WO2007058539A2

WO2007058539A2 - Modular supramolecular materials for biomedical uses

Info

Publication number: WO2007058539A2
Application number: PCT/NL2006/050292
Authority: WO
Inventors: Patricia Yvonne Wilhelmina Dankers; Gaby Maria Leonarda Van Gemert; Henricus Marie Janssen; Egbert Willem Meijer; Anton Willem Bosman
Original assignee: Suprapolix B.V.
Priority date: 2005-11-21
Filing date: 2006-11-17
Publication date: 2007-05-24
Also published as: WO2007058539A3

Abstract

The present invention relates to a supramolecular biomedical material comprising a polymer comprising at least two 4H-units and a biologically active compound. Optionally, the supramolecular biomedical material comprises a bioresorbable polymer as third component. The supramolecular biomedical material is especially suitable for the use in biomedical coatings with controlled release of drugs, biomedical coatings that have anti-thrombogenic or anti-microbial activity, biomedical coatings that have enhanced lubrication, or for the use in biomedical coatings used for medical imaging technologies (for example MRI).

Description

MODULAR SUPRAMOLECULAR MATERIALS FOR BIOMEDICAL USES

FIELD OF THE INVENTION

The invention relates to new supramolecular biomedical materials, as well as to a process to prepare biologically active biomedical materials in a modular way, in order to obtain biomedical materials that allow easy fine-tuning of the material properties, bioresorption and bioactivity by making use of reversible supramolecular interactions. The new materials of this invention can be used in a variety of biomedical applications that will benefit from said properties. The supramolecular biomedical materials according to the present invention are in particular suitable for use in biomedical coating compositions.

BACKGROUND OF THE INVENTION

Biomedical materials are distinguished in bioresorbable materials and non- bioresorbable materials. A wide variety of bioresorbable materials are known that are mostly based on aliphatic polyesters (Uhrich et al. Chem. Rev. 99, 3181-3198, 1999). The mechanical properties of current bioresorbable materials are strongly related to their high molecular weights that are in general over 100 kDa, the presence of chemical cross-links, and the presence of crystalline domains in these polymers. Although the crystalline domains are beneficial for the mechanical properties of the material (strength and elasticity), they do have a strong impact on the biodegradation process of the material as the biodegradation of crystalline domains is in general very slow and crystalline domains may cause immunological responses. Moreover, the need for high molecular weight polymers, in order to get the desired material properties, usually implies that high processing temperatures are required, and these are unfavorable as thermal degradation processes become more likely, especially when biologically active species are involved. There are also several examples of biologically active species that have been covalently attached to polymers for biomedical uses. Especially, oligo-peptide based cell-adhesion promoters such as RGD-sequences have had considerable attention in this respect. RGD-peptides have been covalently attached to a synthetic polymer by copolymerizing RGD-containing monomers, in order to obtain biologically active polynorbornenes (Grubbs et al, J. Am. Chem. Soc. 123, 1275, 2001). Unfortunately, in this way it was only possible to obtain biologically active polynorbornenes, a polymer that is not bioresorbable, and one needs complex chemistry to change the specific bio functionality. As a result, one is limited in the amount and choice of (combinations) of biologically active molecules. Consequently, this approach lacks freedom in the choice of polymers and bioactivities. Further known in the art are biomedical coatings that are used to improve the biocompatibility of medical devices. For example, stents may be coated to reduce thrombosis (cf. for example US 6.702.850, incorporated by reference) and implants may be coated to reduce the risks of rejection. Biomedical coatings may further comprise biologically active agents that are released in a controlled manner. Such biomedical coatings may be prepared by mixing a biologically active agent with a polymeric coating formulation.

A biological active agent that has been covalently attached to several polymers for biomedical coatings are heparin-derivatives. For example heparins have been copolymerized in polystyrene and poly(ethylene glycol) systems (Feijen et al., J. Mater. Sci. Mat. Med. 4, 353, 1997), or heparins have been covalently attached to polyurethanes as disclosed in WO98/23307. These heparin-polymer conjugates are used as anti-thrombogenic coatings for structures to be introduced into living systems. In both cases aromatic diisocyanates are used that are known for their toxic biodegradation profile and a relative low amount of heparin is available at the surface of the coating resulting in a low anti-thrombogenic activity.

WO 2002/034312 discloses polymers to which heparin is covalently attached.via functional groups.

Although a strong anchoring of the biologically active molecules to the polymer backbone is preferred in order to guarantee strong cell-adhesion or prolonged bio- activity, there are also materials in which biologically active molecules are only mixed with polymers and are thus not covalently attached to the polymer chain. As a consequence, the biologically active molecules leak out of the material and, therefore, such materials only find uses in drug delivery applications. Examples are hydrogels and microcapsules. Unfortunately, in hydrogels, the rate of drug delivery is hard to tune, while these systems generally suffer from poor material properties. Additionally, the chemical cross-links in their structure limit their biodegradation behavior. Microcapsules, on the other hand, are prepared from polymers with high glass- transition or melting temperatures, limiting their mechanical performance. Also, microcapsules frequently need bio-incompatible organic solvents to process them.

Another example of non-covalently attached biological active molecules are heparins that are ionically bound to cationic coatings due to heparin's intrinsic negative charge caused by the presence of carboxylates and sulfonates in the molecule, as disclosed for example in US 4.229.838. This method is however rather limited because the bio-active compound is leached over time from the surface due to the relative low ionic binding strength.

Alternatively, hydrophobic interactions have been used to non-covalently attach heparin to polymeric surfaces by end-group functionalizing heparin with an alkyl chain (Matsuda et al, Biomacromolecules, 2, 1169, 2001). However, the hydrophobic interactions are rather poor, resulting in a fast decrease in activity due to leakage of the heparins from the polymeric surfaces.

In general, "supramolecular chemistry" is understood to be the chemistry of non- covalent, oriented, multiple (at least two), co-operative interactions. For instance, a "supramolecular polymer" is an organic compound that has polymeric properties - for example with respect to its rheological behavior - due to specific and strong secondary interactions between the different molecules. These non-covalent supramolecular interactions contribute substantially to the properties of the resulting material.

