 15% or about 20% or about 25% or about 30% or about 35% to about 95% or about 90% or about 85% or about 80% or about 75%.

[0042] The unit area can have any suitable dimensions, defined as, for example, a rectangle, a square, a circle, an oval, or other regular or irregular shape, hi some embodiments, the unit is a rectangle, with each side measuring 10-20 mm, e.g., 10-15 mm, or about 10 mm.

[0043] The unit dimensions are tested for homogeneity and represent the properties of the entire coating. Thus, if it is desired to obtain a coating with less rough, finer inhomogeneity, a smaller unit area can be selected to determine whether the desired inhomogeneity is observed at a smaller scale, such as a rectangular unit area of ​​less than 10×10 mm, e.g., 5×5 mm, 2×2 mm, or 1×1 mm, and the desired coating coverage is within an area within any of the above coverage ranges.

[0044] The thickness of the coating after immersion in aqueous or PBS solution is adjustable. Coatings from homogeneous methods generally swell to a thickness of 2-10 times, or 5-15 times, or more typically 6-12 times, their dry thickness. For heterogeneous methods, the thickness of the coating may range from 5-20 times, or 10-25 times, or typically 10-20 times, its dry thickness.

[0045] The initial thickness of the coating can be influenced by the drying temperature and the type of aqueous solvent or fluid used to prepare the PDC solution. The coating may be dried by treatment at temperatures ranging from -40°C to 100°C or 0 to 80°C or more typically 15 to 75°C. However, if any suitable solvent, for example an alcohol such as ethanol or any other suitable primary alcohol or mixtures thereof, is introduced into the aqueous solution used to dissolve the PDC, the effect of the drying temperature on the initial thickness of the swollen film is more limited.

[0046] The fluid for preparing the PDC solution is preferably a water-miscible solvent that is mixed with the aqueous solution at a solvent:water ratio in the ranges of 1:10 to 2:1, 1:5 to 2:1, 1:4 to 2:1, 1:3 to 2:1, or 1:2 to 2:1. The fluid used to prepare the PDC solution, including, for example, water alone or a water / alcohol mixture, can affect the swelling characteristics and drying rate of the film, as well as protective measures against microbial contamination during the drying step.

[0047] It is also possible to provide two or more coating layers on the surgical implant. The coatings may be essentially similar or identical (i.e. homogeneous or heterogeneous), or the coatings may be different. For example, there may be two (or more) coating steps forming two (or more) coating layers, with a first coating step providing a homogeneous coating on the surface, followed by a second or more coating steps that are essentially heterogeneous. In this way, the surface of the implant may be essentially completely coated with a first homogeneous layer providing a smooth and complete coating of the surface, and a second or more subsequent coatings providing a heterogeneous coating, which may be provided by a colloidal coating suspension. In this way, it is ensured that the entire surface of the implant is covered by at least one coating layer, while there may be roughness or irregularities throughout the coating.

[0048] The PDC in the coating has a DD in the range of about 30% to about 75%, preferably in the range of about 35% to about 60%, for example about 50%. The coating, in some embodiments, has a dry thickness in the range of about 2 to about 25 μm, or more typically in the range of about 2 μm or about 4 μm or about 5 μm or about 10 μm to about 25 μm or about 20 μm or about 15 μm. The pre-dry thickness can be in the range of 10 to 50 μm or 10 to 250 μm, with the greater the pre-dry thickness being the greater the dry thickness. Upon implantation, the PDC swells to a pre-designed thickness to accommodate the interface between the implant and the body surface.

[0049] The coating density of a coating or film is the amount of N-acetyl-D-glucosamine (NAG) per unit area, i.e., mg NAG / cm 2 Typical NAG coating densities are between 0.01 and 15 mg / cm. 2 , or 0.3 to 5 mg / cm 2 , or more preferably 0.3 to 1.5 mg / cm 2It may extend to.

[0050] The surface coating compositions disclosed herein can be used to coat any suitable surgical implant, such as implants that include or consist of metals or alloys, such as stainless steel, titanium, titanium alloys, cobalt chromium alloys, bioglass, hydroxyapatite / calcium phosphate, or mixtures thereof. The implants can be pretreated before coating, i.e., some form of pretreatment may be beneficial for certain applications. However, those skilled in the art will understand that surface pretreatment is not essential to practice the present invention. Thus, in some embodiments, the surface of the implant to be coated is pretreated before coating, such as by oxidation with an acid treatment or washing with an alkaline solution.