Supramolecular polymers comprising (macro)molecules that bear hydrogen bonding units can have polymer properties in bulk and in solution, because of the H- bridges between the molecules. Sijbesma et al. (see WO 98/14505 and Science 278, 1601, 1997) have shown that in cases where the self-complementary quadruple hydrogen unit (4H-unit) is used, the physical interactions between the molecules become so strong that polymers with much better material properties can be prepared. WO 2004/016598, incorporated by reference, discloses chemistry to acquire polymers with grafted quadruple H-bonding units. For example, polyacrylates and polymethacrylates with grafted 4H-units have been produced using different kinds of polymerization techniques. However, the disclosed polymers are not bioresorbable. WO 2004/052963, incorporated by reference, discloses polysiloxanes comprising 4H-units in the polymer backbone. More precisely, polysiloxanes are disclosed having (a) 4H-units directly incorporated in the polymer backbone, or (b) 4H-units pending from the polymer backbone, wherein the 4H-units are covalently attached via one linker through a silicon-carbon bond. However, the disclosed polymers are not bioresorbable.

Low molecular weight telechelic polycaprolactone endcapped with 4H-units has been described by Dankers et al. (Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, United States, March 23-27, 2003; see PMSE, 88, 52, 2003). It was found that films of this material were biocompatible based on the observed attachment of fibroblast cells to the films. The study on the biodegradation of this polymer showed the presence of crystallites which is not favorable for bioresorption. Moreover, in a paper by ten Cate et al. (Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, United States, March 23-27, 2003; see Polymer Preprints, 2003, 44(1), 618) it was shown that the elasticity of the material was rather poor, as elongations beyond 130% were not possible.

Non-prepublished European Patent Application No. 05103764.6, filed 4 May 2005, discloses supramolecular bioresorbable materials comprising a polymer comprising at least two 4H-units and a biologically active compound. The supramolecular bioresorbable materials are useful in biomedical applications including controlled release of drugs, tissue-engineering, prostheses and implants.

Hence there is a need for versatile biomedical materials that have good and tunable mechanical properties and tunable bio functionality. Additionally, it is desired that these materials are tunable in their biodegradation behavior. Furthermore, it is desired that they can easily be prepared and processed. The present invention addresses these needs by introducing a supramolecular modular approach, wherein different ingredients (or modules or components) are blended - with each module contributing its own specific characteristic (i.e. mechanical performance, bioresorption, bioactivity, etc.) - to produce a material displaying the combined characteristics. This modular approach is usually not easily possible, but is enabled here, as quadruple hydrogen bonding units (4H-units) are used in at least one of the modules that are applied, resulting in contact between the modules in the final material. The presented approach eliminates the need for extensive covalent synthesis, as blending experiments with the various modules can be used to fine-tune the properties of the final material. Also, every module can be prepared in a controlled way, leading to well defined structures that result in products of controllable high quality.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel supramolecular biomedical materials as well as the process to prepare such materials with the aim to obtain biomedical materials with better characteristics than those of the prior art. In particular, the supramolecular biomedical material is a supramolecular coating composition.

It is another object of the present invention to provide supramolecular biomedical materials having the additional feature that they are easily fine-tuned with respect to their characteristics (e.g. mechanical properties, bioresorption, bioactivity, etc.). The present invention therefore relates to a supramolecular biomedical material comprising the following components:

(a) a polymer comprising at least two 4H-units; and

(b) a biologically active compound; wherein the 4H-unit is represented by the general formulas (1) or (2):

(!) (2)

wherein the C-X, and the C-Y, linkages each represent a single or double bond, n is 4 or more, and X, represent donors or acceptors that form hydrogen bridges with the H- bridge forming monomeric unit containing a corresponding general form (2) linked to them with X, representing a donor and Y, an acceptor and vice versa. The structure of these 4H-units is in detail disclosed in WO 98/14505 which is expressly incorporated by reference. Component (a) is preferably bioresorbable. According to the present invention, the terms "bioresorbable" and "bioresorption" encompasses cell-mediated degradation, enzymatic degradation or hydro lytic degradation of the supramolecular biomedical material, and/or elimination of the surpamolecular biomedical material from living tissue as is will be appreciated by the person skilled in the art.

In addition, a biologically active compound is to be understood as a biomedically relevant compound that can induce a biological or biochemical effect in a mammal but does not include biological systems such as cells and cell organelles.

DETAILED DESCRIPTION OF THE INVENTION

When investigating supramolecular polymers comprising quadruple hydrogen bonding units (4H-units), it was surprisingly found that by blending different polymers, optionally modified with 4H-units, not only the mechanical properties of the blends could be modified and improved, but also their biodegradation behavior. Moreover, biologically active compounds, optionally modified with 4H-unit(s), could be added to these materials, making the biomedical material biologically or biochemically active by blending in the desired biologically active compound. This invention therefore enables the use of bioactive materials with improved mechanical properties, while being able to tune separately the biodegradation rate and the bioactivity of the material. Thus, this invention surpasses the state of the art in biomedical materials, as a simplified way of designing and preparing new biologically active biomedical materials is introduced by using the supramolecular modular approach.

Component (a)

Accordingly, component (a), is a polymer comprising at least two 4H-units, preferably 2 - 50, more preferably 3 - 50, even more preferably 3 - 20, and most preferably 4 - 15 4H-units that are covalently attached to the polymer chain. The 4H- units may be attached at the termini of the polymer chain as well as to the backbone of the polymer chain or both. Obviously, the supramolecular biomedical polymer may comprise more than one of component (a), e.g. polymers of different chemical nature, of different molecular weight, and/or different numbers of 4H-units. It is also possible that component (a) is constituted from components of different chemical nature and/or of different molecular weight.

It is preferred that component (a) is a bioresorbable polymer. However, if the supramolecular biomedical material is a supramolecular biomedical coating composition, it may be more preferred that component (a) is not bioresorbable.

Component (a) can be any type of polymer, the polymer can be of synthetic origin or of natural origin, such as chitosan, collagen, fibrin, or proteoglycans.

However, it is preferred that component (a) is selected from the group consisting of polyethers, aliphatic polyesters, aromatic polyesters, polyurethanes, polyamides, polyacrylates, polymethacrylates, polyacrylamides, (hydrogenated) polyolefms, polysiloxanes, polycarbonates, polyorthoesters, polysaccharides, poly(N- vinylcapro lactam), polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer and polyvinylalcohols (preferably partly esterified), or copolymers of these polymers.

According to a more preferred embodiment of the invention, component (a) is selected from the group consisting of polyethers, aliphatic polyesters, polycarbonates, polysiloxanes, polyorthoesters and polycarbonates. Even more preferably, component

(a) is selected from the group consisting of polyethers, aliphatic polyesters and polycarbonates. Most preferably, component (a) is an aliphatic polyester.

In another more preferred embodiment of this invention, component (a) is selected from the group consisting of polyamides, polyacrylates, polymethacrylates, polyacrylamides, N- vinylcapro lactam, or copolymers of these polymers.

The number average molecular weight M_n of component (a) is preferably in the range from 100 to 100000, more preferably from 100 to 60000, even more preferably

800 to 40000, most preferably from 2000 to 35000 Dalton. Preferably, component (a) is prepared from relatively low molecular weight polymers having two hydroxy end-groups, primary amino end-groups, or a combination thereof. Examples of relatively low molecular weight polymers having two hydroxy end-groups are:

(i) polyether diols having a polyoxyalkylene structure and OH end-groups; (ii) polyesters and copolyesters having OH end-groups;

(iii) polycarbonates and copolycarbonates having OH end-groups;

(iv) polyorthoesters having OH end-groups;

(v) polyolefine diols; and (vi) polymers and copolymers based on combinations of these preferred polymers (i) - (v).

Suitable examples of polymers (i) are polyetherdiols having a polyoxyalkylene structure and OH end-groups, e.g. polyethylene glycol, polypropylene glycol, poly(ethylene-co-propylene) glycol (random or block), polytetramethylene glycol. Examples of polymers (ii) are polyesters and copolyesters made by polycondensation of dicarboxylic acids, e.g. adipic acid, and diols, e.g. 1,6-hexanediol, or by polycondensation of hydroxyacids, e.g. lactic acid; polyesters and copolyesters made by ringopening polymerisation of e.g. ε-caprolactone, glycolide, lactide, δ- valero lactone, l,4-dioxane-2-one, l,5-dioxepan-2-one, oxepan-2,7-dione, and the like. Examples of polymers (iii) are polycarbonates and copolycarbonates based on e.g. 1,6- hexanediol polycarbonate, polycarbonates and copolycarbonates made by ringopening polymerization of e.g. trimethylenecarbonate, l,3-dioxepane-2-one, l,3-dioxanone-2- one, l,3,8,10-tetraoxacyclotetradecane-2,9-dione. An example of polymers (iv) is a polyorthoester based on e.g. 3,9-diethylene-2,4,8,10-tetraoxaspiro[5.5]undecane. Examples of polymers (v) are OH functionalized polybutadiene and OH functionalized poly(ethylene-butylene). An example of polymers (vi) are OH functionalized block copolymers of polycapro lactone and polyethyleneglycol.

Examples of relatively low molecular weight polymers having two amino end- groups are are Jeffamines® (polyoxyalkylenea amines produced and marketed by Huntsman), or other polyethers, aliphatic polyamides or polysiloxanes.

Preferably, the polymers have two hydroxyl end-groups, primary amine end- groups, or a combination thereof have a number average molecular weight M_n of 500 to and 10000, more preferably of 750 to 7000. According to a first preferred embodiment of the present invention, the supramolecular biomedical material comprises 50.0 - 99.99 percent by weight of component (a) and 0.01 - 50.0 percent by weight of component (b) if no component (c) is present (vide infra). More preferably, the supramolecular biomedical material comprises 70.00 - 99.99 percent by weight of component (a) and 0.01 - 30.00 percent by weight of component (b). Most preferably, the supramolecular biomedical material comprises 90.00 - 99.95 percent by weight of component (a) and 0.05 - 10 percent by weight of component (b). All these weight ranges are based on the total weight of the supramolecular biomedical material. Component (a) may have all kinds of different architectures, e.g. a linear

(co)polymer with the 4H-units attached to it as end groups, and/or in the polymer backbone, and/or grafted onto the polymer chain; a star shaped (co)polymer with the

4H-units somehow covalently attached to it, preferably as end groups; a dendritic structure with the 4H-units attached to it as end groups, and/or in the dendritic arms; or a (multifunctional) branched or hyperbranched structure with the 4H-units attached to it as end groups, and/or in the branches. The (co)polymers may have any kind of microstructure, such as a random, a block, a segmented or a randomly segmented structure, with the 4H-units attached to this co-polymer in any fashion, such as end- capped, incorporated in the polymer chain or grafted from the backbone.

In a preferred embodiment of this invention, component (a) comprises a star shaped polymer that is (partly) end-functionalized with 4H-units, or component (a) comprises a linear polymer to which several 4H-units are grafted, or component (a) comprises a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone. The preferred ranges of the number of 4H-units are disclosed above.

More preferably, component (a) comprises a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone. Most preferably, component (a) comprises a linear (co)polymer with the 4H-units attached to it in the polymer backbone.

It is furthermore preferred to use components (a) with relative low number average molecular weights M_n, preferably in the range from 100 to 100000, more preferably from 100 to 60000, even more preferably 800 to 40000, most preferably from 2000 to 35000, in order to allow melt -processing of the supramolecular biomedical material at temperatures preferably lower than 200 ⁰C, more preferably lower than 150 ⁰C, and most preferably lower than 100 ⁰C, or to process them from solutions at concentrations higher than 10% by weight, preferably higher than 15% by weight.

Optionally, ionic or ionogenic groups may be incorporated in component (a) in order to make the material more hydrophilic and thereby facilitating water-solubility or water swelling of the supramolecular biomedical material (i.e. gelling). Preferred ionogenic groups are N-methyl-diethanolamine, 2,6-bis-(hydroxymethyl)-pyridine and

2,2-bis(hydroxymethyl)-propionic acid. In addition, component (a) may contain one or more hydrophilic polymeric blocks in its polymer chain in order to facilitate water-solubility or water swelling of the supramolecular biomedical material (i.e. gelling). These hydrophilic polymeric blocks are preferably derived from polyethylene glycol polymers, preferably having a number average molecular weight M_n from 200 to 50000, more preferably from 500 to 6000.

In a preferred embodiment of this invention, component (a) has an elongation at break of at least 140%.

Preferably, component (a) contains at least three 4H-units on average to counterbalance components (b) if component (b) has less than two 4H-units, the latter optionally acting as supramolecular chain stopper.

The 4H-unit

It is preferred that in formulas (1) and (2) n equals 4 so and that the 4H-unit comprises four donors or acceptors X₁₁₁₁X₄ and Y₁₁₁₁Y₄. The 4H-unit may be self- complementary (i.e. the two hydrogen bonded units have an equal array of donors and acceptors), or non self-complementary (i.e. the two hydrogen bonded units have two different arrays of donors and acceptors). Preferably, the 4H-unit comprises two successive donors, followed by two successive acceptors, i.e. that it is preferred that Xi and X₂ are donors and X₃ and X₄ are acceptors. Preferably, the donors and acceptors are O, S, and N atoms. The 4H unit is in detail disclosed in WO 98/14505 and in US 6.320.018 which are expressly incorporated by reference.