[0051] A surgical implant is generally any medical device manufactured to replace missing biological structures, support damaged biological structures, or augment the function or structure of existing biological structures. The implant may be a neural or sensing implant, a cardiovascular implant, an orthopedic implant to alleviate bone and / or joint problems in the body, an electrical implant, a contraceptive implant, or a cosmetic implant. The implant may be permanent or temporary. In a particular embodiment, the implant is a dental implant.

[0052] The PDC coatings disclosed herein, and compositions for use in producing such coatings, are compatible for use with any such implant or portion thereof. The implant may include titanium or titanium alloys, cobalt chromium alloys, stainless steel, tantalum, hydroxyapatite / calcium phosphate, or bioglass surfaces. The implant may also consist of or be comprised of a mixture of two or more of the foregoing materials, or in combination with other materials commonly used in prosthetics or other implants.

[0053] The lower end of the DD range can be about 30% or about 33% or about 35% or about 40%. The upper end of the DD range can be about 65% or about 60% or about 58% or about 55% or about 50% or about 45%. Thus, the DD range can be about 30% to 70%, about 35% to about 65%, about 40% to about 60%, about 45% to about 60%, about 45% to about 55%.

[0054] Within this DD range, the PDC can be effectively substantially dissolved to provide a homogenous concentration of PDC and a homogenous coating on the treated surface.

[0055] The immersion (coating) solution in certain embodiments preferably has a pH greater than about 6, more preferably greater than about 7, such as about 7.0 or in the range of about 7.2 to about 7.5, such as about 7.4. The coating solution may also be a non-acidified solution having a pH greater than 6, preferably in the range of 7 to 8, more preferably in the range of 7.3 to 7.5, and most preferably about 7.4.

[0056] In other embodiments, the soaking solution is acidic, e.g., having a pH in the range of about 2 to about 4.5. Such an acidic soaking solution can be acidified, e.g., with acetic acid at a concentration in the range of about 0.5% to about 2% or 0.1 to 10%, e.g., about 1%.

[0057] PDC is advantageously provided in the soaking solution at a concentration within the range of about 0.5% to about 1.0%, for example, but not limited to, about 0.5% or about 0.75% or about 1-20%.

[0058] The immersion time may range from several minutes to several days. Thus, the immersion time may generally range from 1 minute to several days, for example, 5 days. In certain embodiments, the immersion time is relatively short, or within the range of about 1 to about 60 minutes, for example, about 1 to about 30 minutes, for example, about 1 to about 10 minutes, or about 1 to about 5 minutes. In certain embodiments, the immersion time is relatively long, or within the range of about 1 hour to 5 days, for example, about 2 hours to 2 days, for example, 2 hours to 1 day, for example, 2 hours to 12 hours, or 2 hours to 6 hours.

[0059] The implant surface is suitably dried after completion of the desired immersion time sufficient to evaporate the solvent from the surface. Drying can be carried out at a temperature generally within the range of 0-100°C, such as within the range of 10°C-100°C, within the range of 20°C-100°C, within the range of 20°C-90°C, or within the range of 20°C-80°C.

[0060] PDC having the above degree of deacetylation and the preferred particle size described herein below can be solubilized in an aqueous solution, such as water, to obtain a gel-like colloidal matrix containing micro-sized PDC particles suspended in the gel matrix. The gel matrix thus obtained can be used as a dipping solution in a coating process to produce the desired high strength coating of the present invention.

[0061] For particulate coatings, the particle size of the PDC particles is typically less than 50 μm, preferably less than 30 μm, more preferably less than 20 μm, and even more preferably less than 10 μm, meaning that more than 95% of the particles have a widest cross section less than a given number (e.g., more than 95% of the particles have a widest cross section less than 30 μm, or 20 μm, or 10 μm).

[0062] Thus, in some embodiments, the PDC particles have a particle size distribution within the range of about 1 μm or about 2 μm or about 3 μm or about 4 μm or about 5 μm to about 20 μm or about 15 μm or about 12 μm or about 10 μm, e.g., an average (arithmetic mean) or median maximum diameter of about 5 μm or about 8 μm or about 10 μm or about 12 μm or about 15 μm.

[0063] In some embodiments, the PDC particles have an average particle size of less than about 50 μm, preferably less than about 20 μm, and more preferably less than about 10 μm.