According to a preferred embodiment of the present invention the 4H-unit has the general formula (3) or formula (4), and tautomers thereof:

(3) (4) wherein X is nitrogen atom or a carbon atom bearing a substituent R³ and wherein R¹, R² and R³ are selected from the group consisting of:

(a) hydrogen;

(b) C₁ - C₂₀ alkyl;

(c) C₆ - Ci₂ aiyl;

(d) C₇ - Ci₂ alkaryl;

(e) C₇ - Ci₂ alkylaiyl;

(f) polyester groups having the formula (5)

(5)

wherein R is independently selected from the group consisting of hydrogen and Ci - C₆ linear or branched alkyl, n is 1 - 6 and m is 10 to 100;

(g) Ci - Cio alkyl groups substituted with 1 - 4 ureido groups according to the formula (6)

R⁵-NH-C(O)-NH-

(6)

wherein R is selected from the group consisting of hydrogen and Ci - C₆ linear or branched alkyl; (h) polyether groups having the formula (7)

(V) wherein R⁶ and R⁷ are independently selected from the group consisting of hydrogen and Ci - Ce linear or branched alkyl and o is 10 - 100; (i) oligopeptide groups consisting of sequences of 1 to 50, preferably 1 to 10, amino acids; and wherein the 4H-unit is bonded to a polymer backbone via R¹, R² and/or R³ (so that R¹, R² or R³ represent a direct bond) with the other R groups representing, independently a side chain according to (a) - (i).

Preferably, the 4H-unit is bonded to a polymer backbone via R¹ or R³ (so that R¹ or R³ constitutes a direct bond), while R² is any one of the groups (a) - (f) defined above, preferably group (a), more preferably 2-ethylpentyl or methyl and most preferably methyl. Alternatively, the 4H-unit is bonded to a polymer backbone via R¹, while R² and R³ are any of the groups (a) - (f) defined above, preferably group (a), more preferably 2-ethylpentyl or methyl and most preferably methyl. Most preferably, the 4H-unit is bonded to a polymer backbone via R¹ and R³.

As will be apparent to the person skilled in the art, the groups (b) - (i) defined above may be linear, branched or cyclic where appropriate.

Component (b)

Additionally, the supramolecular biomedical material of the present invention comprises a biologically active compound (b). Preferably, the biologically active compound (b) is selected from the group consisting of biologically active compounds with at least one 4H-unit up to a maximum of ten 4H-units, preferably one to four, and most preferably two to four 4H-units. These 4H-units are covalently attached to the biologically active compound.

If no component (c) is present (vide infra), then the amount of biologically active compound (b) is 0.01 to 50.00 percent by weight and the amount of component (a) is 50.00 - 99.99 percent by weight, based on the total weight of the supramolecular biomedical material, as is disclosed above. According to this embodiment, it is preferred that the weight range of (a) is 70.00 - 99.99 percent by weight, and even more preferably 90.00 - 99.95 percent by weight, whereas the preferred weight range for (b) is 0.01 - 30 percent by weight, and even more preferably 0.05 - 10.00 percent by weight. All these weight ranges are based on the total weight of the supramolecular biomedical material. Moreover, the biologically active compound (b) species may comprise one or more different biologically active compounds.

The biologically active compound can be any compound that displays bioactivity as disclosed above. A 'biologically active compound', as used herein, is a compound that is biomedically relevant and includes a compound which provides a therapeutic, diagnostic, cosmetic, medicinal or prophylactic effect, a compound that effects or participates in tissue growth, cell growth, cell differentiation, cell signaling, cell homing, protein adsorption, a compound that may be able to invoke a biological action, or could play any other role in one or more biological processes. Such compounds include, but are not limited to, antimicrobial agents (including antibacterial and antifungal agents), anti-viral agents, anti-tumor agents, anti-thrombogenic agents, anticoagulant agents, lubricating agents, imaging agents, drugs, medicines, hormones, immunogenic agents, growth factors, cytokines, chemokines, (fluorescent) dyes, contrast agents, nucleic acids such as for example single or double stranded DNA and single or double stranded RNA, lipids, lipopolysaccharides, (poly)saccharides, vitamins, and peptides, polypeptides and proteins in general, biotinylated compounds or other compound that target biologically relevant molecules.

A non-limiting, preferred and important group of species that can be used as component (b) according to the present invention is formed by oligopeptides and polysaccharides.

In a preferred embodiment, component (b) comprises a growth factor, an antimicrobial agent, a thrombin inhibitor, or an anti-thrombogenic agent. A growth factor is defined as a protein or peptide that has a beneficial effect on the growth, proliferation and/or differentiation of living cells. According to a more preferred embodiment of this invention, the supramolecular bioabsorbable material is advantageously used as a scaffold for tissue engineering, wherein the growth factor is non-covalently bound to a polymer.

Examples of preferred growth factors are Bone Morphogenetic Proteins (BMP), epidermal growth factors, e.g. Epidermal Growth Factor (EGF), fibroblast growth factors, e.g. basic Fibroblast Growth Factor (bFGF), Nerve Growth Factor (NGF), Bone Derived Growth Factor (BDGF), transforming growth factors, e.g. Transforming Growth Factor-.beta.1 (TGF- .beta.1), and human Growth Hormone (hGH). According to another more preferred embodiment of this invention, the supramolecular bioabsorbable material is advantageously used as a biomedical coating composition, wherein the anti-thrombogenic agent is non-covalently bound to a polymer. Non-limiting examples of preferred anti-thrombogenic agents are heparin, heparin analogues, heparin complexes, and molecules comprising a sulfonated glycosaminoglycan moiety. The anti-thrombogenic agent may also be a heparinised polymer as disclosed in WO 02/34312, incorporated by reference herein.

Further examples of peptides or proteins which may advantageously be included in the supramolecular bioresorbable material include immunogenic peptides or immunogenic proteins, e.g. toxins, viral surface antigens or parts of viruses, bacterial surface antigens or parts of bacteria, surface antigens of parasites causing disease or portions of parasites, immunoglobulins, anititoxins, antigens.

Although, in view of the thermal instability of polysaccharides and peptides, the method according to the present invention is particularly useful for preparing materials loaded with polysaccharides and peptides, it is of course also possible to load a material with a substance other than a polysaccharide or peptide. Such biologically active agents which may be incorporated include non-peptide, non-protein drugs and inorganic compounds. It is possible within the scope of the present invention to incorporate drugs of a polymeric nature, but also to incorporate drugs or vitamins of a relatively small molecular weight of less than 1500, or even less than 500.

Examples of non-peptide, non-protein drugs which may be incorporated include the following: anti-tumor agents, antimicrobial agents such as antibiotics or hemotherapeutic agents, antifungal agents, antiviral agents, anti-inflammatory agents, anti-gout agents, centrally acting analgesics, local anesthetics, centrally active muscle relaxants, hormones and hormone antagonistics, corticosteroids such as mineralocorticosteroids or glucocorticosteroids, androgents, estrogens, progestins.

Examples of inorganic compounds, which may be incorporated, include, but are not limited to reactive oxygen scavengers or bone-extracts like apatite or hydroxy apatite. Component (b) can be used as such, or can be chemically modified with one or more 4H-units. This chemical modification can be done by regular organic synthesis procedures, such as coupling methods using succinimide esters, sulfhydryl reactive agents, azides, (thio)isocyanates, carbiodiimides, aldehydes, or Cu(I)-catalyzed Huisgen [2+3] dipolar cycloadditions, or solid phase synthesis procedures which are known to persons skilled in the art. Moreover, in case of peptides and proteins, this chemical modification can be done using native chemical ligation with a peptide or protein containing a C-terminal thio-ester and a 4H-unit with a N-terminal cysteine, native chemical ligation is known to people skilled in the art.

Optionally, the 4H-unit can be bound to component (b) via a (bio)degradable linker that can be cleaved in vivo. In such a way the native component (b) is gradually released from the material, for example to induce an enhanced therapeutic effect. Non- limiting examples of cleavable linkers are esters or oligopeptides that are cleaved by enzymatic activity, such as the cleavage of the peptide Gly-Phe-Leu-Gly by cysteineproteases.

Additionally, two or more different components (b) may be present in the supramolecular biomedical material. This is especially beneficial when the bioactivity is based on multivalent and/or synergistic interactions. A non-limiting example of such interaction is the cell adhesion advantageously mediated by a combination of RGD and

PHSRN peptides.

Component (c)

The supramolecular biomedical material according to the present invention preferably also comprises a third component (c), said third component (c) being a bioresorbable polymer.

Preferably, this bioresorbable polymer comprises one up to a maximum of fifty 4H-units, preferably one to thirty, more preferably two to twenty, and most preferably four to twenty. These 4H-units are covalently attached to the polymer chain. The supramolecular biomedical material can obviously comprise different types of bioresorbable polymers, wherein these polymers are for example of different chemical nature and/or of different molecular weight, and can contain different numbers of 4H- units. It is obviously also possible that these polymers are constituted from components of different chemical nature and/or of different molecular weight.

Component (c) may be any bioresorbable polymer. However, it is preferred that component (c) is selected from the group consisting of polyethers (preferably aliphatic), aliphatic polyesters, aromatic polyesters, polyamides (preferably aliphatic; for example polypeptides), polycarbonates (preferably aliphatic), polyorthoesters, polysaccharides, polyvinylalcohols (preferably partly esterified). It is even more preferred that component (c) is selected from the group consisting of aliphatic polyethers, aliphatic polyesters, aliphatic polyamides, aliphatic polycarbonates, aliphatic polyorthoesters, polysaccharides and partially hydrolyzed polyvinylalcohols.

In another embodiment of this invention, component (c) contains any combination of polymer types, for example combinations of the preferred group of polymers disclosed above. According to a preferred embodiment of the invention, the polymer backbone is selected from the group consisting of polysaccharides, polyether and copolyethers based on, for example, ethyleneoxide, propyleneoxide, or tetrahydrofuran; polyesters and copolyesters made by polycondensation, based on, for example, adipic acid and diols or hydroxyacids, such as lactic acid; polyesters and copolyesters made by ringopening polymerisation, based on, for example, ε- caprolactone, glycolide, lactide, δ-valerolactone, l,4-dioxane-2-one, l,5-dioxepan-2- one, oxepan-2,7-dione; polycarbonates and copolycarbonates based on, for example, 1,6-hexanediol polycarbonate; polycarbonates and copolycarbonates made by ringopening polymerization based on, for example, trimethylenecarbonate, 1,3- dioxepane-2-one, l,3-dioxanone-2-one, l,3,8,10-tetraoxacyclotetradecane-2,9-dione; or polyorthoesters, based on, for example, 3,9-diethylene-2,4,8,10- tetraoxaspiro[5.5]undecane; polymers and copolymers based on combinations of these preferred polymers. Also different combinations of these preferred polymers can be present in component (c).

The number average molecular weight M_n of component (c) is preferably in the range from 100 to 100000, more preferably from 100 to 60000, even more preferably 800 to 40000, most preferably from 2000 to 35000 Dalton.

Component (c) can have all kinds of different architectures: a linear (co)polymer with the 4H-units attached to it as endgroups, and/or in the polymer backbone and/or grafted onto the polymer chain; a star shaped (co)polymer with the 4H-units somehow attached to it, preferably as endgroups; a dendritic structure with the 4H-units attached to it as endgroups, and/or in the dendritic arms; or a (multifunctional) branched or hyperbranched structure with the 4H-units attached to it as endgroups, and/or in the branches. The co-polymers can have any kind of microstructure, such as a random, a block, a segmented or a randomly segmented structure, with the 4H-units attached to this co-polymer in any fashion, such as end-capped, incorporated in the polymer chain or grafted from the backbone.

Preferably, component (c) comprises a star shaped polymer that is (partly) end- functionalized with 4H-units, a linear polymer to which several 4H-units are grafted, or a linear (co)polymer with the 4H-units attached to it as end groups and in the polymer backbone. More preferably, component (c) comprises a linear (co)polymer with the 4H- units attached to it as end groups and in the polymer backbone. Most preferably, component (c) comprises a linear (co)polymer with the 4H-units attached to it in the polymer backbone. Like component (a), ionic or ionogenic groups may optionally be incorporated in component (c) in order to make the material more hydrophilic and thereby facilitating water-solubility or water swelling of the material (i.e. gelling). Preferred ionogenic groups are disclosed for component (a). In addition, component (c) may contain one or more hydrophilic polymeric blocks in its polymer chain in order to facilitate water- solubility or water swelling of the material (i.e. gelling). These hydrophilic polymeric blocks are preferably derived from polyethylene glycol polymers, preferably having a number average molecular weight from 200 to 50000, and more preferably from 500 to 6000.