[0064] The concentration of PDC in the immersion gel matrix can be, for example, in the range of 0.2% by weight to about 20% by weight, preferably about 0.5% to about 10%, for example, in the range of about 0.5% or about 1% or about 2% to about 10% or about 5% or about 4%.

[0065] It may be beneficial to pretreat the implant to be coated to enhance its adhesive properties and / or its biocompatibility. Pretreatment can be performed by treatment with an oxidizing agent such as an acid or mixture of acids (e.g., sulfuric acid, hydrofluoric acid, phosphoric acid), or hydrogen peroxide, or mixtures thereof. Alternatively, pretreatment can be performed by treatment with an alkaline solution such as sodium hydroxide. Other suitable pretreatment methods are known in the art and are also contemplated by the coatings described herein.

[0066] Exemplary embodiments of the present invention include the following. 1. A chitosan-based coating for a surgical implant, the coating comprising non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 30-75%.

[0067] 2. The chitosan-based coating according to item 1, wherein the degree of deacetylation is within the range of about 35% to about 70%, within the range of about 35% to about 60%, within the range of about 40% to about 75%, within the range of about 40% to about 60%, or within the range of about 45% to about 55%.

[0068] 3. The chitosan-based coating according to item 1 or 2, wherein the degree of deacetylation is about 50%.

[0069] 4. The chitosan-based coating according to any one of items 1 to 3, wherein the coating has a dry thickness in the range of 2 to 25 μm, preferably in the range of 5 to 15 μm.

[0070] 5. The chitosan-based coating according to any one of items 1 to 4, wherein the coating has a wet thickness in the range of 20 to 250 μm, preferably in the range of 40 to 100 μm.

[0071] 6. The chitosan-based coating according to any one of items 1 to 5, wherein the coating has a surface roughness of less than 500 μm.

[0072] 7. The chitosan-based coating according to any one of items 1 to 6, wherein the coating has a surface roughness in the range of about 25 to 500 μm, in the range of 5 to 250 μm, in the range of about 20 to 100 μm, in the range of about 25 to 100 μm, in the range of about 5 to 100 μm, or in the range of 5 to 50 μm.

[0073] 8. The chitosan-based coating according to any one of paragraphs 1 to 7, wherein the coating coats a surface in a manner that conforms to the topography of the surface to which it is applied in order to promote cell attachment or cell proliferation on the coating.

[0074] 9. The chitosan-based coating according to any one of items 1 to 8, wherein the coating comprises a heterogeneous layer having a coverage over a unit area on the surgical implant in the range of about 10% to about 90%, preferably in the range of about 25% to about 75%.

[0075] 10. Unit area is 25 to 100 mm 2 Within the range of, for example, 35 to 100 mm 2 Within the range of, for example, 50 to 100 mm 2 Item 10. The chitosan-based coating according to item 9, wherein the chitosan-based coating is within the range of

[0076] 11. Unit area is 1 to 25 mm 2 Within the range of, for example, 5 to 25 mm 2 Within the range of, for example, 10 to 25 mm 2 Item 11. The chitosan-based coating according to item 10, wherein the chitosan-based coating is within the range of

[0077] 12. The chitosan-based coating according to any one of paragraphs 1 to 11, wherein the coating comprises PDC in the form of microparticles having an average particle size of less than 50 μm, less than 30 μm, or less than 10 μm.

[0078] 13. The chitosan-based coating according to any one of paragraphs 1 to 12, wherein the particulate PDC has an average particle size of less than about 50 μm, preferably less than about 20 μm, more preferably less than about 10 μm.

[0079] 14. A composition comprising microparticles containing partially deacetylated chitosan having a degree of deacetylation within the range of about 35% to about 70%, within the range of about 35% to about 60%, within the range of about 40% to about 75%, within the range of about 40% to about 60%, or within the range of about 45% to about 55%, wherein the microparticles have an average particle size of less than 50 μm.

[0080] 15. The composition according to item 14, which is in the form of a colloidal suspension in an aqueous solution.

[0081] 16. The composition according to item 15, which is in the form of a colloidal suspension in water or a physiological fluid.

[0082] 17. The composition according to item 15, which is in the form of a colloidal suspension in a solution comprising a mixture of water and a water-miscible organic solvent, such as a primary alcohol.