Method of preparing the supramolecular biomedical material

The present invention also provides a method of preparing the supramolecular biomedical material. This method comprises blending component (a) which predominantly attributes to the mechanical strength of the supramolecular biomedical material and component (b) which predominantly attributes to the biological activity of the supramolecular biomedical material. According to a preferred embodiment of the present invention, this method comprises blending component (a), component (b) and component (c), the latter predominantly attributing to the bioresorption of the supramolecular biomedical material. The blending of the components (a), (b) and (c) results in supramolecular biomedical materials with the desired material properties. In particular, if all components comprise 4H-units, they will all strongly contribute to strong physical interactions between the different components. In particular, it is therefore preferred according to the present invention that all three components (a) - (c) have at least one 4H-unit. The blending of all components can be done by conventional processes, i.e. solution processing or melt-processing, or a combination of both.

The concept of supramolecular blending of the different components also allows tuning the biodegradation behavior of the supramolecular biomedical materials, as this behavior is determined by the degradation behavior of all the added components.

Description of the preparation and processing of the supramolecular biomedical material

According to the supramolecular modular approach, the supramolecular biomedical material can be obtained in three different ways: method (i) comprises blending the different components (a), (b) and optionally (c) with each other in conjunction with a medium consisting of one or more solvents, in which these components are dissolved or dispersed, preferably dissolved. This first method (i) is preferably followed by processes for dissolved polymers known in the art.

A second method (ii) comprises blending the different components (a), (b) and optionally (c) with each other in the bulk at elevated temperatures, preferably 40° to 150°C {vide infra). This second method (ii) is preferably followed by solventless processes for polymers known in the art. A third method (iii) comprises a combination of methods (i) and (ii). Hence, method (iii) comprises for example first blending component (b) with component (c) according to method (i), followed by blending component (a) and the blend of components (b) and (c) according to method (ii). Alternatively, method (iii) comprises first blending component (a) with component (b) according to method (i), followed by blending component (c) and the blend of components (a) and (b) according to method (ii). Other alternatives will be apparent to the person skilled in the art. According to an especially preferred embodiment of the invention, methods (i) and (ii) comprises the in situ preparation of components (a) and/or (c).

Processing according to method i) can be done from organic solvents or aqueous media, depending on the solubility of different components. Preferably, a solvent or mixture of solvents is used that is acceptable for biomedical uses, such as water, acetone, methyl ethyl ketone, THF, DMSO, NMP, scCO2 or aliphatic alcohols. The supramolecular biomedical material is preferably obtained by solvent casting, dip- coating, freeze-drying, precipitation casting, spray coating, painting, roll-coating, foaming, solvent spinning, wet spinning, electro-spinning, micro-contact printing, ink jet printing, particulate-leaching techniques, phase-separation techniques or emulsion processes. The choice of solvents should be such that the desired viscosity of the solution for the coating process is obtained, preferably polar solvents should be used to reduce hydrogen bonding between the polymers. Moreover, the solvent has preferably a low boiling point in order to facilitate removal from the material after the coating process, and the solvent has preferably only limited toxicity. Therefore, drying of the material is required after the coating process and is preferably followed by extensive washings with water or water containing pH-buffer.

As will be known by persons skilled in the art, special care needs to be taken to clean the substrate surface when the supramolecular material is applied as a coating to this substrate. For example, wettability of the substrate can be improved by liquid etching techniques, such as the use of chromic acid, aqueous sodium hydroxide and fuming sulfuric acid, or plasma etching techniques.

Processing according to method (ii) is done at temperatures sufficient high to allow processing of the components although temperatures should be not too high to prevent degradation of the different components, especially component (b). Preferably, processing temperatures are in between 40 ⁰C and 150 ⁰C, most preferably in between 50⁰C and 120⁰C. The supramolecular biomedical materials are preferably obtained by extrusion, reactive extrusion, micro-extrusion, fused deposition modeling, molding, lamination, film-blowing, reaction injection molding (RIM), spinning techniques, rapid prototyping or by thermal- or photocuring of a coating. The amount of component (a) in the supramolecular biomedical material is preferably 50.00 - 99.99 percent by weight if no component (c) is present. According to this embodiment, component (a) is more preferably present between 70.00 - 99.99 percent by weight, and most preferably between 90.00 - 90.95 percent by weight

The amount of component (b) in the supramolecular biomedical material is preferably 0.01 - 50.00 percent by weight if no component (c) is present. According to this embodiment, component (b) is more preferably present between 0.01 - 30.00 percent by weight, and most preferably between 0.05 - 10.00 percent by weight. If component (c) is present in the supramolecular biomedical material according to the invention, the weight ratios of components (a) - (c) are preferably as follows: 20 - 59.99 percent by weight of (a), 0.01 - 40.00 percent by weight of (b), and 0.01 - 40.00 percent by weight of (c). More preferably, the weight ratios of components (a) - (c) are 40.00 - 69.99 percent by weight of (a), 0.01 - 30.00 percent by weight of (b), and 0.01 - 30.00 percent by weight of (c). All percentages by weight enlisted here for the supramolecular biomedical material are based on the total weight of the supramolecular biomedical material.

Highly porous structures can be obtained by techniques known in the art, such as freeze-drying, particulate leaching using salts or sugars, and electro-spinning. Highly porous (interconnecting) structures or non-woven fabrics are beneficial towards cell- attachment or proliferation, and allow the growth of tissue inside the scaffold. These structures can, for example, be used as porous scaffolds used in tissue-engineering, as prosthesis or implants. Optionally, the supramolecular biomedical material can be obtained as a hydrogel, i.e. a gel in which the liquid is water. Hydrogels can be obtained by persons skilled in the art by balancing the ratio of hydrophilic and hydrophobic components in components (a) and optionally (c) in the formulation. Hydrogel materials have a high water content, potentially mimicking different roles of the extracellular matrices in tissue. Consequently, hydrogels find many uses in biomedical applications such as controlled drug delivery, delivery matrices or as coatings.

According to this invention, additional ingredients other than (a), (b), or optionally (c), may be added to the material such as excipients known in the art such as for example anti-oxidants and pH-buffers.

Applications

The supramolecular biomedical materials according to the invention are preferably suitable for applications related to biomedical applications such as materials for tissue-engineering, materials for the manufacture of a prosthesis or an implant. More preferably, the supramolecular biomedical materials are useful for biomedical coatings with controlled release of drugs, biomedical coatings that have anti- thrombogenic or anti-microbial activity, biomedical coatings that have enhanced lubrication, or are used for medical imaging technologies (for example MRI). The biomedical coating can be applied on protheses, implants, stents, catheters, or other medical devices that come in contact with living tissue. According to another more preferred application, the supramolecular biomedical material is useful as filling material for cosmetic and reconstructive plastic surgery.