[0083] 18. The composition according to item 15, which is in the form of a colloidal suspension in a mixture of ethanol and water.

[0084] 19. The composition according to paragraph 18, comprising physically dispersed microparticles suspended in an aqueous solution to obtain a colloidal gel-like matrix comprising the microparticles suspended in the matrix.

[0085] 20. The composition according to any one of items 16 to 19, wherein the aqueous solution has a pH in the range of about 7 to about 8, preferably about 7.3 to about 7.5, and more preferably about 7.4.

[0086] 21. The composition according to any one of paragraphs 15 to 20, wherein the aqueous solution comprises a physiological body fluid or other suitable fluid, such as saline.

[0087] 22. The composition according to any one of items 14 to 21, wherein the microparticles have an average particle size within the range of about 5 μm to about 50 μm, preferably within the range of about 5 μm to about 25 μm, and more preferably within the range of about 5 μm to about 15 μm.

[0088] 23. The composition according to any one of items 14 to 22, wherein the microparticles have an average particle size of about 10 μm.

[0089] 24. The composition according to any one of items 14 to 23, wherein the partially deacetylated chitosan has a degree of deacetylation of about 50%.

[0090] 25. A surgical implant or a portion thereof, characterized in that its outer surface or a portion thereof is coated with a surface coating comprising non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 30-75%.

[0091] 26. The surgical implant or part thereof according to item 25, wherein the degree of deacetylation is within the range of about 30% to 75%, within the range of about 35% to 60%, within the range of about 40% to 60%, within the range of about 45% to 55%, or about 50%.

[0092] 27. A surgical implant or part thereof according to item 25 or 26, wherein the chitosan coating has a dry thickness in the range of 2 to 25 μm, preferably in the range of 5 to 15 μm.

[0093] 28. The surgical implant or part thereof according to item 25 or 26, wherein the coating has a wet thickness in the range of 20 to 250 μm, in the range of 50 to 250 μm, in the range of 30 to 150 μm, or in the range of 40 to 100 μm.

[0094] 29. A surgical implant or part thereof according to any one of items 25 to 28, wherein the chitosan-based coating is obtainable by immersing the implant in a non-acidified solution comprising PDC having a pH greater than 6, preferably in the range of 7 to 8, more preferably in the range of 7.3 to 7.5, and most preferably about 7.4.

[0095] 30. A surgical implant or part thereof according to any one of items 25 to 29, wherein the chitosan-based coating is obtainable by immersing the implant in a non-acidified colloidal solution or gel containing PDC.

[0096] 31. A surgical implant or part thereof according to any one of items 25 to 30, wherein the chitosan-based coating is obtainable by immersing the implant in a non-acidified gel containing dispersed particulate PDC.

[0097] 32. The surgical implant or portion thereof of any one of paragraphs 25 to 31, wherein the coating comprises particulate PDC having an average particle size of less than about 50 μm.

[0098] 33. A surgical implant or a part thereof according to any one of items 25 to 32, wherein the microparticles have an average particle size within the range of about 5 μm to about 50 μm, preferably within the range of about 5 μm to about 25 μm, and more preferably within the range of about 5 μm to about 15 μm.

[0099] 34. A surgical implant or part thereof according to any one of claims 29 to 33, wherein the colloidal solution or gel or suspension comprises PDC in the range of 0.1% to 20%, or PDC in the range of 0.5 to 10%, or preferably PDC in the range of about 1% to about 5%.

[0100] 35. The density of N-acetylglucosamine (NAG) on the surface of the implant or part thereof is 0.01-15 mg / cm 2 , or 0.3 to 5 mg / cm 2 , preferably 0.5 to 1.5 mg / cm 2 Item 35. The surgical implant or a part thereof according to any one of items 25 to 34, wherein the range is within the range.

[0101] 36. A surgical implant or a part thereof according to any one of items 25 to 35, wherein the chitosan coating is a heterogeneous coating within the range of about 10% to about 90%, preferably about 25% to about 75%, of the outer surface or part of the unit area of ​​the implant.

[0102] 37. A 1-5 mm membrane having a chitosan coating in the range of 10% to 90%, preferably in the range of about 25% to about 75%. 2 Item 37. The surgical implant or part thereof according to any one of items 25 to 36, having a non-uniform coating having a coverage rate per unit area of ​​100 nm to 100 nm.