EXAMPLES

The following examples further illustrate the preferred embodiments of the invention. When not specifically mentioned, chemicals are obtained from Sigma Aldrich.

Example 1: Preparation of UPyI

1,6-Hexyldiisocyanate (650 g) and methylisocytosine (or 2-amino-4-hydroxy-6- methyl-pyrimidine, 65.1 g) were suspended in a 2-liter flask. The mixture was stirred overnight at 100 ⁰C under an argon atmosphere. After cooling to room temperature, a litre of pentane was added to the suspension, while stirring was continued. The product was filtered, washed with several portions of pentane and dried in vacuum. The resulting 2(6-isocyanatohexylaminocarbonylamino)-6-methyl-4[lH]pyrimidinone was obtained as a white powder. ¹U NMR (400 MHz, CDCl₃): δ 13.1 (IH), 11.8 (IH), 10.1 (IH), 5.8 (IH), 3.3 (4H), 2.1 (3H), 1.6 (4H), 1.4 (4H). FT-IR (neat): V (cm^"1). 2935, 2281, 1698, 1668, 1582, 1524, 1256.

Example 2: Preparation of UPy 2

2-Amino-4-hydroxy-5-(2-hydroxy ethyl)-6-methyl-pyrimidine (12 gram) was suspended in isophoronediisocyanate (IPDI, 150 mL) and was stirred overnight at 90 ⁰C under an argon atmosphere. A clear solution developed. The solution was cooled and precipitated in hexane. The solid was filtered, stirred in another portion of hexane, and then the product was isolated by filtration, washing with hexane and drying of the residu, resulting in the ureidopyrimidinone with two IPDI units. Yield: 98%. ¹H NMR (400 MHz, CDCl₃): δ 13.1 (IH), 11.9 (IH), 10.2 (IH), 4.8-4.5 (IH), 4.2 (2H), 4.0-3.2 (3H), 3.1-2.9 (3H), 2.7 (2H), 2.3 (3H), 1.9-1.6 (4H), 1.4-0.8 (26H). FT-IR (neat): V (cm^"1) 2954, 2254, 1690, 1664, 1637, 1590, 1532, 1461, 1364, 1307, 1257, 1034, 791. MALDI-TOF-MS, [M⁺]=614, [M+Na⁺]=636.

Example 3: Preparation of UPy 3

A mixture of methylisocytosine (10 g) and carbodiimidazole (20.7 g) in dried DMSO (50 mL) was heated and stirred at 100 ⁰C under an argon atmosphere for 2 hours. The resulting solid was filtered and washed with dry acetone until a white powder remained in the filter, that subsequently was dried in vacuo resulting in the imidazolide of methylisocytosine that was stored over P2O5. FT-IR (neat): V (cm^"1) 3174, 1701, 1644, 1600, 1479, 1375, 1320, 1276.

Example 4: Preparation of UPy 4

Methyl isocytosine (5.2 g) was added to isophoronediisocyanate (IPDI, 50 mL) and subsequently stirred at 90 ⁰C under an argon atmosphere for 3 days. The resulting clear solution was precipitated in heptane. The white gom was collected, heated in 150 mL heptane, cooled on ice, and filtered. The same procedure was repeated once more with the white residue, resulting in a white powder consisting of ureidopyrimidinone with one IPDI unit. This product (10.22 g) was subsequently dissolved in chloroform (20 mL), and thereafter hydroxy ethyl acrylate (HEA, 3.6 mL) and 1 drop of dibutyl tin dilaurate (DBTDL) were added. The mixture was stirred at an oil bath temperature of 65 ⁰C for 4 hours, and was then cooled and filtered. The filtrate was concentrated and dropped into an excess of diethylether. The precipitate was collected by filtration, and was washed with diethylether. Drying in vacuo gave a solid product. ¹H NMR (400 MHz, CDCl₃): δ 13.1 (IH), 11.7-12.0 (IH), 9.8-10.0 (IH), 6.4 (IH), 6.2 (IH), 5.8 (2H), 5.2 (IH), 4.3 (4H), 4.1-3.6 (IH), 3.1-2.9 (2H), 2.1 (3H), 2.0 (3H), 1.8-1.5 (2H), 1.4-0.8 (13H) 1.9 (3H), 1.7-1.2 (8H). FT-IR (neat): V 3212, 2954, 1697, 1660, 1572, 1520, 1242, 1165. Example 5: Preparation of UPy5

UPy3 (0.9 g) and 1,6-diaminohexane (0.54 g; 1.1 eq.) were stirred for 72 hours at room temperature in 15 mL of THF. The mixture was kept under argon. Ethanol (25 mL) was added, and the suspension was stirred for half an hour. The solid was filtered, washed with several 10 mL portions of ethanol and dried. Resulting in 0.86 g of 2(6- aminohexylaminocarbonylamino)-6-methyl-4[lH]pyrimidinone. ¹H NMR (400 MHz, D₂O with a drop Of CH₃COOH): δ = 5.9 (IH), 3.2 (2H), 2.9 (2H), 2.2 (3H), 1.7-1.2 (8H).

Example 6: Preparation of polymer A

Telechelic PEO- 1500 (5.83 g) was stripped three times with toluene and was then dissolved in toluene (30 mL). UPy2 (2.39 g) in toluene (14 mL) was added as well as a few drops of dibutyl tin dilaurate and the solution was heated overnight under argon (oil bath temperature of 120 ⁰C). The polymer was isolated by precipitation into diethylether. The material is white (semi-crystalline), elastic and tough. ¹H NMR (300 MHz, CDCI₃/CD₃OD): δ 4.1, 3.6, 2.8, 2.2, 1.8-1.4, 1.2-0.8. SEC (THF, PS-standards): M_w= 7.O kD.

Example 7: Preparation of bioactive component 1

Heparin sodium salt (1.0 g, Mn = 12000, activity = 195 IU/mg, Porcine Intestinal Mucosa, obtained from Merck Biosciences, Germany) was dissolved in water and passed through a Dowex 50X8 (H+) column, followed by dialyzing (MW cut-off = 12000 - 14000) against water and lyophilization to obtain heparin (0.95 g). The carboxylic acid groups of Heparin were activated by adding N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS) to 2% solution by weight of lyophilized heparin in 0.05 M buffer of 2- morpholinoethane sulfonic acid (MES-buffer, pH = 5.60), at a molar ratio of NHS:EDC:heparin-CO₂H of 0.24:0.40:1.0. After 10 minutes pre-activation, UPy5 (64 mg) was dissolved in MES-buffer (3 mL, pH = 5.60) and added to the NHS/EDC activated heparin solution (25 mL), resulting in a molar ratio of 6 to 1 (UPy4 to heparin). After 3h the reaction mixture was dialyzed once against MES-buffer (pH = 5.60), followed by extensive dialysis against water, followed by lyophilization to obtain heparin functionalized with approximately six 4H-units.

Example 8: Preparation of bioactive component 2

Heparin sodium salt (1.0 g, Mn = 12000, activity = 195 IU/mg, Porcine Intestinal Mucosa, obtained from Merck Biosciences, Germany) was dissolved in water and passed through a Dowex 50X8 (H+) column, followed by dialyzing (MW cut-off = 12000 - 14000) against water and lyophilization to obtain heparin (0.95 g). The reducing end of heparin was oxidized with iodide (0.2 g) in 20% aqueous methanol solution (25 mL) for 6h at room temperature. The reaction solution was added to ethanol containing 4% by weight potassium hydroxide (50 mL). The resulting white precipitate was filtered, dissolved in water and dialyzed (MW cut-off = 12000-14000). Oxidized heparin was obtained after lyophilization The oxidized heparin was subsequently dissolved in water and passed through a Dowex 50X8 (H+) column followed by freeze drying to obtain the lactone-heparin (0.74 g). A 10-fold molar excess of UPy5 (45 mg) was dissolved in DMF (2 mL) and subsequently added to lactone-heparin (200 mg) dissolved in DMF (10 mL). The reaction was stirred for 16h at 8O⁰C. The reaction mixture was concentrated in vacuo followed by dissolving in water. The dilute reaction mixture was subsequently passed through a Dowex 50X8 (H+) column. The eluate was extensively dialyzed against water, followed by lyophilization resulting in heparin terminally functionalized with a 4H-unit.

Example 9: Heparin-containing supramolecular hydrogel

Aqueous solutions of acrylamide (1.3 mL; 40% w/v in water) and bisacrylamide

(0.6 mL; 2% w/v in water) were mixed. This mixture was diluted with tris(hydroxymethyl)aminomethane-buffer (Tris, 1.2 mL; 0.4 M Tris-HCl, pH 8.8) and water (1.5 mL) followed by the addition of the 4H-unit functionalized heparin of example 8 (123 mg). This mixture was heated to 8O⁰C and subsequently, UPy4 (48 mg) dissolved in acrylamide (0.20 mL) was added. The mixture was polymerized after the addition of ammoniumpersulfate (50 μL; endconcentration 0.1%) and N,N,N',N'- tetramethylethylenediamine (TEMED, 2.5 μL; endconcentration 0.1%), resulting in a 12% acrylamide gel containing functionalized with 4H-units and containing 2% by weight of bioactive component 2.

Example 10: UV-cured supramolecular coating

Polymer A (2.5 g) and UPy4 (1.5 g) were dissolved in hydroxyethyl acrylate (HEA, 10 g) together with tetraethyleneglycol diacrylate (TEGDA, 1.0 g), Irgacure

907™(150 mg, obtained from Ciba, Switzerland) at 8O⁰C. Then a 100 μm film was mechanically drawn on a glass substrate and UV-cured under a nitrogen atmosphere with a Fusion F600 D-bulb (Io = 5 W/cm²) with a belt speed of 10.4 m/min, equivalent to a radiation time of 0.3 s. A clear coating was obtained with good mechanical properties.

Claims

1. Supramolecular biomedical material comprising the following components:

(a) a polymer comprising at least two 4H-units; and (b) a biologically active compound; wherein the 4H-unit is represented by the general formulas (1) or (2):

(1) (2)

wherein the C-X, and the C-Y, linkages each represent a single or double bond, n is 4 or more, and X, represent donors or acceptors that form hydrogen bridges with the H-bridge forming monomeric unit containing a corresponding general form (2) linked to them with X, representing a donor and Y, an acceptor and vice versa.

2. Supramolecular biomedical material according to Claim 1, wherein component

(a) is a bioresorbable polymer.

3. Supramolecular biomedical material according to Claim 1 or Claim 2, wherein component (a) comprises three to fifty 4H-units.

4. Supramolecular biomedical material according to any one of the preceding claims, wherein component (a) has a M_n of 100 to 100.000.

5. Supramolecular biomedical material according to any one of the preceding claims, wherein component (a) is derived from polymers having two terminal hydroxy groups or two terminal primary amino groups.

6. Supramolecular biomedical material according to Claim 5, wherein the polymers having two terminal hydroxy groups or two terminal primary amino groups have a M_n of500 - 10000.

7. Supramolecular biomedical material according to any one of the Claims 1 to 6, wherein component (a) is derived from the group consisting of polyamides, polysaccharides, polyacrylates, polymethacrylates, polyacrylamides, N- vinylcapro lactam, or copolymers thereof.

8. Supramolecular biomedical material according to any one of the preceding claims, wherein the supramolecular biomedical material comprises a third component (c), said third component (c) being preferably a bioresorbable polymer.

9. Supramolecular biomedical material according to Claim 8, wherein (c) comprises one to fifty 4H-units.

10. Supramolecular biomedical material according to any one of the preceding claims, wherein component (b) comprises one to ten 4H-units.

11. Supramolecular biomedical material according to any one of the preceding claims, wherein component (b) is selected from the group consisting of antimicrobial agents, anti-viral agents, anti-tumor agents, anti-thrombogenic agents, hormones, immunogenic agents, growth factors, (fluorescent) dyes, contrast agents, nucleic acids, lipids, lipopolysaccharides, (poly)saccharides, vitamins, peptides, oligopeptides and proteins.

12. Supramolecular biomedical material according to any one of the preceding claims, wherein the supramolecular biomedical material comprises 50.00 - 99.99 percent by weight of component (a) and 0.01 - 50.00 percent by weight of component (b), based on the total weight of the supramolecular biomedical material.

13. Supramolecular biomedical material according to any one of the preceding claims, wherein the supramolecular biomedical material comprises 20.00 - 59.99 percent by weight of component (a), 0.01 - 40.0 percent by weight of component (b) and 0.01 - 40.00 percent by weight of component (c), based on the total weight of the supramolecular biomedical material.

14. Use of the supramolecular biomedical material according to any one of Claims 1 - 13 in implants and biomedical coating compositions and for the controlled release of drugs.

15. Biomedical coating composition comprising a supramolecular biomedical material according to any one of claims 1 - 13.