[0103] 38. A surgical implant or a part thereof according to any one of claims 25 to 37, wherein the implant or part thereof is made from one or more materials selected from hydroxyapatite, bioglass, titanium or a titanium alloy.

[0104] 39. A surgical implant or part thereof according to item 38, wherein the surface of the implant is pretreated by oxidation through acid treatment.

[0105] 40. A surgical implant or part thereof according to item 38, wherein the surface of the implant has been pretreated by washing with an alkaline solution.

[0106] 41. A method for coating a surface of a surgical implant with non-crosslinked partially deacetylated chitosan (PDC), comprising immersing the implant surface in an aqueous solution or gel containing PDC having a degree of deacetylation in the range of about 30-65%, removing the implant surface from the solution, and drying the treated surface.

[0107] 42. The method according to item 41, wherein the PDC has a degree of deacetylation in the range of about 35% to about 60%, preferably about 40% to about 60%, more preferably about 45% to about 55%, and even more preferably about 50%.

[0108] 43. The method of claim 41 or 42, wherein the aqueous solution has a pH greater than about pH 6, preferably within the range of about 7.2 to about 7.5.

[0109] 44. The method according to paragraph 43, wherein the composition is in the form of a colloidal suspension in water or a physiological fluid.

[0110] 45. The method of claim 41, wherein the composition is in the form of a colloidal suspension in a solution comprising a mixture of water and a water-miscible organic solvent, such as a primary alcohol.

[0111] 46. ​​The method according to paragraph 45, wherein the composition is in the form of a colloidal suspension in a mixture of ethanol and water.

[0112] 47. The method of any one of paragraphs 41 to 46, wherein drying the treated surface comprises incubation at a temperature in the range of 20 to 80°C.

[0113] 48. The method of any one of paragraphs 41 to 47, wherein the coated surface has a surface coating distribution in the range of about 10 to about 100%.

[0114] 49. The method according to any one of items 41 to 47, wherein the coated surface has a surface coating distribution in the range of about 10% to about 90%, preferably in the range of about 25% to about 75%.

[0115] 50. The method of any one of claims 41 to 49, further comprising pretreating the surface prior to immersion, the pretreatment comprising oxidation by acid treatment and subsequent washing with alkali and optional rinsing to neutralize the solution.

[0116] 51. The method according to any one of paragraphs 41 to 50, wherein the method comprises at least two coating cycles, each cycle comprising immersing the implant surface in an aqueous solution or gel comprising PDC having a degree of deacetylation in the range of about 30-65%, removing the implant surface from the solution, and drying the treated surface, wherein the aqueous solution or gel comprising PDC is different in each coating cycle.

[0117] 52. The method according to paragraph 51, wherein the first coating cycle comprises immersing the implant surface in an aqueous solution containing PDC to obtain an essentially complete coating of the surface, and the second coating cycle comprises immersing the implant surface in an aqueous gel or suspension to obtain a second coating layer on the surface.

[0118] As used herein, singular terms, including terms, should be construed to include the plural and vice versa, unless the context indicates otherwise. Thus, it should be noted that as used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0119] Throughout the specification and sections, the terms "comprise," "including," "having," and "contain" and variations thereof are to be understood to mean "including but not limited to" and are not intended to exclude other elements.

[0120] The present invention also encompasses exact terms, features, values, ranges, and the like, which are used in conjunction with terms such as about, approximately, generally, substantially, essentially, at least, and the like (i.e., "about 3" shall also cover exactly 3, or "substantially constant" shall also cover exactly constant).

[0121] The term "at least one" should be understood to mean "one or more," and therefore includes both embodiments including one or more components. Furthermore, a dependent claim that refers to an independent claim reciting a feature having "at least one" has the same meaning both when that feature is referred to as "the" and "at least one of the."

[0122] It will be understood that modifications to the foregoing embodiments of the invention can be made while still falling within the scope of the invention. Features disclosed herein, unless expressly stated otherwise, can be replaced by alternative features serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each disclosed feature represents one example of a generic series of equivalent or similar features.

[0123] The use of exemplary language such as "for instance," "such as," "for example," and the like, is intended merely to better describe the invention and does not imply a limitation on the scope of the invention unless so stated. Any steps described herein may be performed in any order or simultaneously unless the context clearly dictates otherwise.

[0124] All of the features and / or steps disclosed herein may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. In particular, the preferred features of the invention are applicable to all aspects of the invention and may be used in any combination.

[0125] The invention is further illustrated by the following non-limiting examples. EXAMPLES

[0126] Example 1 Partially deacetylated chitosan (PDC) The production of PDC involves a series of processes. Chitin is first deacetylated in concentrated sodium hydroxide at low temperatures, e.g., below 60°C, to a 50% deacetylated material, in order to minimize the formation of block distributions of NAG and thus the crystalline nature of the material. This is important because more clustered NAG increases the interchain interactions, which hinders chain separation upon protonation of the polymer and therefore its solubility. Furthermore, this clustered NAG increases the interaction forces between the chains upon drying of the material, resulting in a less amorphous material.

[0127] This is followed by a thorough washing process to remove the alkali and recover the material. The material is then dissolved in acid (e.g. citric acid) to facilitate the removal of all insoluble material in the acidic fluid by a series of filtrations. The solution is then neutralized by the addition of NaOH and the polymer is precipitated by adding salt to the fluid. The resulting chitosan polymer is then collected and washed thoroughly. The purified partially deacetylated chitosan (PDC) material is recovered and dried. Finally, the material is bagged and sealed.

[0128] The PDC thus prepared has many different characteristics than the classical chitosan available on the market.

[0129] These characteristics indicate that the PDC is highly amorphous, with uniform fine circular particles of about 10 μm in size, as shown in FIG. 1. In contrast to classical chitosan, where dissolution of solid chitosan to obtain a chitosan solution can take many hours or even overnight, dissolution of the PDC obtained by the above method is nearly instantaneous. For example, when PDC is dispersed in a fluid, such as water, the addition of a suitable acid (e.g., citric acid or any other suitable organic or inorganic acid) converts the colloidal fluid into a clear / homogeneous crystalline solution within seconds. The PDC solution is more resistant to precipitation near and above physiological pH than classical chitosan.

[0130] This PDC has a nearly equal ratio of NAG and GluN, or a more balanced hydrophobic / hydrophilicity. As a result, PDC can easily form stable mixtures with either aqueous or most oil-based fluids. Furthermore, the amorphous and fine particle nature of dry PDC allows it to absorb more than 20 times pure water relative to its weight. All these extraordinary properties make PDC challenging for more demanding preparations and open new application areas to meet future biopharmaceutical / medical needs.

[0131] The %DD of PDC is generally in the range of 45-60% and can have a weight average molecular weight (Mw) of 80-350 kDa. The following table lists typical examples of the general properties of PDC.

[0132] [Table 1]

[0133] Example 2 Coating Method The titanium plates used in this experiment were Ti ASTM B265 G2 and cut to a size of 2 cm x 1 cm. Prior to coating, the titanium plates were treated with 10 N sodium hydroxide in a bath at 60 °C for 24 hours. The plates were then washed without alkali, dried and the weight of each plate was recorded. The specified concentration of PDC was 0.75% (w / v in 1% acetic acid). The theoretical loading was 0.655 mg / cm 2 PDC or 87.5 μL / cm 2 The loading volume of 0.75% PDC solution was 100 μl.

[0134] To study the swelling index, all film-coated titanium plates were immersed in a pool of deionized (DI) water for 2 hours and the weights were recorded before and after immersion. The swelling index was determined as the percentage ratio of the net wet film weight divided by the net dry film weight.

[0135] Example 3 Analysis of Coatings Film thickness measurements were performed using a profilometer (Solarius Profilometer). To do so, half of the plate was gold coated to prevent the light source from penetrating the transparent film during measurements (Figure 2(b)). The height difference between the gold coated and uncoated areas is the dry film thickness (Figure 2(c)). This measurement showed that the average coating film thickness at this loading concentration and loading amount was 11 ± 2 μm.

[0136] Example 4 Determination of surface roughness The surface topography of dry PDC-coated titanium was measured by a profilometer, as shown in Figure 3. In (a) a 3D view of the surface roughness of a typical titanium plate coated with 1% PDC (w / v) is shown. In (b) a 2D view of the topographical image of the coated surface is shown. In (c) the actual recorded surface roughness along the line shown in Figure 3(a) is shown. In (d) the distribution of surface roughness along the line shown in Figure 3(a) is shown.

[0137] As can be seen, the PDC coating provides a smooth, uniform coating across the titanium surface.

[0138] Example 5 Swelling properties of PDC films The swelling properties of the PDC coated surfaces were determined by measuring the swelling index of the coated PDC before and after immersion in water for 4 weeks. Films were prepared using only 1% aqueous acetic acid or a 0.75% solution of PDC in an ethanol / water mixture. The results are shown in Figure 4. In (a) the effect of temperature is shown for a PDC solution prepared using only water, and in (b) the swelling is shown for a PDC solution prepared using a 1:1 ratio of ethanol:water.

[0139] There was a significant difference in the swelling index between the treatments before and after 4 weeks of soaking (p<0.05), with the swelling index decreasing significantly during soaking. There was also a significant difference as a function of drying temperature, with higher temperatures resulting in lower swelling index.

[0140] When ethanol:water (1:1) was used to prepare the PDC solution (Figure 4b), there was a significant difference in the swelling index between the treatments before and after immersion for 4 weeks (p<0.05). However, the drying temperature does not significantly affect the swelling index of the films.

[0141] Example 6 Control of Swelling Index The relationship between the drying temperature and the swelling behavior of PDC films in water was investigated, as shown in Figure 5. The results show that the initial thickness of the film is controllable by changing the temperature of the drying step.

[0142] Example 7 Coating surface evaluation by SEM Scanning electrode microscopy (SEM) was used to study the coating of the treated surfaces. In Figure 6, scanning electrode microscopy (SEM) images of a titanium plate coated with PDC dissolved in acetic acid are shown, (a) at 2000x magnification and (b) at 100,000x magnification. As can be seen, there is an almost completely uniform coating of the titanium surface.

[0143] The coatings obtained by the different methods and their coverage on the coated surface were also determined, as shown in Figures 7 to 9. In Figure 7, examples of PDC coatings on titanium substrates are shown. (a) shows the coating obtained by immersion in a completely dissolved PDC solution (true solution) and (b) shows the coating obtained by immersion in colloidal PDC. The surface coating using the true solution is almost complete (more than 99%), whereas the coating using the colloidal method is inhomogeneous, with about 41% of the surface area being coated.

[0144] The results for coated bioglass and hydroxyapatite surfaces are shown in Figures 8 and 9, respectively, and the numerical results are given below. For all surfaces, essentially complete coating (>99%) is obtained using fully dissolved PDC, whereas treatment with colloidal PDC results in coating coverage of approximately 50%.

[0145] [Table 2]

[0146] Example 8 Film Material Loss After Long-Term Water Immersion To investigate the influence of the fluids used for the preparation of the PDC solutions and the long-term incubation of the treated surfaces in an aqueous environment, i.e., water alone and an ethanol / water mixture, the treated surfaces were incubated in water for 4 weeks and the loss of surface coating material was determined.

[0147] As can be seen from Figure 10, there is a difference in the net dry weight of the films in the water-only aqueous system (Figure 10(a), p<0.05), but not in the films prepared by the solvent / water aqueous system (ethanol:water 1:1, Figure 10(b), p>0.05). After immersion in water for 4 weeks (RT drying), there is a maximum loss of up to 10% of material.

[0148] However, the majority of the film was found to be intact, indicating that the coating method results in a reliable film for coating purposes.

[0149] Example 9. Determination of surface distribution by SEM upon treatment with PDC in PBS solution The effect of physiological buffer solutions on the surface distribution of PDC coatings was determined by SEM. Titanium was coated with PDC dispersed in PBS (phosphate buffered saline) solution. The resulting coatings were subsequently investigated by SEM, as shown in Figure 11. In (a), the coated PDC (darker grey areas) can be seen with an organic distribution on the titanium surface at 100x magnification. In (b), the roughness can be seen at 2500x magnification, and the thickness of the coating on the surface is non-uniform. The relatively rough surface promotes cell adhesion, so the coatings obtained by this method are suitable for in vivo use.

[0150] Example 10 AFM coated with PDC in acetic acid solution and dispersed in PBS solution Atomic force microscopy (AFM) was used to study the PDC coating of dried coating films obtained by different coating methods, namely homogeneous true solution coating (PDC completely dissolved in acetic acid) and heterogeneous coating of PDC dispersed in PBS buffer. The results are shown in Figure 12. (a) shows chitosan completely dissolved in acid and coated on titanium by the homogeneous method, and (b) shows PDC dispersed in PBS solution and coated on titanium by the heterogeneous method. As can be seen, the heterogeneous method produces coatings with greater variation in both film thickness and roughness.

Claims

1. 1. A chitosan-based coating for a surgical implant, the coating comprising non-crosslinked partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 45 to about 55%, the PDC being in the form of microparticles having an average particle size of less than 50 μm.

2. The chitosan-based coating of claim 1 , wherein the microparticles have a spherical shape.

3. 10. The chitosan-based coating of claim 1, wherein the PDC is amorphous.

4. The chitosan-based coating of claim 1, wherein the coating has a dry thickness in the range of 2 to 25 μm.

5. The chitosan-based coating of claim 1, wherein the coating has a wet thickness in the range of 20 to 250 μm.

6. The chitosan-based coating of claim 1, wherein the coating has a surface roughness in the range of about 25 to 500 μm.

7. 10. The chitosan-based coating of claim 1, wherein the coating comprises PDC in the form of microparticles having an average particle size of less than 30 μm or less than 10 μm.

8. 1. A composition for coating a surgical implant, comprising microparticles containing partially deacetylated chitosan (PDC) having a degree of deacetylation in the range of about 45% to about 55%, said microparticles having an average particle size of less than 50 μm.

9. The composition of claim 8, in the form of a colloidal suspension in a non-acidified aqueous solution having a pH greater than 6.

10. 10. The composition of claim 9, wherein the PDC is amorphous.

11. 11. The composition of claim 10, comprising physically dispersed microparticles suspended in said aqueous solution to obtain a colloidal gel-like matrix comprising microparticles suspended in said colloidal gel-like matrix.

12. The composition of claim 8, wherein the microparticles have an average particle size in the range of about 5 μm to about 50 μm.

13. 1. A surgical implant or portion thereof, characterized in that its exterior surface or a portion thereof is coated with a surface coating comprising non-crosslinked partially deacetylated chitosan (PDC) in the form of microparticles having an average particle size of less than 50 μm, said PDC having a degree of deacetylation in the range of about 45 to about 55%.

14. 14. The surgical implant or portion thereof of claim 13, wherein the PDC is amorphous.

15. The surgical implant or part thereof of claim 13, wherein the surface coating has a dry thickness in the range of 2 to 25 μm.

16. The surgical implant or part thereof of claim 13, wherein the surface coating has a wet thickness in the range of 20 to 250 μm.

17. 14. The surgical implant or portion thereof of claim 13, wherein the surface coating is obtainable by immersing the implant in a non-acidified colloidal solution or gel comprising the PDC.

18. 14. The surgical implant or part thereof of claim 13, wherein the density of N-acetylglucosamine (NAG) on the surface of the implant or part thereof is in the range of 0.01 to 15 mg / cm2.

19. 14. The surgical implant or portion thereof of claim 13, wherein the chitosan coating is a heterogeneous coating of about 10 to about 90% of the outer surface of a unit area of ​​the implant or portion thereof.

20. 1. A method for coating a surface of a surgical implant with non-crosslinked partially deacetylated chitosan (PDC), the method comprising: immersing the implant surface in a non-acidified aqueous solution or gel having a pH greater than 6, the PDC being in the form of microparticles having an average particle size of less than 50 μm and having a degree of deacetylation in the range of about 45-55%, wherein the PDC is in the form of a colloidal suspension in the aqueous solution or gel; removing the implant surface from the solution; and drying the treated surface.

21. 21. The method of claim 20, wherein the composition is in the form of a colloidal suspension in a solution comprising a mixture of water and a water-miscible organic solvent, such as a primary alcohol.

22. 21. The method of claim 20, wherein the PDC is amorphous.

23. 21. The method of claim 20, wherein the method comprises at least two coating cycles, each cycle comprising immersing the implant surface in an aqueous solution or gel comprising PDC, removing the implant surface from the solution, and drying the treated surface, and wherein the PDC-containing aqueous solution or gel is different in each of the coating cycles.

24. 24. The method of claim 23, wherein a first coating cycle comprises immersing the implant surface in an aqueous solution containing PDC to obtain an essentially complete coating of the surface, and a second coating cycle comprises immersing the implant surface in an aqueous gel or suspension to obtain a second coating layer on the surface.

25. 21. The method of claim 20, wherein the surface is made of a material selected from stainless steel, titanium, titanium alloy, cobalt chromium alloy, bioglass, hydroxyapatite / calcium phosphate, or mixtures thereof.

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